Polyclonal B cell response

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This article deals with immune response in the vertebrates, more specifically, mammals.
Blind Monks Examining an Elephant: An allegory for the polyclonal response: Each clone or antibody recognizes different parts of a single, larger antigen.

Polyclonal response is a natural mode of immunological response exhibited by the adaptive immune system of mammals. It ensures that a single antigen is recognized and attacked through its multiple overlapping parts, called epitopes, by multiple clones of B lymphocytes.[1][2]

In the course of normal immune response, a foreign substance present on a pathogen such as an invading bacterium, is recognized by the body. The immune system reacts against the substance to eliminate it or to reduce the damage it causes. Such a recognizable foreign substance present on the invading pathogen is known as an antigen. The immune system may respond in multiple ways to an antigen; a key feature of this response is the production of antibodies by the B cells (or B lymphocytes). This arm of the adaptive immune system is known as humoral immunity. The antibodies are soluble and do not require direct cell-to-cell contact to attack the pathogen.

Antigens can be large and complex substances, and any single antibody can only bind to a small, specific area on the antigen. Consequently, an effective immune response often involves the production of many different antibodies by many different B cells. Together, the response by these B cells is called a polyclonal immune response, and the antibodies thus produced are known as polyclonal antibodies.

The opposite of polyclonal are the monoclonal antibodies, which are not usually produced in a natural immune response, but only in diseased states like the multiple myeloma (which is not an immune response), or through specialized techniques like the hybridoma and the recombinant DNA technology.

Infection

There are several diseases that can be transmitted from one organism to another. These are known as infectious diseases, and the biological agent involved is known as a pathogen. The process by which the pathogen is introduced into the body is known as inoculation,[note 1][3]and the organism it affects is known as a biological host. When the pathogen establishes itself in a step known as colonization[4], it can result in an infection[5] consequently harming the host directly or through the harmful substances called toxins it can produce.[6] This results in the various symptom and signs characteristic of an infectious disease like pneumonia or botulism.

The immune system

Countering the various infectious diseases is very important for the survival of the susceptible organism, in particular, and the species, in general. This is achieved by the host by eliminating the pathogen and its toxins or rendering them nonfunctional. The collection of various cells, tissues and organs that specializes in protecting the body is known as the immune system. White blood cells are types of cells found not only in blood but also in various organs and tissues like the bone marrow, lymph nodes, spleen, liver, lymph, etc. They are involved in functions of the immune system. An important property of many white blood cells is that they can move from one tissue to another (including blood) and then return back, yet still retain their functions in the process. They are also known as leukocytes (leuko=white and cyte=cell).[7] The immune system accomplishes this through direct contact of certain white blood cells with the invading pathogen involving an arm of the immune system known as the cell mediated immunity, or by producing substances that move to sites distant from where they are produced, "seek" the disease-causing cells and toxins by specifically binding with them, and neutralize them in the process–known as the humoral arm of the immune system. Such substances are known as soluble antibodies and perform important functions in countering them.[8][note 2]

Both types of above responses (cell-mediated and humoral) are very specific, and tend to improve with repeat exposures to the same pathogen and constitute the adaptive immune response. Specificity means that two different pathogens will be actually viewed as two distinct entities, and countered by different antibody molecules.

There are other elements present in mammals that provide relatively nonspecific protection against various pathogens, which together are called as the innate immune system. Nonspecificity means that even widely differing pathogens will be countered by the same mechanism (e.g., acidity of stomach juice).

The major histocompatibility complex is a region on the DNA that codes for the synthesis of Major histocompatiblity class I molecule, Major histocompatiblity class II molecule and other proteins involved in the function of complement system (MHC class III)[9]. The products of this gene region are important in antigen presentation. MHC-compatibility is a major consideration in organ transplantation.[10]

B cell response

Figure 1: Schematic diagram to explain mechanisms of clonal selection of B cell, and how secondary immune response is stronger, quicker and more specific in comparison with the primary one.[11]

Antibodies serve various functions in protecting the host against the pathogen. Their soluble forms which carry out these functions are produced by the plasma B cells, which are a type of white blood cells. But this production is tightly regulated and requires the activation of B cells by activated T cells (again, a type of white blood cell), which is a sequential procedure. The major steps involved are:[12]

