Are IgE antibodies capable of binding water molecules?

Are IgE antibodies capable of binding water molecules?

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I learned in med school, that they are too small to trigger the IgE reaction that causes the release of histamine. However, I came across reports of this condition;

Some people with this cannot drink plain water without experiencing symptoms in their mouths and throats. In some cases, they report anaphylaxis if they drink a sip of water. The drug 'Xolair' blocks IgE and is effective in people with this condition.

But, I thought the water molecule is too small to bind to IgE antibodies? At least, that was what I learned in med school. Now I'm kind of confused. Aren't IgE antibodies literally dissolved in/surrounded by water on a constant basis? Wouldn't the water in the liquid these cells are always in be triggering a 24/7 reaction in their skin and their throats? Not just when they drink some water or take a shower. The epidermis is just dead cells, the mast cells in the skin have to be submerged in a mostly water medium to survive.

These people rely on milk and orange juice to drink, as it does not elicit the internal allergy reactions.

It is as you suggest: IgE antibodies are incapable of binding to water.

The immunogenicity of water is not explainable that simply. It is also important to know that it is a variant of physical urticaria, which presents the same symptoms but via different provocation, such as pressure, cold, heat, or exercise and sweating (cholinergic urticaria). There is some discussion on the topic here.

Some competing explanations in the links you provide are:

  • water reacts with something on the body, and the product of the reaction is immunogenic, or water solubilizes a surface antigen that penetrates the skin, and
  • contaminants or impurities in the water elicit the immune response.

First, I will offer my amateur thoughts on the matter, and then provide you with transcripts of what doctors who have had experience with treating this have come to understand. Do note that this is still an incompletely understood (rare) disease and that there exists no definitive mechanistic understanding, though histopathological examination has been performed, and it does indeed seem like the presence of water induces an immune reaction. It also seems immunologic due to the fact that patients respond well to antihistamines and related treatments that suppress the immune system.

As you can guess, this is a very rare disorder and it is difficult to rule out things such as an uncommon reaction to (perhaps) improperly cleaned or cleared water. However, some studies have been done to rule out impurities in water by the use of a water provocation test, or "water challenge test", where source of the water has been shown to not matter, thereby likely ruling out the impurities hypothesis. Patients also have similar responses to rain, tap water and swimming pool water. It too may be that the preparation, processing or chemistry of milk or orange juice renders an aqueous medium as incapable of eliciting a reaction on the skin, perhaps due to the presence of molecules or simply by virtue of things like pH being different than that of water. Reportedly, pH and temperature do need seem to play a role. It is also possible, though unlikely, that the immune response to water is psychogenic, and seems to occur more predominantly in females around puberty, and has been anecdotally reported to co-occur with some diseases like Bernard-Soulier syndrome, polymorphic light eruption, familial lactose intolerance and papillary carcinoma of the thyroid.

Anyway, I doubt anyone here at this SE can do a better job than the summaries I have here below.

A discussion of the cases and literature from 2011 can be found here:

The pathogenesis of AU is not fully known; however, several mechanisms have been proposed. Interaction with water with a component in or on the stratum corneum or sebum, generating a toxic compound, has been suggested. Absorption of this substance would exert an effect of perifollicular mast cell degranulation with release of histamine. A study by Sibbald et al. demonstrated that complete removal of the stratum corneum appeared to worsen the reaction, rather than prevent urticaria. These authors also demonstrated that pretreatment with organic solvents enhances wheal formation in contact with water. They suggested that enhancement of the ability of water to penetrate the stratum corneum increases wheal formation. Czarnetzki et al. hypothesized the existence of a water-soluble antigen at the epidermal layer. The antigen diffuses into the dermis by water and then causes release of histamine from mast cells. Tkach hypothesized that hypotonic water sources could lead to osmotic pressure changes, resulting in indirect provocation of urticaria. Others have recently stated that 5% saline was more effective than distilled water for eliciting the wheal-and-flare reaction. They hypothesized that the salt concentration and/or water osmolarity may influence the pathogenic process of AU, possibly by enhancing solubilization and penetration of a hypothetical epidermal antigen, in the same way as has been postulated for enhancement of organic solvents. Another proposed chemical mediator in AU is acetylcholine because of the ability of the acetylcholine antagonist scopolamine to suppress wheal formation when applied to the skin before water contact. However, another study failed to reproduce this finding when pretreatment with atropine did not result in suppression of subsequent wheal formation. Methacholine injection testing is negative in patients with AU; however, it is often positive in cholinergic urticaria. Serum histamine levels are variable from patient to patient. Antihistamines have been used to treat AU; however, the therapeutic effect and prognosis vary. In some cases, complete control of symptoms with antihistamine has been reported, whereas in other cases, there is a failure to adequately control symptoms. Refractory cases have been treated with ultraviolet (UV) radiation (both psoralen plus UVA therapy and UVB), either alone or in combination with antihistamines. It is hypothesized that the effect of ultraviolet therapy is mediated by thickening of the epidermis, which may prevent water penetration, interaction with dendritic cells, and immunosuppression or a decreased mast cell response. Barrier methods involving application of oil-in-water emulsion creams on the skin for water protection are effective. AU responds to stanazolol treatment in human immunodeficiency virus-positive patients.

Another discussion, from a paper from 2017:

Many of these histopathologic findings are the same as those of acute urticaria, in which interstitial dermal edema, dilated venules, endothelial swelling, and sparse infiltration of inflammatory cells have been described. Mast cells are concentrated around the blood vessels of normal dermis, with one to three cells per cross-sectional vessel profile, but in this patient there were slightly increased numbers of mast cells around blood vessels.

Antihistamines are the first line treatment for aquagenic urticaria. In recalcitrant cases, the dose can be increased by as much as four-fold the conventional dose. Phototherapy and barrier cream are alternative or additional treatments if antihistamines fail to prevent recurrence. The efficacy of phototherapy is related to its induction of both immunosuppression, including a decreased mast cell response, and epidermal thickening, which disturbs the penetration of water and thus also inhibits mast cell stimulation. Barrier cream prevents the penetration of water into the dermis. However, the various emollients and water-resistant creams investigated have not yielded conspicuous success, except in a few cases in which a petrolatum-containing ointment was applied before water exposure. Anticholinergics such as scopolamine may also offer relief. Most of the patients were successfully controlled with antihistamines, although some of them changed treatment modalities because of drowsiness.

Are IgE antibodies capable of binding water molecules? - Biology

We describe the design, synthesis, and characterization of a heterobivalent ligand (HBL) system that competitively inhibits allergen binding to mast cell bound IgE antibody, thereby inhibiting mast cell degranulation. HBLs are composed of a hapten conjugated to a nucleotide analog allowing simultaneous targeting of the antigen-binding site as well the “unconventional nucleotide binding site” on IgE Fab domains. Simultaneous bivalent binding to both sites provides HBLs with over 100-fold enhancement both in avidity for IgE DNP (Kd = 0.33 μM) and in inhibition of allergen binding to IgE DNP (IC50 = 0.45 μM) than the monovalent hapten (Kd mono = 41 μM IC50 mono = 55.4 μM, respectively). In cellular assays, HBL2 effectively inhibits mast cell degranulation (IC50 = 15 μM), whereas no inhibition is detected by the monovalent hapten. In conclusion, this study establishes the use of multivalency in a novel HBL design to inhibit mast cell degranulation.

Graphical Abstract


► Nucleotide binding site is a conserved site in all immunoglobulins ► Heterobivalent ligands bind to IgE with 124-fold enhancement over monovalent hapten ► Heterobivalent ligands inhibit allergen binding with >100-fold enhancement ► Heterobivalent ligands effectively inhibit allergen induced mast cell degranulation

House dust mites produce potent allergens, Der p 1 and Der f 1, that cause allergic sensitization and asthma. Der p 1 and Der f 1 are cysteine proteases that elicit IgE responses in 80% of mite-allergic subjects and have proinflammatory properties. Their antigenic structure is unknown. Here, we present crystal structures of natural Der p 1 and Der f 1 in complex with a monoclonal antibody, 4C1, which binds to a unique cross-reactive epitope on both allergens associated with IgE recognition. The 4C1 epitope is formed by almost identical amino acid sequences and contact residues. Mutations of the contact residues abrogate mAb 4C1 binding and reduce IgE antibody binding. These surface-exposed residues are molecular targets that can be exploited for development of recombinant allergen vaccines.

The atomic coordinates and structure factors (codes 3RVT, 3RVU, 3RVV, 3RVW, and 3RVX) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (

This work was supported, in whole or in part, by National Institutes of Health Grants AI077653, GM53163, and AI120565.

Both authors contributed equally to this work and should be considered co-first authors.

  1. Term Paper on the Meaning of Immune System
  2. Term Paper on the Types of Immune System
  3. Term Paper on the Mechanisms of Immune System
  4. Term Paper on the Organs of Immune System
  5. Term Paper on the Disorders of Immune System

Term Paper # 1. Meaning of Immune System:

The immune system is a remarkably adaptive defence system that has evolved in vertebrates to protect them from invading pathogenic microorganisms and cancer. This system has the ability to generate an enormous variety of cells and molecules capable of specifically recognising and eliminating a limitless variety of foreign invaders.

These cells and molecules act together in an adaptable dynamic network whose ability rivals that of any other system in our body. The immune system also has other abilities besides the recognition and killing of invading pathogens. It can kill cancer cells and in experimental animals at least, it can protect the body against certain tumors. This system also prevents tissue transplantation between individuals.

Term Paper # 2. Types of Immune System:

Immunology is the science that studies the structure and functioning of the immune system.

The science began long before anyone knew about disease-causing microbes or even that individuals had an immune system that protected the body against diseases, e.g. in about c. 200 BC, Charak (the Indian ‘Father of Medicine’) gives a clear idea of Immunology just as Hippocrates (460-377 BC)—the European ‘Father of Medicine’ did.

