Clinicopathological Manifestations and Immune Phenotypes in Adult-Onset Immunodeficiency with Anti-interferon-γ Autoantibodies.

PURPOSE: Anti-interferon (IFN)-γ autoantibodies (anti-IFN-γ Abs) is an emerging adult-onset immunodeficiency syndrome. Immune dysfunction in this distinct disorder remains to be clarified. METHODS: We prospectively collected blood samples of 20 patients with anti-IFN-γ Abs and 40 healthy normal subjects. The percentages of lymphocyte subpopulations, most relevant to T, B, and NK cells, and the percentages of stimulated lymphocytes with cytokine production were assessed using eight-color flow cytometry. The results were adjusted to age and absolute lymphocyte counts. RESULTS: Most (85%) patients presented nontuberculous mycobacterial infection. Skin lesions were predominantly manifested by neutrophilic dermatoses. The involved lymph nodes had granulomatous inflammation, except 22.2% showing atypical lymphoid hyperplasia without granuloma formation. The percentages of CD4 + T cells and nonactivated subpopulations (recent thymic emigrants and naïve subtypes) decreased significantly with increased expression of activation markers and polarization to differentiated cells. The percentage of NK cells increased, but that of two major NK subpopulations, CD161 + CD56bright and CD161 + CD56 + CD16 + subsets, decreased. Increased CD161dim, CD161 + CD56 - CD16 + , and CD57 + NK cell subsets coupled with the decreased expression of NKp30 and NKp46 indicate reconfiguration of the NK cell population and acquisition of adaptive features. Intracellular cytokine production of the lymphocyte subpopulations was significantly low in the patients compared with the control group. CONCLUSION: We conclude that the immune system in patients with anti-IFN-γ Abs could be exhausted in T cells and be adaptive in NK cells, contributing to the distinct clinicopathologic features.

Disseminated Mycolicibacter arupensis and Mycobacterium avium co-infection in a patient with anti-interferon-γ neutralizing autoantibody-associated immunodeficiency syndrome.

BACKGROUND: Disseminated infections of Mycolicibacter arupensis, a slowly growing nontuberculous mycobacteria (NTM) which causes synovitis, osteomyelitis, or pulmonary infections have rarely been reported. We report a case of disseminated M. arupensis and Mycobacterium avium co-infection in a patient with anti-interferon (IFN)-γ neutralizing autoantibody-associated immunodeficiency syndrome. CASE PRESENTATION: A 68-year-old Japanese male without human immunodeficiency virus infection was referred with complaints of persistent low-grade fever, arthralgia of the upper limbs, and weight loss of 10 kg. Cervical and mediastinal lymphadenopathies as well as a nodular opacity in the right lung were detected, and biopsy specimens of the cervical lymph node yielded M. arupensis without evidence of malignant cells. M. arupensis was also detected in sputum and peripheral blood. Computed tomography (CT) revealed deterioration of the right supraclavicular lymphadenopathy with internal necrosis and multiple low-density splenic lesions. Bone marrow and aspirates from the cervical lymph node collected at initiation of treatment yielded M. avium. The presence of anti-IFN-γ neutralizing autoantibodies was detected, leading to a diagnosis of co-infection of M. arupensis and M. avium with anti-IFN-γ neutralizing autoantibody-associated immunodeficiency syndrome. Post initiation of treatment with clarithromycin, ethambutol, and rifabutin, his fever declined, and his polyarthritis resolved. He developed disseminated varicella zoster during treatment; however, a follow-up CT scan six months after treatment revealed improvement of the lymphadenopathies, consolidation in the right lung, and splenic lesions. CONCLUSION: This is the first report of disseminated M. arupensis and M. avium co-infection in a patient with anti-IFN-γ neutralizing autoantibody-associated immunodeficiency syndrome.

Chylous ascites, anti-interferon-gamma autoantibody, and angioimmunoblastic T-cell lymphoma: a rare but intriguing connection over Mycobacterium avium.

