Characteristics and Clinical Implications of Anti-IFN- cytokine antibodies in partial Recombinase Activating Gene Deficiency patients before and during the COVID-19 Pandemic

Introduction: With the onset of the COVID-19 pandemic, there was increased attention on anti- IFN-α autoantibodies and its correlation with severe clinical outcomes in a large group of patients. However, this correlation has not been extensively investigated in patients with partial Recombinase Activating Gene Deficiency (pRD) who are known to have increased prevalence of anti- IFN-α autoantibodies. Therefore, there is a need to assess the presence of anti- IFN-α antibodies in pRD patients before and after the COVID-19 pandemic and explore the relationship between anti- IFN-α antibody presence and clinical outcomes. Sera was collected from the whole blood after informed consent and Enzyme-Linked Immunosorbent Assay was conducted to confirm the presence of IgG-specific anti- IFN-α autoantibodies. Positive samples were determined as OD values above 3 standard deviations of the healthy donor OD mean. Our cohort included both adult (n = 13) and pediatric (n = 9) patients with variants in RAG1 and RAG2. Eleven patients (50%) out of the 22 showed elevated anti- IFN-α autoantibodies levels. Five patients (23%) were defined as low positive for anti- IFN-α autoantibodies, and 6 patients had no autoantibody titers. Of the 22 patients, 16 were symptomatic with infectious and non-infectious complications including recurrent viral and/or bacterial infections, autoimmune cytopenias, and lymphoproliferation. Ten (63%) of the symptomatic patients demonstrated high anti-IFN-α autoantibodies titers. Of the 11 patients with no or low neutralizing anti- IFN-α autoantibodies levels, 5 were asymptomatic. In temporal comparison, 16 samples were collected pre-COVID-19 pandemic; 8 samples were collected during the pandemic, 2 of which belonged to patients with samples collected before and during the pandemic. In the pre-pandemic cohort, 66% had anti- IFN-α autoantibodies. Conversely, during the COVID-19 pandemic, 89% had anti- IFN-α autoantibodies. Of note, one patient who had neutralizing anti- IFN-α autoantibodies remained positive both before and during the pandemic despite HSCT. Patient also had a SARS-CoV-2 infection in summer of 2022 with a mild clinical course. Conclusions & Next Steps: We observed persistence of anti-IFN-α autoantibodies in our cohort post-pandemic and even post-HSCT. It is unclear whether the presence of anti-cytokine antibodies are risk factor for severe COVID-19.