There are two types of natural immune systems recognised in human bodies viz., humoral (antibodies) and cellular (immune cells) immune system (Fig. 33.1). These constitute the innate immunity of the body system.

These innate immunity are non-specific and protects through two mechanisms viz.:

(a) Non- specifically clears the infectious agents using preformed components, or

(b) Produces specific cells and molecules directed against the foreign invader.

This is a natural resistance which operates non-specifically during the early phase of an immune response. The innate immunity serves as the first line of defense and includes both external and internal nonspecific responses.

The external innate immunity (Skin body secretions and mucous membranes) prevents the penetration of pathogens into host tissues. If a pathogen breeches the external innate defenses and invades the tissues, the internal defense mechanisms provide protection.

Internal innate immunity includes three general mechanisms:

Human immune sites are shown in Fig. 33.2.

In contrast, acquired immunity develops during a host’s lifeline and is based partly on the host’s experiences. The exposure process is called immunization.

Acquired immunity is the surveillance mechanism of vertebrates that specifically recognises foreign antigens and selectively eliminates them and, on reencountering the antigens, has an enhanced response. Once a host has been exposed to a specific disease, the host will probably not catch the disease again.

The persistence of a foreign antigen in a host initiates, or induces, acquired immunity. The recognition of and response to the antigen are highly specific. In human system there are also two types of acquired immunity—Humoral and cell-mediated. Such may last few years as active, or disappear after a short period, i.e., passive only (Fig. 33.3).

Term Paper # 3. Mechanisms of Immune System:

The immune system is a complex functional system consisting of diverse organs, tissues and cells debuted throughout most of the body. Despite the system’s complexity, its components are interrelated and act in a highly coordinated and specific manner when they recognise, eliminate and remember foreign macromolecules and cells.

Any foreign substance (living or non-living) that induces an immune response when introduced into a host is called an immunogenic, or more generally, an antigen. Most antigens are large, complex macro- molecules not recognised as such.

Only small parts of antigens, called antigenic determinants or epitopes induce and, react with immune elements such as antibodies or lymphocytes. Antibodies recognize antigens through their surface characteristics, particularly by the antigen’s pattern or shape and charge.

The binding sites of the antibody are precisely complementary or specific for the right antigenic determinants. When antigens enters the body, it usually induces the production of antibodies that react only with that particular antigen. The immune system also has pre-existing lymphocytes capable of reacting with the specific antigen.

The first time we are exposed to an antigen, the result is a primary immune response. The second exposure to the same antigen leads to a secondary immune response, which is much faster and stronger. This phenomenon is moderated by immunologic memory and accounts for a person’s long term immunity against infectious diseases.

To monitor against antigen intrusion anywhere within the body, the immune system stations the lymphoid system or immune system. The tissues are generally called lymphoid organs and include the bone marrow, thymus, lymph nodes, spleen and mucosa associated with lymphoid tissue.

Two main groups of mononuclear leukocytes also participate in immune responses-lymphocytes and macrophages Other cells crucial in the immune response are peripheral blood lymphocytes that do not express the classical characteristics of mature lymphocytes—they are called null cells.

An antigen, when introduced into a host, induces the formation of specific antibodies and T lymphocytes that are reactive against the antigen.

Each antigen has four common characteristics:

In each antigen there are usually two components, viz., epitopes (antigenic determinants) i e immunologically active portion, and haptens, i.e., non-immunogenic part of the antigen.

The chief characteristics of the antigenic determinants are:

(a) Antigenic determinants are small

(b) All of the surface of a protein may be immunogenic and antigenic

(c) Antigenic determinants must be accessible and are composed of assembled topographic determinants

(d) Charge and polarity add to antigenic determinant immunogenicity

(e) Antigenic determinants are conformation dependent and also have immunodominant building blocks

(f) Antigen site mobility contributes to protein antigenicity

(g) An individual’s immune response to a protein antigen (a) Is dictated by its genetic make-up (b) Depends on the structural differences between the antigen and the recipient’s self-proteins,’ and (c) Depends on the immuno regulatory mechanisms operating in that individual’s immune systems.

The recognition proteins found in the serum and other body fluids of vertebrates that react specifically with the antigens that induced their formation are called antibodies. Antibodies belong to a family of globular proteins called immunoglobulin’s.

The antibodies have three important features:

(b) Binding specificity, and

A typical antibody molecule e g IgG is made up of four polypeptide chains with a molecular weight of about 150 kd. The four chains are divided into two identical light chains and two identical heavy chains. An antibody molecule is Y-shaped, with two identical antigen-binding sites at the ends of the arms of the Y (Fig. 33, 5).

The light and heavy chains contribute to the antigen-binding sites. Each antibody molecule can bind to two identical antigenic determinants. There are five different classes of immunoglobulin’s —IgG, IgA, IgM, IgD and IgE—each with a distinctive heavy chain designated. IgG is found in blood, IgA in tissue fluid, IgM in glands, IgD in membrane and, finally, IgE also in blood.

When antibody forming cells are fused with myeloma cells, the resulting clone of cells is a hybridoma. Hybridoma cultures are the source of monoclonal antibodies of predefined antigen specificity.

(iii) Antigen-Antibody Reactions:

Serology is the science dealing with the in vitro interactions of antibodies with antigens. The interaction of an antigenic determinant and an antibody molecule is called a primary antigen-antibody reaction. Cardinal characteristic of primary antigen-antibody reactions is that they are invisible.

The conversion of invisible primary reactions to macroscopically visible ones leads to secondary antigen-antibody reactions such as precipitation and agglutination. Primarily, antigen-antibody reactions can be measured using fluorescence quenching, radioimmunasosay (RIA), enzyme linked immunosorbent assay (ELISA) and Immunofluorescence. Precipitation test is done by ring test.

(iv) Autoimmunity:

It is the mirror mage of tolerance self-tolerance is the lack of reactivity to self, while autoimmunity reactivity to self, or the loss of tolerance to self. Self-reactivity (or auto-immunity) leads to immunity .but abnormal or excessive ant self responses may cause harm to the host.

There are a number of diseases which are considered as autoimmune type. Examples of cell-mediated autoimmune diseases are Hashimoto s thyroiditis, and insulin-dependent diabetes mellitus, while antibody mediated autoimmune diseases are Grave’s disease, rheumatoid arthritis and rheumatic fever etc.

Term Paper # 4. Organs of Immune System:

The cells of immune system generally remain localised and concentrated in anatomi­cally defined tissues or organs to optimize the cellular interactions necessary for specific immune responses. Such organs are also the sites where foreign antigens are transported and concentrated.

However, such anatomic compartmentalization is not fixed because, as we will see later that many lymphocytes recirculate and are constantly exchanged between the circulation and immune organs.

Immune organs are classified as:

(i) Generative organs or primary lymphoid organs, where lymphocytes first express antigen receptors and attain phenotypic and functional maturity,

(ii) Peripheral organs or secondary lymphoid organs, where lympho­cyte’s response to foreign antigens are initiated and develop (Fig. 6.27).

1. Primary Lymphoid Organs:

In mammals, the primary lymphoid organs include:

(a) Bone marrow, where all lymphocytes arise and

(b) Thymus, where T cells mature and reach a stage of functional competence. In birds bursa of Fabricius is the site for B cell maturation.

In mammals the generation of blood cells or the process of haematopoiesis in foetal life occurs initially in blood islands and later in liver and spleen. Following birth, this function is gradually taken over by bone marrow and increasingly by the marrow of flat bones (like sternum, vertebrae, iliac, ribs etc.) during puberty.

Thymus is a primary lymphoid organ and is the site of T cell maturation. It is a flat, bilobed organ, situated above the heart (Fig. 6.27). Each lobe is surrounded by a capsule and is divided into lobules, which are separated from each other by trabeculae. Each lobule is organised into an outer compartment or cortex and an inner medulla.

From the early sites of haematopoiesis, the progenitor T cells migrate to thymus at about 11 day of gestation in mice and 8th or 9th week of gestation in humans and are called thymocytes.

These cells rapidly proliferate within the cortex, which is coupled with an enormous rate of cell deaths, therefore, a small subset of more mature thymocytes then migrate from cortex to medulla, where they continue to mature and finally leave the thymus through post capillary venules.

Scattered throughout the thymus are non-lymphoid epithelial cells with abundant cytoplasm, bone marrow derived dendritic cells and macrophages. In the medulla, tightly packed whorls of remnants of degenerated cells, called Hassall’s corpuscles are found. The thymus has a rich vascular supply.

2. Secondary Lymphoid Organs:

Secondary lymphoid organs are those organs which capture the antigens and provide sites where lymphocytes interact with antigen and undergo clonal proliferation and differentiation into effector cells. These are also called peripheral organs.

The following lymphoid organs play important role in immunity:

Clustered at junction of lymphatic vessels, lymph nodes are small, nodular, bean-shaped encapsulated struc­tures containing a reticular network packed with lymphocytes, dendritic cells and macro­phages.

Each lymph node can roughly be divided into three regions:

The outermost layer consists of mainly B cells, macrophage and follicular dendritic cells arranged in follicles. Some follicles contain central areas called germinal centres, which stain lightly with commonly used histological stains. Follicles without germinal centres are called primary follicles and those with germinal centres are secondary follicles. After antigenic challenge primary follicles enlarge into secondary follicles.

Beneath the cortex is the para-cortex which is populated with T cells and some interdigitating dendritic cells.

The innermost layer is the medulla which is sparsely populated with lymphoid-lineage cells like plasma cells secreting antibody molecules.

The spleen is a major site of immune responses to blood-borne antigens as it is not supported by any lymphatic vessels. Antigens and lymphocytes are carried to spleen through splenic artery. It is a large, ovoid secondary lymphoid organ situated high in the left abdominal cavity.

Spleen is surrounded by a capsule that extends many trabeculae into the interior of the spleen, dividing the organ into many compartments which are of two types:

It consists of network of sinusoids populated by macrophages and red blood cells. Here macrophages engulf old and defective red blood cells.

