Date of Award
Medical Doctor (MD)
Martin A. Kriegel
The gut microbiome is increasingly recognized to play an important role in shaping human health and disease. Recently, translocation of gut commensals to internal organs has been shown to initiate autoimmunity. Previous studies from the Kriegel lab have demonstrated that the gut pathobiont Enterococcus gallinarum spontaneously translocates to internal organs of male (NZW x BXSB)F1 mice, which are susceptible to early lupus-like autoimmunity because of a duplication of the tlr7 gene on the Y chromosome. E. gallinarum translocation has been linked to development of systemic autoimmune disease in this mouse model, and autoimmunity is suppressed by either administration of antibiotics or vaccination against E. gallinarum. In this study, we extended these findings and investigated whether bacterial translocation could drive autoimmunity depending on gender and gut homing of lymphocytes. We tested germ-free non-autoimmune prone C57BL/6 mice as well as female (NZW x BXSB)F1 mice that lack the Y-chromosomal tlr7 duplication and develop only late-onset, mild autoimmunity. We found that although E. gallinarum was a normal commensal in female (NZW x BXSB)F1 mice, it rarely translocated to mesenteric lymph nodes (MLN). Translocation to MLN was only promoted if the pathobiont was introduced after first depleting bacteria from the intestinal niche with broad-spectrum antibiotics. E. gallinarum translocation was also observed in germ-free female C57BL/6 mice that were monocolonized with this bacterium and, under these conditions, mice developed lupus-like autoantibodies. Gut-homing α4β7+ CD4+ T cells were significantly increased in spleens, suggesting that lymphocytes previously imprinted in the gut migrate to sites that E. gallinarum colonizes. To determine the role of lymphocyte gut homing in this model, we tested whether interrupting migration of gut-homing α4β7+ lymphocytes influenced disease. Interestingly, monocolonized mice treated with an anti-α4β7 mAb developed heightened bacterial translocation and greater autoantibody production. These data suggest that lymphocyte homing to the gut may be important for containing bacteria in the lumen as well as dampening systemic autoimmunity. In support of this, we found that circulating CD4+ T cells expressing α4β7 or CCR9 increased with age in male (NZW x BXSB)F1 mice, but were reduced after subcutaneous vancomycin. Systemic vancomycin depleted E. gallinarum in MLN and spleens, and reduced serum autoantibodies even after autoimmunity was established. Taken together, our results highlight the importance of translocation of gut bacteria across weakened barriers in the induction of autoimmunity and reveal that gut-primed α4β7+ T cells may have a protective role. Because E. gallinarum has been detected in human livers from patients with autoimmune hepatitis and lupus, similar processes may occur in humans and warrant further studies. Overall, these discoveries represent a new paradigm of host-microbiota interactions in autoimmunity and reveal a potential treatment target aimed at the microbiota.
Fine, Rebecca, "Gut Commensal Translocation And Lymphocyte Migration To Internal Organs In Autoimmunity" (2019). Yale Medicine Thesis Digital Library. 3492.