We enrolled 212 patients into five groups: including those with disseminated nontuberculous mycobacterial disease, severe opportunistic infections, pulmonary tuberculosis, disseminated tuberculosis, and normals. We identified anti-interferon gamma autoantibodies in approximately 90% of those with severe opportunistic infections. All these patients were HIV uninfected and had no other recognized cause of immune dysfunction. Interestingly, one patient with cryptococcal meningitis had anti-GM-CSF autoantibodies. Therefore, we have shown in a large cohort of patients in Thailand and Taiwan with severe opportunistic infections, including nontuberculous mycobacteria, that autoantibodies to interferon gamma account for the defect and reproduce a state of severe immunodeficiency. As a result of this project and in order to extend these diagnostic opportunities to the field, we have developed a simple screening assay for anti-interferon gamma autoantibodies that will allow us to identify, follow, and titer activity. The recognition of anti-interferon gamma autoantibodies as the cause of severe opportunistic infections has led to the use of rituximab for control of their antibodies and therefore their infections. We are now engaged in characterizing the epitope or epitopes that are being recognized by these autoantibodies. We have also identified autoantibodies to GM-CSF in Cryptococcus gattii infection and extra pulmonary Nocardia infection

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Holland, Steven M; Pierce, Virginia M; Shailam, Randheer et al. (2017) Case 28-2017. A 13-Month-Old Girl with Pneumonia and a 33-Year-Old Woman with Hip Pain. N Engl J Med 377:1077-1091
Marciano, Beatriz E; Holland, Steven M (2017) Primary Immunodeficiency Diseases: Current and Emerging Therapeutics. Front Immunol 8:937
Crum-Cianflone, Nancy F; Lam, Pamela V; Ross-Walker, Sarah et al. (2017) Autoantibodies to Granulocyte-Macrophage Colony-Stimulating Factor Associated With Severe and Unusual Manifestations of Cryptococcus gattii Infections. Open Forum Infect Dis 4:ofx211
Ku, Cheng-Lung; Lin, Chia-Hao; Chang, Su-Wei et al. (2016) Anti-IFN-? autoantibodies are strongly associated with HLA-DR*15:02/16:02 and HLA-DQ*05:01/05:02 across Southeast Asia. J Allergy Clin Immunol 137:945-8.e8
Xie, Yingda L; Chen, Ray Y; Sereti, Irini et al. (2016) Reply to Tham et al. Clin Infect Dis 63:573-4
Xie, Yingda L; Rosen, Lindsey B; Sereti, Irini et al. (2016) Severe Paradoxical Reaction During Treatment of Disseminated Tuberculosis in a Patient With Neutralizing Anti-IFN? Autoantibodies. Clin Infect Dis 62:770-773
Wu, Un-In; Holland, Steven M (2016) A genetic perspective on granulomatous diseases with an emphasis on mycobacterial infections. Semin Immunopathol 38:199-212
Szymanski, Eva P; Leung, Janice M; Fowler, Cedar J et al. (2015) Pulmonary Nontuberculous Mycobacterial Infection. A Multisystem, Multigenic Disease. Am J Respir Crit Care Med 192:618-28
Burbelo, Peter D; Keller, Jason; Wagner, Jason et al. (2015) Serological diagnosis of pulmonary Mycobacterium tuberculosis infection by LIPS using a multiple antigen mixture. BMC Microbiol 15:205
Martinez, Bianca; Browne, Sarah K (2014) Good syndrome, bad problem. Front Oncol 4:307

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