Recognition of pathogens

Template:Details3

Main article: Molecular recognition

Pathogens exhibit " recognizable" antigens (usually proteins) on the their surface. Likewise, the substances the pathogenic cells produce can also act as antigens. What makes these substances recognizable is that they bind very specifically and somewhat strongly to certain proteins produced by the host known as antibodies. The same antibodies can be anchored to the surface of cells of the immune system, in which case they serve as receptors, or they can be secreted in the blood, known as soluble antibodies. On a molecular scale, the proteins are relatively large, so they cannot be recognized as a whole; instead, their segments, called epitopes, can be recognized.[13]

Antigens interact (bind) with antibodies. But, the entire antigen (owing to large size) cannot interact as a whole, rather only the epitopes that compose them come in contact with a very small region (of 15-22 amino acids) known as paratope present on the antibody molecules.[14] In the immune system, membrane-bound antibodies are the B cell receptor. Also, while the T cell receptor is not biochemically classified as an antibody, it serves a similar function in that it specifically binds to epitopes complexed with major histocompatibility (MHC) molecules. The binding between a paratope and its corresponding antigen is very specific, owing to its structure, and is guided by various noncovalent bonds, not unlike the pairing of other types of ligands (any atom, ion or molecule that binds with any receptor with at least some degree of specificity and strength).

Macrophages and related cells employ a different mechanism to recognize the pathogen. Their receptors recognize certain motifs present on the invading pathogen that are very unlikely to be present on a host cell. Such repeating motifs are recognized by pattern recognition receptors (PRRs) like the Toll-like receptors (TLRs) expressed by the macrophages.[15] Since, the same receptor could bind to widely disparate microorganisms, this mode of recognition is relatively nonspecific, and constitutes an innate immune response.

Antigen processing

Further information: Antigen processing and antigen processing

After an antigen presenting cell, such as the macrophage or the B lymphocyte, specifically recognizes the antigen, it engulfs it completely by a process called phagocytosis. The engulfed particle, along with some material surrounding it, forms the endocytic vesicle or phagosome, which fuses with lysosomes. Within the lysosome, the antigen is broken down into smaller pieces called peptides. The individual peptides are then complexed with major histocompatibility complex class II (MHC class II) molecules located in the lysosome – this method of "handling" the antigen is known as the exogenous or endocytic pathway of antigen processing in contrast to the endogenous or cytosolic pathway,[16] which complexes the abnormal proteins produced within the cell (e.g under the influence of a viral infection or in a tumor cell) with MHC class I molecules.

Antigen presentation

Main articles: antigen presentation and Major histocompatibility complex

After the processed antigen (peptide) is complexed to the MHC molecule, they both migrate together to the cell membrane, and it is exhibited there (elaborated) as a complex that can be recognized by the CD 4+ (T helper cells) – a type of white blood cell.[note 3][17] This is known as antigen presentation. Note, however, that the epitopes (conformational epitopes) that are recognized by the B cell prior to their digestion may not be present on the peptides presented with the MHC class II molecules. Major histocompatibility complex is a region on the DNA containing genes present in all the nucleated cells of all jawed vertebrates, that codes for many products involved in antigen presentation (class I and II MHC molecules), functioning of the complement system, and production of immune response.[18] The complement system is an important additional tool of the body in directly attacking the individual microorganisms. The MHC molecules in humans are also known as human leukocyte antigen.

T helper cell stimulation

Further information: T helper cell and T helper cell

The CD 4+ cells through their T cell receptor- CD3 complex recognize the epitope-bound MHC II molecules on the surface of the antigen presenting cells, and get 'activated'. Upon this activation, these T cells proliferate and differentiate in to Th2 cells.[19] This makes them produce chemical soluble chemical signals that promote their own survival. However, another important function that they carry out is the stimulation of B cell by establishing direct physical contact with them.[20]

Costimulation of B cell by activated T helper cell

Template:Details3 Complete stimulation of T helper cells requires the B7 molecule present on the antigen presenting cell to bind with CD28 molecule present on the T cell surface (in close proximity with the T cell receptor).[21] Likewise, a second interaction between the CD40 ligand or CD154 (CD40L) present on T cell surface and CD40 present on B cell surface, is also necessary.[22] The same interactions that stimulate the T helper cell also stimulate the B cell, hence the term costimulation. The entire mechanism ensures that an activated T cell only stimulates a B cell that recognizes the antigen containing the same epitope as recognized by the T cell receptor of the "costimulating" T helper cell. The B cell gets stimulated, apart from the direct costimulation, by certain growth factors, viz., interleukins 2, 4, 5, and 6 in a paracrine fashion. These factors are usually produced by the newly activated T helper cell.[23] However, this activation occurs only after the B cell receptor present on a memory or a naive B cell itself would have bound to the corresponding epitope, without which the initiating steps of phagocytosis and antigen processing would not have occurred.

