Polyclonal B cell response
Polyclonal B cell response is a natural mode of immune response exhibited by the
In the course of normal immune response, parts of
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 against the same antigen. Hence the term "polyclonal", which derives from the words poly, meaning many, and clones from Greek klōn, meaning sprout or twig;[3][4][5] a clone is a group of cells arising from a common "mother" cell. The antibodies thus produced in a polyclonal response are known as polyclonal antibodies. The heterogeneous polyclonal antibodies are distinct from monoclonal antibody molecules, which are identical and react against a single epitope only, i.e., are more specific.
Although the polyclonal response confers advantages on the immune system, in particular, greater probability of reacting against pathogens, it also increases chances of developing certain autoimmune diseases resulting from the reaction of the immune system against native molecules produced within the host.
Humoral response to infection
Diseases which can be transmitted from one organism to another are known as
Countering the various infectious diseases is very important for the survival of the
B cell response
Antibodies serve various
- Specific or nonspecific recognition of the pathogen (because of its antigens) with its subsequent engulfing by B cells or macrophages. This activates the B cell only partially.
- Antigen processing.
- Antigen presentation.
- Activation of the T helper cells by antigen-presenting cells.
- Co-stimulation of the B cell by activated T cell resulting in its complete activation.
- Proliferation[note 4] of B cells with resultant production of soluble antibodies.
Recognition of pathogens
Pathogens synthesize
Specific recognition of epitope by B cells
In figure at left, 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 (i.e., the antigen recognition by the B cell), this explanation is too simplistic. Such epitopes are known as sequential or linear epitopes, as all the amino acids on them are in the same sequence (line). This mode of recognition is possible only when the peptide is small (about six to eight amino acids long),[1] and is employed by the T cells (T lymphocytes).
However, the B memory/naive cells recognize intact proteins present on the pathogen surface.[note 6] In this situation, the protein in its tertiary structure is so greatly folded that some loops of amino acids come to lie in the interior of the protein, and the segments that flank them may lie on the surface. The paratope on the B cell receptor comes in contact only with those amino acids that lie on the surface of the protein. The surface amino acids may actually be discontinuous in the protein's primary structure, but get juxtaposed owing to the complex protein folding patterns (as in the adjoining figure). Such epitopes are known as conformational epitopes and tend to be longer (15–22 amino acid residues) than the linear epitopes.[1] Likewise, the antibodies produced by the plasma cells belonging to the same clone would bind to the same conformational epitopes on the pathogen proteins.[12][13][14][15]
The binding of a specific antigen with corresponding BCR molecules results in increased production of the MHC-II molecules. This assumes significance as the same does not happen when the same antigen would be internalized by a relatively nonspecific process called pinocytosis, in which the antigen with the surrounding fluid is "drunk" as a small vesicle by the B cell.[16] Hence, such an antigen is known as a nonspecific antigen and does not lead to activation of the B cell, or subsequent production of antibodies against it.
Nonspecific recognition by macrophages
Antigen processing
After recognizing an antigen, an
An alternate pathway of endocytic processing had also been demonstrated wherein certain proteins like
Antigen presentation
After the processed antigen (peptide) is complexed to the MHC molecule, they both migrate together to the cell membrane, where they are exhibited (elaborated) as a complex that can be recognized by the CD 4+ (T helper cell) – a type of white blood cell.[note 7][20] This is known as antigen presentation. However, the epitopes (conformational epitopes) that are recognized by the B cell prior to their digestion may not be the same as that presented to the T helper cell. Additionally, a B cell may present different peptides complexed to different MHC-II molecules.[16]
T helper cell stimulation
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 into Th1 or Th2 cells.[16][21] This makes them produce 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.[10]
Co-stimulation of B cell by activated T helper cell
Complete stimulation of T helper cells requires the
Proliferation and differentiation of B cell
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. The activation of a naive or a memory B cell is followed by a manifold proliferation of that particular B cell, most of the progeny of which terminally differentiate into
Basis of polyclonality
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. To be able to react to innumerable antigens, as well as multiple constituent epitopes, the immune system requires the ability to recognize a very great number of epitopes in all, i.e., there should be a great diversity of B cell clones.
