Detection of Anticytokine Autoantibodies and Clinical Applications

Abstract

Anticytokine autoantibodies are an emerging mechanism of disease pathogenesis that have been shown to elicit a broad range of clinical phenotypes. Some anticytokine autoantibodies can lead to immune susceptibility, with examples including nontuberculous mycobacteria, salmonellae, or fungi due to autoantibodies against gamma interferon (IFN-γ) (1); staphylococcal infection due to anti-interleukin-6 (IL-6) autoantibodies (2); Burkholderia gladioli infection due to anti-IL-12p70 autoantibodies (3); chronic mucocutaneous candidiasis due to anti-IL-17 and anti-IL-22 autoantibodies (4, 5); and cryptococcal meningitis (6) or Nocardia infection due to anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies (7). Other diseases in which immunodeficiency is not the primary presentation include the severe lung disease pulmonary alveolar proteinosis (PAP) caused by anti-GM-CSF autoantibodies; pure red cell aplasia (8); pure red-cell aplasia due to antierythropoietin autoantibodies (9); and severe osteoporosis associated with antiosteoprotegerin autoantibodies (10). For other anticytokine autoantibodies, such as anti-IFN-α autoantibodies detected in thymoma or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome, their biological effect is not immediately apparent (11). Diagnosis has important implications for management because therapies can be used to directly target the underlying mechanism, i.e., a neutralizing antibody, and not just their ultimate clinical consequences, with approaches such as B-cell depletion (12–14) or receptor agonists (15).