Dense lymphoid tissues constitute the white pulp that surrounds the branches of the splenic artery, forming a peri-arteriolar lymphoid sheath (PALS). It is populated mainly by T cells. The marginal zone, located peripheral to PALS, is rich in B cells organised into primary lymphoid follicles (Fig. 6.30 A, B).

(c) Cutaneous Immune Tissues/System:

The skin is the largest organ in the body and contains a specialised cutaneous immune system consisting of lymphocytes and APCs. Many foreign antigens gain entry into body through the skin so that many immune responses are initiated in this tissue.

The principal cells present is the epider­mis include keratinocytes, melanocytes, epidermal Langerhans cells and intraepithe­lial T cells (Fig. 6.31). Of these, melanocytes do not play any role in immune responses. Keratinocytes contribute some activities to innate immune reactions and cutaneous inflammation.

Langerhans cells form an almost continuous meshwork that enables them to capture antigens that enter through the skin. Upon stimulation by pro-­inflammatory cytokines, these cells retract their processes, lose their adhesiveness for epidermal cells and migrate into the dermis and subsequently home to lymph nodes through lymphatic vessels.

The intra-epidermal T cells may express a more restricted set of antigen receptors than do other T cells. For example, in mice these cells express receptor formed by Ƴ and δ chains that can recognise microbes that are commonly encountered at epithelial surface.

The dermis contains CD4 + and CD8 + T cells and some macrophages. Many dermal T cells express a carbohydrate epitope, called the cutaneous lymphocyte antigen-I, that may play a role in specific homing of the cells to the skin.

Term Paper # 5. Disorders of Immune System:

An allergy is an immune response to a harmless antigen, such as pollen or a specific food. Allergens are substances that cause allergies and include dust, molds, pollen, certain foods and medicines such as penicillin.

IgE antibodies are normally found in small amounts in the circulation. But when the body suffers an allergy, large quantity of IgE antibodies are released into the blood (Fig. 14). These antibodies are called reagins. Allergic reaction typically results because of the action of mast cells and basophils. Both the cells are found throughout the body, especially in the linings of the nasal passage.

IgE antibodies have a property to become attached to mast cells and basophils. Thus, when an allergen binds to an IgE antibody, which is already bound to a mast cell or basophil, release of specific chemicals occurs in the mast and basophil cells. These chemicals include histamine, heparin and other activating factors.

These substances cause the following effects:

a. Dilatation of blood vessels

b. Attraction of eosinophil’s and neutrophils to the reaction site

c. Increase in permeability of capillaries

d. Contraction of smooth muscles

Certain individuals have allergies due to their genetic constitution, external factors like pollution and or a defective immune system. Allergies can usually be treated with anti­histamines, drugs and other medicines. An anti-histamine is a chemical, which competes with histamine for receptor sites on the nose/skin cells. More recently, mast cell inhibitors, such as cromolyn sodium have been developed that stop the mast cells from synthesising histamine.

Different types of abnormal tissue responses occur depending on the type of tissue where the allergen-reagin occurs.

Some of them are elaborated below:

When an allergen enters the circulation, it causes widespread allergic reaction. Histamine released cause body vasodilatation and increased permeability of capillaries. A person who experiences this reaction dies of shock. Other than histamine another chemical, slow reacting substance of anaphylaxis, is released that causes spasm of the smooth muscle of the bronchiole that can cause asthma like attack and sometimes also cause death by suffocation.

When an allergen enters specific skin areas histamine released locally causes vasodilatation that causes a red flare and increased permeability of capillaries that causes swelling of the skin. The swellings are called ‘hives’.

The allergen-reagin reaction occurs in the nose. Histamine release causes vasodilatation in the nasal blood vessels and increased permeability. This causes increased nasal secretion and swelling in the nose. The affected individuals also suffer from continuous sneezing.

The allergen-reagin reaction occurs in the bronchioles of the lungs. The bronchiolar smooth muscles have irregular spasms and the person has difficulty in breathing. The slow reacting substance of anaphylaxis causes these effects more than histamines.

ii. Autoimmune Diseases:

The immune system is capable of differentiating between cells of the body and that of the foreign invaders, i.e. ‘self from the ‘non-self’. In autoimmune response, the immune system turns against the ‘self’, developing antibodies against its own antigens and destroying its own cells. Some of the autoimmune diseases are myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis and juvenile diabetes.

a. Myasthenia Gravis (MG) is muscle weakness caused by destruction of muscle- nerve connections. It is caused by antibodies that destroy the acetylcholine receptors at the neuromuscular junctions. This may lead to paralysis.

b. Multiple Sclerosis (MS) is caused by antibodies attacking the myelin of nerve cells.

c. In Systemic Lupus Erythematosus (SLE) the person produces a series of antibodies against many different tissues, i.e. connective tissues and major organs of the body, at the same time. This causes extensive damage and rapid death.

d. Rheumatoid Arthritis sufferers have damage to their joints.

e. Some evidence supports Type I diabetes as an autoimmune disease. Juvenile diabetes results from the destruction of insulin-producing cells in the pancreas.

f. In chronic anemia, the RBC is destroyed.

g. In chronic hepatitis, the liver cells are destroyed.

h. Rheumatic fever resulting from ceil death and scarring to the heart lining and the heart valves.

iii. Immunodeficiency Diseases:

Immunodeficiency diseases result from the lack or failure of one or more parts of the immune system. Affected individuals are susceptible to a number of diseases. Genetic disorders, Hodgkin’s disease, cancer chemotherapy and radiation therapy can cause immunodeficiency diseases. SCID and AIDS are two examples of immunodeficiency diseases.

a. Severe Combined Immunodeficiency Disease (SCID):

SCID results from a complete absence of the cell mediated and antibody mediated immune responses. This is a defect that exists from birth. In these individuals, the T and B-cells are absent. The individual with this defect has to be kept in a completely sterile environment to avoid infection.

Affected individuals suffer from a series of seemingly minor infections and usually die at an early age. Gene therapy is being done in a small group suffering from adenosine deaminase (ADA) deficiency, a type of SCID, to provide them with normal copies of the defective gene.

b. Acquired Immunodeficiency Syndrome (AIDS):

AIDS is the most dreaded among the immunodeficiency diseases. AIDS is a collection of disorders resulting from the destruction of T cells by the Human Immunodeficiency Virus or HIV, a retrovirus. When the body is attacked by HIV, the T4 helper cells of the cell-mediated immune response are incapacitated. This causes a breakdown of the immune system and the individual is prone to suffer from various diseases due to the lowered resistance. Thus, people with AIDS usually die from secondary infections.


IgE-mediated food allergies are characterized by a T helper 2 (Th2) skewed immune response toward otherwise innocuous food proteins. 16 Sensitization to food allergens can occur via allergen exposure to gut epithelial cells, but also via allergen exposure to damaged skin. This might explain the high prevalence of food allergies among patients with atopic dermatitis (AD). 17, 18 AD appears to be associated with higher levels of IgE somatic hypermutation (SHM). Indeed, recent data from longitudinal analysis of the B cell repertoires have demonstrated that infants with AD show increased IgE SHM, even within the first 2 years of life. 19 Because more mutated antibody genes often correlate with increased affinity of the antibody, elevated IgE SHM may be an important contributing factor to the development of allergic disease. 20

Key epithelial cytokines leading to the allergic response include interleukin (IL-)25, IL-33, and thymic stromal lymphopoietin (TSLP), which induce a shift toward Th2 cell differentiation by activating type 2 innate lymphoid cells, basophils, and dendritic cells (DCs). 21, 22 Upon exposure to the antigen, DCs engulf the antigen and migrate to the lymph node to present an antigen-derived peptide to naive cognate T cells, which become activated and undergo clonal expansion. 22 Afterwards, IgE class switch recombination, plasma cell differentiation, and allergen-specific IgE production may occur locally in the GI tissues including stomach and duodenum as well as in secondary or tertiary lymphoid organs (Figure 2).

Human intestinal epithelial cells can directly take up allergen-IgE complexes via the low-affinity IgE receptor CD23. 23 CD23 is a type II transmembrane glycoprotein with a carboxy-terminal C-type lectin head that binds to IgE. 24 Human CD23 exists in two different isoforms: CD23a and CD23b. These two isoforms display distinctive functions, particularly, CD23a has been shown to act as a bidirectional transporter of IgE across the intestinal epithelial barrier. 25 Interestingly, food allergens that bind to CD23 as allergen-IgE complexes are protected from lysosomal degradation in gut epithelium. 26 As a result, these food antigenic complexes are conserved during the transcytosis and later captured by gut DCs or activated mast cells. For this reason, allergen-IgE complexes with CD23 mainly engage in food-induced pathophysiology of the gastrointestinal tract.

B cells carrying a specific B cell receptor (BCR) for the allergen can capture allergens directly or indirectly through follicular DCs, and present allergen-derived peptides to cognate CD4+ T cells. Antigen-stimulated B cells can be activated upon interaction between CD40 on B cells and CD40 ligand (CD40L) on activated CD4+ T cells, together with the secretion of type 2 cytokines such as IL-4, IL-5, IL-13, and IL-9. 12 IL-9 is often produced along with IL-4 by Th2 cells and the major source of IL-9 is mucosal mast cells in intestine. 27

Although Th2 cells have long been considered the main cell type responsible for the induction of class switching recombinant (CSR) to IgE, more recent studies indicate that this process is largely dependent on T follicular helper (TFH) cells. 28 A distinct subset of TFH cells was recently reported to drive the production of high-affinity IgE antibodies to respiratory and food allergens. These cells termed TFH13 cells are capable of producing high levels of IL-4, IL-13 and IL-5 and relatively modest levels of the prototypical TFH cytokine IL-21. 29 Activated B cells stimulated by Th2 cytokines undergo CSR to IgE and can subsequently differentiate into IgE + plasma cells. 12 It should be noted that the anatomical sites of CSR, either at the margin of GCs, or within GCs, or in extrafollicular sites, are still a topic of active investigation, particularly for IgE. 30 There may also be significant differences between humans and mice in IgE + B cell differentiation sites.