We report a case of non-AIDS (acquired immunodeficiency syndrome), non-CAPD (Continuous Ambulatory Peritoneal Dialysis), non-cirrhotic, Mycobacterium avium peritonitis, which is a rare form of mycobacterial infection. A 66-year-old Japanese man who had been treated previously for angioimmunoblastic T-cell lymphoma (AITL), had developed disseminated M. avium infection. Antimycobacterial regimen improved his symptoms; however, following an interruption in treatment, he developed chylous ascites. The patient died of uncontrolled peritonitis despite intensive treatment. Anti-interferon-γ autoantibody was positive, and AITL was presumed to be involved in autoantibody production. A rare coexistence of chylous ascites, autoantibody, and AITL taught us an intriguing lesson on the pathogenesis of M. avium infection. Particularly, we conclude that treatment strategies for M. avium infection should aim to restore immunity.

Rituximab Restores IFN-γ-STAT1 Function and Ameliorates Disseminated Mycobacterium avium Infection in a Patient with Anti-Interferon-γ Autoantibody.

A 67-year-old Japanese female with back pain and severe cachexia visited our hospital. The diagnosis was disseminated Mycobacterium avium complex infection (dMAC) with multiple bone involvement. Anti-mycobacterial chemotherapy was started, but fever persisted and dislocation of cervical vertebrae has made her bedridden. Because anti-interferon (IFN)-γ autoantibody was positive, four doses of rituximab 375 mg/m2, every 7 day, were administered. Soon after treatment, progression of osteolytic lesions and wasting has stopped. We proved that rituximab has recovered IFN-γ signaling as shown by IFN-γ-induced STAT1 phosphorylation. It can be a promising option for dMAC cases with anti-IFN-γ autoantibody.

Th1 cell immune response in Talaromyces marneffei infection with anti-interferon-γ autoantibody syndrome.

Anti-interferon-γ autoantibody (AIGA) syndrome may be the basis of disseminated Talaromyces marneffei infection in human immunodeficiency virus (HIV)-negative adults. However, the pathogenesis of Th1 cell immunity in T. marneffei infection with AIGA syndrome is unknown. A multicenter study of HIV-negative individuals with T. marneffei infection was conducted between September 2018 and September 2020 in Guangdong and Guangxi, China. Patients were divided into AIGA-positive (AP) and AIGA-negative (AN) groups according to the AIGA titer and neutralizing activity. The relationship between AIGA syndrome and Th1 immune deficiency was investigated by using AP patient serum and purification of AIGA. Fifty-five HIV-negative adults with disseminated T. marneffei infection who were otherwise healthy were included. The prevalence of AIGA positivity was 83.6%. Based on their AIGA status, 46 and 9 patients were assigned to the AP and AN groups, respectively. The levels of Th1 cells, IFN-γ, and T-bet were higher in T. marneffei-infected patients than in healthy controls. However, the levels of CD4+ T-cell STAT-1 phosphorylation (pSTAT1) and Th1 cells were lower in the AP group than in the AN group. Both the serum of patients with AIGA syndrome and the AIGA purified from the serum of patients with AIGA syndrome could reduce CD4+ T-cell pSTAT1, Th1 cell differentiation and T-bet mRNA, and protein expression. The Th1 cell immune response plays a pivotal role in defense against T. marneffei infection in HIV-negative patients. Inhibition of the Th1 cell immune response may be an important pathological effect of AIGA syndrome.IMPORTANCEThe pathogenesis of Th1 cell immunity in Talaromyces marneffei infection with anti-interferon-γ autoantibody (AIGA) syndrome is unknown. This is an interesting study addressing an important knowledge gap regarding the pathogenesis of T. marneffei in non-HIV positive patients; in particular patients with AIGA. The finding of the Th1 cell immune response plays a pivotal role in defense against T. marneffei infection in HIV-negative patients, and inhibition of the Th1 cell immune response may be an important pathological effect of AIGA syndrome, which presented in this research could help bridge the current knowledge gap.

SERPINB3, Adult-Onset Immunodeficiency, and Generalized Pustular Psoriasis.

