My laboratory works on our long-standing interest: the role of microbes in autoimmune disease with a unique focus, mucosal immunity. Imbalance of gut microbiota can lead to many diseases including those located systemically (outside the gut; e.g. rheumatoid arthritis, type 1 diabetes, lupus, etc.). Accordingly, the big question that my laboratory is focusing on is how gut microbiota remotely exert systemic effects. We have established a new system to examine commensal-host interactions by manipulating the status of the commensal, segmented filamentous bacteria (SFB), in the K/BxN arthritis model housed in a specific pathogen free (SPF) facility. We also developed a state-of-the-art photoconverting technique to track single cell migration between gut and systemic tissues. With these systems, we were able to show that SFB remotely trigger systemic autoimmune arthritis by driving the induction and egression of gut T follicular helper (Tfh) cells.
Lung complications are common and a major cause of death in patients with rheumatoid arthritis (RA) and we are very interested in understanding how do microbiota residing in the gut affect autoimmune disease in the lung. A long-standing question in the host-microbe field is, “how are microbes involved in the development of autoimmunity?” Although molecular mimicry is the dominant theory, we discovered that commensal SFB actually trigger autoimmunity in lung by a different mechanism, by inducing dual TCR-expressing Th17 cells derived from the gut-lung axis. SFB selectively expand autoimmune T cells co-expressing SFB-specific TCRs in addition to their auto-reactive TCRs. This additional SFB-specific TCR provides a proliferative advantage for autoimmune Th17 cells in SFB+ hosts. We are now using single cell TCR analysis to unbiasedly determine whether microbiota promote autoimmunity by skewing the dual TCR repertoire. To further identify the gut-lung axis related autoimmunity, we have lung function (flexiVent) data suggesting that the middle-aged K/BxN lung displays increased total respiratory resistance similar to RA patients.
For translational purposes, we are actively pursuing a project studying human commensals isolated from spondyloarthritis (SpA) patients. Recently, we reported that commensals from human SpA patients cause augmentation of autoimmune arthritis, and we are hoping to further understand the mechanisms behind this disease phenotype. With our strong interest, knowledge, and tools in mucosal immunity, including lung and gut immunity, and also through our collaborative efforts, my lab aims to continually contribute to this exciting field by elucidating the crucial mechanisms through which gut microbiota affect non-gut diseases in the joints and lung.