Immunodeficiency and Autoantibodies to Cytokines

Anti-cytokine autoantibodies (AAbs) associated with an infectious phenotype are now included along with anti-complement AAbs and somatic pathogenic gene variants as a distinct category termed 'phenocopies of primary immunodeficiencies' in the classification of inborn errors of immunity. Anti-cytokine AAbs target specific cytokine pathways, leading to inordinate susceptibility to specific organisms, generally in the setting of immunocompetence.

Anti-cytokine AAbs are detected in the majority of healthy individuals and may play a regulatory role in limiting exaggerated responses to cytokines. While it is not well understood why some individuals with anti-cytokine AAbs develop increased susceptibility to organisms of low pathogenicity and others do not, it is likely that genetics and environment play a role. To date, AAbs to interferon gamma (IFNγ), interferon alpha (IFNα), interleukins-17 and 22 (IL-17/IL-22), interleukin-6 and granulocyte macrophage colony stimulating factor (GM-CSF) and their association with increased susceptibility to nontuberculous mycobacteria and other intracellular organisms, viral infections, Candida albicans, Staphylococcus aureus and other pyogenic organisms, and fungal infections respectively, have been described. The clinical phenotype of these patients is very similar to that of individuals with pathogenic gene variants in the specific cytokine pathway that the autoantibody targets, hence the term 'phenocopy.' Recognition of anti-cytokine AAbs as a distinct cause of immunodeficiency or immune dysregulation is important for appropriate management of such patients.

Understanding the roles that anti-cytokine AAbs play in health and disease continues to be a fascinating area of research. Evaluating generally immunocompetent individuals who present with chronic, treatment refractory, or unusual infections for anti-cytokine AAbs is critical as it may direct therapy and disease management.