Proliferation and differentiation of B cell

Template:Details3 A naive (or inexperienced) B cell is one which belongs to a clone which has never encountered the epitope to which it is specific. In contrast, a memory B cell is one, which derives from an activated naive or memory B cell. This is followed by a manifold proliferation of that particular B lymphocyte, most of the progenies of which terminally differentiate into plasma cells, which secrete the antibodies (first immunoglobulin M, and then immunoglobulin G, in that sequence) that bind to the same epitope structure that had stimulated the B cell in the first place by binding to its B cell receptor. The rest survive as memory B cells. So, when the naive cells belonging to a particular clone encounter their specific antigen to give rise to the plasma cells (that neutralize the same antigen by binding it), and also leave a few memory cells, this is known as the primary immune response. In the course of this proliferation, the B cell receptor genes can undergo frequent (one in every two cell divisions)[24] mutations in the genes coding for paratopes of various receptors. These frequent mutations are termed somatic hypermutation. Each such mutation alters the epitope-binding ability of the paratope slightly, creating new clones of B cells in the process. Some of the newly created paratopes bind more strongly to the same epitope (leading to the selection of the clones possessing them), which is known as affinity maturation.[note 4][25] And others bind better to epitopes that are slightly different from the original epitope that stimulated proliferation in the first place. Variations in the epitope structure are also usually produced by mutations in the genes of pathogen coding for their antigen. This makes the B cell receptors and the soluble antibodies in subsequent encounters with antigens, more inclusive in their antigen recognition potential, as well as more specific for the antigen that induced proliferation in the first place. When the memory cells get stimulated by the antigen to produce plasma cells (just like in the primary response), and leave even more memory cells in the process, this is known as a secondary immune response,[26] which just like the soluble antibodies that plasma cells of the clone produce, also recognize the corresponding antigen faster and bind more strongly with them (e.g. greater affinity of binding; both owing to affinity maturation). Additionally, more memory cells translates into greater numbers of plasma cells. This results in higher antibody concentrations being reached in blood for longer periods.

Basis of polyclonality

Figure 2: Schematic diagram showing polyclonal response by B cells against linear epitopes[27]

Polyclonal derives from the words poly, meaning many, and clones ("Klon"=to sprout)[28]. A clone is a group of cells with common ancestry ("mother" cell). Responses are polyclonal in nature as each clone somewhat specializes in producing antibodies against a given epitope, and because, each antigen contains multiple epitopes, each of which in turn can be recognized by more than one clone of B cells.

Clonality of B cells

Memory and naïve B cells normally exist in relatively small numbers. As the body needs to be able to respond to a large number of potential pathogens, it maintains a pool of B cells with a wide range of specificities.[29] Consequently, while there is almost always at least one B (naive or memory) cell capable of responding to any given epitope, there are very few exact duplicates. However, when a single B cell encounters an antigen to which it can bind, it can proliferate very rapidly.[30] Each such group of cells with identical specificity towards the epitope is known as a clone, and is derived from a common "mother" cell. All of the "daughter" B cells match the original "mother" cell and secrete antibodies with identical paratopes. So, in this context, a polyclonal response is one in which multiple clones of B cells react to the same antigen.

