Page 134 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 7 B-Cell Development and Differentiation 117

Both mechanisms, SHM and CSR, need to be tightly controlled, on survival factors, such as APRIL and IL-6. Eosinophils have
since the introduction of double-strand breaks into the DNA can been shown to be the main providers of these cytokines, and
not only pose a risk to the longevity of the B cell but also permit when they are depleted, plasma cells rapidly go into apoptosis. 35
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translocations involving and activating oncogenes. For example, By continuously secreting antibodies, long-lived plasma cells
for Burkitt lymphoma cells and for plasma cell–derived myeloma provide the individual with long-term humoral protection.
cells, the translocation and ectopic expression of the c-MYC
gene is an apparent consequence of abnormal SHM and CSR. CLINICaL rELEVaNCE
Abnormal B-Cell Development and Diseases of
B-CELL MEMORY Immune Function
One of the key features of the immune system is immunological • Failure to generate B cells or a normal repertoire of antibodies leads
memory for antigens encountered in the past. In humoral immune to humoral immune deficiency, which is commonly marked by recurrent
responses, there are two layers of memory, long-lived B memory sinopulmonary infections.
cells and B effector cells (i.e., plasma cells). The generation of • Failure to prevent the formation of antibodies with high avidity or high
these long-lived cells is dependent on antigen activation of B affinity to self antigens can lead to autoimmune diseases.
cells in the presence of T helper cells and thus the induction of • The process of antibody repertoire diversification lends itself to the
creation of mutations that can activate and modify oncogenes as well,
germinal centers. leading to leukemia or lymphoma. Mechanisms include:
Memory B Cells • Recombinase activating gene (RAG)1/2-catalyzed juxtaposition of
an oncogene to an immunoglobulin promoter or enhancer, activating
Although long-term protection of the organism is provided by the oncogene.
both memory B and plasma cells, their contribution varies; some • Activation-induced cytidine deaminase (AID)–induced DNA double-
individuals are protected mainly by memory B cells, whereas strand breaks and chromosome alterations.
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others are primarily protected by plasma cells. This can be of • AID-induced somatic hypermutation (SHM) of oncogene, altering
its function.
vital importance in special situations, such as transplantation,
where activation of the immune system should be avoided. For
example, treatment of transplant recipients with rituximab, an ECTOPIC LYMPHOID TISSUE AND
mAb specific for CD20, depletes memory B cells but has no B-CELL DEVELOPMENT
effect on long-living plasma cells secreting transplant-specific
antibodies. In autoimmune diseases, in infection, and in tumors (cancer),
After a lag-phase of 1–2 days, primary B-cell responses start ectopic lymphoid tissue can develop in the affected tissue or
with secreted low-affinity IgM antibodies. High-affinity antibodies organ. Inflammatory cytokines and the presence of B cells can
of other Ig classes require the passage of time to be generated. support the development of additional lymphoid tissue. 32
In contrast, a second encounter with antigen induces a rapid The growth of ectopic lymphoid tissue in the rheumatoid
development of memory B cells into new plasma cells, secreting synovium (Chapter 52) offers an excellent example of this disease-
antibodies of high quality (Fig. 7.6). related phenomenon. In healthy individuals, the synovium is made
up by a thin lining layer of synoviocytes. In contrast, in patients
Plasma Cells with rheumatoid arthritis, the diseased joint is highly infiltrated
Protective humoral memory is provided by long-lived plasma by varying numbers of T cells, B cells, plasma cells, macrophages,
cells. 33,34 These cells are generated in the secondary lymphoid and DCs. In the majority of patients, these mononuclear cells
organs and then migrate to bone marrow or to a site affected are dispersed loosely throughout the synovium. However,
by inflammation. In bone marrow, plasma cells survive in highly well-organized, large lymphoid structures, which are similar
specialized niches provided by the underlying reticular stromal in appearance to the lymphoid follicles seen in the secondary
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cells. Here they can live on for long periods without further lymphoid organs, can develop in some patients. At the center
activation and proliferation, but their maintenance is dependent of these cell clusters, a network of FDCs are found. Antigen
presented by FDCs appears to activate B cells, which induces
proliferation. The central B cells are surrounded by a layer of T
cells, which may support local B-cell differentiation. A central
question concerns which antigens drive these immune responses
and select B cells to differentiate into memory and plasma cells.
Activation of Protective Reactive humoral memory The ectopic lymphoid tissue may function as additional lymphoid
(memory B cells)
memory B cells
Concentrations in the body naive B cells (long-lived plasma cells) [Antibodies] • Elucidation of the mechanisms used to control the antibody repertoire
tissue. Equally likely, it may support a self-specific immune
Activation of
response. These questions remain topics of active investigation.
humoral memory
ON THE HOrIZON
and shape B-cell epitope recognition offer the promise of being able
to direct immunity toward production of broadly neutralizing or anti-
tumorigenic antibodies, and away from pathogenic autoantibodies.
Time (years) [Antigen] • Elucidation of the mechanisms that prevent the development of
FIG 7.6 Active and Reactive B-Cell Memory. Memory B cells self-reactivity during affinity maturation could yield new insights into
provide reactive memory, whereas long-lived plasma cells provide autoimmunity, as well as vaccination.
active protective memory. The relative concentrations of antibody • A better understanding of the mechanisms that lead to long-lived
plasma cells could lead to single, long-lasting vaccination strategies.
and antigen over time are indicated.