Autoimmune hepatitis in a murine autoimmune polyendocrine syndrome type 1 model is directed against multiple autoantigens

Abstract

Autoimmune polyendocrine syndrome type 1 (APS-1) is caused by mutations of the autoimmune regulator (AIRE) gene. Mouse studies have shown that this results in defective negative selection of T cells and defective early seeding of peripheral organs with regulatory T cells (Tregs). Aire deficiency in humans and mice manifests as spontaneous autoimmunity against multiple organs, and 20% of patients develop an autoimmune hepatitis (AIH). To study AIH in APS-1, we generated a murine model of human AIH on a BALB/c mouse background, in which Aire is truncated at exon 2. A subgroup of 24% of mice is affected by AIH, characterized by lymphoplasmacytic and periportal hepatic infiltrates, autoantibodies, elevated aminotransferases, and a chronic and progressive course of disease. Disease manifestation was dependent on specific Aire mutations and the genetic background of the mice. Though intrahepatic Treg numbers were increased and hyperproliferative, the intrahepatic CD4/CD8 ratio was decreased. The targets of the adaptive autoimmune response were polyspecific and not focussed on essential autoantigens, as described for other APS-1-related autoimmune diseases. The AIH could be treated with prednisolone or adoptive transfer of polyspecific Tregs. Conclusion: Development of AIH in APS-1 is dependent on specific Aire mutations and genetic background genes. Autoimmune response is polyspecific and can be controlled by steroids or transfer with Tregs. This might enable new treatment options for patients with AIH. (HEPATOLOGY 2015;61:1295-1305 A utoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenetic recessive disorder caused by mutations in the autoimmune regulator (Aire) gene. The disease manifests in early childhood, and APS-1 patients suffer from at least a triad of mucocutaneous candidiasis, Addison's disease, and hypoparathyroidism. In addition, patients also exhibit Sj€ ogren's syndrome, premature ovarian/gonad failure, anemia, diabetes, alopecia, vitiligo, gastritis, and autoimmune hepatitis (AIH), 1 the latter affecting up to 20% of APS-1 patients. 2

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis

“…Furthermore, druginduced immune-mediated liver injury has been associated with genetic predispositions [188][189][190][191][192][193][194] and molecular mimicries [27,185,195] that are reminiscent of the pathogenic mechanisms associated with idiopathic autoimmune hepatitis. Drug-metabolizing enzymes of the P450 cytochrome family have been the principal autoantigens implicated in type 2 autoimmune hepatitis (CYP2D6) [119], autoimmune-like hepatitis associated with tienilic acid (CYP2C9) [196,197], and autoimmune polyglandular syndrome type 1 which includes autoimmune hepatitis (CYP1A2, CYP2A6) [142,198,199]. Reactive drug metabolites that bind to proteins on the hepatocyte surface or to the enzymes that produce them can serve as haptens that generate antigenic complexes [195,[200][201][202].…”

Regulatory T-cell therapy for autoimmune and autoinflammatory diseases: The next frontier

“…88 The development of a preclinical model for AIH has been challenging. [91][92][93] AIRE-deficient mice have an AIH-like disease with autoantibodies and lymphoplasmatic and hepatic infiltrates. Treg cell numbers were decreased, and ACT of 8 3 10 5 polyclonal nonexpanded Treg cells reversed the AIH histological lesions.…”

Immunopathogenic Mechanisms of Autoimmune Hepatitis: How Much Do We Know from Animal Models?

“…Mice with a defect in the autoimmune-regulator ( AIRE ) gene also possess a defective central tolerance and develop a murine-autoimmune polyendocrine syndrome type 1 (APS-1). Among other autoimmune manifestations, such AIRE -deficient mice suffer from AIH and develop autoantibodies to a variety of liver autoantigens [116]. AIRE -deficient mice also displayed an elevated intrahepatic Treg frequency, which however was not sufficient to control AIH.…”

“…AIRE -deficient mice also displayed an elevated intrahepatic Treg frequency, which however was not sufficient to control AIH. In contrast, transfer of polyspecific Treg could ameliorate AIH [116]. …”