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Antibody

An antibody is a protein produced by B cells which is able to recognize and bind to specific protein sequences with very high specificity, allowing for the targeting of immune responses against only certain molecules. There are 5 different classes of antibody, each with unique biological functions that contribute to the overall ability of these molecules to coordinate immune reactions. Antibodies are also known as immunoglobulins (Ig). Antibodies are an essential component of the immune system, and are found in all organisms that have evolved since the split with jawed fish hundreds millions of years ago. Animals without adaptive immune systems, such as insects and other smaller animals, lack antibodies and have immune systems that rely solely on the innate detection of an invading pathogen which they must then fight off. In contrast, animals with an innate immune system can make antibodies that are specific for the pathogen that they encounter. In this way, they can produce a huge immune response that is also very specific, which cannot be done for insects with only innate immune systems where all inflammatory damage will prove to be relatively nonspecific in its action. In addition, antibodies against pathogens you have encountered will persist even after that pathogen has disappeared from your system such that you will be protected from being infected by that bacteria or virus again in the future. This phenomenon is known as immunological memory, and is part of what makes antibodies and the adaptive immune response so powerful.

Structure

Each antibody molecule is composed of four protein molecules - two identical heavy chain proteins, and two identical light chain proteins. These proteins are held together by relatively strong disulfide bonds, ensuring that antibodies remain stable when they are release from the B cells that produce that. Each pair of heavy and light chains combine to form a region which confers the antibody its specificity - this region is known as the antigen binding pocket, and every person with a functional immune system can produce billions of different antibody specificities, as they arise through random chance. These antibodies are produced while B cells develop from stem cell precursor cells in your bone marrow (or, in birds, in a specialized organ known as the Bursa of Fabricius in which B cell development occurs), and during B cell development random segments of DNA are spliced together in a controlled fashion to produce a new potentially unique antibody structure. As this process creates antibodies that recognize self proteins that are present within your own body, additional processes are needed to remove self reactive antibodies from your body by killing off these B cells of modifying their antibody structures through a process known as negative selection of B cells. It is important to eliminate autoreactive cells because they would otherwise have the potential to contribute to autoimmune disease and other conditions in which an aberrant inflammatory immune response develops in the absence of any true infection.

Production

Antibodies are produced excusively by B cells and these cells only exist in jawed vertebrates. Each B cell produces antibodies of only one specificity and one class (see below), although each cell can produce thousands-millions of individual antibody proteins, they will all be of identical specificity in order to ensure a consistently specific immune response. B cells constitutively produce low levels of antibody, however when they recognize their specific antigen (for example, if it is expressed by a pathogen which infects the body) then they will be activated by T cells, causing them to divide and produce large amounts of antibody. As the cells divide, new daughter cells may begin to produce different classes of antibody through a process which is often known as class switching. Class switching can be initiated by the recognition of a specific antigen by the B cells specific for that antigen, ensuring that only B cells that are needed during an inflammatory response will multiply, thereby maximizing your ability to produce antibodies against an invading pathogen or other source of inflammatory insult.

Classes

There are five primary classes of immunoglobulins. The antigen binding region of these antibodies is the same across classes, however the conserved region of the antibody (which is not involved in recognizing proteins) is altered in each class, conferring unique properties to the corresponding antibodies.

IgA

IgA antibodies are secreted by B cells and form dimers of two antibodies each, creating molecules with a total of four antibody binding pockets thereby increasing the effective avidity of these molecules. IgA are released from the body in secretions, such as in mucus in the lungs and gut, or in tears or vaginal secretions. When released, IgA are able to neutralize pathogens and toxins found in the external environment, preventing them from exerting a negative impact on the host. As a result, IgA are essential to the proper functioning of the immune system, and are needed to control infections in the gut and airways. IgA molecules can also help to export antigens and toxins that make it inside your body from the gut back out into the gut, thus once again preventing them from acting on teh body and also preventing the body from recognizing them, which would have the potential to start an inflammatory bowel disease such as Crohn's disease that would be quite maladaptive.

IgD

Unlike the other four classes of antibody, the biological function of IgD is uncertain. It is very rare in the body, and unlike other antibodies it exists only in a cell surface form and it is not secreted. Because of this it does not participate in immunological processes, and it may not be important in modern vertebrates although this remains to be seen.

IgE

IgE antibodies are secreted by B cells and exist as monomers. Once released, they associate with unique receptors on the surface of Mast cells. When these cells then encounter the antigen for which those IgE molecules are specific, the mast cells are activated and release various immunomodulatory compounds such as histamine. Classically, IgE molecules are important for eliminating infections with parasites such as nematodes or infectious worms. In the developed world, however, IgE has also been shown to play a role allergic responses and anaphylaxis, as well as in asthma and similar airway diseases.

