Polyclonal B cell response

Polyclonal response is a natural mode of response exhibited by the adaptive immune system. It ensures that a single antigen is recognized through its multiple overlapping parts (epitopes) by multiple clones of B lymphocytes.

A foreign substance (usually present on disease-causing-pathogens) or "germs" is recognized by the body, which reacts against it trying to eliminate it or reducing the damage caused by invading pathogens. This is known as an immune response, and such a recognizable foreign substance is known as an antigen. A very important component of this response is the production of antibodies, which are produced by the B cells (or B lymphocytes), which are a type of white blood cells (WBCs). This article attempts to explain the process of recognition of antigens, and how "the body attempts to look at the same antigen from different views"

B cell response

An antigen is any substance (usually a protein) that can be ‘recognized’ by the host organism. At molecular scale, the proteins are relatively large, so they cannot be recognized as a whole; instead, their segments called epitopes can be recognized. So, when an antigen is engulfed through phagocytosis by an antigen presenting cell (APC) like the macrophage or the B lymphocyte, it is broken down into various peptides in its lysosomes.

The individual peptides are then complexed (attached loosely) with major histocompatibility class II (MHC class II) molecules located in the lysosome—exogenous pathway of antigen processing. From here the complex migrates to the plasma membrane, and is exhibited there (elaborated) as a complex that can be recognized by the CD 4+ (T helper cells). 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.

Whatever the cell type, recognizing an antigen or a segment thereof (epitope) requires binding of the antigen with the corresponding paratope present on the receptor present on the surface of the recognizing cell. In the immune system, these are the T (TCR) and the B (BCR) cell receptors. The binding between a paratope and its corresponding antigen is very specific owing to their structures and is guided by various noncovalent bonds not unlike pairing of other types of ligands and their corresponding receptors.

The CD 4+ cells through their TCR recognize the epitope-bound MHC II molecules on the surface of the APCs, and get 'activated'. However, complete stimulation requires the B7 molecule present on the APC to bind with CD28 molecule present on the T cell surface close to the TCR. When this activated T cell encounters a B cell that recognizes the antigen containing the same epitope as recognized by TCR, the latter (B cell) gets stimulated because of secretion of certain growth factors, viz., interleukins 2, 4, 5, and 6 in a paracrine fashion. However, this activation occurs only when the BCR present on a memory or a naive B cell itself is bound to the corresponding epitope.

This is followed by a manifold proliferation of that particular B lymphocyte, most of the progenies of which terminally differentiate into Plasma (or B effector) cells, which secrete the antibodies (first IgM, and then IgG, in that sequence) that have the same paratope as that present on the B and the T cells that had got stimulated initially.

In the course of this proliferation, the BCR genes can undergo somatic hypermutation (frequent {1 in 1700 cell divisions} mutations in the genes coding for paratopes of various receptors), making the subsequent encounters with antigens more inclusive in their antigen recognition potential.

Basis of polyclonal response

Figure 1: Schematic diagram showing polyclonal response to a single antigen

Polyclonal derives from the words poly, meaning many, and clones. A clone is a group of cells with common ancestry (mother cell).

In natural immune response the memory or naïve B cells exist in only small numbers, which can proliferate upon encountering an antigen to which they are specific. Each such group of cells with identical specificity towards the epitope is known as a colony or a clone, and is essentially derived from a common mother cell. Also, the paratopes contained on the antibodies secreted by the derivatives (plasma cells) will be the same.

However, the same epitope can be recognized by naïve/memory cells belonging to different clones. The binding affinities for respective epitope-paratope pairs are varying, with certain epitopes being more "immunogenic" than others. This bonding requires both the paratope and the epitope to undergo slight conformational changes in each others' presence. The clones that bind to a particular epitope with sufficient strength are 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—a clone that gets selected in one of the encounters stands lesser chance of getting selected if the epitope structure changes somewhat.

Moreover, if the same epitope can elicit response from multiple clones, a single antigen can be broken down into multiple peptides, which in turn contain overlapping epitopes (see Figure 1), imparting even greater multiplicity to the overall response.

Epitope recognition by B cell

Figure 2: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

In Figure 1, 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., antigen recognition by the B cell, this explanation would prove to be too simplistic. These are known as 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 in question would be small (to the order of 10 amino acids long), and is employed by the T cells (T lymphocytes)

However, the B memory/naive cells recognize intact (meaning, undigested, and not that the whole protein structure is recognized at the same time) proteins present on the pathogen surface. In this situation, the proteins in their tertiary (the three dimensional structure as against the linear or primary structure) structure are so much folded that it is very unlikely that all the continuous segments of the protein will lie close to each other in space while interacting with the receptor. So, the paratope on the BCR 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 adjoining Figure 2). Such epitopes are known as conformational epitopes and tend to be longer in length than the linear epitopes. 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.

Significance

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. An analogy could be helpful: 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 unlikelier that you will miss the person. Here the concept of mutation of pathogenic organisms is being explained, which 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 body's immune response.

Limitation of immune system against rapidly mutating viruses

Many viruses have enzymes (polymerases) defective in 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 would have recognized the protein in prior encounter still recognize the protein (antigen), but the antibodies that they produce upon proliferation do not bind with the antigen sufficiently strongly. Of course, some or the other clone that would have come into existence because of somatic hypermutation (see above), would produce soluble antibodies that would bind sufficiently strongly and neutralize the pathogen, but the clone as of now would consist of naive cells, and because of an unfortunate phenomenon, such cells are not allowed to proliferate by the weakly binding antibodies produced by the priorly exposed clone. This doctrine is known as the Original antigenic sin.

This phenomenon comes into play particularly in immune responses against the Influenza, the Dengue and the AIDS (HIV) viruses.

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

The phenomenon of autoimmunity can be most simply explained in terms of the immune system making 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 will not be eliminated in course of time, the responses against them get stronger with time resulting in worsening of the situation. 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 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, greater the chance that one or the other will react against self-antigens (native molecules of the body).

Monoclonal antibodies have to be produced by specialized techniques

Monoclonal antibodies are structurally identical immunoglobulin molecules with identical epitope-specificity (all of them bind with the same epitope with same strength {avidity}) 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.

See also

• Polyclonal antibodies
• MHC class II
• Antigen processing