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B cell activation factor of the TNF family (BAFF) is a potent B cell survival factor. BAFF overexpressing transgenic mice (BAFF-Tg mice) exhibit features of autoimmune disease, including B cell hyperplasia and hypergammaglobulinemia, and develop fatal nephritis with age. However, basal serum IgA levels are also elevated, suggesting that the pathology in these mice may be more complex than initially appreciated. Consistent with this, we demonstrate here that BAFF-Tg mice have mesangial deposits of IgA along with high circulating levels of polymeric IgA that is aberrantly glycosylated. Renal disease in BAFF-Tg mice was associated with IgA, because serum IgA was highly elevated in nephritic mice and BAFF-Tg mice with genetic deletion of IgA exhibited less renal pathology. The presence of commensal flora was essential for the elevated serum IgA phenotype, and, unexpectedly, commensal bacteria-reactive IgA antibodies were found in the blood. These data illustrate how excess B cell survival signaling perturbs the normal balance with the microbiota, leading to a breach in the normal mucosal-peripheral compartmentalization. Such breaches may predispose the nonmucosal system to certain immune diseases. Indeed, we found that a subset of patients with IgA nephropathy had elevated serum levels of a proliferation inducing ligand (APRIL), a cytokine related to BAFF. These parallels between BAFF-Tg mice and human IgA nephropathy may provide a new framework to explore connections between mucosal environments and renal pathology.

Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA + PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA + PC. Furthermore, mice with an over-abundance of IgA + PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA + PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.

The authors regret the error.

Chlamydiae are obligate intracellular pathogens that likely require type III secretion (T3S) to invade cells and replicate intracellularly within a cytoplasmic vacuole called an inclusion body. Chlamydia pneumoniae possess a YscL ortholog, CdsL, that has been shown to interact with the T3S ATPase (CdsN). In this report we demonstrate that CdsL down-regulates CdsN enzymatic activity in a dose-dependent manner. Using Pepscan epitope mapping we identified two separate binding domains to which CdsL binds viz. CdsN221–229 and CdsN265–270. We confirmed the binding domains using a pull-down assay and showed that GST–CdsN221–270, which encompasses these peptides, co-purified with His–CdsL. Next, we used orthology modeling based on the crystal structure of a T3S ATPase ortholog from Escherichia coli, EscN, to map the binding domains on the predicted 3D structure of CdsN. The CdsL binding domains mapped to the catalytic domain of the ATPase, one in the central channel of the ATPase hexamer and one on the outer face. Since peptide mimetics have been used to disrupt essential protein interactions of the chlamydial T3S system and inhibit T3S-mediated invasion of HeLa cells, we hypothesized that if CdsL–CdsN binding is essential for regulating T3S then a CdsN peptide mimetic could be used to potentially block T3S and chlamydial invasion. Treatment of elementary body with a CdsN peptide mimetic inhibited C. pneumoniae invasion into HeLa cells in a dose-dependent fashion. This report represents the first use of Pepscan technology to identify binding domains for specific T3S proteins viz. CdsL on the ATPase, CdsN, and demonstrates that peptide mimetics can be used as anti-virulence factors to block bacterial invasion.

Stromal cell microenvironments within lymphoid tissues are designed to support immune cell homeostasis and to regulate ongoing immune responses to pathogens. Such stromal cell networks have been best characterized within lymphoid tissues including the spleen and peripheral lymph nodes, and systems for classifying stromal cell phenotypes and functions are emerging. In response to inflammation, stromal cell networks within lymphoid tissues change in order to accommodate and regulate lymphocyte activation. Local inflammation in non-lymphoid tissues can also induce de novo formation of lymphoid aggregates, which we term here “follicle-like structures.” Of note, the stromal cell networks that underpin such follicles are not as well characterized and may be different depending on the anatomical site. However, one common element that is integral to the maintenance of stromal cell environments, either in lymphoid tissue or in extra-lymphoid sites, is the constitutive regulation of stromal cell phenotype and/or function by the lymphotoxin (LT) pathway. Here we discuss how the LT pathway influences stromal cell environments both in homeostasis and in the context of inflammation in lymphoid and non-lymphoid tissues.

is a national coordinating investigator for the Calliditas NEFIGARD study, and is a site investigator for therapeutic trials in IgAN funded by Alnylam and Omeros. She has provided consultation outside of the submitted work for Novartis, Chinook, and Travere. She is a site investigator for a study in FSGS sponsored by Pfizer. The GN Fellowship at University Health Network is supported by the Louise Fast Foundation.Dr. Hladunewich reports participation as a site lead for studies in IgAN funded by Ionis, Calliditas, Pfizer, and Alnylam, with consultation outside of the submitted work. She also is a site lead for a Chemocentryx study of FSGS. She is the section editor for the kidney disease and pregnancy section of Uptodate. She is the medical lead for glomerulonephritis and pregnancy for the Ontario Renal Network.Dr. Novak is a co-founder and co-owner of and consultant for Reliant Glycosciences, LLC and a co-inventor on US patent application 14/318,082 (assigned to UAB Research Foundation) and has a sponsored research agreement with Travere.

A Corrigendum on Chlamydia pneumoniae CdsL regulates CdsN ATPase activity, and disruption with a peptide mimetic prevents bacterial invasion