BACKGROUND: Generalized pustular psoriasis (GPP; MIM 614204) is a rare and severe pustular autoinflammatory skin disease in which acute generalized erythema and scaling develop with numerous sterile pustules. GPP shares skin manifestations, especially pustular skin reaction, with adult-onset immunodeficiency (AOID) with anti-interferon-γ autoantibodies, an autoimmune disease. METHODS: Clinical examinations and whole-exome sequencing (WES) were performed on 32 patients with pustular psoriasis phenotypes and 21 patients with AOID with pustular skin reaction. Immunohistochemical and histopathological studies were performed. RESULTS: WES identified three Thai patients presenting with similar pustular phenotypes-two with a diagnosis of AOID and the other with GPP. A heterozygous missense variant chr18:g.61325778C>A NM_006919.2: c.438G>T; NP_008850.1: p.Lys146Asn; rs193238900 in SERPINB3 was identified in two patients: one with GPP and the other with AOID. The other patient who had AOID carried a heterozygous missense variant chr18:g.61323147T>C NM_006919.2: c.917A>G; NP_008850.1: p.Asp306Gly in SERPINB3. Immunohistochemical studies showed overexpression of SERPINA1 and SERPINB3, a hallmark of psoriatic skin lesions. CONCLUSIONS: Genetic variants in SERPINB3 are associated with GPP and AOID with pustular skin reaction. The skin of patients with GPP and AOID carrying SERPINB3 mutations showed overexpression of SERPINB3 and SERPINA1. Clinically and genetically, GPP and AOID appear to share pathogenetic mechanisms.

Anti-Interferon-γ Autoantibodies Impair T-Lymphocyte Responses in Patients with Talaromyces marneffei Infections.

Background: Although anti-IFN-γ autoantibodies predispose patients to Talaromyces marneffei infection, whether this is mediated by T cell attenuation remains elusive. Methods: Total peripheral blood mononuclear cells (PBMCs) from healthy donors or patients with T. marneffei infection were stimulated with M158-66, and immunodominant influenza H1N1 peptide, or heat-inactivated T. marneffei in the presence of serum from anti-IFN-γ autoantibody-positive patients or healthy controls. The percentages of IFN-γ+TNF+CD8+ T cells and IFN-γ+CD4+ T cells were determined by flow cytometry and cytokines released in the supernatant were detected by Cytometric Bead Array. Furthermore, PBMCs from patients with T. marneffei infection and healthy individuals were stimulated with IFN-γ and anti-CD3/CD28 beads, and the levels of STAT1 and STAT3 phosphorylation were detected by Western blot. Results: The M1-reactive CD8+ T cells that expressed IFN-γ+ TNF-α+ of healthy controls were clearly reduced in serum with high-titer anti-IFN-γ autoantibodies. In addition, the CD4+ T cell response, designated by the expression of IFN-γ, against T. marneffei in PBMCs of patients were significantly decreased when cultured in high-titer anti-IFN-γ autoantibody serum culture, compared to the healthy compartments. Moreover, the release of the cytokines IFN-γ, TNF-α and IL-2 was significantly decreased, while IL-10 was significantly increased. There was no significant difference in the phosphorylation levels of STAT1 and STAT3 protein between patients and healthy controls after IFN-γ or anti-CD3/CD28 beads stimulation. Conclusion: Anti-IFN-γ autoantibodies presence in the serum inhibited CD4+ Th1 and CD8+ T cell immune responses. There was no congenital dysfunction of STAT1 and STAT3 in anti-IFN-γ autoantibody-positive patients with T. marneffei infection. These results suggest that the production of anti-IFN-γ autoAbs impair T-lymphocyte responses.

Adult-onset immunodeficiency due to anti-interferon-gamma autoantibody-associated Sweet syndrome: A distinctive entity.