150 kDa) proteins of about 10 nm in size, [7] arranged in three globular regions that roughly form a Y shape.

In humans and most mammals, an antibody unit consists of four polypeptide chains two identical heavy chains and two identical light chains connected by disulfide bonds. [8] Each chain is a series of domains: somewhat similar sequences of about 110 amino acids each. These domains are usually represented in simplified schematics as rectangles. Light chains consist of one variable domain VL and one constant domain CL, while heavy chains contain one variable domain VH and three to four constant domains CH1, CH2, . [9]

Structurally an antibody is also partitioned into two antigen-binding fragments (Fab), containing one VL, VH, CL, and CH1 domain each, as well as the crystallisable fragment (Fc), forming the trunk of the Y shape. [10] In between them is a hinge region of the heavy chains, whose flexibility allows antibodies to bind to pairs of epitopes at various distances, to form complexes (dimers, trimers, etc.), and to bind effector molecules more easily. [11]

In an electrophoresis test of blood proteins, antibodies mostly migrate to the last, gamma globulin fraction. Conversely, most gamma-globulins are antibodies, which is why the two terms were historically used as synonyms, as were the symbols Ig and γ. This variant terminology fell out of use due to the correspondence being inexact and due to confusion with γ heavy chains which characterize the IgG class of antibodies. [12] [13]

Antigen-binding site Edit

The variable domains can also be referred to as the FV region. It is the subregion of Fab that binds to an antigen. More specifically, each variable domain contains three hypervariable regions – the amino acids seen there vary the most from antibody to antibody. When the protein folds, these regions give rise to three loops of β-strands, localised near one another on the surface of the antibody. These loops are referred to as the complementarity-determining regions (CDRs), since their shape complements that of an antigen. Three CDRs from each of the heavy and light chains together form an antibody-binding site whose shape can be anything from a pocket to which a smaller antigen binds, to a larger surface, to a protrusion that sticks out into a groove in an antigen. Typically however only a few residues contribute to most of the binding energy. [2]

The existence of two identical antibody-binding sites allows antibody molecules to bind strongly to multivalent antigen (repeating sites such as polysaccharides in bacterial cell walls, or other sites at some distance apart), as well as to form antibody complexes and larger antigen-antibody complexes. [2] The resulting cross-linking plays a role in activating other parts of the immune system.

The structures of CDRs have been clustered and classified by Chothia et al. [14] and more recently by North et al. [15] and Nikoloudis et al. [16] In the framework of the immune network theory, CDRs are also called idiotypes. According to immune network theory, the adaptive immune system is regulated by interactions between idiotypes.

Fc region Edit

The Fc region (the trunk of the Y shape) is composed of constant domains from the heavy chains. Its role is in modulating immune cell activity: it is where effector molecules bind to, triggering various effects after the antibody Fab region binds to an antigen. [2] [11] Effector cells (such as macrophages or natural killer cells) bind via their Fc receptors (FcR) to the Fc region of an antibody, while the complement system is activated by binding the C1q protein complex.

Another role of the Fc region is to selectively distribute different antibody classes across the body. In particular, the neonatal Fc receptor (FcRn) binds to the Fc region of IgG antibodies to transport it across the placenta, from the mother to the fetus.

Antibodies are glycoproteins, [17] that is, they have carbohydrates (glycans) added to conserved amino acid residues. [17] [18] These conserved glycosylation sites occur in the Fc region and influence interactions with effector molecules. [17] [19]

Protein structure Edit

The N-terminus of each chain is situated at the tip. Each immunoglobulin domain has a similar structure, characteristic of all the members of the immunoglobulin superfamily: it is composed of between 7 (for constant domains) and 9 (for variable domains) β-strands, forming two beta sheets in a Greek key motif. The sheets create a "sandwich" shape, the immunoglobulin fold, held together by a disulfide bond.

Antibody complexes Edit

Secreted antibodies can occur as a single Y-shaped unit, a monomer. However, some antibody classes also form dimers with two Ig units (as with IgA), tetramers with four Ig units (like teleost fish IgM), or pentamers with five Ig units (like mammalian IgM, which occasionally forms hexamers as well, with six units). [20]

Antibodies also form complexes by binding to antigen: this is called an antigen-antibody complex or immune complex. Small antigens can cross-link two antibodies, also leading to the formation of antibody dimers, trimers, tetramers, etc. Multivalent antigens (e.g., cells with multiple epitopes) can form larger complexes with antibodies. An extreme example is the clumping, or agglutination, of red blood cells with antibodies in the Coombs test to determine blood groups: the large clumps become insoluble, leading to visually apparent precipitation.

B cell receptors Edit

The membrane-bound form of an antibody may be called a surface immunoglobulin (sIg) or a membrane immunoglobulin (mIg). It is part of the B cell receptor (BCR), which allows a B cell to detect when a specific antigen is present in the body and triggers B cell activation. [21] The BCR is composed of surface-bound IgD or IgM antibodies and associated Ig-α and Ig-β heterodimers, which are capable of signal transduction. [22] A typical human B cell will have 50,000 to 100,000 antibodies bound to its surface. [22] Upon antigen binding, they cluster in large patches, which can exceed 1 micrometer in diameter, on lipid rafts that isolate the BCRs from most other cell signaling receptors. [22] These patches may improve the efficiency of the cellular immune response. [23] In humans, the cell surface is bare around the B cell receptors for several hundred nanometers, [22] which further isolates the BCRs from competing influences.

Antibodies can come in different varieties known as isotypes or classes. In placental mammals there are five antibody classes known as IgA, IgD, IgE, IgG, and IgM, which are further subdivided into subclasses such as IgA1, IgA2. The prefix "Ig" stands for immunoglobulin, while the suffix denotes the type of heavy chain the antibody contains: the heavy chain types α (alpha), γ (gamma), δ (delta), ε (epsilon), μ (mu) give rise to IgA, IgG, IgD, IgE, IgM, respectively. The distinctive features of each class are determined by the part of the heavy chain within the hinge and Fc region. [2]

The classes differ in their biological properties, functional locations and ability to deal with different antigens, as depicted in the table. [8] For example, IgE antibodies are responsible for an allergic response consisting of histamine release from mast cells, contributing to asthma. The antibody's variable region binds to allergic antigen, for example house dust mite particles, while its Fc region (in the ε heavy chains) binds to Fc receptor ε on a mast cell, triggering its degranulation: the release of molecules stored in its granules. [24]

Antibody isotypes of mammals
Class Subclasses Description
IgA 2 Found in mucosal areas, such as the gut, respiratory tract and urogenital tract, and prevents colonization by pathogens. [25] Also found in saliva, tears, and breast milk.
IgD 1 Functions mainly as an antigen receptor on B cells that have not been exposed to antigens. [26] It has been shown to activate basophils and mast cells to produce antimicrobial factors. [27]
IgE 1 Binds to allergens and triggers histamine release from mast cells and basophils, and is involved in allergy. Also protects against parasitic worms. [5]
IgG 4 In its four forms, provides the majority of antibody-based immunity against invading pathogens. [5] The only antibody capable of crossing the placenta to give passive immunity to the fetus.
IgM 1 Expressed on the surface of B cells (monomer) and in a secreted form (pentamer) with very high avidity. Eliminates pathogens in the early stages of B cell-mediated (humoral) immunity before there is sufficient IgG. [5] [26]

The antibody isotype of a B cell changes during cell development and activation. Immature B cells, which have never been exposed to an antigen, express only the IgM isotype in a cell surface bound form. The B lymphocyte, in this ready-to-respond form, is known as a "naive B lymphocyte." The naive B lymphocyte expresses both surface IgM and IgD. The co-expression of both of these immunoglobulin isotypes renders the B cell ready to respond to antigen. [28] B cell activation follows engagement of the cell-bound antibody molecule with an antigen, causing the cell to divide and differentiate into an antibody-producing cell called a plasma cell. In this activated form, the B cell starts to produce antibody in a secreted form rather than a membrane-bound form. Some daughter cells of the activated B cells undergo isotype switching, a mechanism that causes the production of antibodies to change from IgM or IgD to the other antibody isotypes, IgE, IgA, or IgG, that have defined roles in the immune system.

Light chain types Edit

In mammals there are two types of immunoglobulin light chain, which are called lambda (λ) and kappa (κ). However, there is no known functional difference between them, and both can occur with any of the five major types of heavy chains. [2] Each antibody contains two identical light chains: both κ or both λ. Proportions of κ and λ types vary by species and can be used to detect abnormal proliferation of B cell clones. Other types of light chains, such as the iota (ι) chain, are found in other vertebrates like sharks (Chondrichthyes) and bony fishes (Teleostei).

In animals Edit

In most placental mammals the structure of antibodies is generally the same. Jawed fish appear to be the most primitive animals that are able to make antibodies similar to those of mammals, although many features of their adaptive immunity appeared somewhat earlier. [29] Cartilaginous fish (such as sharks) produce heavy-chain-only antibodies (lacking light chains) which moreover feature longer chains, with five constant domains each. Camelids (such as camels, llamas, alpacas) are also notable for producing heavy-chain-only antibodies. [2] [30]

Antibody classes not found in mammals
Class Types Description
IgY Found in birds and reptiles related to mammalian IgG. [31]
IgW Found in sharks and skates related to mammalian IgD. [32]

The antibody's paratope interacts with the antigen's epitope. An antigen usually contains different epitopes along its surface arranged discontinuously, and dominant epitopes on a given antigen are called determinants.

Antibody and antigen interact by spatial complementarity (lock and key). The molecular forces involved in the Fab-epitope interaction are weak and non-specific – for example electrostatic forces, hydrogen bonds, hydrophobic interactions, and van der Waals forces. This means binding between antibody and antigen is reversible, and the antibody's affinity towards an antigen is relative rather than absolute. Relatively weak binding also means it is possible for an antibody to cross-react with different antigens of different relative affinities.

