BACKGROUND: Anti-interferon-gamma autoantibody-associated immunodeficiency syndrome is a rare and underrecognized adult onset immunodeficiency syndrome associated with severe opportunistic infections such as disseminated nontuberculous mycobacterium. Few cases have documented a relationship with IgG4-related disease. Concomitant diagnoses of these diseases present a diagnostic and management challenge.
METHODS: A 61 year old man of Southeast Asian descent with pulmonary mycobacterium avium complex infection presented to our hospital system with a new skin rash and worsening lymphadenopathy. He was eventually diagnosed with IgG4-related disease through excisional nodal biopsy. He was managed with immunosuppressive treatment with prednisone, rituximab and cyclophosphamide. He later re-presented with disseminated mycobacterium avium complex infiltration of his joints, bones and prostate. Original titers of anti-interferon-gamma autoantibodies were falsely negative due to being on immunosuppressive therapy for his IgG4-related disease. However, anti-interferon-gamma autoantibody titers were re-sent after immunosuppression was held and returned strongly positive.
CONCLUSIONS: This case reviews diagnostic criteria and discusses management strategies with existing challenges in treating a patient with concomitant adult onset immunodeficiency syndrome, IgG4-related disease and a disseminated mycobacterial avium complex infection.

BACKGROUND: High-titer anti-interferon (IFN)-γ autoantibodies are strongly associated with intracellular pathogens such as nontuberculous mycobacteria and Talaromyces marneffei, but they are not as commonly associated with Talaromyces marneffei co-infected with Mycobacterium tuberculosis.
METHODS: Herein, we report a case of an HIV-negative Chinese man with a severe, disseminated co-infection of Talaromyces marneffei and Mycobacterium tuberculosis, who had a high-titer of anti IFN-γ autoantibodies and a CFI heterozygous nonsense gene mutation. The patient rapidly developed sepsis and died. Through by flow cytometry for CD4+ T cells\' intracellular phosphorylated STAT-1 and Th1 cells (CD4+ IFN-γ+ cells), we found that the patient\'s serum can inhibited IFN γ-induced CD4+ T cells\' STAT-1 phosphorylation and Th1 cell differentiation in normal peripheral blood mononuclear cells, but this phenomenon was not observed in normal control\'s serum. In addition, the higher serum concentration in the culture medium, the more obvious inhibition of Th1 cell differentiation.
CONCLUSIONS: For HIV-negative individuals with relapsing, refractory, fatal double or multiple intracellular pathogen infections, especially Talaromyces marneffei, clinicians should be aware that if they might be dealing with adult-onset immunodeficiency syndrome due to high-titer anti-IFN-γ autoantibodies. Systematic genetic and immunological investigations should also be performed.

A 77-year-old Japanese man with disseminated Mycobacterium avium complex (MAC) disease due to anti-interferon-gamma autoantibodies received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy because of non-Hodgkin lymphoma complication. The hepatobiliary nodules due to MAC resolved with R-CHOP and multidrug antimycobacterial treatment. R-CHOP could serve as an alternative adjunctive therapy for patients with anti-interferon-gamma autoantibodies.

A 72-year-old man who was diagnosed as pulmonary mycobacterium avium complex (MAC) disease had suffered from antibiotics resistant fever with left renal enlargement surrounded by inflammatory change and multiple osteolytic lesions on computed tomography (CT). The renal biopsied samples pathologically showed immunoglobulin G4 (IgG4) positive plasma cell infiltration and many acid-fast bacilli without granuloma formation. Nucleic acid identification test for MAC from the samples of vertebral osteolytic lesion was positive. In the autopsy samples from left kidney, epithelioid cell granuloma and Langhans giant cell with many acid-fast bacilli were shown pathologically. In addition to osteolytic lesions on CT study, these pathological findings were not consistent with IgG4-related disease (IgG4-RD). The diagnosis of disseminated nontuberculous mycobacteriosis was made, and plasma anti-interferon-gamma (IFN-γ) autoantibody was found as the cause of underlying immunodeficiency. Disturbed function of IFN-γ resulted in impaired ability of phagocytic cells against pathogens and leading to spread of infection. T-helper type 2 dominant immune response was induced by prolonged antigenic stimulation of mycobacteria, which might have contributed to form the pathological features of IgG4-RD.

