An 8-year-old boy is brought to the office due to fever and sore throat for the past several days. He has had no runny nose or cough. Temperature is 38.4 C (101.1 F). Physical examination shows erythematous pharyngeal mucosa with enlarged tonsils covered by exudates. There are enlarged and tender anterior cervical lymph nodes. A representative image of one of the enlarged nodes is shown below; the structures indicated by the arrows are increased in size and number. The predominant cell type within these regions is most likely undergoing which of the following processes?
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After development in the bone marrow, mature B cells migrate to peripheral lymphoid organs (eg, lymph nodes), where they are exposed to antigens. On first exposure to a new antigen, naïve B cells become activated and undergo clonal expansion. Some differentiate into short-lived plasma cells that release antigen-specific IgM through a T-cell–independent process. However, most activated B cells migrate to lymphoid follicles located in the lymph node cortex where they form germinal centers, the major sites of B-cell proliferation and affinity maturation during the immune response. Ultimately, some of these B cells become long-lived memory cells that remain dormant until the next encounter with the same antigen, but the majority transform into long-lived, antibody-secreting plasma cells.
Isotype switching (ie, immunoglobulin class switching) occurs in the germinal centers late in the primary response and allows B cells to produce antibodies of isotypes other than IgM. The immunoglobulin heavy-chain constant regions are isotype specific and distinguish the 5 isotypes (ie, IgM, IgG, IgA, IgE, IgD), whereas the variable regions are antigen specific; light chains are antigen specific and do not determine isotype.
Isotype switching requires interaction of the CD40 receptor on activated B cells with the CD40 ligand on activated helper T cells (costimulation). The subsequent genetic rearrangement of the heavy-chain constant regions is modulated by T-cell cytokines (eg, interferon-gamma, IL-4, IL-5). After the primary IgM immune response, later encounters with the same antigen typically generate a predominantly IgG response (or IgA for mucosal pathogens).
(Choices A and C) Self-tolerance (ie, immunologic unresponsiveness to self-antigens) develops via 2 mechanisms: central and peripheral. Central tolerance, acquired during lymphocyte maturation, occurs in the primary lymphoid organs (eg, bone marrow [B cells], thymus [T cells]). During this process, immature lymphocytes go through negative selection, in which cells that strongly recognize self-antigens undergo apoptosis (ie, deletion).
(Choices D and E) Recombination of the V, D, and J regions of immunoglobulin heavy chains and the V and J regions of light chains occurs via DNA rearrangement during B-cell maturation within the bone marrow. Although an enormous variety of immunoglobulins can be produced through recombination, after undergoing this process, each B cell makes antibodies of a single specificity.
Educational objective:
The primary immune response to a new antigen initially results in plasma cells that produce only IgM. Isotype switching occurs later in germinal centers and gives B cells the ability to produce antibodies of differing isotypes (eg, IgG, IgA).