Single antigen contains multiple overlapping epitopes

A single antigen can be broken down into multiple overlapping epitopes (see Figure 2). Many unique B cells may be able to bind to these different epitopes. This imparts even greater multiplicity to the overall response.[31] All of these B cells can become activated and produce large colonies of plasma cell clones, each of which can secrete up to 1000 antibody molecules against each epitope per second.[32]

Multiple clones recognize single epitope

In addition to different B cells reacting to different epitopes on the same antigen, B cells belonging to different clones may also be able to react to the same epitope. An epitope that can be attacked by many different B cells is said to be highly immunogenic. In these cases, the binding affinities for respective epitope-paratope pairs vary, with some B cell clones producing antibodies that bind strongly to the epitope, and others producing antibodies that bind weakly. This binding requires both the paratope and the epitope to undergo slight conformational changes in each others' presence.[33]

Clonal selection

Template:Details3 The clones that bind to a particular epitope with greater strength are more likely to be selected for further proliferation in the germinal centers of the follicles in various lymphoid tissues like the lymph nodes. This is not very different from Darwinian concept of natural selection: clones are selected for their fitness to attack the epitopes (strength of binding) on the encountered pathogen.[34] What makes the analogy even stronger is that the B lymphocytes have to compete with each other for signal promoting survival in the germinal centers.

Diversity of B cell clones

In spite of the fact that there are so many diverse pathogens, many of which constantly keep on mutating, it is a great surprise that a majority of individuals remain infection-free. This maintenance of disease-free state requires the body to recognize as many pathogens (antigens they present or produce) as known to exist. This is achieved by maintaining a pool of immensely large (about 109) clones of B cells[35], each of which reacts against a specific antigenic determinant, recognizing it and producing antibodies against it. Thus, approximately 107 different epitopes can be recognized by all the B cell clones combined.[36]. However, at any given time very few clones actually remain receptive to their specific epitope. Moreover, in a lifetime, an individual usually requires the generation of antibodies against very few antigens in comparison with the number that the body can recognize and respond against.[37]

Recognition of epitope by B cells

Figure 3: Recognition of conformational epitopes by B cells. Note how the segments widely separated in the primary structure have come in contact in the three dimensional tertiary structure forming part of the same epitope[38]

In Figure 2, the various segments that form the epitope have been shown to be continuously collinear, meaning that they have been shown as sequential, however, for the situation being discussed here (e.g. the antigen recognition by the B cell), this explanation would prove to be too simplistic. These are known as linear or sequential epitopes as all the amino acids on them are in the same sequence (line). This mode of recognition is possible only when the peptide in question would be small (to the order of six to eight amino acids long),[39] and is employed by the T cells (T lymphocytes).

However, the B memory/naive cells recognize intact proteins present on the pathogen surface (meaning, undigested protein, and not that the paratope on B cell receptor comes in contact with the whole protein structure at the same time) In this situation, the proteins in their tertiary structure are so folded that it is very unlikely that all of the continuous segments of the protein would lie close enough to each other in space while interacting with the receptor. So, the paratope on the B cell receptor in these cases actually recognizes the discontinuous segments of proteins that would have come close to each other owing to complex folding patterns of the protein (see Figure 3). Such epitopes are known as conformational epitopes and tend to be longer in length (15-22 amino acid residues) than the linear epitopes.[40] Likewise, the antibodies produced by the same plasma cells belonging to the same clone would bind to the same conformational epitopes located on the pathogen proteins.[41][42][43][44]

In the above analogy of a whorl of wool, if it would be possible to cut out a chunk of it that would correspond to a conformational epitope which upon unfolding will give many short segments. And, cutting a stretched strand into short segments would give us a linear epitope.

Significance of the phenomenon

Increased probability of recognizing any antigen

If an antigen can be recognized by more than one components of its structure, it is less likely to be "missed" by the immune system.[note 5] Mutation of pathogenic organisms can result in modification of antigen (and, hence, epitope-) structure. Now, if the immune system "remembers" what the other epitopes look like, the antigen, and the organism will still be recognized and subjected to the body's immune response. Thus, the polyclonal response widens the range of pathogens that can be recognized.[45]

Limitation of immune system against rapidly mutating viruses

Figure 4: The clone 1 that got stimulated by first antigen gets stimulated by second antigen, too, which best binds with naive cell of clone 2. However, antibodies produced by plasma cells of clone 1 inhibit the proliferation of clone 2.[46]
Main article: Original antigenic sin

