The intestinal mucosa harbors the largest population of antibody (Ab)-secreting plasma cells (PC) in the human body, producing daily several grams of immunoglobulin A (IgA). IgA has many functions, serving as a first-line barrier that protects the mucosal epithelium from pathogens, toxins and food antigens (Ag), shaping the intestinal microbiota, and regulating host-commensal homeostasis. Signals induced by commensal colonization are central for regulating IgA induction, maintenance, positioning and function and the number of IgA(+) PC is dramatically reduced in neonates and germ-free (GF) animals. Recent evidence demonstrates that the innate immune effector molecules tumor necrosis factor α (TNFα) and inducible nitric oxide synthase (iNOS) are required for IgA(+) PC homeostasis during the steady state and infection. Moreover, new functions ascribed to PC independent of Ab secretion continue to emerge, suggesting that PC, including IgA(+) PC, should be re-examined in the context of inflammation and infection. Here, we outline mechanisms of IgA(+) PC generation and survival, reviewing their functions in health and disease.
Keywords: AID, activation-induced deaminase; APC, antigen-presenting cell; APRIL, a proliferation-inducing ligand; Ab, antibody; Ag, antigen; Arg, arginase; Atg, autophagy-related gene; B cell; BAFF, B-cell activating factor; BCMA, B-cell maturation antigen; BM, bone marrow; Blimp, B-lymphocyte-induced maturation protein; CCL, CC chemokine ligand; CCR, CC chemokine receptor; CD, cluster of differentiation; CSR, class-switch recombination; CXCL, CXC chemokine ligand; DC, dendritic cell; ER, endoplasmic reticulum; FDC, follicular dendritic cells; FcαR, Fc fragment of IgA receptor; GALT, gut-associated lymphoid tissues; GC, germinal center; GF, germ-free; GM-CSF, granulocyte-macrophage colony-stimulating factor; GRP, glucose-regulated proteins; HIV, human immunodeficiency virus; IEC, intestinal epithelial cells; IFN, interferon; IL, interleukin; ILC, innate lymphoid cells; ILF, isolated lymphoid follicles; IRE, inositol-requiring enzyme; IRF, interferon regulatory factor; Id, inhibitor of DNA binding; IgA, immunoglobulin A; IgAD, selective IgA deficiency; L-Arg, L-Arginine; L-Cit, L-citrulline; L-Glu, L-Glutamate; L-Orn, L-Ornithine; L-Pro, L-Proline; LIGHT, homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes; LP, lamina propria; LT, lymphotoxinLTβR, LTβ-receptor; LTi, lymphoid tissue-inducer; LTo, lymphoid tissue organizing; Ly, lymphocyte antigen; MHC, major histocompatibility complex; MLN, mesenteric lymph nodes; NO, nitric oxide; PC, plasma cells; PP, Peyer's patch; Pax, paired box; ROR, Retionic acid receptor (RAR)- or retinoid-related orphan receptor; SC, stromal cells; SHM, somatic hypermutation; SIGNR, specific intercellular adhesion molecule-3-grabbing non-integrin-related; SIgAsecretory IgA; TACI, transmembrane activator and calcium-modulator and cyclophilin ligand interactor; TD, T-dependent; TFH, T-follicular helper cells; TGFβR, transforming growth factor β receptor; TI, T-independent; TLR, Toll-like receptor; TNFR, TNF receptor; TNFα, tumor necrosis factor α; Th, T helper cell; Treg, T-regulatory cell; UPR, unfolded protein response; XBP, X-box binding protein; bcl, B-cell lymphoma; cGMP, cyclic guanosine monophosphate; iNOS, inducible nitric oxide synthase; immunoglobulin A (IgA); inducible nitric oxide synthase (iNOS); innate immune recognition; intestinal microbiota; mucosa; pIgA, polymeric IgA; pIgR, polymeric Ig receptor; plasma cell.