Anti-interferon (IFN)-γ autoantibodies are linked to varicella zoster virus (VZV) infection. Given the elevated risks of herpes zoster (HZ) in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis), we aimed to examine the relationship between anti-IFN-γ autoantibodies with HZ development in JAKi-treated patients. Serum titers of anti-IFN-γ autoantibodies, plasma levels of IFN-γ, monocyte chemoattractant protein-1 (MCP-1), and IFN-γ-inducible protein-10 (IP-10) were measured by ELISA. Among the 66 enrolled RA patients, 24 developed new-onset HZ. Significantly lower MCP-1 levels were observed in patients with HZ compared to those without (median, 98.21 pg/mL, interquartile range (IQR) 77.63-150.30 pg/mL versus 142.3 pg/mL, IQR 106.7-175.6 pg/mL, p < 0.05). There was no significant difference in anti-IFN-γ titers, IFN-γ levels, or IP-10 levels between patients with and without HZ. Three of 24 patients with HZ had severe HZ with multi-dermatomal involvement. Anti-IFN-γ titers were significantly higher in patients with severe HZ than in those with non-severe HZ (median 24.8 ng/mL, IQR 21.0-38.2 ng/mL versus 10.5 ng/mL, IQR 9.9-15.0 ng/mL, p < 0.005). Our results suggest an association between reduced MCP-1 levels and HZ development in JAKi-treated RA patients. High-titer anti-IFN-γ autoantibodies may be related to severe HZ in these patients.

BACKGROUND: Autoantibodies against interferon-γ (IFN-γ) can inhibit IFN-γ-dependent signal transducer and activator of transcription 1 phosphorylation and thus increase the risk of infection with intracellular pathogens, such as Talaromyces marneffei (TM), nontuberculous mycobacteria (NTMs), and Mycobacterium tuberculosis (TB). Here, we report a rare case of triple infection caused by TM, NTM, and TB in a human immunodeficiency virus-negative patient.
METHODS: A middle-aged female was admitted to our hospital after experiencing recurrent rash, cough, and expectoration for 4 months. She was successively diagnosed with NTM, TM, and TB infections without conventional immunosuppression-associated factors. However, after effective anti-infective treatment, the patient was confirmed to have allergic conjunctivitis and was successfully treated with corticosteroids and immunosuppressants. The most conspicuous characteristics were recurrent infection and immune disorders.
CONCLUSIONS: High-titer anti-IFN-γ autoantibodies are strongly associated with severe and disseminated infections, such as NTM, TM, and TB. It is characterized by persistently high degree of inflammation and high immunoglobin levels.

BACKGROUND: The clinical presentation of adult-onset immunodeficiency with anti-interferon (IFN)-γ autoantibodies with intracellular pathogens can be highly variable, which can lead to misdiagnosis during the early stage of disease.
METHODS: We report a complex case of a 54-year-old Chinese male who was human immunodeficiency virus-negative. He had a presence of anti-IFN-γ autoantibodies and suffered from various intracellular pathogenic infections. The patient was admitted to our hospital for the first time in July 2016 with severe pneumonia, and he experienced multiple pneumonia infections between 2017 and 2019. In March 2019, the patient was hospitalized due to pulmonary lesions and multiple-bone destruction. During hospitalization, the patient was confirmed to have disseminated Talaromyces marneffei infection and was successfully treated with antifungal therapy for 1 year. In June 2021, Mycobacterium kansasii infection was detected by positive culture and progressive bone destruction. A high concentration of anti-IFN-γ antibodies was observed in the patient\'s serum. In addition, Listeria monocytogenes was isolated by blood culture, and the presence of L. monocytogenes in cerebrospinal fluid was confirmed by next-generation sequencing. Following anti-non-tuberculous mycobacteria (NTM) therapy and anti-bacterial therapy, the patient\'s symptoms, pulmonary lesions, and bone destruction gradually improved.
CONCLUSIONS: Although the clinical presentation of adult-onset immunodeficiency with anti-IFN-γ autoantibodies can be highly variable, the diagnosis should be considered if patients suffer from unexplained repeated bacterial or opportunistic infections. Conventional and advanced molecular testing should be used, as needed, for microbiological diagnoses among this special immunodeficient population.

