Altered Expression of Lymphocyte Homing Chemokines in the Pathogenesis of IgA Nephropathy

Abstract

Defective adaptive humoral immune responses to mucosal immunogens, but intact systemic responses, are increasingly recognized in patients with IgA nephropathy (IgAN). Reduced expression of IgA+, J chain+ cells in the gut lamina propria, with collateral increases in these cells in the marrow, is also documented. Thus, there seems to be a derangement in a 'mucosa-marrow axis' in IgAN patients. Recent evidence indicates that chemokines regulate the localization of B cells and their progeny into respiratory and intestinal lamina propria, and into other lymphoid organs as well. Particularly, secretory epithelial cells express the chemokine CCL28, whereas small bowel cells uniquely express CCL25. Extramucosal sites preferentially express CXCL12, CXCL13 and/or CXCL16. Reciprocally, plasmablasts committed to IgA synthesis ubiquitously express the receptor (CCR10) for CCL28, and a subset also express the receptor (CCR9) for CCL25; neither of these is present on cells committed to IgG or IgM synthesis. Herein, the potential contributions of virally induced innate responses to defective mucosal immunity and overproduction of oligomeric IgA in the marrow and tonsils will be reviewed, particularly with respect to the influence that viral infection exerts upon the expression of selected chemokine and receptor pairs. The ramifications for pathogenesis of IgAN will be considered.

IgA Production and Tonsillar Focal Infection in IgA Nephropathy

“…24 This observation suggests the fascinating possibility that, in IgA nephropathy, there is no real defect in IgA1 O-glycosylation, but rather an increase in "mucosal-type" IgA1 in serum, possibly related to the migration of mucosal B cells to bone marrow, where they produce their "correct" poorly galactosylated IgA. 25 This is consistent with the observation that homing of lymphocytes between mucosal and systemic sites is altered in IgA nephropathy, 26,27 and this may ultimately explain how mucosally derived plasma cells might take up residence in systemic immune sites. 28 The initial site of antigen encounter heavily influences the ultimate phenotype of T and B cells, and despite displacement, such plasma cells might be expected to continue to produce mucosal-type antibodies in systemic sites.…”

Emerging therapies in immunoglobulin A nephropathy

“…It is therefore postulated that the poorly galactosylated IgA1 in IgAN may originate from the mucosal immune system as an exaggerated mucosally primed B cell response to commonly encountered mucosal pathogens. Whether this response is limited to the mucosa‐associated lymphoid tissue or involves B cells that have mis‐trafficked to the bone marrow is currently not known . A number of separate studies have reported high levels of IgA antibodies in the serum against a variety of mucosal antigens including Helicobacter pylori , oral polio vaccine, gliadin, ovalbumin and dextran B512 in patients with IgAN …”

“…Whether this response is limited to the mucosa-associated lymphoid tissue or involves B cells that have mis-trafficked to the bone marrow is currently not known. 23,24 A number of separate studies have reported high levels of IgA antibodies in the serum against a variety of mucosal antigens including Helicobacter pylori, oral polio vaccine, gliadin, ovalbumin and dextran B512 in patients with IgAN. [25][26][27][28][29] Furthermore, the well-recognized association of mucosal infection with episodes of visible haematuria suggests a close relationship between the mucosal immune system and nephritogenic IgA1 production in IgAN.…”

An update on the pathogenesis and treatment of IgA nephropathy

“…This mis-trafficking may occur because of faulty expression of surface homing receptors on lymphocyte subsets or defective expression of mucosal chemokines and homing counterreceptors on mucosal vascular endothelium. 28,[34][35][36] These translocated cells take up residence in the bone marrow, and perhaps tonsils, where they secrete 'normal' mucosal-type IgA into the systemic circulation. Over time there is a gradual accumulation of mucosally derived IgA plasma cells in systemic sites; levels of poorly galactosylated IgA1 O-glycoforms increase and plateau, forming a circulating pool of molecules, which, in susceptible individuals, provide the antigenic stimulus for autoantibody formation and immune complex generation.…”