BACKGROUND: Good\'s syndrome (GS) is characterized by immunodeficiency, and can lead to severe infection, which is the most significant complication. Although Mycobacterium rarely causes infection in patients with GS, disseminated nontuberculous mycobacterial (NTM) infection frequently occurs in GS patients that are also positive for the human immunodeficiency virus (HIV) or anti-interferon (IFN)-γ autoantibodies. Here, we report a rare case of GS with NTM without HIV or IFN-γ autoantibodies.
METHODS: A 57-year-old Japanese male with GS and myasthenia gravis (treated with prednisolone and tacrolimus) was diagnosed with disseminated NTM infection caused by Mycobacterium abscessus subsp. massiliense. He presented with fever and back pain. Blood, lumbar tissue, urine, stool, and sputum cultures tested positive for M. abscessus. Bacteremia, spondylitis, intestinal lumber abscess, and lung infection were confirmed by bacteriological examination and diagnostic imaging; urinary and intestinal tract infections were suspected by bacteriological examination but not confirmed by imaging. Despite multidrug combination therapy, including azithromycin, imipenem/cilastatin, levofloxacin, minocycline, linezolid, and sitafloxacin, the patient ultimately died of the infection. The patient tested negative for HIV and anti-IFN-γ autoantibodies.
CONCLUSIONS: Since myasthenia gravis symptoms interfere with therapy, patients with GS and their physicians should carefully consider the antibacterial treatment options against disseminated NTM.

BACKGROUND: The most common infection in patients positive for anti-interferon-gamma autoantibodies (anti-IFN-γ AAbs) is disseminated nontuberculous mycobacterial (dNTM) infection. Here, we report a rare case of triple infection caused by Cryptococcus, varicella-zoster virus (VZV), and nontuberculous mycobacterium in a patient with anti-IFN-γ AAbs.
METHODS: A 53-year-old Thai man presented with a progressively enlarging right cervical mass with low-grade fever and significant weight loss for 4 months. He also developed a lesion at his left index finger. A biopsy of that lesion showed granulomatous inflammation with yeast-like organisms morphologically consistent with cryptococcosis. Serum cryptococcal antigen was positive. Histopathology of a right cervical lymph node revealed chronic granulomatous lymphadenitis, and the lymph node culture grew Mycobacterium abscessus. One month later, he complained of vision loss in his left eye and subsequently developed a group of painful vesicles at the right popliteal area of S1 dermatome. Lumbar puncture was performed and his cerebrospinal fluid was positive for VZV DNA. His blood test for anti-HIV antibody was negative. Anti-IFN-γ AAbs was positive, but test for anti-granulocyte-macrophage colony-stimulating factor autoantibodies (anti-GM-CSF AAbs) was negative. He was treated with amphotericin B plus fluconazole for cryptococcosis; a combination of amikacin, imipenem, azithromycin, and levofloxacin for dNTM infection; and, intravenous acyclovir for disseminated VZV infection. After treatment, our patient\'s fever and cervical lymphadenopathy were subsided, and his vision and visual acuity were both improved.
CONCLUSIONS: This is the first case of triple infection with cryptococcosis, VZV, and dNTM in a patient who tested positive for anti-IFN-γ AAbs and negative for anti-GM-CSF AAbs. This case will increase awareness and heighten suspicion of these infections in patients with the described presentations and clinical characteristics, and this will accelerate diagnosis and treatment.

