Novel Defects in Host Defense Evinced As Nontuberculous Mycobacterial and Dimorphic Mold Infections: GATA2 Deficiency, STAT1 Mutations, Anticytokine Autoantibodies

Abstract SCI-20

Nontuberculous mycobacteria are relatively ubiquitous organisms of low virulence, disseminated infection with which suggests an underlying defect in host defense. Dimorphic molds (e.g., histoplasmosis, coccidioidomycosis, penicilliosis) are regionally limited and cause severe infections only in the immune compromised. We have focused on severe cases of these infections to identify genetic and acquired syndromes of immune deficiency that have not been previously recognized. 1. The syndrome of monocytopenia, NK, and B cell lymphopenia and lack of circulating dendritic cells is associated with severe infections with mycobacteria, dimorphic molds, human papilloma virus, and molluscum cantagiosum. These patients also develop myelodysplasia and pulmonary alveolar proteinosis and may progress to frank leukemia. Mutations in GATA2 are responsible for the syndrome (monoMAC for monocytopenia and M. avium complex infection). Hematopathologically, patients have micromegakaryocytes and cytogenetic abnormalities, most commonly monosomy 7 and trisomy 8. Both protein-positive and protein-negative heterozygous mutations have been identified, suggesting that haploinsufficiency is a unifying cause of disease. The spectrum of pathologic mutations is broad and likely extends into phenotypes that are distinct from those recognized initially. 2. Mutations in STAT1 have been associated with mycobacterial disease (dominant negative inhibitory), fatal viral and bacterial disease (recessive), and mucocutaneous candidiasis (dominant gain of function). We have identified distinct and independent STAT1 mutations in three patients that have led to severe, refractory disseminated coccidioidomycosis or histoplasmosis. These mutations lead to hypomethylation of STAT1, which leads to its persistent hyperphosphorylation, and impairment of restimulation activity. These mutations are important because they lie in the same plane of the molecule and cause severe invasive dimorphic yeast infections. 3. Autoantibodies are common, especially in adult women. We have previously recognized East Asia-born adult women living in the United States who have high titer autoantibodies to interferon gamma (IFNγ). We have recently recognized large cohorts of similar patients in Thailand and Taiwan and conducted a prospective trial of their phenotype and the presence and type of anti-IFNγ autoantibodies. We found a significant population of patients with disseminated nontuberculous mycobacterial infections (but not tuberculosis), salmonella, cryptococcosis, histoplasmosis, or varicella zoster in Asia whose sole identifiable risk factor was extremely elevated anti-IFNγ autoantibodies. We have characterized the severity of the blockade and the subclass of the antibodies and explored the rate in several control populations as well. These apparently adult-onset acquired autoantibodies profoundly inhibit IFNγ signaling, leading to infections with IFNγ-responsive organisms. These emerging syndromes cross the lines of infectious disease, cancer, and rheumatology.