![]() ![]() Arrows indicate possible B cell differentiation pathways. Antigen-dependent pathways include extrafollicular and germinal center pathways, as indicated with associated indicated features tied to primary (prime) and secondary (boosting) responses. Innate-like B cells produce natural antibodies in an antigen-independent pathway ( top). Three main pathways for antibody production are shown. Schematic of antibody producing pathways. The GC pathway takes more time due to SHM and T-cell selection, and it is generally believed that GC-derived antibody-secreting plasma cells can be longer-lived. Extrafollicular antibodies appear quickly, may or may not be (see later) refined by SHM and affinity maturation, and are in general shorter-lived owing to less durable antibody-secreting cells. Both of the latter can lead to antibody-secreting cells and memory cells, but they differ in speed of antibody production, antibody maturation state, and longevity of antibody-secreting cells produced. The other 2 are antigen-dependent pathways-an extrafollicular pathway and a GC pathway. One is natural antibody secretion-usually IgM spontaneously emitted from innate-like B cells and requires no known exogenous stimulus. Antibody secretion occurs through at least 3 different paths with different activation requirements and time scales ( Fig 1 5 In certain circumstances, anticytokine antibodies could potentially provide a regulatory effect akin to negative feedback.īCR, B-cell receptor VH, heavy-chain variable region.Īdditional B cell dynamic features that likely influence the probability of autoantibody production include the timing, context, and frequency of production. 4 The propensity of the agnostically generated early B-lineage cell repertoire toward autoreactivity suggests that there may be some value in an autoreactive repertoire to provide necessary B-cell receptor signals required ontogenetically or as a reservoir for polyreactivity for the potential benefit of on-demand expanded antigen recognition under more pressing infectious stresses. The antibody gene assembly process generates specificities that tend to be autoreactive to a level perhaps beyond what might be expected from random sequence generation, particularly in fetal and newborn B-cell development. If it is purely a bug, the tolerance filters are leakier than one might expect.Īlthough a simple breakdown of tolerance is a likely major contributor on its own to autoantibody production, there are some findings that are consistent with an autoreactivity-as-a-feature component to the repertoire ( Table I In this context, it makes sense that antigen-specific T cells are required to guide selection of SHM-diversifying antibodies in GCs, as they have experienced a more complex selection process.ĭespite tolerance filters, there appears to be substantial autoreactivity in the baseline antibody repertoires of healthy controls, and the degree to which this is a “bug” (ie, an unavoidable negative consequence of a complex system) or a “feature” (ie, an aspect that provides perhaps not-so-obvious benefit)-or whether it has aspects of both-is not yet clear. T-cell receptor selection appears to be more stringent after their own V(D)J-mediated T-cell receptor diversification, they can experience a more complete array of autoantigens through an autoimmune regulator–dependent mechanism to guide thymic T-cell tolerogenesis. Autoreactivity encountered in the periphery can result in B cell anergy or deletion, further eliminating autoreactive specificities. Strong ligand engagement with cell surface–expressed antibody (the antigen-binding part of the B-cell receptor) during precursor B-cell development in bone marrow encourages antibody light chain exchange, allowing for more innocuous specificities to advance to later stages of B-cell development and exit from bone marrow as transitional naive B cell. 3 The presence of secreted autoantibodies that react to self are generally thought of as breakdowns of tolerance mechanisms. Several mechanisms are in place to handle specificities that recognize self at several stages of development, including the early developmental phases and the GC diversification stage. Antibody genes can further diversify through somatic hypermutation (SHM) in germinal centers (GCs), leading to improved affinities toward antigens. ![]() The antibody variable region responsible for binding to antigen is encoded by an exon that is assembled from gene segments through V(D)J recombination during early B-cell development in bone marrow. Reports that autoantibodies are correlated with coronavirus disease 2019 (COVID-19) severity 1, 2 shed further light on relationships between infection and autoimmunity and remind us of our need to understand more deeply how antibody specificity is regulated and its role in balancing health and disease. ![]()
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