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Abstract B cells and T cells collaborate in multiple sclerosis (MS) pathogenesis. IgH[MOG] mice possess a B cell repertoire skewed to recognize myelin oligodendrocyte glycoprotein (MOG). Here, we show that upon immunization with the T cell-obligate autoantigen, MOG[35-55], IgH[MOG] mice develop rapid and exacerbated experimental autoimmune encephalomyelitis (EAE) relative to wildtype (WT) counterparts, characterized by aggregation of T and B cells in the IgH[MOG] meninges and by CD4+ T helper 17 (Th17) cells in the CNS. Production of the Th17 maintenance factor IL-23 is observed from IgH[MOG] CNS-infiltrating and meningeal B cells, and in vivo blockade of IL-23p19 attenuates disease severity in IgH[MOG] mice. In the CNS parenchyma and dura mater of IgH[MOG] mice, we observe an increased frequency of CD4+PD-1+CXCR5- T cells that share numerous characteristics with the recently described T peripheral helper (Tph) cell subset. Further, CNS-infiltrating B and Tph cells from IgH[MOG] mice show increased reactive oxygen species (ROS) production. Meningeal inflammation, Tph-like cell accumulation in the CNS and B/Tph cell production of ROS were all reduced upon p19 blockade. Altogether, MOG-specific B cells promote autoimmune inflammation of the CNS parenchyma and meninges in an IL-23-dependent manner.

IgA nephropathy (IgAN) is a leading cause of kidney failure, yet little is known about the immunopathogenesis of this disease. IgAN is characterized by deposition of IgA in the kidney glomeruli, but the source and stimulus for IgA production are not known. Clinical and experimental data suggest a role for aberrant immune responses to mucosal microbiota in IgAN, and in some countries with high disease prevalence, tonsillectomy is regarded as standard-of-care therapy. To evaluate the relationship between microbiota and mucosal immune responses, we characterized the tonsil microbiota in patients with IgAN versus nonrelated household-matched control group participants and identified increased carriage of the genus Neisseria and elevated Neisseria-targeted serum IgA in IgAN patients. We reverse-translated these findings in experimental IgAN driven by BAFF overexpression in BAFF-transgenic mice rendered susceptible to Neisseria infection by introduction of a humanized CEACAM-1 transgene (B × hC-Tg). Colonization of B × hC-Tg mice with Neisseria yielded augmented levels of systemic Neisseria-specific IgA. Using a custom ELISPOT assay, we discovered anti-Neisseria–specific IgA-secreting cells within the kidneys of these mice. These findings suggest a role for cytokine-driven aberrant mucosal immune responses to oropharyngeal pathobionts, such as Neisseria, in the immunopathogenesis of IgAN. Furthermore, in the presence of excess BAFF, pathobiont-specific IgA can be produced in situ within the kidney.

Multiple sclerosis (MS) is characterized by demyelinated and inflammatory lesions in the brain and spinal cord that are highly variable in terms of cellular content. Here, we used imaging mass cytometry (IMC) to enable the simultaneous imaging of 15+ proteins within staged MS lesions. To test the potential for IMC to discriminate between different types of lesions, we selected a case with severe rebound MS disease activity after natalizumab cessation. With post-acquisition analysis pipelines we were able to: (1) Discriminate demyelinating macrophages from the resident microglial pool; (2) Determine which types of lymphocytes reside closest to blood vessels; (3) Identify multiple subsets of T and B cells, and (4) Ascertain dynamics of T cell phenotypes vis-à-vis lesion type and location. We propose that IMC will enable a comprehensive analysis of single-cell phenotypes, their functional states and cell-cell interactions in relation to lesion morphometry and demyelinating activity in MS patients.

The mechanisms that contribute to the maintenance of serological memory are still unclear. Rotavirus (RV) memory B cells (mBc) are enriched in IgM(+) and CD27- subpopulations, which are associated with autoimmune diseases pathogenesis. In patients with autoimmune diseases treated with Rituximab (RTX), some autoantibodies (auto-Abs) decrease after treatment, but other auto-Abs and pathogen-specific IgG Abs remain unchanged. Thus, maintenance of autoimmune and pathogen-specific serological memory may depend on the type of antigen and/or Ab isotype evaluated. Antigen-specific mBc and antigen-specific Abs of different isotypes have not been simultaneously assessed in patients after RTX treatment. To study the relationship between mBc subpopulations and serological memory we characterized total, RV- and tetanus toxoid (TT)-specific mBc by flow cytometry in patients with autoimmune diseases before and after treatment with RTX. We also measured total, RV- and TT-Abs, and some auto-Abs by kinetic nephelometry, ELISA, and EliA tests, respectively. Minor differences were observed between the relative frequencies of RV-mBc in healthy controls and patients with autoimmune disease. After RTX treatment, naïve Bc and total, RV- and TT-specific mBc [IgM(+), switched (IgA(+)/IgG(+)), IgM(+) only, IgD(+) only, and CD27- (IgA(+)/IgG(+)/IgM(+))] were significantly diminished. An important decrease in total plasma IgM and minor decreases in total IgG and IgA levels were also observed. IgM rheumatoid factor, IgG anti-CCP, and IgG anti-dsDNA were significantly diminished. In contrast, RV-IgA, RV-IgG and RV-IgG1, and TT-IgG titers remained stable. In conclusion, in patients with autoimmunity, serological memory against RV and TT seem to be maintained by long-lived plasma cells, unaffected by RTX, and an important proportion of total IgM and serological memory against some auto-antigens seem to be maintained by short-lived plasma cells, dependent on mBc precursors depleted by RTX.

BackgroundThe foreskin is the site of most HIV acquisition in uncircumcised heterosexual men. Although HIV-exposed, seronegative (HESN) uncircumcised men demonstrate HIV-neutralizing IgA and increased antimicrobial peptides (AMPs) in the foreskin prepuce, no prospective studies have examined the mucosal immune correlates of HIV acquisition.MethodsTo assess the association of foreskin immune parameters with HIV acquisition, antimicrobial peptides and IgA with the capacity to neutralize a primary clade C HIV strain were quantified by blinded investigators, using sub-preputial swabs collected longitudinally during a randomized trial of male circumcision for HIV prevention in Rakai, Uganda.ResultsParticipants were 99 men who acquired HIV (cases) and 109 randomly selected controls who remained HIV seronegative. At enrollment, 44.4% of cases vs. 69.7% of controls demonstrated IgA neutralization (adjusted OR = 0.31; 95% CI, 0.16-0.61). IgA neutralization was detected in 38.7% of cases and 70.7% of controls at the last seronegative case visit prior to HIV acquisition and the comparable control visit (adjusted OR 0.21; 95% CI, 0.11-0.39). Levels of the α-defensins and secretory leukocyte protease inhibitor (SLPI) were over ten-fold higher in the foreskin prepuce of cases who acquired HIV, both at enrollment (mean 4.43 vs. 3.03 and 5.98 vs. 4.61 log(n) pg/mL, P = 0.005 and 0.009, respectively), and at the last seronegative visit (mean 4.81 vs. 3.15 and 6.46 vs. 5.20 log(n) pg/mL, P = 0.0002 and 0.013).ConclusionsThis prospective, blinded analysis is the first to assess the immune correlates of HIV acquisition in the foreskin. HIV-neutralizing IgA, previously associated with the HESN phenotype, was a biomarker of HIV protection, but other HESN associations correlated with increased HIV acquisition. This emphasizes the importance of prospective epidemiological studies or in vitro tissue studies to define the impact of mucosal parameters on HIV risk.