Many viruses have enzymes (DNA polymerases) that are defective in the proofreading of their genetic material during replication. This allows certain changes in amino acid composition of their important proteins (mutations). When these proteins can perform their assigned functions (generally binding to some host protein) even in the face of these mutations, the B memory cell(s) that have recognized the protein (antigen) in prior encounters still recognize the protein, but the antibodies that they produce upon proliferation do not bind with the antigen with sufficient strength, and hence, do not perform their functions. This is unfortunate because somatic hypermutation does give rise to clones capable of producing soluble antibodies that would have bound the pathogen strong enough to neutralize it. But these clones would consist of naive cells which are not allowed to proliferate by the weakly binding antibodies produced by the priorly stimulated clone. This doctrine is known as the original antigenic sin.[47] This phenomenon comes into play particularly in immune responses against influenza, dengue and HIV viruses.[48] This limitation, however, is not imposed by the phenomenon of polyclonal response, but rather, against it by an immune response that is biased in favor of experienced memory cells against the "novice" naive cells.

Increased chances of autoimmune reactions

Further information: Autoimmunity and autoimmunity

The phenomenon of autoimmunity can be simply explained in terms of the immune system making a mistake by wrongly recognizing certain native molecules in the body as foreign, and in turn mounting an immune response against them. Since these native molecules, as normal parts of the body, will naturally always exist in the body, the attacks against them can get stronger over time. Moreover, many organisms exhibit molecular mimicry, which involves showing those antigens on their surface that are antigenically similar to the host proteins. This has two possible consequences: first, either the organism will be spared, as a self antigen, or secondly, that the antibodies produced against it will also bind to the proteins that the organism would have mimicked, and the harboring tissue will come under attack by various mechanisms like the complement activation and antibody-dependent, cell-mediated cytotoxicity. Hence, if the body produces more varieties (differing specificities as a result of polyclonal response) of the antibodies, the greater the chance that one or the other will react against self-antigens (native molecules of the body).[49][50]

Difficulty in producing monoclonal antibodies

Main article: Monoclonal antibodies

Monoclonal antibodies are structurally identical immunoglobulin molecules with identical epitope-specificity (all of them bind with the same epitope with same affinity) as against their polyclonal counterparts which have varying affinities for the same epitope. Monoclonal antibodies find use in various diagnostic modalities (see: western blot and immunofluorescence) and therapies—particularly of cancer and diseases with autoimmune component. But, since virtually all responses in nature are polyclonal, it makes production of immensely useful monoclonal antibodies less straightforward.[51]

History

The concept that each clone of B cell produces two types of cells with distinct functions was first proposed by Frank Macfarlane Burnet with input from David W. Talmadge.[52]

The next major development came about when Sir Gustav Nossal and Joshua Lederberg showed that one clone of B cell always produces only one antibody, which was the first evidence for clonal selection theory.[53]

See also

Notes

  1. ^ The term "inoculation" is usually used in context of active immunization, i.e., deliberately entering the antigenic substance into the host's body. But, in many discussions of infectious diseases, it is not uncommon to use the term to imply a spontaneous (that is, without human intervention) event resulting in introduction of the causative organism into the body, say some one ingesting water contaminated with Salmonella typhi—the causative organism for typhoid fever. In such cases the causative organism itself is known as the inoculum, and the number of organisms introduced as the "dose of inoculum".
  2. ^ Actions of antibodies:
    • Coat the pathogen not allowing it to adhere to the host cell, and thus preventing colonization.
    • Precipitating (making the particles "sink" by attaching with them) the soluble antigens and promoting their clearance by other cells of immune system from the various tissues and blood
    • Coating the microorganisms to attract cells that can engulf the pathogen. This is known as opsonization. And thus the antibody acts as an opsonin. And the process of engulfing is known as phagocytosis (phagocytosis literally means cell eating).
    • Activating the complement system, which most importantly pokes holes into the pathogen's outer covering known as cell membrane killing it in the process.
    • Marking up host cells infected by viruses for destruction in a process known as Antibody-dependent cell-mediated cytotoxicity (ADCC)
  3. ^ There are many types of white blood cells. The common way of classifying them is according to their appearance under the light microscope after they are stained by chemical dyes. But with advancing technology newer methods of classification has emerged. One of the methods employs the use of molecules called monoclonal antibodies that can bind specifically to each type of cell. Moreover, the same type of white blood cell would express molecules typical to typical to it on its cell membrane at various stages of development. The monoclonal antibodies that can specifically bind with a particular surface molecule would be regarded as one cluster of differentiation (CD). Any monoclonal antibody or a group of monoclonal antibodies that do not react with known surface molecules of lymphocytes, but rather to a yet-unrecognized surface molecule would be clubbed as a new cluster of differentiation and numbered accordingly. Each cluster of differentiation is abbreviated as "CD", and followed by a number (usually indicating the order of discovery). So, a cell possessing a surface molecule (called ligand) that binds specifically to cluster of differentiation 4 would be known as CD4+ cell. Likewise, a CD8+ cell is one that would possess the CD8 ligand and bind to CD8 monoclonal antibodies.
  4. ^ Affinity roughly translates as attraction from Latin. See also: Definition of Affinity from Online Etymology Dictionary and Definition of Affinity from TheFreeDictionary by Farlex
  5. ^ Analogically, if in a crowded place, one is supposed to recognize a person, it is better to know as many physical features as possible. If you know the person only by the hairstyle, there is a chance of overlooking the person if that changes. Whereas, if apart from the hairstyle, if you also happen to know the facial features and what the person will wear on a particular day, it becomes much more unlikely that you will miss that person.

