Autoantibodies against Interferons underlying Infectious Diseases – AI2D

There is a vast clinical variability among infected individuals, ranging from silent infection to lethal disease. There is also an age-dependent U-shape prevalence curve of life-threatening infections, with children and elderly being most vulnerable. Several inborn errors of cytokines or their response pathway, typically described in young patients, disrupt immunity to specific microorganisms. Neutralizing autoantibodies (auto-Ab) against cytokines, typically in older patients, are clinical phenocopies of the corresponding inborn errors. The emblematic example is provided by auto-Abs neutralizing type I or type II interferons (IFNs), which mimic rarer inborn errors of type I or II IFNs. While auto-Abs to type II IFNs underlie severe mycobacterial diseases, auto-Abs to type I IFNs underlie critical COVID-19 pneumonia. The causes, the prevalence in patients with a given infection and in the general population, the longitudinal course in life, the biochemical nature and diversity, the T and B cell epitopes, and the clinical consequences of these auto-Abs, remain largely unknown. We hypothesize that (i) neutralizing auto-Abs to IFNs are associated with specific T and B cell epitopes, (ii) their causes can be genetic, and (iii) their consequences can be more diverse than appreciated. Our aims are to: (i) characterize the immunological bases of these auto-Abs, by studying autoreactive T and B cells, and identifying their respective epitopes; (ii) to search for germline or somatic genetic causes of these auto-Abs; (iii) to identify new infectious phenotypes for neutralizing anti-IFN auto-Abs in our unique international cohort of ~13,000 patients with unexplained viral, mycobacterial, or other infectious diseases. Our project will provide novel and unique insights into the mechanisms by which human autoimmunity can paradoxically underlie infectious diseases. It will facilitate precision medicine, in terms of diagnosis, counselling, prevention, and treatment.