Screening patients with autoimmune endocrine disorders for cytokine autoantibodies reveals monogenic immune deficiencies

Autoantibodies targeting type I interferons: Prevalence, mechanisms of induction, and association with viral disease susceptibility

“…Defective AIRE therefore leads to loss of tolerance, and autoreactivity directed towards self-antigens, which includes a poorly understood dominance towards IFN-Is (particularly IFN-α/IFN-ω). Furthermore, genetic mutations in NFKB2, as well as other non-canonical NF-κB pathway genes (such as MAP3K14 (NIK) and RELB), have recently been identified in a number of patients who developed anti-IFN-I autoAbs [32][33][34][35][36][37]. Interestingly, NFKB2 is required for the correct expression of AIRE [38], and patients with defects in these non-canonical NF-κB pathway genes have a lower thymic expression of AIRE [37], again likely impacting the establishment of self-tolerance and promoting development of autoAbs, including those against IFN-Is.…”

“…A similar picture is noted in patients with mutations in RAG1/RAG2, who have a high prevalence of anti-IFN-I autoAbs [25], and who exhibit a disorganized thymus lacking AIRE expression in medullary thymic epithelial cells [39,40]. Along this theme, mutations in other genes that may impact different aspects of self-tolerance, the canonical NF-κB pathway, or B-cell/T-cell function have also been identified in patient cohorts with anti-IFN-I autoAbs, including FOXP3 [17], IKBKG (NEMO) [6], CTLA4 [36], and IKZF2 [36,41]. In addition, there is some evidence that specific HLA alleles and genetic variants can predispose to developing high-titer anti-IFN-I autoAbs (at least against IFN-β) in patients treated with IFN-β [42][43][44], which could relate to the resulting MHC class II molecules mis-presenting IFN-I-derived immunopeptides during the self-tolerance selection process.…”

“…Thus, an overall picture is emerging where genetic dysregulation of normal self-tolerance, particularly with regard to thymus function, is highly associated with development of anti-IFN-I autoAbs. Rare variants in other human genes, including in genes with known immuno-regulatory properties, have also been detected sporadically in patients with anti-IFN-I autoAbs [36,42], and a somatic gain-of-function mutation in JAK2 may have a protective role against the development of anti-IFN-I autoAbs under certain circumstances [20]. It will be critical to determine the spectrum of genetic susceptibility traits, either in tolerance-related genes or other currently-unappreciated pathways, that associate with development of anti-IFN-I autoAbs.…”

Diagnostic Accuracy of Methods for Detection of Antibodies against Type I Interferons in Patients with Endocrine Disorders

“…At the same time, the work on the development and implementation of screening tests for anti-cytokine antibodies, including antibodies against IFN-1 for patients with endocrine diseases, is in progress. For instance, recently Sjøgren et al using screening tests for auto-Abs against IFN-ω and interleukin-22 (IL-22) on a large cohort of patients with endocrine diseases, followed by subsequent genetic testing of positive samples, identified patients with undiagnosed APS-1 as well as several patients with previously unknown monogenic or oligogenic causes of organ-specific autoimmunity and immunodeficiency [14]. Identification of patients with endocrine autoimmune conditions is important to ensure targeted treatment and personalised follow-up aimed at preventing complications.…”

Diagnostic Accuracy of Methods for Detection of Antibodies against Type I Interferons in Patients with Endocrine Disorders

“…At the same time, the work on the development and implementation of screening tests for anti-cytokine antibodies, including antibodies against IFN-1 for patients with endocrine diseases, is in progress. For instance, recently Sjøgren et al using screening tests for auto-Abs against IFN-ω and interleukin-22 (IL-22) on a large cohort of patients with endocrine diseases, followed by subsequent genetic testing of positive samples, identified patients with undiagnosed APS-1 as well as several patients with previously unknown monogenic or oligogenic causes of organ-specific autoimmunity and immunodeficiency [15]. Identification of patients with endocrine autoimmune conditions is important to ensure targeted treatment and personalised follow-up aimed at preventing complications.…”