The main categories of antibody action include the following:

    , in which neutralizing antibodies block parts of the surface of a bacterial cell or virion to render its attack ineffective , in which antibodies "glue together" foreign cells into clumps that are attractive targets for phagocytosis , in which antibodies "glue together" serum-soluble antigens, forcing them to precipitate out of solution in clumps that are attractive targets for phagocytosis (fixation), in which antibodies that are latched onto a foreign cell encourage complement to attack it with a membrane attack complex, which leads to the following:
      of the foreign cell
    • Encouragement of inflammation by chemotactically attracting inflammatory cells

    More indirectly, an antibody can signal immune cells to present antibody fragments to T cells, or downregulate other immune cells to avoid autoimmunity.

    Activated B cells differentiate into either antibody-producing cells called plasma cells that secrete soluble antibody or memory cells that survive in the body for years afterward in order to allow the immune system to remember an antigen and respond faster upon future exposures. [4]

    At the prenatal and neonatal stages of life, the presence of antibodies is provided by passive immunization from the mother. Early endogenous antibody production varies for different kinds of antibodies, and usually appear within the first years of life. Since antibodies exist freely in the bloodstream, they are said to be part of the humoral immune system. Circulating antibodies are produced by clonal B cells that specifically respond to only one antigen (an example is a virus capsid protein fragment). Antibodies contribute to immunity in three ways: They prevent pathogens from entering or damaging cells by binding to them they stimulate removal of pathogens by macrophages and other cells by coating the pathogen and they trigger destruction of pathogens by stimulating other immune responses such as the complement pathway. [33] Antibodies will also trigger vasoactive amine degranulation to contribute to immunity against certain types of antigens (helminths, allergens).

    Activation of complement Edit

    Antibodies that bind to surface antigens (for example, on bacteria) will attract the first component of the complement cascade with their Fc region and initiate activation of the "classical" complement system. [33] This results in the killing of bacteria in two ways. [5] First, the binding of the antibody and complement molecules marks the microbe for ingestion by phagocytes in a process called opsonization these phagocytes are attracted by certain complement molecules generated in the complement cascade. Second, some complement system components form a membrane attack complex to assist antibodies to kill the bacterium directly (bacteriolysis). [34]

    Activation of effector cells Edit

    To combat pathogens that replicate outside cells, antibodies bind to pathogens to link them together, causing them to agglutinate. Since an antibody has at least two paratopes, it can bind more than one antigen by binding identical epitopes carried on the surfaces of these antigens. By coating the pathogen, antibodies stimulate effector functions against the pathogen in cells that recognize their Fc region. [5]

    Those cells that recognize coated pathogens have Fc receptors, which, as the name suggests, interact with the Fc region of IgA, IgG, and IgE antibodies. The engagement of a particular antibody with the Fc receptor on a particular cell triggers an effector function of that cell phagocytes will phagocytose, mast cells and neutrophils will degranulate, natural killer cells will release cytokines and cytotoxic molecules that will ultimately result in destruction of the invading microbe. The activation of natural killer cells by antibodies initiates a cytotoxic mechanism known as antibody-dependent cell-mediated cytotoxicity (ADCC) – this process may explain the efficacy of monoclonal antibodies used in biological therapies against cancer. The Fc receptors are isotype-specific, which gives greater flexibility to the immune system, invoking only the appropriate immune mechanisms for distinct pathogens. [2]

    Natural antibodies Edit

    Humans and higher primates also produce "natural antibodies" that are present in serum before viral infection. Natural antibodies have been defined as antibodies that are produced without any previous infection, vaccination, other foreign antigen exposure or passive immunization. These antibodies can activate the classical complement pathway leading to lysis of enveloped virus particles long before the adaptive immune response is activated. Many natural antibodies are directed against the disaccharide galactose α(1,3)-galactose (α-Gal), which is found as a terminal sugar on glycosylated cell surface proteins, and generated in response to production of this sugar by bacteria contained in the human gut. [35] Rejection of xenotransplantated organs is thought to be, in part, the result of natural antibodies circulating in the serum of the recipient binding to α-Gal antigens expressed on the donor tissue. [36]

    Virtually all microbes can trigger an antibody response. Successful recognition and eradication of many different types of microbes requires diversity among antibodies their amino acid composition varies allowing them to interact with many different antigens. [37] It has been estimated that humans generate about 10 billion different antibodies, each capable of binding a distinct epitope of an antigen. [38] Although a huge repertoire of different antibodies is generated in a single individual, the number of genes available to make these proteins is limited by the size of the human genome. Several complex genetic mechanisms have evolved that allow vertebrate B cells to generate a diverse pool of antibodies from a relatively small number of antibody genes. [39]

    Domain variability Edit

    The chromosomal region that encodes an antibody is large and contains several distinct gene loci for each domain of the antibody—the chromosome region containing heavy chain genes ([email protected]) is found on chromosome 14, and the loci containing lambda and kappa light chain genes ([email protected] and [email protected]) are found on chromosomes 22 and 2 in humans. One of these domains is called the variable domain, which is present in each heavy and light chain of every antibody, but can differ in different antibodies generated from distinct B cells. Differences, between the variable domains, are located on three loops known as hypervariable regions (HV-1, HV-2 and HV-3) or complementarity-determining regions (CDR1, CDR2 and CDR3). CDRs are supported within the variable domains by conserved framework regions. The heavy chain locus contains about 65 different variable domain genes that all differ in their CDRs. Combining these genes with an array of genes for other domains of the antibody generates a large cavalry of antibodies with a high degree of variability. This combination is called V(D)J recombination discussed below. [40]

    V(D)J recombination Edit

    Somatic recombination of immunoglobulins, also known as V(D)J recombination, involves the generation of a unique immunoglobulin variable region. The variable region of each immunoglobulin heavy or light chain is encoded in several pieces—known as gene segments (subgenes). These segments are called variable (V), diversity (D) and joining (J) segments. [39] V, D and J segments are found in Ig heavy chains, but only V and J segments are found in Ig light chains. Multiple copies of the V, D and J gene segments exist, and are tandemly arranged in the genomes of mammals. In the bone marrow, each developing B cell will assemble an immunoglobulin variable region by randomly selecting and combining one V, one D and one J gene segment (or one V and one J segment in the light chain). As there are multiple copies of each type of gene segment, and different combinations of gene segments can be used to generate each immunoglobulin variable region, this process generates a huge number of antibodies, each with different paratopes, and thus different antigen specificities. [41] The rearrangement of several subgenes (i.e. V2 family) for lambda light chain immunoglobulin is coupled with the activation of microRNA miR-650, which further influences biology of B-cells.

    RAG proteins play an important role with V(D)J recombination in cutting DNA at a particular region. [41] Without the presence of these proteins, V(D)J recombination would not occur. [41]

    After a B cell produces a functional immunoglobulin gene during V(D)J recombination, it cannot express any other variable region (a process known as allelic exclusion) thus each B cell can produce antibodies containing only one kind of variable chain. [2] [42]

    Somatic hypermutation and affinity maturation Edit

    Following activation with antigen, B cells begin to proliferate rapidly. In these rapidly dividing cells, the genes encoding the variable domains of the heavy and light chains undergo a high rate of point mutation, by a process called somatic hypermutation (SHM). SHM results in approximately one nucleotide change per variable gene, per cell division. [43] As a consequence, any daughter B cells will acquire slight amino acid differences in the variable domains of their antibody chains.

    This serves to increase the diversity of the antibody pool and impacts the antibody's antigen-binding affinity. [44] Some point mutations will result in the production of antibodies that have a weaker interaction (low affinity) with their antigen than the original antibody, and some mutations will generate antibodies with a stronger interaction (high affinity). [45] B cells that express high affinity antibodies on their surface will receive a strong survival signal during interactions with other cells, whereas those with low affinity antibodies will not, and will die by apoptosis. [45] Thus, B cells expressing antibodies with a higher affinity for the antigen will outcompete those with weaker affinities for function and survival allowing the average affinity of antibodies to increase over time. The process of generating antibodies with increased binding affinities is called affinity maturation. Affinity maturation occurs in mature B cells after V(D)J recombination, and is dependent on help from helper T cells. [46]

    Class switching Edit

    Isotype or class switching is a biological process occurring after activation of the B cell, which allows the cell to produce different classes of antibody (IgA, IgE, or IgG). [41] The different classes of antibody, and thus effector functions, are defined by the constant (C) regions of the immunoglobulin heavy chain. Initially, naive B cells express only cell-surface IgM and IgD with identical antigen binding regions. Each isotype is adapted for a distinct function therefore, after activation, an antibody with an IgG, IgA, or IgE effector function might be required to effectively eliminate an antigen. Class switching allows different daughter cells from the same activated B cell to produce antibodies of different isotypes. Only the constant region of the antibody heavy chain changes during class switching the variable regions, and therefore antigen specificity, remain unchanged. Thus the progeny of a single B cell can produce antibodies, all specific for the same antigen, but with the ability to produce the effector function appropriate for each antigenic challenge. Class switching is triggered by cytokines the isotype generated depends on which cytokines are present in the B cell environment. [47]

    Class switching occurs in the heavy chain gene locus by a mechanism called class switch recombination (CSR). This mechanism relies on conserved nucleotide motifs, called switch (S) regions, found in DNA upstream of each constant region gene (except in the δ-chain). The DNA strand is broken by the activity of a series of enzymes at two selected S-regions. [48] [49] The variable domain exon is rejoined through a process called non-homologous end joining (NHEJ) to the desired constant region (γ, α or ε). This process results in an immunoglobulin gene that encodes an antibody of a different isotype. [50]

    Specificity designations Edit

    An antibody can be called monospecific if it has specificity for the same antigen or epitope, [51] or bispecific if they have affinity for two different antigens or two different epitopes on the same antigen. [52] A group of antibodies can be called polyvalent (or unspecific) if they have affinity for various antigens [53] or microorganisms. [53] Intravenous immunoglobulin, if not otherwise noted, consists of a variety of different IgG (polyclonal IgG). In contrast, monoclonal antibodies are identical antibodies produced by a single B cell.

