The pathogenesis of IgAN: Where is pathogenic IgA produced?

Immunoglobulin A (IgA) serves as a first line of defence preventing entry of pathogens from mucosal surfaces into the bloodstream and plays a critical role in maintaining balance between host commensal microbiota and immune responses. The source and triggers for production of pathogenic IgA in IgA nephropathy (IgAN) are unknown, and new research provide compelling new hypotheses regarding the immunopathogenesis of this disease. The largest proportion of IgA produced in humans is found within mucosal secretions (ex. gastrointestinal, respiratory), where it has been locally produced by IgA-producing plasma cells subsequently secreted to mucosal surfaces. The bulk of IgA produced by mucosal cells is subsequently covalently linked to a secretory glycoprotein component upon its transepithelial transport to mucosal surfaces.1 Humans produce two subclasses of IgA – IgA1 and IgA2 – that differ largely in the sequence of their hinge region and potential glycosylation sites. There are IgA1 possesses two conserved sites for N-glycosylation, and several O-glycosylation sites in its hinge region; IgA2 possesses four conserved sites for N-glycosylation.2 These structural differences may underlie some of the functional differences in IgA1 and IgA2 that dictate their relative importance in producing immune defence, tolerance or autoimmunity.3 Mucosal-source secretory IgA found in external secretions is typically present in dimers and polymers, created by linking of IgA molecules by the joining (J) chain polypeptide.4 The ratio of IgA1/IgA2 in mucosal secretions is generally even, varying according to the mucosal surface or body fluid. In contrast, the IgA detected within the circulation is typically monomeric (90%), and produced by antibody-secreting cells within the bone marrow and some peripheral lymphoid organs.1 In the circulation, the ratio of IgA1/IgA2 is highly biased toward IgA1 at a ratio of 9:1.5 It is now well recognized that circulating and mesangial immune complexes in patients with IgAN are characterized by aberrantly glycosylated IgA1. In IgA nephropathy, the O-linked glycans at the IgA1 hinge region are galactose-deficient,6 a heritable trait potentially linked to genetic differences in genes encoding glycosylation machinery.7 Several lines of evidence suggest that potentially pathogenic IgA in IgAN is mucosal in origin and clinical observations first led to a link between IgAN and dysregulation of the mucosal immune system. First, flares of disease activity characterized by gross hematuria and proteinuria are commonly associated with mucosal infections such as pharyngitis or gastroenteritis. This supports the notion that perturbations in the healthy flora at mucosal surfaces are a trigger for IgA production by cells within mucosal associated lymphoid tissue, such as tonsillar tissue and the intestinal lamina propria. Similarly, IgAN is observed in patients with inflammatory bowel disease,8 a well-recognized condition associated with destructive mucosal immune dysregulation. Beyond the clinical association, the pathogenic IgA-containing immune complexes characterizing IgAN have features suggesting mucosal origin. While circulating IgA1 in healthy subjects is typically monomeric, patients with IgAN have increased serum levels of immune complexes containing polymeric IgA1, and the polymeric IgA immune complexes may contain the secretory component.9 Mesangial and circulating immune complexes contain polymeric galactose-deficient IgA10 and J chain.11 Finally, genome-wide association studies indicate that genes conferring susceptibility to IgAN are implicated in the development of inflammatory bowel disease.12 The source of pathogenic IgA in IgAN remains under investigation. Data have supported both mucosal origin as well as contribution of IgA-secreting cells in the bone marrow. Work in experimental models supported an enteric source, with induction of IgAN in susceptible mice exposed to oral protein antigens and gluten.13, 14 Dietary antigens, however, have not been identified in circulating IgA immune complexes in IgAN. The recent finding of a clinical benefit of treatment of IgAN with nefecon, a targeted-release formulation of budesonide impacting primarily mucosal induction and activation of IgA-producing cells, supports the hypothesis that pathogenic IgA production occurs in the gut.15 The tonsils are another potential mucosal source of IgA production. Immune cells extracted and cultured from tonsillectomy samples taken from patients with IgAN demonstrate IgA-biased immune responses to antigenic stimuli.16, 17 In contrast, a series of studies have focused on a possible humoural source of pathogenic IgA. Bone marrow samples and plasma cell cultures obtained from patients with IgAN demonstrate a trend toward a greater proportion of IgA1 isotype-producing plasma cells compared with healthy controls.18 Further, the finding of a reduction in J chain mRNA-positive IgA plasma cells in duodenal biopsies of patients with IgAN argued against the gastrointestinal mucosal associated lymphoid tissue as a source of pathogenic IgA. Subsequently the authors also demonstrated an increase in the proportion of B cells producing IgA and expressing J chain mRNA in the bone marrow of patients with IgAN.19 To reconcile these findings, it was proposed that in IgAN, mis-homing of B cells induced in the mucosal associated lymphoid tissue results in their deposition in the bone marrow and subsequent differentiation to IgA+ PCs within the marrow. Both mucosal and marrow IgA production may therefore be important sources of pathogenic IgA. Emerging data in other disease models suggest that the source of pathogenic IgA production should be revisited. It is increasingly recognized that IgA-producing plasma cells can be localized to non-mucosal tissue and may even be observed in typically immune-privileged sites such as the central nervous system (CNS). Rotavirus-specific IgA-producing cells previously generated in response to an intestinal rotavirus infection 30 days prior are rapidly recruited to the lungs upon a subsequent influenza infection in mice.20 Similarly, in experimental and human multiple sclerosis, IgA-producing plasma cells arising from the gut are observed in the CNS where they may play an important immune-regulatory role.20 Early data support the concept that mucosal-derived IgA-producing cells may migrate to locations outside of the mucosal compartment to cause IgA nephropathy (Figure 1). In mice overexpressing the B-cell activating factor (BAFF) cytokine and rendered susceptible to infection with Neisseria meningitidis, anti-neisseria IgA-producing cells are even detectable within the kidneys following infection.21 In conclusion, our understanding of the nature of pathogenic IgA has driven investigations into the source of production of galactose-deficient pathogenic IgA1 in IgAN. The prevailing hypotheses have suggested that the IgA-containing immune complexes are produced by antibody-secreting cells either located within the mucosal associated lymphoid tissue, or by bone marrow resident cells that are of mucosal origin. Emerging data suggest that we should expand these ideas further, and consider that mucosal-derived IgA-producing cells may migrate through the bloodstream to establish niches at other sites. In order to apply this knowledge to develop new treatment strategies, it is critical that we further characterize the nature of these antibody-secreting cells, and elucidate the factors that drive these cells to migrate outside of the gut. Dr. Reich has provided consultation for Calliditas, Chinook, Novartis, and Omeros, and received support for conference lectures from Travere Therapeutics and Vera. She serves on the steering committee of IgA studies for Calliditas and Chinook (a Novartis company). She has attended advisory meetings for Otsuka, Pfizer and Eledon, and was a clinical trial site investigator for trials by Calliditas, Novartis, Omeros and Alnylam. She directs the Louise Fast Foundation fellowship. This work is supported by the Canadian Institutes of Health Research, and the Kidney Foundation of Canada through the John and Leslie Pearson. Dr. Makita's work is supported by the Japanese Society for the Promotion of Science.