Intestinal Dysbiosis and Autoimmune Pancreatitis

Abstract

Autoimmune pancreatitis (AIP) is a chronic fibro-inflammatory disorder of the pancreas. Recent clinicopathological analysis revealed that most cases of AIP are pancreatic manifestations of systemic IgG4-related disease (IgG4-RD), a newly established disease characterized by enhanced IgG4 antibody responses and the involvement of multiple organs. Although the immuno-pathogenesis of AIP and IgG4-RD has been poorly defined, we recently showed that activation of plasmacytoid dendritic cells (pDCs) with the ability to produce large amounts of IFN-α and IL-33 mediates chronic fibro-inflammatory responses in experimental and human AIP. Moreover, M2 macrophages producing a large amount of IL-33 play pathogenic roles in the development of human IgG4-RD. Interestingly, recent studies including ours provide evidence that compositional alterations of gut microbiota are associated with the development of human AIP and IgG4-RD. In addition, intestinal dysbiosis plays pathological roles in the development of chronic pancreatic inflammation as dysbiosis mediates the activation of pDCs producing IFN-α and IL-33, thereby causing experimental AIP. In this Mini Review, we focus on compositional alterations of gut microbiota in AIP and IgG4-RD to clarify the mechanisms by which intestinal dysbiosis contributes to the development of these disorders.

Misdiagnosis and delayed diagnosis of atypical autoimmune pancreatitis: Experience from clinical cases

“…Nakano and Takano reported two cases with negative serum and histological IgG4 levels, 6,7 and Hart et al also reported similar cases 8 . The pathogenic function of IgG4 in AIP is still unknown, and studies suggest that IgG4 antibodies have weak complement system activation and FC‐γ binding ability, and their elevated levels may be a result of chronic inflammation 9,10 . Low serum IgG4 levels may also be due to false‐negative results caused by the prozone phenomenon 11 .…”

“…8 The pathogenic function of IgG4 in AIP is still unknown, and studies suggest that IgG4 antibodies have weak complement system activation and FCγ binding ability, and their elevated levels may be a result of chronic inflammation. 9,10 Low serum IgG4 levels may also be due to falsenegative results caused by the prozone phenomenon. 11 Histological negativity for IgG4 is closely related to the extent of fibrosis, and severe fibrosis can hinder immune cell infiltration, especially in RPF, 12 which is consistent with the results of histological IgG4−/+ staining in our three cases (Table 1).…”

Multi-Organ Crosstalk with Endocrine Pancreas: A Focus on How Gut Microbiota Shapes Pancreatic Beta-Cells

“…There have been related alterations in microbiota with autoimmune pancreatitis in experimental models, suggesting that indeed dysbiosis is responsible, at least in part, for inflammatory processes such as pancreatitis [ 80 ]. However, not only in pancreatitis but changes in the microbiome have been associated with different diseases such as type 1 diabetes and even pancreatic cancer [ 81 ].…”

The oral microbiome in autoimmune diseases: friend or foe?

“…Accumulating evidence has demonstrated that microbiota dysbiosis is the critical factor for engendering autoimmune diseases [ 77 ]. For instance, the in vivo results showed that intestinal microbial imbalance promoted the initiation of autoimmune pancreatitis by enhancing the production of IFN-α and IL-33 released by plasmacytoid dendritic cells [ 78 ]. In addition, intestinal microbiota dysbiosis caused by constipation increased the number of Th17 cells and Teff17 cells in the brain and spinal cord as well as promoted the secretion of cytokines in serum, which deteriorated experimental autoimmune encephalomyelitis in mice [ 79 ].…”