    Asymmetrical antibodies Edit

    Heterodimeric antibodies, which are also asymmetrical antibodies, allow for greater flexibility and new formats for attaching a variety of drugs to the antibody arms. One of the general formats for a heterodimeric antibody is the "knobs-into-holes" format. This format is specific to the heavy chain part of the constant region in antibodies. The "knobs" part is engineered by replacing a small amino acid with a larger one. It fits into the "hole", which is engineered by replacing a large amino acid with a smaller one. What connects the "knobs" to the "holes" are the disulfide bonds between each chain. The "knobs-into-holes" shape facilitates antibody dependent cell mediated cytotoxicity. Single chain variable fragments (scFv) are connected to the variable domain of the heavy and light chain via a short linker peptide. The linker is rich in glycine, which gives it more flexibility, and serine/threonine, which gives it specificity. Two different scFv fragments can be connected together, via a hinge region, to the constant domain of the heavy chain or the constant domain of the light chain. [54] This gives the antibody bispecificity, allowing for the binding specificities of two different antigens. [55] The "knobs-into-holes" format enhances heterodimer formation but doesn't suppress homodimer formation.

    To further improve the function of heterodimeric antibodies, many scientists are looking towards artificial constructs. Artificial antibodies are largely diverse protein motifs that use the functional strategy of the antibody molecule, but aren't limited by the loop and framework structural constraints of the natural antibody. [56] Being able to control the combinational design of the sequence and three-dimensional space could transcend the natural design and allow for the attachment of different combinations of drugs to the arms.

    Heterodimeric antibodies have a greater range in shapes they can take and the drugs that are attached to the arms don't have to be the same on each arm, allowing for different combinations of drugs to be used in cancer treatment. Pharmaceuticals are able to produce highly functional bispecific, and even multispecific, antibodies. The degree to which they can function is impressive given that such a change of shape from the natural form should lead to decreased functionality.

    The first use of the term "antibody" occurred in a text by Paul Ehrlich. The term Antikörper (the German word for antibody) appears in the conclusion of his article "Experimental Studies on Immunity", published in October 1891, which states that, "if two substances give rise to two different Antikörper, then they themselves must be different". [57] However, the term was not accepted immediately and several other terms for antibody were proposed these included Immunkörper, Amboceptor, Zwischenkörper, substance sensibilisatrice, copula, Desmon, philocytase, fixateur, and Immunisin. [57] The word antibody has formal analogy to the word antitoxin and a similar concept to Immunkörper (immune body in English). [57] As such, the original construction of the word contains a logical flaw the antitoxin is something directed against a toxin, while the antibody is a body directed against something. [57]

    The study of antibodies began in 1890 when Emil von Behring and Kitasato Shibasaburō described antibody activity against diphtheria and tetanus toxins. Von Behring and Kitasato put forward the theory of humoral immunity, proposing that a mediator in serum could react with a foreign antigen. [61] [62] His idea prompted Paul Ehrlich to propose the side-chain theory for antibody and antigen interaction in 1897, when he hypothesized that receptors (described as "side-chains") on the surface of cells could bind specifically to toxins – in a "lock-and-key" interaction – and that this binding reaction is the trigger for the production of antibodies. [63] Other researchers believed that antibodies existed freely in the blood and, in 1904, Almroth Wright suggested that soluble antibodies coated bacteria to label them for phagocytosis and killing a process that he named opsoninization. [64]

    In the 1920s, Michael Heidelberger and Oswald Avery observed that antigens could be precipitated by antibodies and went on to show that antibodies are made of protein. [65] The biochemical properties of antigen-antibody-binding interactions were examined in more detail in the late 1930s by John Marrack. [66] The next major advance was in the 1940s, when Linus Pauling confirmed the lock-and-key theory proposed by Ehrlich by showing that the interactions between antibodies and antigens depend more on their shape than their chemical composition. [67] In 1948, Astrid Fagraeus discovered that B cells, in the form of plasma cells, were responsible for generating antibodies. [68]

    Further work concentrated on characterizing the structures of the antibody proteins. A major advance in these structural studies was the discovery in the early 1960s by Gerald Edelman and Joseph Gally of the antibody light chain, [69] and their realization that this protein is the same as the Bence-Jones protein described in 1845 by Henry Bence Jones. [70] Edelman went on to discover that antibodies are composed of disulfide bond-linked heavy and light chains. Around the same time, antibody-binding (Fab) and antibody tail (Fc) regions of IgG were characterized by Rodney Porter. [71] Together, these scientists deduced the structure and complete amino acid sequence of IgG, a feat for which they were jointly awarded the 1972 Nobel Prize in Physiology or Medicine. [71] The Fv fragment was prepared and characterized by David Givol. [72] While most of these early studies focused on IgM and IgG, other immunoglobulin isotypes were identified in the 1960s: Thomas Tomasi discovered secretory antibody (IgA) [73] David S. Rowe and John L. Fahey discovered IgD [74] and Kimishige Ishizaka and Teruko Ishizaka discovered IgE and showed it was a class of antibodies involved in allergic reactions. [75] In a landmark series of experiments beginning in 1976, Susumu Tonegawa showed that genetic material can rearrange itself to form the vast array of available antibodies. [76]

    Disease diagnosis Edit

    Detection of particular antibodies is a very common form of medical diagnostics, and applications such as serology depend on these methods. [77] For example, in biochemical assays for disease diagnosis, [78] a titer of antibodies directed against Epstein-Barr virus or Lyme disease is estimated from the blood. If those antibodies are not present, either the person is not infected or the infection occurred a very long time ago, and the B cells generating these specific antibodies have naturally decayed.

    In clinical immunology, levels of individual classes of immunoglobulins are measured by nephelometry (or turbidimetry) to characterize the antibody profile of patient. [79] Elevations in different classes of immunoglobulins are sometimes useful in determining the cause of liver damage in patients for whom the diagnosis is unclear. [1] For example, elevated IgA indicates alcoholic cirrhosis, elevated IgM indicates viral hepatitis and primary biliary cirrhosis, while IgG is elevated in viral hepatitis, autoimmune hepatitis and cirrhosis.

    Autoimmune disorders can often be traced to antibodies that bind the body's own epitopes many can be detected through blood tests. Antibodies directed against red blood cell surface antigens in immune mediated hemolytic anemia are detected with the Coombs test. [80] The Coombs test is also used for antibody screening in blood transfusion preparation and also for antibody screening in antenatal women. [80]

    Practically, several immunodiagnostic methods based on detection of complex antigen-antibody are used to diagnose infectious diseases, for example ELISA, immunofluorescence, Western blot, immunodiffusion, immunoelectrophoresis, and magnetic immunoassay. Antibodies raised against human chorionic gonadotropin are used in over the counter pregnancy tests.

    New dioxaborolane chemistry enables radioactive fluoride ( 18 F) labeling of antibodies, which allows for positron emission tomography (PET) imaging of cancer. [81]

    Disease therapy Edit

    Some immune deficiencies, such as X-linked agammaglobulinemia and hypogammaglobulinemia, result in partial or complete lack of antibodies. [87] These diseases are often treated by inducing a short term form of immunity called passive immunity. Passive immunity is achieved through the transfer of ready-made antibodies in the form of human or animal serum, pooled immunoglobulin or monoclonal antibodies, into the affected individual. [88]

    Prenatal therapy Edit

    Rh factor, also known as Rh D antigen, is an antigen found on red blood cells individuals that are Rh-positive (Rh+) have this antigen on their red blood cells and individuals that are Rh-negative (Rh–) do not. During normal childbirth, delivery trauma or complications during pregnancy, blood from a fetus can enter the mother's system. In the case of an Rh-incompatible mother and child, consequential blood mixing may sensitize an Rh- mother to the Rh antigen on the blood cells of the Rh+ child, putting the remainder of the pregnancy, and any subsequent pregnancies, at risk for hemolytic disease of the newborn. [89]

    Rho(D) immune globulin antibodies are specific for human RhD antigen. [90] Anti-RhD antibodies are administered as part of a prenatal treatment regimen to prevent sensitization that may occur when a Rh-negative mother has a Rh-positive fetus. Treatment of a mother with Anti-RhD antibodies prior to and immediately after trauma and delivery destroys Rh antigen in the mother's system from the fetus. It is important to note that this occurs before the antigen can stimulate maternal B cells to "remember" Rh antigen by generating memory B cells. Therefore, her humoral immune system will not make anti-Rh antibodies, and will not attack the Rh antigens of the current or subsequent babies. Rho(D) Immune Globulin treatment prevents sensitization that can lead to Rh disease, but does not prevent or treat the underlying disease itself. [90]

    Specific antibodies are produced by injecting an antigen into a mammal, such as a mouse, rat, rabbit, goat, sheep, or horse for large quantities of antibody. Blood isolated from these animals contains polyclonal antibodies—multiple antibodies that bind to the same antigen—in the serum, which can now be called antiserum. Antigens are also injected into chickens for generation of polyclonal antibodies in egg yolk. [91] To obtain antibody that is specific for a single epitope of an antigen, antibody-secreting lymphocytes are isolated from the animal and immortalized by fusing them with a cancer cell line. The fused cells are called hybridomas, and will continually grow and secrete antibody in culture. Single hybridoma cells are isolated by dilution cloning to generate cell clones that all produce the same antibody these antibodies are called monoclonal antibodies. [92] Polyclonal and monoclonal antibodies are often purified using Protein A/G or antigen-affinity chromatography. [93]

    In research, purified antibodies are used in many applications. Antibodies for research applications can be found directly from antibody suppliers, or through use of a specialist search engine. Research antibodies are most commonly used to identify and locate intracellular and extracellular proteins. Antibodies are used in flow cytometry to differentiate cell types by the proteins they express different types of cell express different combinations of cluster of differentiation molecules on their surface, and produce different intracellular and secretable proteins. [94] They are also used in immunoprecipitation to separate proteins and anything bound to them (co-immunoprecipitation) from other molecules in a cell lysate, [95] in Western blot analyses to identify proteins separated by electrophoresis, [96] and in immunohistochemistry or immunofluorescence to examine protein expression in tissue sections or to locate proteins within cells with the assistance of a microscope. [94] [97] Proteins can also be detected and quantified with antibodies, using ELISA and ELISpot techniques. [98] [99]

    Antibodies used in research are some of the most powerful, yet most problematic reagents with a tremendous number of factors that must be controlled in any experiment including cross reactivity, or the antibody recognizing multiple epitopes and affinity, which can vary widely depending on experimental conditions such as pH, solvent, state of tissue etc. Multiple attempts have been made to improve both the way that researchers validate antibodies [100] [101] and ways in which they report on antibodies. Researchers using antibodies in their work need to record them correctly in order to allow their research to be reproducible (and therefore tested, and qualified by other researchers). Less than half of research antibodies referenced in academic papers can be easily identified. [102] Papers published in F1000 in 2014 and 2015 provide researchers with a guide for reporting research antibody use. [103] [104] The RRID paper, is co-published in 4 journals that implemented the RRIDs Standard for research resource citation, which draws data from the as the source of antibody identifiers [105] (see also group at Force11 [106] ).