BACKGROUND: Disseminated nontuberculous mycobacterial (NTM) infection usually occurs in immunodeficient patients, such as those with human immunodeficiency virus infection and idiopathic CD4 lymphopenia. However, disseminated NTM diseases have also been reported in immunocompetent patients. Autoantibodies to interferon-gamma (IFN-γ) are known to be involved in disseminated NTM disease, although anti-IFN-γ antibodies are mainly seen in immunocompetent patients rather than those with immunodeficiency. Here, we report a rare case of disseminated NTM patient with idiopathic CD4 lymphopenia and anti-IFN-γ antibodies.
METHODS: A 64-year-old Asian male presented with fever, back pain, anorexia and weight loss. Physical examination revealed subcutaneous masses in the forehead, sternoclavicular joint, and right inguinal region. Computed tomography showed multiple osteosclerotic changes with soft structures and osteolytic changes. Both blood and sputum cultures were positive for Mycobacterium intracellulare, confirming the presence of disseminated NTM infection. Histopathological evaluation of the subcutaneous mass in the right inguinal region showed numerous granulomas consisting of epithelioid cells with Langhans-type giant cells. He was diagnosed with idiopathic CD4 lymphocytopenia. Interestingly, he also had anti-IFN-γ autoantibodies with suppression of IFN-γ-dependent signal transducer and activator of transcription 1 (STAT1) phosphorylation. Two-drug combination therapy with clarithromycin and ethambutol was started for the NTM infection, which resulted in a favorable disease course.
CONCLUSIONS: In patients with disseminated NTM infection, idiopathic CD4 lymphocytopenia and anti-IFN-γ autoantibody-positive immunodeficiency can be coexisted. It is necessary to clarify the pathogenesis and clinical course of CD4 lymphocytopenic conditions and IFN-γ neutralizing antibody-positive in the disseminated NTM disease.

UNASSIGNED: Neutralizing anti-interferon (IFN)-γ autoantibodies are linked to opportunistic infections (OIs). To explore the association between anti-IFN-γ autoantibodies and OIs in patients with adult-onset Still\'s disease (AOSD), we aimed to examine the ability of these autoantibodies to blockade signal transducer and activator of transcription (STAT1)-phosphorylation and chemokines production.
UNASSIGNED: Serum titers of anti-IFN-γ autoantibodies were quantified using ELISA in 29 AOSD and 22 healthy controls (HC). The detectable autoantibodies were verified with immunoblotting assay, and their neutralizing capacity against IFN-γ-signaling was evaluated with flow-cytometry analysis and immunoblotting. IFN-γ-mediated production of supernatant chemokines, including monocyte chemoattractant protein-1 (MCP-1) and IFN-γ inducible protein-10 (IP-10), were measured by ELISA.
UNASSIGNED: Among 29 AOSD patients, high titers of anti-IFN-γ neutralizing autoantibodies were detectable in two patients with OIs. Immunoblotting assay revealed more effective inhibition of STAT1-phosphorylation in THP-1 cells treated with sera from autoantibody-positive AOSD patients (56.7 ± 34.79%) compared with those from HC (104.3 ±29.51%), which was also demonstrated in flow-cytometry analysis (47.13 ± 40.99 vs. 97.92 ± 9.48%, p < 0.05). Depleted serum IgG from anti-IFN-γ autoAbs-positive AOSD patients with OIs restored phosphorylated STAT-1 upon IFN-γ treatment. Sera from autoantibody-positive AOSD patients more effectively inhibited IFN-γ-mediated production of MCP-1 (45.65 pg/ml) and IP-10 (22.44 pg/ml) than sera from HC (263.1 pg/ml and 104.0 pg/ml, both p < 0.05). Serum samples showing the strongest inhibition of IFN-γ-signaling were from two patients with high-titer autoantibodies and OIs.
UNASSIGNED: AOSD patients have a high positive rate and titers of anti-IFN-γ autoantibodies. The remarkable blockade effect of high-titer autoantibodies on IFN-γ-mediated STAT1-phosphorylation and chemokines could make these patients susceptible to OIs.

Francisella is an intracellular, fastidious, Gram-negative bacterium that is difficult to identify using routine microbiological methods in the laboratory. We studied the isolation of Francisella sp. (strain IDAMR664) from the blood of a patient with anti-interferon-γ (IFN-γ) autoantibodies who presented with septicemia and cholestatic hepatitis. Analysis of the strain IDAMR664 genome sequence revealed the isolate was closely related to the strain GA01-2794 that had been isolated from a human in the USA. In addition, it was clustered with F. orientalis, a fish pathogen. The isolate contained several virulence factors and had Francisella pathogenicity island pattern no. 3.

