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.
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.
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.
Prevalence of high anti-cytokine autoantibodies.
Positive anti-cytokine autoantibody | All 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-GMCSF | 1^ (1.6%) | 1x (5%) | ||||
| Anti-IFNg | 2x (3.2%) | |||||
| Anti-IL12 | 2 (3.5%) | |||||
| Anti-IL23 | ||||||
| Anti-IFNa | 1^ (1.9%) | 1^ (6.25%) | ||||
| Anti-IFNw | 1^ (1.9%) | 1^ (6.25%) | ||||
| Anti-IFNL2 | 1 (1.8%) | 2^ (12.5%) | 1^ (6.25%) | |||
| Anti-IFNL3 | 1 (1.8%) | 1^ (6.25%) | 1^ (6.25%) | |||
| Anti-TNFa | 1 (1.9%) | 2 (3.5%) | 2 (12.5%) | |||
| Anti-TNFb | ||||||
| Anti-IL6 | 1 (6.25%) | |||||
| Anti-IL17A | ||||||
| Anti-IL10 | 1 (1.8%) | |||||
| Anti-IL22 | 1 (1.8%) |
Positive anti-cytokine autoantibody | All 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-GMCSF | 1^ (1.6%) | 1x (5%) | ||||
| Anti-IFNg | 2x (3.2%) | |||||
| Anti-IL12 | 2 (3.5%) | |||||
| Anti-IL23 | ||||||
| Anti-IFNa | 1^ (1.9%) | 1^ (6.25%) | ||||
| Anti-IFNw | 1^ (1.9%) | 1^ (6.25%) | ||||
| Anti-IFNL2 | 1 (1.8%) | 2^ (12.5%) | 1^ (6.25%) | |||
| Anti-IFNL3 | 1 (1.8%) | 1^ (6.25%) | 1^ (6.25%) | |||
| Anti-TNFa | 1 (1.9%) | 2 (3.5%) | 2 (12.5%) | |||
| Anti-TNFb | ||||||
| Anti-IL6 | 1 (6.25%) | |||||
| Anti-IL17A | ||||||
| Anti-IL10 | 1 (1.8%) | |||||
| Anti-IL22 | 1 (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.
Non-neutralizing binding antibodies.
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.