    Production and testing Edit

    Traditionally, most antibodies are produced by hybridoma cell lines through immortalization of antibody-producing cells by chemically-induced fusion with myeloma cells. In some cases, additional fusions with other lines have created "triomas" and "quadromas". The manufacturing process should be appropriately described and validated. Validation studies should at least include:

    • The demonstration that the process is able to produce in good quality (the process should be validated)
    • The efficiency of the antibody purification (all impurities and virus must be eliminated)
    • The characterization of purified antibody (physicochemical characterization, immunological properties, biological activities, contaminants, . )
    • Determination of the virus clearance studies

    Before clinical trials Edit

    • Product safety testing: Sterility (bacteria and fungi), In vitro and in vivo testing for adventitious viruses, Murine retrovirus testing. Product safety data needed before the initiation of feasibility trials in serious or immediately life-threatening conditions, it serves to evaluate dangerous potential of the product.
    • Feasibility testing: These are pilot studies whose objectives include, among others, early characterization of safety and initial proof of concept in a small specific patient population (in vitro or in vivo testing).

    Preclinical studies Edit

    • Testing cross-reactivity of antibody: to highlight unwanted interactions (toxicity) of antibodies with previously characterized tissues. This study can be performed in vitro (Reactivity of the antibody or immunoconjugate should be determined with a quick-frozen adult tissues) or in vivo (with appropriates animal models).
    • Preclinical pharmacology and toxicity testing: preclinical safety testing of antibody is designed to identify possible toxicity in humans, to estimate the likelihood and severity of potential adverse events in humans, and to identify a safe starting dose and dose escalation, when possible.
    • Animal toxicity studies: Acute toxicity testing, Repeat-dose toxicity testing, Long-term toxicity testing
    • Pharmacokinetics and pharmacodynamics testing: Use for determinate clinical dosages, antibody activities, evaluation of the potential clinical effects

    The importance of antibodies in health care and the biotechnology industry demands knowledge of their structures at high resolution. This information is used for protein engineering, modifying the antigen binding affinity, and identifying an epitope, of a given antibody. X-ray crystallography is one commonly used method for determining antibody structures. However, crystallizing an antibody is often laborious and time-consuming. Computational approaches provide a cheaper and faster alternative to crystallography, but their results are more equivocal, since they do not produce empirical structures. Online web servers such as Web Antibody Modeling (WAM) [107] and Prediction of Immunoglobulin Structure (PIGS) [108] enables computational modeling of antibody variable regions. Rosetta Antibody is a novel antibody FV region structure prediction server, which incorporates sophisticated techniques to minimize CDR loops and optimize the relative orientation of the light and heavy chains, as well as homology models that predict successful docking of antibodies with their unique antigen. [109]

    The ability to describe the antibody through binding affinity to the antigen is supplemented by information on antibody structure and amino acid sequences for the purpose of patent claims. [110] Several methods have been presented for computational design of antibodies based on the structural bioinformatics studies of antibody CDRs. [111] [112] [113]

    There are a variety of methods used to sequence an antibody including Edman degradation, cDNA, etc. albeit one of the most common modern uses for peptide/protein identification is liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). [114] High volume antibody sequencing methods require computational approaches for the data analysis, including de novo sequencing directly from tandem mass spectra [115] and database search methods that use existing protein sequence databases. [116] [117] Many versions of shotgun protein sequencing are able to increase the coverage by utilizing CID/HCD/ETD [118] fragmentation methods and other techniques, and they have achieved substantial progress in attempt to fully sequence proteins, especially antibodies. Other methods have assumed the existence of similar proteins, [119] a known genome sequence, [120] or combined top-down and bottom up approaches. [121] Current technologies have the ability to assemble protein sequences with high accuracy by integrating de novo sequencing peptides, intensity, and positional confidence scores from database and homology searches. [122]

    Antibody mimetics are organic compounds, like antibodies, that can specifically bind antigens. They are usually artificial peptides or proteins with a molar mass of about 3 to 20 kDa. Nucleic acids and small molecules are sometimes considered antibody mimetics, but not artificial antibodies, antibody fragments, and fusion proteins are composed from these. Common advantages over antibodies are better solubility, tissue penetration, stability towards heat and enzymes, and comparatively low production costs. Antibody mimetics have being developed and commercialised as research, diagnostic and therapeutic agents. [123]

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      at University of Cambridge Discussion of the structure of antibodies at RCSB Protein Data Bank at University of South Carolina History and applications of antibodies in the treatment of disease at University of Oxford from Cells Alive! Fluorescent antibody image library, University of Birmingham

    80 ms 8.2% Scribunto_LuaSandboxCallback::match 80 ms 8.2% select_one 80 ms 8.2% type 60 ms 6.1% 40 ms 4.1% Scribunto_LuaSandboxCallback::lc 40 ms 4.1% [others] 160 ms 16.3% Number of Wikibase entities loaded: 1/400 -->

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    21.6 The Complement System

    The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to “complement” the killing of pathogens by antibodies. Complement is the major humoral component of the innate immune response. Many species have complement systems, including non-mammals like plants, fish, and some invertebrates.

    Figure 21.12: The complement system is made up of about 25 proteins that work together to “complement” the action of antibodies in destroying bacteria. Complement proteins circulate in the blood in an inactive form. When the first protein in the complement series is activated— typically by antibody that has locked onto an antigen—it sets in motion a domino effect. Each component takes its turn in a precise chain of steps known as the complement cascade. The end product is a cylinder inserted into—and puncturing a hole in—the cell’s wall. With fluids and molecules flowing in and out, the cell swells and bursts.

    In humans, this response is activated by complement binding to antibodies that have attached to these microbes or the binding of complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a rapid killing response. The speed of the response is a result of signal amplification that occurs after sequential proteolytic activation of complement molecules, which are also proteases. After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback. The cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their plasma membrane.

    Bacteria (and perhaps other prokaryotic organisms), utilize a unique defense mechanism, called the restriction modification system to protect themselves from pathogens, such as bacteriophages. In this system, bacteria produce enzymes, called restriction endonucleases, that attack and destroy specific regions of the viral DNA of invading bacteriophages. Methylation of the host’s own DNA marks it as “self” and prevents it from being attacked by endonucleases. Restriction endonucleases and the restriction modification system exist exclusively in prokaryotes.

    Invertebrates do not possess lymphocytes or an antibody-based humoral immune system, and it is likely that a multicomponent, adaptive immune system arose with the first vertebrates. Nevertheless, invertebrates possess mechanisms that appear to be precursors of these aspects of vertebrate immunity. Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with microbial pathogens. Toll-like receptors are a major class of pattern recognition receptor, that exists in all coelomates (animals with a body-cavity), including humans. The complement system, as discussed above, is a biochemical cascade of the immune system that helps clear pathogens from an organism, and exists in most forms of life. Some invertebrates, including various insects, crabs, and worms utilize a modified form of the complement response known as the prophenoloxidase (proPO) system.

    Antimicrobial peptides are an evolutionarily conserved component of the innate immune response found among all classes of life and represent the main form of invertebrate systemic immunity. Several species of insect produce antimicrobial peptides known as defensins and cecropins.

    In invertebrates, pattern recognition proteins (PRPs) trigger proteolytic cascades that degrade proteins and control many of the mechanisms of the innate immune system of invertebrates—including hemolymph coagulation and melanization. Proteolytic cascades are important components of the invertebrate immune system because they are turned on more rapidly than other innate immune reactions because they do not rely on gene changes. Proteolytic cascades have been found to function the same in both vertebrate and invertebrates, even though different proteins are used throughout the cascades.

    In the hemolymph, which makes up the fluid in the circulatory system of arthropods, a gel-like fluid surrounds pathogen invaders, similar to the way blood does in other animals. There are various different proteins and mechanisms that are involved in invertebrate clotting. In crustaceans, transglutaminase from blood cells and mobile plasma proteins make up the clotting system, where the transglutaminase polymerizes 210 kDa subunits of a plasma-clotting protein. On the other hand, in the horseshoe crab species clotting system, components of proteolytic cascades are stored as inactive forms in granules of hemocytes, which are released when foreign molecules, like lipopolysaccharides enter.

    Members of every class of pathogen that infect humans also infect plants. Although the exact pathogenic species vary with the infected species, bacteria, fungi, viruses, nematodes, and insects can all cause plant disease. As with animals, plants attacked by insects or other pathogens use a set of complex metabolic responses which lead to the formation of defensive chemical compounds that fight infection or make the plant less attractive to insects and other herbivores. (see: plant defense against herbivory).

