Re-thinking the functions of IgA(+) plasma cells

Abstract

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.

Figure 1.

Schematic diagram of cell intrinsic mechanisms involved in PC survival. The ER stress response, which is triggered by excessive antibody production in PC, can lead to apoptosis. To balance antibody output with survival, PC have several survival strategies, which include autophagy and the unfolded protein response (UPR). The UPR mechanism is also able to generate a short form of XBP-1 (XBP-1s), which promotes the transcription of other genes such as iNOS and IL-6, both of which are involved in PC survival.

Figure 2.

Rethinking PC function. This figure depicts both general antibody-dependent and antibody-independent functions of PC as well as specific functions of IgA and IgA⁺ PC.