Clonality of B cells
Single antigen contains multiple overlapping epitopes
A single antigen can be thought of as a sequence of multiple overlapping epitopes. Many unique B cell clones may be able to bind to the individual epitopes. This imparts even greater multiplicity to the overall response.[3] 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.[21]
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.[1]
Clonal selection
The clones that bind to a particular epitope with greater strength are more likely to be
Diversity of B cell clones
Although there are many diverse pathogens, many of which are constantly mutating, it is a surprise that a majority of individuals remain free of infections. Thus, maintenance of health requires the body to recognize all pathogens (antigens they present or produce) likely to exist. This is achieved by maintaining a pool of immensely large (about 109) clones of B cells, each of which reacts against a specific epitope by recognizing and producing antibodies against it. However, at any given time very few clones actually remain receptive to their specific epitope. Thus, approximately 107 different epitopes can be recognized by all the B cell clones combined.[21] 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.[21]
Significance of the phenomenon
Increased probability of recognizing any antigen
If an antigen can be recognized by more than one component of its structure, it is less likely to be "missed" by the immune system.[note 10] Mutation of pathogenic organisms can result in modification of antigen—and, hence, epitope—structure. 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.[24]
Limitation of immune system against rapidly mutating viruses
Many viruses undergo frequent mutations that result in changes in amino acid composition of their important proteins. Epitopes located on the protein may also undergo alterations in the process. Such an altered epitope binds less strongly with the antibodies specific to the unaltered epitope that would have stimulated the immune system. This is unfortunate because somatic hypermutation does give rise to clones capable of producing soluble antibodies that would have bound the altered epitope avidly 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.[21] This phenomenon comes into play particularly in immune responses against influenza, dengue and HIV viruses.[25] 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
In
Difficulty in producing monoclonal antibodies
History
The first evidence of presence of a neutralizing substance in the blood that could counter infections came when Emil von Behring along with Kitasato Shibasaburō in 1890 developed effective serum against diphtheria. This they did by transferring serum produced from animals immunized against diphtheria to animals suffering from it. Transferring the serum thus could cure the infected animals. Behring was awarded the Nobel Prize for this work in 1901.[28]
At this time though the chemical nature of what exactly in the blood conferred this protection was not known. In a few decades to follow, it was shown that the protective serum could neutralize and precipitate toxins, and clump bacteria. All these functions were attributed to different substances in the serum, and named accordingly as antitoxin, precipitin and agglutinin.
Until this time, cell-mediated immunity and humoral immunity were considered to be contending theories to explain effective immune response, but the former lagged behind owing to lack of advanced techniques.[17] Cell-mediated immunity got an impetus in its recognition and study when in 1942, Merrill Chase successfully transferred immunity against tuberculosis between pigs by transferring white blood cells.[17][30]
It was later shown in 1948 by Astrid Fagraeus in her doctoral thesis that the plasma B cells are specifically involved in antibody production.[31] The role of lymphocytes in mediating both cell-mediated and humoral responses was demonstrated by James Gowans in 1959.[30]
In order to account for the wide range of antigens the immune system can recognize,
The clonal selection theory was proved correct when Sir Gustav Nossal showed that each B cell always produces only one antibody.[32]
In 1974, the role of MHC in antigen presentation was demonstrated by
See also
- Polyclonal antibodies
- Antigen processing
- Antiserum, a polyclonal antibody preparation used to treat envenomation
Notes
- 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".
- ^ Specificity implies that two different pathogens will be actually viewed as two distinct entities, and countered by different antibody molecules.
- ^ Actions of antibodies:
- Coating the pathogen, preventing it from adhering to the host cell, and thus preventing colonization
- Precipitating (making the particles "sink" by attaching to 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. Thus the antibody acts as an opsonin. The process of engulfing is known as phagocytosis (literally, cell eating)
- Activating the complement system, which most importantly pokes holes into the pathogen's outer covering (its 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)
- ^ Proliferation in this context means multiplication by cell division and differentiation
- ^ The major histocompatibility complex is a gene region on the DNA that codes for the synthesis of Major histocompatibility class I molecule, Major histocompatibility class II molecule and other proteins involved in the function of complement system (MHC class III). The first two products are important in antigen presentation. MHC-compatibility is a major consideration in organ transplantation, and in humans is also known as the human leukocyte antigen (HLA).
- ^ Here, intact implies that the undigested protein is recognized, and not that the paratope on B cell receptor comes in contact with the whole protein structure at the same time; the paratope will still contact only a restricted portion of the antigen exposed on its surface.
