The regulation of IgA class switching

Abstract

IgA class switching is the process whereby B cells acquire the expression of IgA, the most abundant antibody isotype in mucosal secretions. IgA class switching occurs via both T-celldependent and T-cell-independent pathways, and the antibody targets both pathogenic and commensal microorganisms. This Review describes recent advances indicating that innate immune recognition of microbial signatures at the epithelial-cell barrier is central to the selective induction of mucosal IgA class switching. In addition, the mechanisms of IgA class switching at follicular and extrafollicular sites within the mucosal environment are summarized. A better understanding of these mechanisms may help in the development of more effective mucosal vaccines.IgA has been selected throughout evolution to provide a first line of immune protection at mucosal surfaces -vulnerable frontline sites that are exposed to potentially harmful commensal, airborne, ingested and sexually transmitted agents. Growing evidence indicates that IgA uses a high-affinity binding system to neutralize microbial toxins and pathogens, and a low-affinity binding system to prevent commensal bacteria from breaching the mucosal surface 1 . This latter process is known as immune exclusion and has a fundamental role in the intestine, which is home to a number of commensal bacteria exceeding that of human cells by an estimated order of magnitude 2 .Remarkably, intestinal IgA achieves both immune protection and immune exclusion in a non-inflammatory manner, thereby promoting the establishment of a sustainable hostmicrobial mutualism 3 . The complex relationship between IgA and the intestinal microbiota is further exemplified by the fact that IgA responses are highly dependent on intestinal colonization by commensal microorganisms. Indeed, the number of IgA-secreting B cells is dramatically reduced in the intestine of germ-free animals and these cells are virtually absent in neonates before their exposure to bacteria 3 .In this Review, I summarize recent advances in our understanding of the function, regulation and geography of IgA class switching. In addition to analysing the signalling pathways underlying IgA class switching, I discuss new evidence indicating that commensal bacteria Competing interests statementThe author declares no competing financial interests. DATABASES Function of IgA class switchingAntibody diversification is essential for the immune system to mount protective humoral responses. B cells diversify their antibody repertoire through three main genetic alterations that occur in two distinct phases of B-cell development. In the antigen-independent phase, B-cell precursors lodged in the bone marrow generate antigen recognition diversity by assembling the exons that encode immunoglobulin heavy (H) and light (L) chain variable regions from individual variable (V), diversity (D) and joining (J) gene segments through V(D)J gene recombination 4 . This process is initiated by a lymphoid-cell-and sequencespecific RAG1 (recombination-activating gene 1...

More robust gut immune responses induced by combining intranasal and sublingual routes for prime-boost immunization

“…36 The, IL-2, IL-4, and IL-5 cytokines were reported to play important roles in inducing class switching and promote IgA production by enhancing post-switch maturation. 23 In the present study, IN priming strongly induced Pd-specific IL-2, IL-4 and IL-5 cytokine-secreting T cells in the spleen. Moreover, systemic T cell priming effect via the IN immunization was well maintained even after two SL boost immunizations (Fig.…”

“…IL-2, IL-4 and IL-5 are essential for the induction of antigen-specific antibody responses, 22 and affect IgM B cells to switch to IgA isotypes. 23 Supernatants from spleen cell cultures re-stimulated with the Pd antigen (5 µg/ml) for 5 days were assayed for IFNγ, IL-4, IL-2, and IL-5. In our previous study, IN route appeared superior to SL in inducing IFNγ producing CD4 + and CD8 + cells.…”

Lower serum IgA levels in horses kept under intensive sanitary management and physical training

“…It is expected that the higher the quantity and variety of environmental antigens that an animal is exposed to, the higher the concentrations of immunoglobulins will be, reflecting the expansion of repertoire activated by the antigenic Lower serum IgA in athlete horses load (Menezes et al, 2003 andCerutti, 2008). In this sense, the higher levels of IgA found in animals raised under 'loose' management could be explained by the constant stimulation of mucosal lymphoid tissue by environmental and social contact antigens.…”

“…Cellular immunity is related to the destruction of intracellular microorganisms, while humoral immunity is associated to neutralization of toxins, opsonization of microbes and antibody-dependent cell death. Immunoglobulin A (IgA) is the main immunoglobulin isotype involved in neutralization of antigens of environmental origin (food-and air-borne) for being the predominant immunoglobulin isotype found in mucosae (Cerutti, 2008). Therefore, IgA is essential for protection of the surfaces of respiratory, gastrointestinal and genitourinary tracts.…”

“…Isotype switching to IgA occurs when B cells are stimulated in the presence of TGF-b1 produced by several cell types, including CD41 T cells (Cerutti, 2008).…”