Unveiling immune system responses that induce and maintain autoimmune pancreatitis

Autoimmune pancreatitis (AIP) is a clinical condition characterized by inflammation of the pancreas, caused by the body’s hypersensitivity to its own proteins. AIP is typically accompanied by other organ inflammations such as autoimmune sialadenitis and cholangitis, together categorized as systemic autoimmune disorder, called IgG4-related disease (IgG4-RD). When induced repeatedly with polyinosinic-polycytidylic acid (poly(I:C)), murine models of AIP (MRL/MpJ mice) were similar to the human AIP with IgG4-RD.

Studies on these models have found that inflamed pancreatic tissue had abundant plasmacytoid dendritic cells (pDCs) producing IFN-α(Interferon-alpha) and IL-33 (Interleukin-33). Depletion of pDCs or inhibition of IFN-α or IL-33-mediated signaling pathways impeded the development of AIP. Strong evidence that experimental AIP is dependent on activated pDCs was established through these studies.

However, the origin of pDCs and their interaction with other immune cells like effector T cells in AIP still remains an important, yet unanswered question. Although pancreatic inflammation is initiated by a toll-like receptor 3 (TLR3) ligand (poly(I:C)), studies have found that AIP-causing pDCs express only low levels of TLR3, leading to ambiguity about the cell initiating murine AIP. Also, AIP/IgG4-RD promotes the generation of diverse T cell types, but how these cells contribute to disease progression remains unclear.

Now, however, a group of researchers, Associate Professor Tomohiro Watanabe, Dr. Akane Hara, Professor Masatoshi Kudo, and Dr. Warren Strober from Kindai University, Japan, and National Institute of Health, U.S., have addressed these questions. In their study published in JCI Insight, they induced poly (I:C) in MRL/MpJ murine models of AIP/IgG4-RD to elucidate the key immune signaling pathways leading to the initiation and sustenance of AIP.

Associate Professor Tomohiro Watanabe, the lead researcher of this study, says, “Our study establishes that the identification of the poly(I:C) ligand by TLR3-bearing conventional DCs (cDCs) initiated AIP in MRL/MpJ model, leading to the production of IFN-α/b.”

To support this conclusion, the researchers demonstrated an inhibition of TLR3 signaling via TLR3-specific inhibitor reduced pancreatic inflammation during initial disease induction. During this period, pancreatic cDCs produced inflammatory mediators like type I IFNs, CXCL9 (C-X-C motif chemokine ligand 9), and CXCL10 that eventually triggered the recruitment of CD4⁺CXCR3⁺ T cells to the pancreas.

Associate Professor Watanabe says, “This is fully consistent with our hypothesis that initial stimulation of pancreatic TLR3-bearing cDCs by poly(I:C) results in IFN-α/b production and that, in turn, leads to induction of Th1 (Type 1 T helper cells) responses in lymph nodes draining the pancreas, followed by early migration of CXCR3⁺(C-X-C chemokine receptor 3) T cells into the pancreas via CXCL9 and CXCL10 secretion.”

To understand the mechanism of pDC accumulation in the inflamed pancreas, the researchers investigated the chemokine interactions that could facilitate pDC migration into the pancreas. The cell surface receptors on pDCs like CCR2 (C-C motif chemokine receptor 2), CCR7 and CCR9 were found to bind and attract to CCL2, CCL21, and CCL25.

Repeated administration of poly(I:C) were found to express increased levels of CCL2 and CCL25, and the researchers speculate that interactions between CCR2 and CCL2 or between CCR9 and CCL25, maybe responsible for promoting pDC migration into the pancreas.

CCL25-mediated pDC recruitment arises from a cDC-T cell interaction in the early induction phase of experimental AIP. As a sufficient number of pDCs migrate into the inflamed pancreas, they produce CXCL9 and CXCL10 that attract CXCR3⁺ Th1 cells into the pancreas, which in turn, produces CCL25 that recruits additional CCR9-expressing pDCs, repeating as a positive feedback loop that establishes the pathology.

Previous studies have found that serum IFN-α and IL-33 levels can be used as biomarkers for diagnosis and disease-monitoring in AIP/IgG4-RD. In this study, researchers showed a positive correlation between serum concentrations of IgG4 and those of IFN-α or IL-33, along with CXCL9 and CXCL10.

Examination of serum composition of patients with AIP/IgG4-RD proved that the elevated levels of immune system elements observed in the murine model of AIP corresponded with those seen in human patients with AIP/IgG4-RD. However, the chronic nature and multi-organ involvement in human AIP/IgG4-RD warrants long-term studies in larger patient groups.

Sharing his concluding thoughts, Associate Professor Watanabe says, “Such studies not only have the potential to provide new biomarkers of AIP/IgG4-RD, but also to identify possible targets for treatment of AIP/IgG4-RD that have minimal effects on overall immune competence and resistance to infection.”

Provided by
Kindai University