References

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  5. ^ Pier, Gerald B. (2005) [1945]. "Molecular mechanisms of microbial pathogenesis (Chapter 105)". In Kasper, Braunwald, Fauci, Hauser, Longo, Jameson (ed.). Harrison's PRINCIPLES OF INTERNAL MEDICINE. Vol. 1 (Sixteenth Edition ed.). McGraw-Hill. p. 700. ISBN 007-123983-9. {{cite book}}: |access-date= requires |url= (help); |edition= has extra text (help); Cite has empty unknown parameter: |origdate= (help)CS1 maint: multiple names: editors list (link)
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  41. ^ "Technical Tips: Immunochemical Applications from EMD biosciences web site". Retrieved 2008-05-07. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
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  44. ^ Khudyakov, Yury (2002). Artificial DNA: Methods and Applications. Florida: CRC Press. p. 227. ISBN 0849314267. {{cite book}}: External link in |publisher= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  45. ^ Greener, Mark (2005-02-14). "Monoclonal antibodies (MAbs) turn 30". The Scientist. 19 (3). Philadelphia: SAGE Publications: 14. Retrieved 2008-06-06. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help)
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  48. ^ "Official Rice University web page of Michael Deem with a short explanation of "Original antigenic sin"". Retrieved 2008-05-08. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  49. ^ Granholm, Norman (1992). "Autoimmunity, Polyclonal B-Cell Activation and Infection (abstract)". Lupus. 1 (2). SAGE Publications: 63–74. doi:10.1177/096120339200100203. Retrieved 2008-05-04. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  50. ^ Montes, Carolina. "Polyclonal B cell activation in infections: infectious agents' devilry or defense mechanism of the host? (abstract)". Journal of Leukocyte Biology. 82. Society for Leukocyte Biology: 1027–1032. doi:10.1189/jlb.0407214. Retrieved 2008-05-04. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  51. ^ Goldsby; et al. Immunology (5 ed.). pp. 99–100. {{cite book}}: Explicit use of et al. in: |last= (help)
  52. ^ Fordyske, Donald (February 1995). "The origins of the clonal selection theory of immunity as a case study for evaluation in science". The FASEB Journal. 9 (2). The Federation of American Societies for Experimental Biology publishers: 164–166. Retrieved 2008-05-28.
  53. ^ Nossal, Gustav (1958-05-17). "Antibody Production by Single Cells (Abstract)" (PDF). Nature. 181. Nature publication group: 1419–1420. doi:10.1038/1811419a0. Retrieved 2008-05-28. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

Further reading

  • Goldsby, Richard (2003). Immunology (Fifth Edition ed.). New York: W. H. Freeman and Company. ISBN 07167-4947-5. {{cite book}}: |edition= has extra text (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  • Kishiyama, Jeffery L. (2006) [1997]. "Disorders of the Immune system (Chapter 3)". In Stephen J. McPhee and William F. Ganong (ed.). Pathophysiology of Disease: An Introduction to Clinical Medicine (5 ed.). Lange Medical Books/McGraw-Hill. pp. 32–58. ISBN 0-07-110523-9. {{cite book}}: |access-date= requires |url= (help); Cite has empty unknown parameter: |month= (help)

External links

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