Anti-interferon-gamma autoantibodies cause adult-onset immunodeficiency disease similar to patients with advanced HIV infection

Work by Browne, S. K. et al (2012) showed that anti–interferon (IFN)-gamma autoantibodies found in a group of Asian adults with disseminated nontuberculous mycobacterial infection, alone or with another opportunistic infection, had an adult-onset immunodeficiency disease similar in nature to that seen in patients with advanced HIV infection. The cause of the anti-interferon-gamma autoantibodies appeared unrelated to a singular genetic predisposition and the authors speculate that an environmental factor or opportunistic infection could be the trigger.

Naturally occurring autoantibodies against human cytokines  including Interleukin (IL)-1 alpha, tumor necrosis factor-alpha, IFN-alpha, IL-2, and IL-6, have been reported and shown to cause such illnesses as pemphigus, myasthenia gravis and Graves’ disease. It is speculated anti-cytokine atibodies may serve as carriers that lengthen the serum half-life of their respective cytokine or act as delivery vehicles  to transport the cytokine a specific cell target. Others speculate that binding of a cytokine–immunoglobulin complex to the infected cell may trigger complement-mediated cytotoxicity that kills infected cell and at same time enhances local immune effector cell function and traffiking.

Clues as to the cause of anti-cytokine autoantibody can be found in such observations as anti-cytokine antibodies are prevalent in certain disease states, including rheumatoid arthritis (IL-1 alpha IFN-a), systemic sclerosis (IL-6), gram-negative bacterial septicemia (TNF-a) and HIV (IL-2). It is thought some form of viral or bacterial antigenic mimicry may occur in these disease states which triggers the production anti-cytokine antibodies. Becasue patients in the present study had anti-IFN-gamma IgG antibodies and not IgM antibodies, this strongly suggest that the trigger arose from chronic exposure to an environmental factor or from a chronic underlying infection. What is puzzling to immunologist is that these anti-cytokine antibodies, including ones found in this current report, are often of  high affinity and have cyokine-neutralizing activities. Their occurrence is in direct conflict with that of a healthy, functioning  immune system, namely have cytokines fight infection.

Since nontuberculous mycobacterial infection was found in 88% of affected indivuduals this could be where the anti-interferon-gamma antibody trigger lies.

Browne, SK et al “Adult-onset immunodeficiency in Thailand and Taiwan” N Engl J Med. 2012 Aug 23;367(8):725-34

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