Clinical implications of interferon-γ genetic and epigenetic variants

Interferon-γ (IFN-γ) is an integral and critical molecule of the immune system, with multiple functions, mostly related to the T helper type 1 (Th1) response to infection. It is critical for defence against mycobacterial infection and is of increasing interest in defence against fungi. In this article, we review the genetic and epigenetic variants affecting IFN-γ expression and investigate its role in disease, with an emphasis on fungal diseases such as invasive and chronic pulmonary aspergillosis. Over 347 IFN-γ gene variants have been described, in multiple ethnic populations. Many appear to confer a susceptibility to disease, especially tuberculosis (TB) and hepatitis, but also some non-infectious conditions such as aplastic anaemia, cervical cancer and psoriasis. Several epigenetic modifications are also described, increasing IFN-γ expression in Th1 lymphocytes and reducing IFN-γ expression in Th2 lymphocytes. Recombinant IFN-γ administration is licensed for the prophylaxis of infection (bacterial and fungal) in patients with the phagocyte functional deficiency syndrome chronic granulomatous disease, although the benefits appear limited. Interferon-γ therapy is given to patients with profound defects in IFN-γ and interleukin-12 production and appears to be beneficial for patients with invasive aspergillosis and cryptococcal meningitis, but the studies are not definitive. A high proportion of patients with chronic pulmonary aspergillosis are poor producers of IFN-γ in response to multiple stimuli and could also benefit from IFN-γ administration. The investigation and management of patients with possible or demonstrated IFN-γ deficiency in adulthood is poorly studied and could be greatly enhanced with the integration of genetic data.