Patients with anti-interferon (IFN)-γ autoantibodies have weakened immune defenses against intracellular pathogens. Because of its low incidence and non-specific symptoms, diagnosis of anti-IFN-γ autoantibody syndrome is difficult to establish during the early stages of infection. Here, we report a patient with high titers of serum anti-IFN-γ autoantibodies suffering from opportunistic infections. The patient presented with intermittent fever for 2 weeks. During his first hospitalization, he was diagnosed with Talaromyces marneffei pulmonary infection and successfully treated with antifungal therapy. However, multiple cervical lymph nodes subsequently became progressively enlarged. Mycobacterium abscessus infection was confirmed by positive cervical lymph node tissue cultures. High-titer serum anti-IFN-γ antibodies were also detected. Following anti-M. abscessus therapy, both his symptoms and lymph node lymphadenitis gradually improved. Anti-IFN-γ autoantibody syndrome should be considered in adult patients with severe opportunistic coinfections in the absence of other known risk factors.

Mycobacterium scrofulaceum is an environmental mycobacterial species rarely reported to cause disseminated infection in adults. We report the case of a disseminated M. scrofulaceum infection in a 55-year-old nonhuman immunodeficiency virus-infected Thai man with anti-interferon-γ autoantibodies. The clinical signs of the infection improved after the induction regimen with amikacin, rifampicin, ethambutol, and clarithromycin, followed by the consolidation regimen with ethambutol, clarithromycin, and trimethoprim/sulfamethoxazole. Our review of previous reported cases of this infection indicates its association with immune deficiency, complex treatment, and a high rate of unfavorable outcomes.

BACKGROUND: Disseminated nontuberculous mycobacteria (NTM) infections occur mostly in immunocompromised patients. Therefore, it is difficult to diagnose disseminated NTM infections in patients without history of immunocompromised diseases or using immunosuppressant. Patients with anti-interferon-γ (IFN-γ) autoantibodies are vulnerable to intracellular infections, such as disseminated NTM. Currently, there is no widely used and efficient technique for the detection of anti-IFN-γ autoantibodies. Herein, we report a case of an apparently healthy patient with disseminated Mycobacterium avium complex (MAC) infection who tested positive for anti-IFN-γ autoantibodies.
METHODS: A 64-year-old non-immunocompromised and apparently healthy Asian male presented to the emergency department with complaints of progressive chest pain for about 6 months and weight loss. A bulging tumour was found in the anterior chest wall. Chest computed tomography showed a lung mass over the right lower lobe and an osteolytic lesion with a soft tissue component at the sternum. Sonography-guided biopsies for the osteolytic lesion and sputum culture confirmed the presence of disseminated MAC infection. In addition, positive test result of anti-IFN-γ autoantibodies was noted. The patient was prescribed antibiotics. The lesions over the right lower lobe and sternum attenuated following the antibiotic treatment.
CONCLUSIONS: Detection of anti-IFN-γ autoantibodies is important among previously healthy people with disseminated NTM infection. Presence of anti-IFN-γ autoantibodies may suggest a high risk of severe intracellular infection, such as disseminated NTM infection.

The natural history of anti-interferon-γ (IFN-γ) autoantibody-associated immunodeficiency syndrome is not well understood.
Data of 74 patients with anti-IFN-γ autoantibodies at Srinagarind Hospital, Thailand, were collected annually (median follow-up duration, 7.5 years). Annual data for 19 patients and initial data for 4 patients with anti-IFN-γ autoantibodies at the US National Institutes of Health were collected (median follow-up duration, 4.5 years). Anti-IFN-γ autoantibody levels were measured in plasma samples.
Ninety-one percent of US patients were of Southeast Asian descent; there was a stronger female predominance (91%) in US than Thai (64%) patients. Mycobacterium abscessus (34%) and Mycobacterium avium complex (83%) were the most common nontuberculous mycobacteria in Thailand and the United States, respectively. Skin infections were more common in Thailand (P = .001), whereas bone (P < .0001), lung (P = .002), and central nervous system (P = .03) infections were more common in the United States. Twenty-four percent of Thai patients died, most from infections. None of the 19 US patients with follow-up data died. Anti-IFN-γ autoantibody levels decreased over time in Thailand (P < .001) and the United States (P = .017), with either cyclophosphamide (P = .01) or rituximab therapy (P = .001).
Patients with anti-IFN-γ autoantibodies in Thailand and the United States had distinct demographic and clinical features. While titers generally decreased with time, anti-IFN-γ autoantibody disease had a chronic clinical course with persistent infections and death. Close long-term surveillance for new infections is recommended.