Aire is not essential for regulating neuroinflammatory disease in mice transgenic for human autoimmune-diseases associated MHC class II genes HLA-DR2b and HLA-DR4.

The human autoimmune disease-associated HLA alleles HLA-DR2b (DRB1*1501) and HLA-DR4 (DRB1*0401) are strongly linked to increased susceptibility for multiple sclerosis (MS) and rheumatoid arthritis (RA), respectively. The underlying mechanisms are not fully understood, but these MHC alleles may shape the repertoire of pathogenic T cells via central tolerance. The transcription factor autoimmune regulator (AIRE) promotes central T cell tolerance via ectopic expression of tissue-specific antigens (TSAs). Aire deficiency in humans causes autoimmune polyendocrinopathy syndrome type 1 (APS1), and Aire knockout mice (Aire-/-) develop spontaneous autoimmune pathology characterized by multi-organ lymphocytic infiltrates. Here, we asked whether impaired TSAs gene expression in the absence of Aire promoted spontaneous MS- or RA-like autoimmune pathology in the context of human HLA alleles in HLA-DR2b or HLA-DR4 transgenic (tg) mice. The results show that reduced TSAs gene expression in the thymus of Aire-deficient HLA-DR2b or HLA-DR4 tg mice corresponded to mild spontaneous inflammatory infiltrates in salivary glands, liver, and pancreas. Moreover, Aire-deficiency modestly enhanced experimental autoimmune encephalomyelitis (EAE) in HLA-DR tg mice, but the animals did not show signs of spontaneous neuroinflammation or arthritis. No significant changes were observed in CD4+ T cell numbers, T cell receptor (TCR) distribution, regulatory T cells (Treg), or antigen-induced cytokine production. Abrogating Treg function by treatment with anti-CTLA-4 or anti-CD25 mAb in Aire-deficient HLA-DR tg mice did not trigger EAE or other autoimmune pathology. Our results suggest a redundant role for Aire in maintaining immune tolerance in the context of autoimmune disease-associated human HLA alleles.

Nalawade SA ，Ji N ，Raphael I ，Pratt A 3rd ，Kraig E ，Forsthuber TG ... -  《-》

HLA-DR4-IE chimeric class II transgenic, murine class II-deficient mice are susceptible to experimental allergic encephalomyelitis.

Ito K ，Bian HJ ，Molina M ，Han J ，Magram J ，Saar E ，Belunis C ，Bolin DR ，Arceo R ，Campbell R ，Falcioni F ，Vidović D ，Hammer J ，Nagy ZA ... -  《-》

Small molecule inhibitor of antigen binding and presentation by HLA-DR2b as a therapeutic strategy for the treatment of multiple sclerosis.

Ji N ，Somanaboeina A ，Dixit A ，Kawamura K ，Hayward NJ ，Self C ，Olson GL ，Forsthuber TG ... -  《-》

A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor.

Madsen LS ，Andersson EC ，Jansson L ，krogsgaard M ，Andersen CB ，Engberg J ，Strominger JL ，Svejgaard A ，Hjorth JP ，Holmdahl R ，Wucherpfennig KW ，Fugger L ... -  《NATURE GENETICS》

Humanized transgenic mice expressing HLA DR4-DQ3 haplotype: reconstitution of phenotype and HLA-restricted T-cell responses.

Chen Z ，de Kauwe AL ，Keech C ，Wijburg O ，Simpfendorfer K ，Alexander WS ，McCluskey J ... -  《-》