Autoantibody Repertoire in APECED Patients Targets Two Distinct Subgroups of Proteins

Abstract

High titer autoantibodies produced by B lymphocytes are clinically important features of many common autoimmune diseases. APECED patients with deficient autoimmune regulator (AIRE) gene collectively display a broad repertoire of high titer autoantibodies, including some which are pathognomonic for major autoimmune diseases. AIRE deficiency severely reduces thymic expression of gene-products ordinarily restricted to discrete peripheral tissues, and developing T cells reactive to those gene-products are not inactivated during their development. However, the extent of the autoantibody repertoire in APECED and its relation to thymic expression of self-antigens are unclear. We here undertook a broad protein array approach to assess autoantibody repertoire in APECED patients. Our results show that in addition to shared autoantigen reactivities, APECED patients display high inter-individual variation in their autoantigen profiles, which collectively are enriched in evolutionarily conserved, cytosolic and nuclear phosphoproteins. The APECED autoantigens have two major origins; proteins expressed in thymic medullary epithelial cells and proteins expressed in lymphoid cells. These findings support the hypothesis that specific protein properties strongly contribute to the etiology of B cell autoimmunity.

Type I interferons in host defence and inflammatory diseases

“…Paradoxically, it is not clear that MS and SLE have ever been described, and the other two conditions are more rare in AIRE-deficient individuals than might have been expected. Casting light on this, Meyer et al 87 performed protoarray analyses and additional techniques to investigate sera from patients with APS-1 and controls 87 88. In addition to global loss of T cell tolerance, patients with APS-1 had two types of B cell dysregulation: (1) diverse or ‘private’ reactivities of up to 100 diverse gene products, many of which were AIRE regulated; and (2) shared reactivities to steroidogenic enzymes and selected cytokines, none of which were obviously AIRE regulated.…”

Identification of novel, clinically correlated autoantigens in the monogenic autoimmune syndrome APS1 by PhIP-Seq

“…there have been rapid advances in large platform approaches for antibody screening; these 90 platforms can overcome problems of antigen abundance by simultaneously screening the majority 91 of proteins from the human genome in an unbiased fashion (Jeong et al, 2012;Larman et al, 2011;92 Sharon & Snyder, 2014; Zhu et al, 2001). In particular, a higher-throughput antibody target 93 profiling approach utilizing a fixed protein microarray technology (ProtoArray) has enabled 94 detection of a wider range of proteins targeted by autoantibodies directly from human serum 95 (Fishman et al, 2017;Landegren et al, 2016;Meyer et al, 2016). Despite initial success of this 96 technology in uncovering shared antigens across APS1 cohorts, it is likely that many shared 97 antigens remain to be discovered, given that these arrays do not encompass the full coding potential 98 of the proteome.…”

Neutralizing Anti-Cytokine Autoantibodies Against Interferon-α in Immunodysregulation Polyendocrinopathy Enteropathy X-Linked

“…Thus, AIRE serves as a key gene in T cell negative selection. APS-1 patients mount autoantibodies to a variety of different antigens ( 14 , 15 ), but why all APS-1 patients mount autoantibodies against type I IFNs with nearly 100% specificity is an enigma. The in vivo consequences of ACAAs against type I IFNs in APS-1 are equally unclear, as APS-1 patients do not suffer increased frequencies of viral infections.…”