SummaryMultiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells. Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells. These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies.

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Widespread antimicrobial resistance generates an urgent need to develop better disease prophylaxis for intestinal bacterial pathogens. While the first phase of infection with any bacterial pathogen is typically colonization of the mucosal surfaces, current vaccine strategies typically target invasive stages of disease. Here we demonstrate the ability to specifically generate sterilizing immunity against Salmonella enterica subspecies enterica serovar Typhimurium (S.Tm) at the level of gut lumen colonization using a combination of oral vaccination and a rationally-designed niche competitor strain. This is based on the proven ability of specific secretory IgA to generate a fitness disadvantage for a targeted bacterium, allowing a non-targeted competitor to rapidly overtake its niche. By hugely decreasing the population size of an intestinal pathogen during the early stages of infection, this improves protection of gut tissue compared to standard licensed animal vaccines. We demonstrate that most effective protection is generated when the niche competitor is derived from the pathogen and therefore occupies an identical niche. However, as this is unrealistic in real-world infections, we further demonstrate that robust protection can also be generated with a more distantly related “probiotic” niche competitor from a distinct species. Interestingly, focusing prophylaxis on the gut lumen reveals an uncoupling of protective mechanisms required for protection in the gut and gut tissues and those required for protecting against colonization of the spleen and liver. Therefore, while there is still potential to improve this approach by adding systemic immune activation, we nevertheless believe this is a fundamental step forward in our ability to manipulate colonization of intestinal bacteria with potential application to a wide-range of entero-pathogens, as well as to manipulation of microbiota composition.

AbstractSecretory antibody responses (Immunoglobulin A, IgA) against repetitive bacterial surface glycans, such as O-antigens, can protect against intestinal pathogenic bacteria. However, vaccines that rely predominantly on secretory IgA for protection against non-Typhoidal salmonellosis often fail. Here we demonstrate that a major contributor to this failure is rapid immune escape, due to strong selective pressure exerted by high-avidity intestinal IgA. Interestingly, we found that IgA-escape initially occurs via a predictable narrow spectrum of Salmonella O-antigen variants that are fitness-neutral in naïve hosts. This could be attributed both to phase-variation, and to loss-of-function mutations in O-antigen-modifying enzymes. Via a vaccination regimen that simultaneously induced IgA against all observed O-antigen variants, rapid bacterial evolution could be switched from a hindrance into an advantage. Here, IgA generated a selective pressure resulting in fixation of mutations causing loss of polymerized O-antigen. When transmitted into naive hosts, these short O-antigen variants display compromised fitness and virulence, i.e. IgA-mediated pressure generates an evolutionary trade-off. Rational induction of IgA specificities that set “evolutionary traps” could reduce virulent enteropathogen reservoirs, even when sterilizing immunity cannot be achieved. This may become a powerful tool in the management of increasingly drug-resistant enteropathogenic bacteria.One sentence summaryIntestinal IgA responses that recognize all rapidly-evolvable O-antigen variants of a Salmonella Typhimurium strain can drive evolutionary trade-offs for the pathogen.