Neutralizing antiinterferon-γ autoantibodies causing disseminated Mycobacterium avium complex infection in an HIV-infected patient on successful combination antiretroviral therapy

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Despite the widespread use of chemoprophylaxis and potent combination antiretroviral therapy (ART), disseminated Mycobacterium avium complex (MAC) and other opportunistic infections continue to occur in HIV-infected patients [1–3]. Here, we describe the first case of high-titer neutralizing anti-interferon-γ (IFN-γ) autoantibodies [4] in an HIV-infected patient who, despite sustainably favorable responses to ART, developed disseminated MAC infection and salmonellosis. By retrieving and analysis of his banked plasma, we also demonstrated that the generation of autoantibodies preceded the occurrence of opportunistic infections.
A 43-year-old Taiwanese man was admitted because of septic arthritis presented with progressive right hip pain for 1 week. Eight years earlier, the patient had received a diagnosis of HIV infection, for which he started receiving tenofovir, lamivudine, and nevirapine with good adherence and response (Fig. 1a). He had no other chronic medical conditions, denied any use of immunosuppressants, and encountered no stressful event before disease onset.
After admission, he underwent debridement of the right hip in addition to empiric antibacterial therapy. Both blood cultures and surgical specimen cultures subsequently grew Salmonella spp. group D. His pain and mobility improved after a 6-week course of ciprofloxacin, and the C-reactive protein (CRP) level gradually decreased from 17.89 to 3.53 mg/dl. However, he reported aggravated right hip pain 1 month later, with an increased CRP level (15.30 mg/dl). MRI of the pelvis showed severe osteomyelitis of the right hip joint with multiple surrounding tiny abscesses, as well as infective spondylodiskitis of the left lumbar spine (Fig. 1b). A second surgical debridement was performed, and the histopathological examination of the excised femoral head and surrounding tissue revealed caseating granuloma with the presence of acid-fast bacilli. A QuantiFERON-TB Gold in-Tube (QFT-GIT; Qiagen, Carnegie, Australia) assay was conducted and the result was indeterminate because of low mitogen response. The culture of the surgical specimen revealed MAC ultimately.
Subsequent immunological investigation showed the patient's monocyte count and lymphocyte subsets were within the reference range, and he had normal IFN-γ receptor 1 (IFNGR1) expression in CD14+ cells. Serum cryptococcal antigen and galactomannan test were both negative. Testing of neutralizing anti-IFN-γ autoantibodies through ELISA (methodologic details are described in the Appendix, revealed that the plasma concentration of anti-IFN-γ autoantibodies was 959 μg/ml (reference value: 15.78 μg/ml). Subsequent flow cytometry showed that the patient's plasma inhibited the phosphorylation of signal transducer and activator of transcription 1 in monocytes after stimulating the cells with human recombinant IFN-γ (Supplementary Fig. 1,, indicating the presence of biologically active autoantibodies in his plasma. Next, to determine the time of appearance of anti-IFN-γ autoantibodies in his blood, we retrieved and analyzed the banked plasma samples of the patient serially collected over the past 7 years. The results showed that neutralizing anti-IFN-γ autoantibodies appeared since 18 months before the current presentation (Fig. 1a). Further human leukocyte antigen (HLA) typing showed the patient carried the risk alleles (HLA-DRB1*16 : 02, HLA-DQB1*05 : 02), which were recently reported to confer predisposition to develop anti-IFN-γ autoantibodies (Appendix, [5].
According to our review of the relevant literature, this is the first report of biologically active anti-IFN-γ autoantibodies in an HIV-infected patient with disseminated MAC infection and salmonellosis. Furthermore, although a few HLA class II alleles were found to be strongly associated with the occurrence of anti-IFN-γ autoantibodies [5], the current study is the first to demonstrate that such pathogenic autoantibodies arose in adulthood, increased gradually before disease onset, and were not triggered by mycobacterial infection. However, the triggering factor underlying the induction of anti-IFN-γ autoantibodies in this patient could not be determined despite detailed history taking.
The present case was unlikely to have immune reconstitution inflammatory syndrome (IRIS) considering his sustained, stable CD4+ cell counts for several years.

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