- monoclonal antibodies, which can bind specifically to each type of cell. Moreover, the same type of white blood cell would express molecules 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 group of monoclonal antibodies that does 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.
- ^ The plasma cells secrete antibodies that bind to the same structure that had stimulated the B cell in the first place by binding to its B cell receptor.
- ^ Affinity roughly translates as attraction from Latin. See also: Definition of Affinity from Online Etymology Dictionary and Definition of Affinity from TheFreeDictionary by Farlex
- ^ 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
- ^ ISBN 978-0716749479.
- ^ "Definition of Polyclonal from MedicineNet.com". Webster's New World Medical Dictionary. Archived from the original on 2012-08-07. Retrieved 2008-05-03.
- ^ ISBN 978-0691095950. Retrieved 2008-06-23.
- ^ "Etymology of "clone"". Online etymology dictionary. Retrieved 2008-06-26.
- ^ Bansal, R.K. (2005). "Reproductive Cloning-An Act Of Human Rights Violation". Journal of Indian Association of Forensic Medicine. 27 (3): 971–973. Archived from the original (PDF) on 2019-12-16. Retrieved 2008-06-23.
- ^ "Definition of inoculation". TheFreeDictionary.com (citing Dorland's Medical Dictionary for Health Consumers. © 2007 by Saunders, an imprint of Elsevier, Inc.). Retrieved 2008-06-10.
- ^ ISBN 978-0-07-123983-7.
- ^ ISBN 978-0-7167-6764-0.)
{{cite book}}
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- ^ ISBN 978-0-7167-6764-0.
- S2CID 14974530. Retrieved 2008-05-03.
- ^ "Immunochemical Applications". Technical Tips. EMD biosciences. Archived from the original on 2008-04-11. Retrieved 2008-05-07.
- ^ Davis, Cheryl. "Antigens". Biology course. Western Kentucky University. Archived from the original on 2008-03-29. Retrieved 2008-05-12.
- ^ Ceri, Howard. "Antigens". Immunology course. University of Calgary. Archived from the original on 2008-10-05. Retrieved 2008-05-12.
- ISBN 978-0-8493-1426-1.
- ^ S2CID 13324439. Retrieved 2008-06-20.
- ^ ISBN 978-0-7167-6764-0.
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- ISBN 978-0-262-03232-2. Retrieved 2008-05-12.
- ^ Greener, Mark (2005-02-14). "Monoclonal antibodies (MAbs) turn 30". The Scientist. 19 (3): 14. Archived from the original on 2007-08-31. Retrieved 2008-06-06.
- ^ Deem, Michael. "Michael W. Deem". Official Web Page. Rice University. Archived from the original on 2008-07-04. Retrieved 2008-05-08.
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- ^ "Emil von Behring: The Founder of Serum Therapy". Nobel Prize in Medicine. Archived from the original on 2008-06-12. Retrieved 2008-06-23.
- ^ Mage, Rose G.; Ten Feizi. "Elvin A. Kabat". Biographical memoirs. Retrieved 2008-06-23.
- ^ a b c d Greenberg, Steven. "A Concise History of Immunology" (PDF). Retrieved 2008-06-23.
- Karolinska Institutet. Archived from the original(PDF) on 2012-02-12. Retrieved 2008-06-23.
- ^ Turner, Stephen (October 2007). "One POWERFUL Idea" (PDF). Australasian Science. Archived from the original (PDF) on 2008-07-21. Retrieved 2008-06-23.
Further reading
- Goldsby, Richard; Kindt, TJ; Osborne, BA; Janis Kuby (2003). Immunology (Fifth ed.). New York: W. H. Freeman and Company. ISBN 978-0-7167-4947-9.
- Kishiyama, Jeffery L. (2006) [1997]. "Disorders of the Immune system (Chapter 3)". In Stephen J. McPhee; William F. Ganong (eds.). Pathophysiology of Disease: An Introduction to Clinical Medicine (5 ed.). Lange Medical Books/McGraw-Hill. pp. 32–58. ISBN 978-0-07-110523-1.
- Nairn, Roderick (2004) [1954]. "Immunology (Chapter 8)". In Geo F. Brooks; Janet S. Butel; Stephen A. Morse (eds.). Jawetz, Melnick, & Adelberg's Medical Microbiology (Twenty-Third Edition International ed.). Lange publications/McGraw-Hill. pp. 133–135, 138–139. ISBN 978-0-07-123983-7.
External links