B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients

Abstract

Autoimmune regulator (Aire)-deficient mice and humans have circulating autoantibodies against a multitude of organs and multiorgan autoinflammatory infiltrates. It is not known to what extent autoantibodies or their source, B lymphocytes, are required for disease onset or progression. We show in this research that B cells must be present for Aire-deficient mice to develop fulminant infiltrates. We found no evidence that autoantibodies were directly pathogenic; rather, B cells appeared to play a critical early role in T cell priming or expansion. A therapeutic reagent directed against B cells, Rituximab, induced remission of the autoimmune disease in Aire-deficient mice, raising the hope of applying it to human patients with autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).autoimmunity ͉ B lymphocytes ͉ tolerance ͉ autoantibody

Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4+ T helper type 1 subset differentiation

“…58 In many models of autoimmunity it is evident that B cell APC function is required for the optimal induction of autoreactive CD4 + T cell responses. [10][11][12][13][14][15][16][17] Of particular interest to this study, is the demonstration that antigenspecific transgenic B cells (incapable of antibody secretion) are required for optimal anti-aggrecan CD4 + T cell activation. 14 Additionally, mice with a B cell-restricted deficiency in the CD80/86 co-stimulatory molecules 16 show reduced susceptibility to PGIA.…”

“…[7][8][9] In the context of autoimmunity, autoantigen-specific B cells have been shown to activate autoreactive CD4 + T cells. [10][11][12][13][14][15][16][17] These findings have led to the development of…”

Mendelian Genetics of Human Susceptibility to Fungal Infection

“…Similar autoantibodies were identified in thymoma patients who also developed CMC (Tarr et al 2001;Kisand et al 2010), suggesting that CMC susceptibility in APECED may have an autoimmune basis. Based on that, B-cell-depleting treatment with rituximab, which was effective in amelioration of autoimmunity in Aire-deficient mice (Gavanescu et al 2008), has been used in APECED patients with varying success (Popler et al 2012). In addition, immunosuppression with tacrolimus and other lymphocyte immunomodulatory agents has been used to treat patients, with reported improvement of CMC (Ulinski et al 2006).…”

Ovarian autoimmune disease: clinical concepts and animal models

“…Experiments in mice have verified the importance of autoreactive T cells; adoptive transfer of these CD4 1 T cells, but not CD8 1 or B cells/serum alone, from AIRE-deficient mice confers autoimmune disease in immunodeficient animals. 94,95 Aire and ovarian autoimmune disease Gonadal insufficiency, albeit not life-threatening in itself, is one of the most common manifestations in female APS-1 patients. Likewise, female mice with targeted Aire deficiency display varying degrees of infertility depending on the genetic background.…”