Talaromyces (formerly Penicillium) marneffei, a dimorphic fungus, is the most common opportunistic pathogen in human immunodeficiency viruses (HIV)-positive patients, but it rarely appears in HIV-negative individuals. Previously, in 2014, we reported the case of an HIV-negative Chinese woman with disseminated T. marneffei infection within an osteolytic lesion. Subsequently, she was followed up for 6 years, and we present an updated report of her clinical condition during the follow-up period. She presented with T. marneffei infection relapse and nontuberculous mycobacterium (NTM) infection. Laboratory tests showed anti-interferon-gamma (anti-IFN-γ) autoantibody-positive. Antifungals and anti-NTM treatment successfully improved her symptoms and laboratory results. This case highlights the type of infectious diseases that occurs as a result of immunodeficiency syndrome associated with anti-IFN-γ autoantibody.

OBJECTIVE: To identify the candidate protein biomarkers of adult-onset-immunodeficiency (AOID) syndrome using serum proteomics.
METHODS: Screening and verification phases were performed in the study. A total of 97 serum samples were classified into three groups: AOID patients with opportunistic infections (active AOID), AOID patients without opportunistic infections (inactive AOID), and healthy control. In the screening phase, pooled sera collected from patients and healthy control in each group were separated by 2D-gel electrophoresis, analyzed for differentially expressed proteins and identified for biomarkers using LC/MS. In the verification phase, the protein candidates were selected for confirmation by western blotting.
RESULTS: The analysis revealed 35 differentially expressed proteins. Three proteins including haptoglobin, gelsolin, and transthyretin, were selected for verification. The results showed that the levels of haptoglobin in both active and inactive AOID groups were significantly higher than that in the control group, while the levels of gelsolin in the active AOID group were significantly lower than that in the inactive AOID group. The level of transthyretin in the active AOID group was also significantly lower than that in the control group.
CONCLUSIONS: The comparison of serum proteins between the three groups revealed three candidates which are related to chronic inflammatory diseases. Haptoglobin and transthyretin biomarkers could be applied in clinical assessment for monitor of disease outcome, including for the study of AOID pathogenesis.

Nontuberculous mycobacteria (NTM) infections involving anti-interferon-gamma (IFN-γ)-neutralizing autoantibodies have been described in previously immunocompetent adults. To investigate the factors underlying various disease manifestations, we reviewed 35 articles published between January 2004 and November 2016 and identified 111 NTM patients with anti-IFN-γ autoantibodies. Rapidly growing mycobacteria (RGM) accounted for 53% of the isolated species. RGM were predominant among the NTM species isolated from Thai (73%), Chinese (58%) and Filipino (56%) patients, whereas M. avium complex (MAC) was predominant among Japanese (58%) and non-Asian (80%) patients. The commonly involved organs included the lymph nodes (79%), bones/joints (34%) and lungs (32%). Compared with the patients with MAC, the patients with RGM had a higher incidence of lymph node lesions (P<0.05) and a lower incidence of bone/joint (P<0.01), lung (P<0.01), soft tissue (P<0.01), bronchus (P<0.01) and muscle (P<0.05) lesions. Clinical manifestations of NTM disease with anti-IFN-γ-neutralizing autoantibodies differ across ethnicities and NTM species.

Disseminated nontuberculous mycobacteria (NTM) infection with concurrent IgG4-related lymphadenopathy has not been reported. We described a patient with neutralizing autoantibodies to interferon-gamma (IFN-γ) and elevated levels of serum IgG4 presenting with generalized lymphadenopathy and reactive dermatosis. Histologically, lymph nodes (LNs) showed effaced nodal architecture with polymorphic infiltrates, mimicking angioimmunoblastic T-cell lymphoma. Both the absolute number and the ratio of IgG4+ plasma cells to IgG+ plasma cells were increased. Mycobacterium abscessus was isolated from cultures of LNs, and demonstrated by polymerase chain reaction-restriction fragment length polymorphism. The skin biopsy showed neutrophilic dermatosis, consistent with Sweet syndrome. The patient met the criteria of both adult-onset immunodeficiency syndrome and IgG4-related lymphadenopathy. This case provides evidence of disseminated NTM infection with concurrent type III IgG4-related lymphadenopathy in the patient with anti-IFN-γ autoantibodies.