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Following cognate antigen encounter, B cells receiving T cell help can enter a couple of different developmental possibilities. Firstly, the cells can undergo plasmacytic differentiation, form extrafollicular plasmablasts and form IgM secreting plasma cells. These cells do not have somatically mutated Ig genes and are short-lived but provide a rapid initial response to antigen.
The second developmental possibility is the establishment of a germinal centre, a specialised structure within which B cells undergo rounds of proliferation accompanied by affinity maturation: an iterative process of Ig gene mutation and selection resulting in a B cell pool which can bind to antigen with the highest affinity.
The cells also undergo class-switch recombination. Immunoglobulin class switching to IgG, IgA and IgE is a major mechanism to diversify B cell responses, and match antibody function to immune challenge. Memory B cells and plasma cells expressing somatically mutated and generally high affinity BCRs of switched isotypes exit the GC. B cells are also able to dampen T-cell driven immune responses, giving rise to the concept of regulatory B cells Bregs. Interestingly, both BAFFR deficient patients have an effective output of immature B cells from bone marrow resulting in high numbers of transitional B cells, which are comparable to much younger adults.
This difference might also be age-related or it might depend on differences regulating the size of the B cell pool, which are not well understood but known to vary between different individuals 98 — Similar to the numbers of switched memory B cells, IgG antibody concentrations, which were build-up before starting the BAFF-neutralizing therapy, remained constant whereas the increase of antibody titers against neoantigens from influenza virus was significantly lower in belimumab-treated patients than in controls In a similar study, the population of switched memory B cells did also not decrease within a half year treatment of rheumatoid arthritis patients with TACI-Ig fusion protein atacicept The mutants were found in patients suffering from common variable immunodeficiency CVID , the most frequent form of primary immunodeficiency which is characterized by low or absent IgM, IgG, and IgA serum titers, low numbers or absent circulating switched memory B cells and the absence of circulating plasma cells , Therefore, their contribution to the development of CVID and antibody deficiency remains to be shown.
In this context, the P21R BAFFR variant, which is encoded by a frequent single nucleotide polymorphism rs , represents one exception. The proline 21 is located in a small loop directly preceding the BAFF binding domain. Functional and biochemical studies showed that this small loop region is essential for ligand-independent association of BAFFR polypeptide chains into multimers.
However, because of the lack of matched control groups, the efficacy of belimumab is still not completely clear. The combination of tabalumab and bortezomib in a phase II study with multiple myeloma patients did not improve progression-free survival of the patients indicating that BAFF plays little or no role in disease progression Since increased BAFF levels correlate with the risk of developing multiple sclerosis 87 , new clinical trials with MS patients with tabalumab are now being performed However, it should be kept in mind that treatment of MS patients with atacicept resulted in severe adverse effects, suggesting that in MS the blockade of BAFF and APRIL removes B cells with regulatory and immunosuppressive function and spares the pathological cells , Different from B1 B cells and from switched memory B cells, the survival of transitional, follicular and marginal zone B cells as well as the differentiation of transitional B cells into follicular and marginal zone B cells depends essentially on BAFFR-induced survival signals, which increase the life span of these cells by stabilizing mitochondria and by enhancing protein synthesis.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Modularity in the TNF-receptor family. Elsevier Science, PubMed Abstract Google Scholar. Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations.
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J Biol Chem, — Cell Death Dis. A common single nucleotide polymorphism impairs B-cell activating factor receptor's multimerization, contributing to common variable immunodeficiency. J Allergy Clin Immunol. B-cell biology and development. J Allergy Clin Immunol, — Science — J Immunol.
Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency. Curr Biol.
Cutting edge: BLyS enables survival of transitional and mature B cells through distinct mediators. Cutting edge: B cell receptor signals regulate BLyS receptor levels in mature B cells and their immediate progenitors.
Hum Pathol, —9. EMBO J, — Science —3. J Leukocyte Biol. Nature, —9. J Exp Med. APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells.
Blood — TACI is required for efficient plasma cell differentiation in response to T-independent type 2 Antigens. Transmembrane activator, calcium modulator, and cyclophilin ligand interactor drives plasma cell differentiation in LPS—activated B cells. Another important difference is that TCRs only recognize protein epitopes, whereas BCRs can recognize epitopes associated with different molecular classes e. Activation of B cells occurs through different mechanisms depending on the molecular class of the antigen.
Because of their dependence on T cells for activation of B cells , protein antigens are classified as T-dependent antigens. In contrast, polysaccharides, lipopolysaccharides, and other nonprotein antigens are considered T-independent antigens because they can activate B cells without antigen processing and presentation to T cells.
Activation of B cells without the cooperation of helper T cells is referred to as T cell-independent activation and occurs when BCRs interact with T-independent antigens. T-independent antigens e. Because T cells are not involved, the second signal has to come from other sources, such as interactions of toll-like receptors with PAMPs or interactions with factors from the complement system.
Once a B cell is activated, it undergoes clonal proliferation and daughter cells differentiate into plasma cells. Plasma cells are antibody factories that secrete large quantities of antibodies.
The T cell-independent response is short-lived and does not result in the production of memory B cells. Thus it will not result in a secondary response to subsequent exposures to T-independent antigens. Figure 2. T-independent antigens have repeating epitopes that can induce B cell recognition and activation without involvement from T cells.
Once activated, the B cell proliferates and differentiates into antibody-secreting plasma cells. Figure 3. Click for a larger image. In T cell-dependent activation of B cells, the B cell recognizes and internalizes an antigen and presents it to a helper T cell that is specific to the same antigen. The helper T cell interacts with the antigen presented by the B cell, which activates the T cell and stimulates the release of cytokines that then activate the B cell.
Activation of the B cell triggers proliferation and differentiation into B cells and plasma cells. T cell-dependent activation of B cells is more complex than T cell-independent activation, but the resulting immune response is stronger and develops memory. T cell-dependent activation can occur either in response to free protein antigens or to protein antigens associated with an intact pathogen.
The presented antigen is then recognized by helper T cells specific to the same antigen. The coordination between B cells and helper T cells that are specific to the same antigen is referred to as linked recognition. Once activated by linked recognition, T H 2 cells produce and secrete cytokines that activate the B cell and cause proliferation into clonal daughter cells.
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