Interferon gamma autoantibodies associated with susceptibility to disseminated mycobacterial infections

Abstract

Disseminated non-tuberculous mycobacterial (NTM) infections typically occur in the context of iatrogenic immunosuppression or inherited genetic mutations. Rarely, cytokine-specific autoantibodies have also been described in patients with disseminated infections. Here, we present two cases of disseminated NTM infection in unrelated healthy adult females associated with autoantibodies to interferon-gamma (IFN-γ). The two HIV-negative patients had Mycobacterium avium and Mycobacterium abscessus infections, respectively, that presented as subacute multifocal bone, lung and lymph node involvement. Routine studies revealed normal immunoglobulin concentrations, T-cell proliferation to mitogens and granulocyte oxidative burst. Blood mononuclear cell stimulation analyses with cytokine bead array revealed normal IL-12p40 production and IFN-γ production in response to exogenous IL-12. Both patients had normal tumour necrosis factor-α (TNF-α) production in response to IFN-γ that was remarkably abrogated in the presence of autologous serum. By ELISA, both patients had high titre (>1:5000) anti-IFN-γ IgG in the serum. The patients' IgG inhibited IFN-γ-induced MHC class II protein upregulation on CD14 + monocytes. Targeted B cell depletion with rituximab has started for one patient. Autoantibodies against cytokines may disrupt normal immunity and predispose to more severe and resistant NTM disease. In the latter circumstances, screening for anti-IFN-γ autoantibodies may clarify the pathophysiology and allow targeted therapy.