Anti-cytokine autoantibodies in infectious diseases

Cytokines serve as critical effector molecules in immune responses against infection. Inherited mutations that disrupt transcription factors or cell surface receptors involved in IL-12/IFN-γ signalling result in susceptibility to non-tuberculous mycobacterial (NTM) infection and provide vivid confirmation of the importance of these pathways. Similarly, monoclonal anti-cytokine antibodies that target TNF-α have established efficacy in the treatment of rheumatoid arthritis and ankylosing spondylitis, but are associated with increased risk of severe mycobacterial, bacterial and fungal infections. Transient non-pathogenic autoantibodies against cytokines have been reported during acute viral and bacterial infections. Over the past decade, pathogenic high-titre autoantibodies against key cytokines have been increasingly reported in adults with atypical patterns of clinical infection. As an example, autoantibodies against IFN-γ have been identified that result in predisposition to more severe and resistant NTM disease. Similarly, anti-GM-CSF autoantibodies have been described in cryptococcal meningitis. In the appropriate clinical context, anti-cytokine autoantibodies may be detected by in-house methodologies that include ELISA and multiplex bead arrays. Ideally, these diagnostic tests should be run in parallel with functional studies to confirm disruption of the involved signaling pathways. Ultimately, screening and detection of anti-cytokine autoantibodies may clarify the pathophysiology for certain clinical infections and facilitate targeted therapy.