PD-1 cooperates with AIRE-mediated tolerance to prevent lethal autoimmune disease.

Immunological tolerance is established and maintained by a diverse array of safeguards that work together to protect against autoimmunity. Despite the identification of numerous tolerogenic processes, the basis for cooperation among them remains poorly understood. We sought to identify synergy among several well-defined tolerance mediators that alone provide protection only from mild autoimmune symptoms in C57BL/6 mice: BIM, AIRE, CBL-B, and PD-1. Survey of a range of compound mutant mice revealed that the combined loss of the autoimmune regulator, AIRE, with PD-1 unleashed a spontaneous, lethal autoimmune disease. Pdcd1−/−Aire−/− mice succumbed to cachexia before adulthood, with near-complete destruction of the exocrine pancreas. Such fatal autoimmunity was not observed in Pdcd1−/−Bim−/−, Bim−/−Aire−/−, or Cblb−/−Bim−/− mice, suggesting that the cooperation between AIRE-mediated and PD-1­mediated tolerance was particularly potent. Immune profiling revealed largely normal development of FOXP3+ regulatory T (Treg) cells in Pdcd1−/−Aire−/− mice, yet excessive, early activation of effector T cells. Adoptive transfer experiments demonstrated that autoimmune exocrine pancreatitis was driven by conventional CD4+ T cells and could not be prevented by the cotransfer of Treg cells from wild-type mice. The development of autoimmunity in mixed bone marrow chimeras supported these observations, indicating that failure of recessive tolerance was responsible for disease. These findings reveal a potent tolerogenic axis between AIRE and PD-1 that has implications for our understanding of how immune checkpoint blockade might synergize with subclinical defects in central tolerance to elicit autoimmune disease.

Autoimmune pancreatitis - An ongoing challenge.

Autoimmune pancreatitis is a rare form of chronic pancreatitis. The first descriptions of the disease date back to the 1990s. Etiology is multifactorial, with the use of genetic, environmental and complex immunological mechanisms. It is classified into two subtypes. Type 1 is part of a group of diseases called IgG4-related disease. Clinically is autoimmune pancreatitis manifested by icterus and abdominal discomfort. It can rarely present as acute pancreatitis. There is also a completely asymptomatic form of the disease. The diagnosis is based on abnormalities in histology, imaging methods, serology, the involvement of other organs in relation to IgG4-related disease, and a significant positive response to corticosteroid therapy. Differential diagnosis between the focal form of autoimmune pancreatitis and pancreatic cancer can be complicated, with endosonography playing an important role. In the treatment, we use corticosteroids and other immunosuppressants including biological therapy. Patients with the asymptomatic disease should also be treated to prevent late complications and exocrine and endocrine insufficiency. In addition to drug treatment, endoscopic and/or surgical treatment may be necessary. Even after recovery, the disease can relapse. The relationship between autoimmune pancreatitis and malignancies has not been clearly confirmed. The goal of this review is to provide a comprehensive look at autoimmune pancreatitis and translate latest scientific knowledge into clinical practice.

Extracellular vesicles microRNA analysis in type 1 autoimmune pancreatitis: Increased expression of microRNA-21.

BACKGROUND: The molecular basis of type 1 autoimmune pancreatitis (AIP) remains unclear. Recent attention on the role of extracellular vesicles microRNA (EV miRNA) in immune homeostasis has prompted us to perform an extensive miRNA screening of serum-derived EV in AIP. METHODS: EV miRNA expression was analyzed using microarrays in AIP, chronic pancreatitis (CP), and healthy adult (HC) samples (n = 10 from each group). Differences in signals, > 3 or <1/3 times, represented significant differences in expression. Another cohort of AIP (n = 14), CP (n = 10), and HC (n = 10) samples of EV miRNA was analyzed using reverse-transcription polymerase chain reaction (RT-PCR). miRNA expression in pancreatic tissues was evaluated using in situ hybridization (ISH) in three additional subjects from each group. RESULTS: Signals of eight miRNAs (miR-659-3p, -27a-3p, -99a-5p, -21-5p, -205-5p, -100-5p, -29c-3p, and -125b-1-3p) were significantly higher, while those of two miRNAs (miR-4252 and -5004-5p) were significantly lower in AIP than in HC. EV miR-21-5p was significantly up-regulated in AIP than in HC (P = 0.035) and CP (P = 0.048). The number of miR-21-5p positive inflammatory cells was significantly elevated in AIP than in CP (P = 0.014). CONCLUSIONS: Circulating EVs exhibited altered miRNA expression patterns with elevated miR-21-5p in AIP when compared with those in HC and CP. miR-21-5p was highly expressed in pancreatic inflammatory cells in AIP. Our data suggests that miR-21-5p may be involved in the regulation of effector pathways in the pathophysiology of AIP, thus differentiating AIP from CP.