    Like invertebrates, plants neither generate antibody or T-cell responses nor possess mobile cells that detect and attack pathogens. In addition, in case of infection, parts of some plants are treated as disposable and replaceable, in ways that very few animals are able to do. Walling off or discarding a part of a plant helps stop spread of an infection.

    Most plant immune responses involve systemic chemical signals sent throughout a plant. Plants use pattern-recognition receptors to recognize conserved microbial signatures. This recognition triggers an immune response. The first plant receptors of conserved microbial signatures were identified in rice (XA21, 1995) and in Arabidopsis (FLS2, 2000). Plants also carry immune receptors that recognize highly variable pathogen effectors. These include the NBS-LRR class of proteins. When a part of a plant becomes infected with a microbial or viral pathogen, in case of an incompatible interaction triggered by specific elicitors, the plant produces a localized hypersensitive response (HR), in which cells at the site of infection undergo rapid programmed cell death to prevent the spread of the disease to other parts of the plant. HR has some similarities to animal pyroptosis, such as a requirement of caspase-1-like proteolytic activity of VPEγ, a cysteine protease that regulates cell disassembly during cell death.

    “Resistance” (R) proteins, encoded by R genes, are widely present in plants and detect pathogens. These proteins contain domains similar to the NOD Like Receptors and Toll-like receptors utilized in animal innate immunity. Systemic acquired resistance (SAR) is a type of defensive response that renders the entire plant resistant to a broad spectrum of infectious agents. SAR involves the production of chemical messengers, such as salicylic acid or jasmonic acid. Some of these travel through the plant and signal other cells to produce defensive compounds to protect uninfected parts, e.g., leaves. Salicylic acid itself, although indispensable for expression of SAR, is not the translocated signal responsible for the systemic response. Recent evidence indicates a role for jasmonates in transmission of the signal to distal portions of the plant. RNA silencing mechanisms are also important in the plant systemic response, as they can block virus replication. The jasmonic acid response, is stimulated in leaves damaged by insects, and involves the production of methyl jasmonate.

    Antibodies of the Mucosal Immune System

    Antibodies synthesized by the mucosal immune system include IgA and IgM. Activated B cells differentiate into mucosal plasma cells that synthesize and secrete dimeric IgA, and to a lesser extent, pentameric IgM. Secreted IgA is abundant in tears, saliva, breast milk, and in secretions of the gastrointestinal and respiratory tracts. Antibody secretion results in a local humoral response at epithelial surfaces and prevents infection of the mucosa by binding and neutralizing pathogens.

    Are IgE antibodies capable of binding water molecules? - Biology

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    Application Notes

    • Pre-Coated 96-well Strip Microplate
    • Wash Buffer
    • Stop Solution
    • Assay Diluent(s)
    • Lyophilized Standard
    • Biotinylated Detection Antibody
    • Streptavidin-Conjugated HRP
    • TMB One-Step Substrate
    • Distilled or deionized water
    • Precision pipettes to deliver 2 µl to 1 µl volumes
    • Adjustable 1-25 µl pipettes for reagent preparation
    • 100 µl and 1 liter graduated cylinders
    • Tubes to prepare standard and sample dilutions
    • Absorbent paper
    • Microplate reader capable of measuring absorbance at 450nm
    • Log-log graph paper or computer and software for ELISA data analysis
    1. Prepare all reagents, samples and standards as instructed in the manual.
    2. Add 100 µl of standard or sample to each well.
    3. Incubate 2.5 h at RT or O/N at 4°C.
    4. Add 100 µl of prepared biotin antibody to each well.
    5. Incubate 1 h at RT.
    6. Add 100 µl of prepared Streptavidin solution to each well.
    7. Incubate 45 min at RT.
    8. Add 100 µl of TMB One-Step Substrate Reagent to each well.
    9. Incubate 30 min at RT.
    10. Add 50 µl of Stop Solution to each well.
    11. Read at 450 nm immediately.

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    224 Disruptions in the Immune System

    By the end of this section, you will be able to do the following:

    A functioning immune system is essential for survival, but even the sophisticated cellular and molecular defenses of the mammalian immune response can be defeated by pathogens at virtually every step. In the competition between immune protection and pathogen evasion, pathogens have the advantage of more rapid evolution because of their shorter generation time and other characteristics. For instance, Streptococcus pneumoniae (bacterium that cause pneumonia and meningitis) surrounds itself with a capsule that inhibits phagocytes from engulfing it and displaying antigens to the adaptive immune system. Staphylococcus aureus (bacterium that can cause skin infections, abscesses, and meningitis) synthesizes a toxin called leukocidin that kills phagocytes after they engulf the bacterium. Other pathogens can also hinder the adaptive immune system. HIV infects TH cells via their CD4 surface molecules, gradually depleting the number of TH cells in the body this inhibits the adaptive immune system’s capacity to generate sufficient responses to infection or tumors. As a result, HIV-infected individuals often suffer from infections that would not cause illness in people with healthy immune systems but which can cause devastating illness to immune-compromised individuals. Maladaptive responses of immune cells and molecules themselves can also disrupt the proper functioning of the entire system, leading to host cell damage that could become fatal.


    Failures, insufficiencies, or delays at any level of the immune response can allow pathogens or tumor cells to gain a foothold and replicate or proliferate to high enough levels that the immune system becomes overwhelmed. Immunodeficiency is the failure, insufficiency, or delay in the response of the immune system, which may be acquired or inherited. Immunodeficiency can be acquired as a result of infection with certain pathogens (such as HIV), chemical exposure (including certain medical treatments), malnutrition, or possibly by extreme stress. For instance, radiation exposure can destroy populations of lymphocytes and elevate an individual’s susceptibility to infections and cancer. Dozens of genetic disorders result in immunodeficiencies, including Severe Combined Immunodeficiency (SCID), Bare lymphocyte syndrome, and MHC II deficiencies. Rarely, primary immunodeficiencies that are present from birth may occur. Neutropenia is one form in which the immune system produces a below-average number of neutrophils, the body’s most abundant phagocytes. As a result, bacterial infections may go unrestricted in the blood, causing serious complications.


    Maladaptive immune responses toward harmless foreign substances or self antigens that occur after tissue sensitization are termed hypersensitivities . The types of hypersensitivities include immediate, delayed, and autoimmunity. A large proportion of the population is affected by one or more types of hypersensitivity.


    The immune reaction that results from immediate hypersensitivities in which an antibody-mediated immune response occurs within minutes of exposure to a harmless antigen is called an allergy . In the United States, 20 percent of the population exhibits symptoms of allergy or asthma, whereas 55 percent test positive against one or more allergens. Upon initial exposure to a potential allergen, an allergic individual synthesizes antibodies of the IgE class via the typical process of APCs presenting processed antigen to TH cells that stimulate B cells to produce IgE. This class of antibodies also mediates the immune response to parasitic worms. The constant domain of the IgE molecules interact with mast cells embedded in connective tissues. This process primes, or sensitizes, the tissue. Upon subsequent exposure to the same allergen, IgE molecules on mast cells bind the antigen via their variable domains and stimulate the mast cell to release the modified amino acids histamine and serotonin these chemical mediators then recruit eosinophils which mediate allergic responses. (Figure) shows an example of an allergic response to ragweed pollen. The effects of an allergic reaction range from mild symptoms like sneezing and itchy, watery eyes to more severe or even life-threatening reactions involving intensely itchy welts or hives, airway contraction with severe respiratory distress, and plummeting blood pressure. This extreme reaction is known as anaphylactic shock. If not treated with epinephrine to counter the blood pressure and breathing effects, this condition can be fatal.

    Delayed hypersensitivity is a cell-mediated immune response that takes approximately one to two days after secondary exposure for a maximal reaction to be observed. This type of hypersensitivity involves the TH1 cytokine-mediated inflammatory response and may manifest as local tissue lesions or contact dermatitis (rash or skin irritation). Delayed hypersensitivity occurs in some individuals in response to contact with certain types of jewelry or cosmetics. Delayed hypersensitivity facilitates the immune response to poison ivy and is also the reason why the skin test for tuberculosis results in a small region of inflammation on individuals who were previously exposed to Mycobacterium tuberculosis. That is also why cortisone is used to treat such responses: it will inhibit cytokine production.


    Autoimmunity is a type of hypersensitivity to self antigens that affects approximately five percent of the population. Most types of autoimmunity involve the humoral immune response. Antibodies that inappropriately mark self components as foreign are termed autoantibodies . In patients with the autoimmune disease myasthenia gravis, muscle cell receptors that induce contraction in response to acetylcholine are targeted by antibodies. The result is muscle weakness that may include marked difficultly with fine and/or gross motor functions. In systemic lupus erythematosus, a diffuse autoantibody response to the individual’s own DNA and proteins results in various systemic diseases. As illustrated in (Figure), systemic lupus erythematosus may affect the heart, joints, lungs, skin, kidneys, central nervous system, or other tissues, causing tissue damage via antibody binding, complement recruitment, lysis, and inflammation.

    Autoimmunity can develop with time, and its causes may be rooted in molecular mimicry. Antibodies and TCRs may bind self antigens that are structurally similar to pathogen antigens, which the immune receptors first raised. As an example, infection with Streptococcus pyogenes (bacterium that causes strep throat) may generate antibodies or T cells that react with heart muscle, which has a similar structure to the surface of S. pyogenes. These antibodies can damage heart muscle with autoimmune attacks, leading to rheumatic fever. Insulin-dependent (Type 1) diabetes mellitus arises from a destructive inflammatory TH1 response against insulin-producing cells of the pancreas. Patients with this autoimmunity must be injected with insulin that originates from other sources.

    Section Summary

    Immune disruptions may involve insufficient immune responses or inappropriate immune targets. Immunodeficiency increases an individual’s susceptibility to infections and cancers. Hypersensitivities are misdirected responses either to harmless foreign particles, as in the case of allergies, or to host factors, as in the case of autoimmunity. Reactions to self components may be the result of molecular mimicry.


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