Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-γ

Abstract

Genetic defects in the IFN-γ response pathway cause unique susceptibility to intracellular pathogens, particularly mycobacteria, but are rare and do not explain mycobacterial disease in the majority of affected patients. We postulated that acquired defects in macrophage activation by IFN-γ may cause a similar immunological phenotype and thus explain the occurrence of disseminated intracellular infections in some patients without identifiable immune deficiency. Macrophage activation in response to IFN-γ and IFN-γ production were studied in whole blood and PBMCs of 3 patients with severe, unexplained nontuberculous mycobacterial infection. In all 3 patients, IFN-γ was undetectable following mitogen stimulation of whole blood, but significant quantities were detectable in the supernatants of PBMCs when stimulated in the absence of the patients' own plasma. The patients' plasma inhibited the ability of IFN-γ to increase production of TNF-α by both autologous and normal donor PBMCs, and recovery of exogenous IFN-γ from the patients' plasma was greatly reduced. Using affinity chromatography, surface-enhanced laser desorption/ionization mass spectrometry, and sequencing, we isolated an IFN-γ-neutralizing factor from the patients' plasma and showed it to be an autoantibody against IFN-γ. The purified anti-IFN-γ antibody was shown to be functional first in blocking the upregulation of TNF-α production in response to endotoxin; second in blocking induction of IFN-γ-inducible genes (according to results of high-density cDNA microarrays); and third in inhibiting upregulation of HLA class II expression on PBMCs. Acquired defects in the IFN-γ pathway may explain unusual susceptibility to intracellular pathogens in other patients without underlying, genetically determined immunological defects.

Anti–IFN-γ autoantibodies in adults with disseminated nontuberculous mycobacterial infections are associated with HLA-DRB1*16:02 and HLA-DQB1*05:02 and the reactivation of latent varicella-zoster virus infection

“…Second, 35% of our patients were coinfected with salmonellosis, a phenotype that is mainly observed in patients who have Mendelian susceptibility to mycobacterial disease (MSMD), 30 but is not typically observed in patients with anti-IFN-␥ autoantibodies. 7,9,11 Third, a high proportion (71%) of our patients suffered from the reactivation of latent VZV infection, a phenotype rarely reported in either MSMD patients or in patients with anti-IFN-␥ autoantibodies. [7][8][9][10][11][12][13]30 Finally and most importantly, 2 HLA alleles, DRB1*16:02 and DQB1*05:02, occurred with unexpectedly high frequencies among our patients.…”

“…[4][5][6][7][8][9] In cases with anti-IFN-␥ autoantibody expression, disseminated NTM (dNTM) infection is the most common clinical presentation. [7][8][9][10][11][12][13] The majority of patients with anticytokine autoantibodies have associated comorbidities, either neoplastic or autoimmune. 4,9,14,15 These comorbidities and their associated therapies may render patients more susceptible to infectious diseases.…”

Anti-cytokine autoantibodies are associated with opportunistic infection in patients with thymic neoplasia

“…Pulmonary alveolar proteinosis, 1,2,34 pure red cell aplasia, 3,4 and mycobacterial disease from anti-IFN-␥ autoantibodies [5][6][7][8] demonstrate clear relationships between autoantibodies and disease. The spectrum of infections we identified in thymic neoplasm suggests that combinations of different autoantibodies may contribute to unique patterns of susceptibility.…”

“…[5][6][7][8] Anticytokine autoantibodies may also have benefits, such as dampening inflammation through neutralizing anti-tumor necrosis factor-␣ (anti-TNF-␣) autoantibodies in rheumatoid arthritis. 9 However, there has been no comprehensive method to detect the prevalence and functional significance of anti-cytokine autoantibodies.…”

Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes

“…Above a certain threshold, aAb may render the individual deficient of the given growth factor or cytokine, however, in most cases, without overt clinical manifestations (Ross et al 1997). Exceptions are: 1) granulocyte-macrophage colony-stimulating factor aAb that plays a role in pulmonary alveolar proteinosis (Uchida et al 2007), 2) interferon-g aAbs that lead to susceptibility to certain infections (Madariaga et al 1998, Hoflich et al 2004, Kampmann et al 2005, Patel et al 2005, and 3) aAb-IL6 that are being associated with recurrent staphylococcal cellulitis and subcutaneous abscesses (Puel et al 2008).…”