Anti-Cytokine Autoantibodies in Inborn Errors of Immunity with Immune Dysregulation

Introduction Anti-cytokine autoantibodies can guide understanding of disease pathogenesis, diagnosis, and treatment. Examples include anti-interferon (IFN) gamma in disseminated nontuberculous mycobacterial infection; anti-GMCSF in pulmonary alveolar proteinosis, disseminated nocardiosis, and cryptococcal meningitis; and anti-IFN alpha autoantibodies exacerbating SARS-Cov-2 (COVID-19) infection. We sought anti-cytokine autoantibodies in inborn errors of immunity (IEI) patients with immune dysregulatory features. Methods We tested the serum of patients with STAT1 gain of function (GOF) (N = 53), DOCK8 deficiency (N = 57), CTLA4 haploinsufficiency (N = 16), and WAS (N = 16) for anti-cytokine autoantibodies using a 21-cytokine panel via a Luminex bead–based multiplex immunoassay. Those with high levels of autoantibodies were assessed for neutralizing activity by flow cytometry if available. Results Patients had more anti-cytokine antibodies of a wider variety than healthy controls (N = 62) despite being younger. Neutralizing anti-GMCSF autoantibodies were found in 1/62 healthy controls, while 2/62 had high non-neutralizing anti-IFNg antibodies. In contrast, high levels of neutralizing anti-IFNa and anti-IFNw antibodies were found in two patients (STAT1 GOF and CTLA4 haploinsufficiency), while neutralizing anti-IFN-lambda2 and anti-IFN-lambda3 antibodies were found in three patients (two WAS and one CTLA4 haploinsufficiency). High levels of different anti-cytokine autoantibodies were detected in 2/16 CTLA4 patients, 2/53 STAT1 GOF patients, 3/16 WAS patients, and 4/57 DOCK8 deficiency patients (see Table 1). Some patients had more than one type of anti-cytokine autoantibodies. Table 1.Prevalence of high anti-cytokine autoantibodies.Positive anti-cytokine autoantibodyAll Healthy Controls (N = 62)Young Healthy Controls (<40y) (subset, N = 21)STAT1 GOF (N = 53)DOCK8 (N = 57)WAS (N = 16)CTLA4 (N = 16)Any high positive N (%)3 (4.8%)1 (5%)2 (3.8%)4 (7.0%)3 (18.8%)2 (12.5%)Anti-GMCSF1^ (1.6%)1x (5%)Anti-IFNg2x (3.2%)Anti-IL122 (3.5%)Anti-IL23Anti-IFNa1^ (1.9%)1^ (6.25%)Anti-IFNw1^ (1.9%)1^ (6.25%)Anti-IFNL21 (1.8%)2^ (12.5%)1^ (6.25%)Anti-IFNL31 (1.8%)1^ (6.25%)1^ (6.25%)Anti-TNFa1 (1.9%)2 (3.5%)2 (12.5%)Anti-TNFbAnti-IL61 (6.25%)Anti-IL17AAnti-IL101 (1.8%)Anti-IL221 (1.8%)High levels of anti-cytokine autoantibodies (median fluorescence intensity >5,000) were detected in some patients with inborn errors of immunity. All values are expressed in number (%).^Neutralizing antibodies.xNon-neutralizing binding antibodies. Conclusions Patients with IEI and immune dysregulation had more anti-cytokine autoantibodies than healthy controls and of a wider variety. Different IEIs had different anti-cytokine autoantibodies, suggesting disease-specific patterns of anti-cytokine autoantibodies. The contributions of these and other autoantibodies to the clinical presentations and outcomes will be important to determine prospectively in future immune deficiency and other cohorts.