Identification of commensal flora-associated antigen as a pathogenetic factor of autoimmune pancreatitis

Outer Membrane Protein of Gut Commensal Microorganism Induces Autoantibody Production and Extra-Intestinal Gland Inflammation in Mice

“…It may be possible that the molecules did not possess the combined functionality of immunogenic antigens and bystander adjuvants [ 37 ], which are indispensable for autoimmunity [ 38 ]. In addition to the microbial molecules investigated in the present study, we previously studied the flagellar filament structural protein FliC, a TLR5-ligand, and an NLR apoptosis inhibitory protein (NAIP) activator, derived from commensal E. coli , which was repeatedly inoculated following the same regimen of injection as the present study [ 17 , 39 ]. In the reports, we had found that sialadenitis and pancreatitis could be induced by FliC in mice within the fifteen weeks of observation after the final inoculation [ 17 , 39 ].…”

“…In addition to the microbial molecules investigated in the present study, we previously studied the flagellar filament structural protein FliC, a TLR5-ligand, and an NLR apoptosis inhibitory protein (NAIP) activator, derived from commensal E. coli , which was repeatedly inoculated following the same regimen of injection as the present study [ 17 , 39 ]. In the reports, we had found that sialadenitis and pancreatitis could be induced by FliC in mice within the fifteen weeks of observation after the final inoculation [ 17 , 39 ]. The results of the present study indicated that OmpA was highly antigenic to induce humoral adaptive immune response to elicit antibodies and to encounter histological inflammation of the Harderian and the salivary glands, but not of the pancreas, indicating that different microbe-derived proteins had initiated inflammation in exocrine glands with tropism.…”

“…In our previous study, pancreas of mice after E. coli -derived FliC treatment showed infiltration of inflammatory cells, and the majority of the infiltrated cells were CD3 + T cells [ 39 ]. In the present study, inflammation of the Harderian glands was reproduced in immune-deficient Rag2 KO mice and in mature T cell-deficient TCRβ-TCRδ KO mice by adoptive transfer of splenocytes or CD4 + T cells, respectively, from E. coli -treated mice.…”

IgG4-Related Disease

“…In line with this case report, the NOD2 ligand, muramyl dipeptide (MDP), has been shown to strongly induce IgG4 production in healthy individuals , which suggests that MAMPs derived from the intestinal microflora may trigger TH2-driven pathogenic responses in IgG4-RD. Repeated administration of heat-killed Escherichia coli to C57BL/6 mice induces activation of the innate immune system and the development of chronic fibroinflammatory disorder of the pancreas, akin to human AIP (Haruta et al 2010;Yanagisawa et al 2014). Taken together, both human and animal studies provide evidence that MAMPs derived from the intestinal microflora might trigger IgG4-RD through activation of PRRs.…”

Thoracic Involvement in IgG4-Related Disease

“…Helicobacter pylori and Escherichia coli are the common ones. [47][48][49][50] Moreover, the fact that there is homology between some bacterial antigens and antigens expressed in pancreatic acinar cells with shared binding motif of the human leukocyte antigen (HLA) molecules reinforces that these bacterial components may behave as autoantibodies by means of molecular mimicry in genetically predisposed patients. 28 There are three main immunologic factors associated with an IgG4 response: (1) the presence of Th2 cytokines such as interleukin (IL)-4 and IL-13, (2) the presence of IL-10, and (3) regulatory T cells (Tregs).…”