IgG

IgG antibodies are secreted by B cells and exist as monomers. IgG are only produced by activated B cells which have undergone class switching, and as a result they are of higher affinity allowing them to detect their target antigen more quickly than other classes of Ig. Accordingly, IgG are important for immune responses and allow hosts to immediately eliminate pathogens that invade the body which have done so in the past. There are several subclasses of IgG, each of which has slighly different biological properties and tissue distributions.

IgM

IgM antibodies are secreted by B cells and exist as pentamers composed of 5 antibody molecules with a total of 10 antigen binding pockets, resulting in a massive increase in avidity. IgM molecules are produced by B cells which have not yet encountered their antigen, and as a result IgM is very common in the human body. IgM are most important for the early parts of the immune response to an invading pathogen, and levels of IgM rise rapidly when an individuals is infected with a new pathogen. Each individual IgM is generally of fairly low affinity.

BcR Development

BcR gene rearrangement is a random process and as such all members of a species are theoretically capable of possessing the same B cell repertoire prior to B cells undergoing central and peripheral tolerance checkpoints during their maturation. There is, however, evidence that certain populations including autoimmune individuals possess distinct B cell repertoires which differ from those of control populations. This suggests that autoimmunity may be linked to genetic defects of B cell tolerance or activation which allow cells that are not normally present in the periphery to escape inactivation, receptor editing, or deletion in order to mediate self-reactivity.

The primary basis of B cell repertoire differences between individuals are mutations of molecules that affect B cell tolerization. Central tolerance relies upon proper BcR and TLR signalling whereas peripheral tolerance checkpoints rely upon cell-cell interactions and cytokines. Accordingly, individuals with defects in signaling components such as BTK or MyD88 exhibit central tolerance defects while patients with MHC, CD40/CD40L, or BAFF defects have defective peripheral tolerance [1]. These tolerance defects are manifested as increased levels of autoreactive B cells comprising a B cell repertoire distinct from that of control patients. Similarly, mutations affecting B cell activation often predispose individuals to autoimmune diseases as in the case of the tyrosine kinase Csk, which is altered by a SNP in a subset of SLE patients resulting in increased mature B cell activation [2].

While rare B cell tolerance-associated defects likely arise spontaneously and exist only in small groups, more common mutations may be selected for by evolutionary pressures which cause the mutant allele to yield a significant fitness advantage in certain contexts despite the risk of autoimmunity. Inactivating mutations in FcγRIIb have been associated with lupus and are most common in humans from regions where malaria is endemic [3]. These mutations have been shown to aid in malarial clearance in murine and human cells while also promoting more vigorous germinal center responses and increased autoantibody production associated with autoimmunity in mice [3,4]. Studies of wild sheep have also identified positive correlations between autoantibody titers and survival of offspring despite a negative correlation between these same autoantibodies and female fecundity [5]. Reports such as these suggest that certain mutations which can lead to autoimmunity are maintained by natural selection due to significant survival advantages which they incur in environments wehre these advantages outweigh the negative costs of immunopathology.

Random reassortment is responsible for the initial B cell repertoire generation, whereas B cell intrinsic and extrinsic factors are responsible for determining which cell remain the mature repertoire. Although many genetic defects of B cell tolerance can lead to deleterious increases in autoreactive cells and a correspondent predisposition to autoimmunity, these same mutations may be selected for under certain circumstances in which they enable more robust/aggressive immune responses. As such the generation of the mature B cell repertoire can be viewed as a complex process wherein an organism must minimize self-reactivity while still maximizing pathogen responsiveness, leading to variations in B cell reactivity between individuals which enable the population to effectively undergo natural selection.

References

  • Meffre E. The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases. Ann NY Acad Sci. 2011; 1246:1–10.
  • Manjarrez-Orduño N, et al. CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation. Nat Gen. 2012; 44(11): 1227-30.
  • Clatworthy MR, et al. Systemic lupus erythematosus-associated defects in the inhibitory receptor FcγRIIb reduce susceptibility to malaria. PNAS. 2007; 104(17): 7169–7174.
  • Espeli M, et al. Analysis of a wild mouse promoter variant reveals a novel role for FcγRIIb in the control of the germinal center and autoimmunity. JEM. 2012; 209(12): 2307-2319.
  • Graham AL, et al. Fitness Correlates of Heritable Variation in Antibody Responsiveness in a Wild Mammal. Science. 2010; 330: 662-4.

Biology


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