Sweet syndrome (SS) has been increasingly reported in patients with adult-onset immunodeficiency (AOID) due to anti-interferon-γ autoantibody who also have concomitant opportunistic infections, especially disseminated non-tuberculous mycobacterial infection (dNTMI). A retrospective study retrieving data from 2011 through 2020 was conducted. We compared clinical characteristics of SS with and without AOID and generated the prediction model and examined the interaction between AOID and dNTMI in the occurrence of SS. Lymphadenopathy, pustular lesions, and leukocytosis are the significant predictors for AOID-associated SS. Adjusted risk differences were 0.58 (95% confidence interval [CI], 0.33-0.83), 0.21 (95% CI, 0.02-0.39), and 0.24 (95% CI, 0.01-0.47), respectively. Based on the analysis of aggregated cross-sectional data, both the overall and the direct effect of AOID increased the prevalence of SS. The indirect effect of AOID on the occurrence of SS might also be mediated through dNTMI or other common opportunistic infections. In addition, there was a trend of positive additive interaction between AOID and dNTMI. Although the test of additive interaction did not reveal statistically significant results, a deviation from additivity of isolated effects might suggest potential causal interaction between AOID and dNTMI. The distinctive clinical syndrome comprising lymphadenopathy, pustular lesions, and leukocytosis in patients with SS should raise the awareness of clinicians to the potential of underlying AOID.

Loss of Function TGFBR2 Variant as a Contributing Factor in Generalized Pustular Psoriasis and Adult-Onset Immunodeficiency.

BACKGROUND: Generalized pustular psoriasis (GPP; MIM 614204) is a rare multisystemic autoinflammatory disease, characterized by episodes of acute generalized erythema and scaling developed with the spread of numerous sterile pustules. Adult-onset immunodeficiency syndrome (AOID) with anti-interferon-γ autoantibodies is an immunodeficiency disorder associated with disruptive IFN-γ signaling. METHODS: Clinical examination and whole exome sequencing (WES) were performed on 32 patients with pustular psoriasis phenotypes and 21 patients with AOID with pustular skin reaction. Histopathological and immunohistochemical studies were performed. RESULTS: WES identified four Thai patients presenting with similar pustular phenotypes-two with a diagnosis of GPP and the other two with AOID-who were found to carry the same rare TGFBR2 frameshift mutation c.458del; p.Lys153SerfsTer35, which is predicted to result in a marked loss of functional TGFBR2 protein. The immunohistochemical studied showed overexpression of IL1B, IL6, IL17, IL23, IFNG, and KRT17, a hallmark of psoriatic skin lesions. Abnormal TGFB1 expression was observed in the pustular skin lesion of an AOID patient, suggesting disruption to TGFß signaling is associated with the hyperproliferation of the psoriatic epidermis. CONCLUSIONS: This study implicates disruptive TGFBR2-mediated signaling, via a shared truncating variant, c.458del; p.Lys153SerfsTer35, as a "predisposing risk factor" for GPP and AOID.

Latticed Gold Nanoparticle Conjugation via Monomeric Streptavidin in Lateral Flow Assay for Detection of Autoantibody to Interferon-Gamma.

Adult-onset immunodeficiency syndrome (AOID) patients with autoantibodies (autoAbs) against interferon-gamma (IFN-γ) generally suffer from recurrent and recalcitrant disseminated non-tuberculous mycobacterial diseases. Since the early stages of AOID do not present specific symptoms, diagnosis and treatment of the condition are not practical. A simplified diagnostic method for differentiating AOID from other immunodeficiencies, such as HIV infection, was created. Anti-IFN-γ is generally identified using enzyme-linked immunosorbent assay (ELISA), which involves an instrument and a cumbersome process. Recombinant IFN-γ indirectly conjugated to colloidal gold was used in the modified immunochromatographic (IC) strips. The biotinylated-IFN-γ was incorporated with colloidal-gold-labeled 6HIS-maltose binding protein-monomeric streptavidin (6HISMBP-mSA) and absorbed at the conjugate pad. The efficacy of the IC strip upon applying an anti-IFN-γ autoAb cut-off ELISA titer of 2500, the sensitivity and specificity were 84% and 90.24%, respectively. When a cut-off ELISA titer of 500 was applied, the sensitivity and specificity were 73.52% and 100%, respectively.

SERPINA1, generalized pustular psoriasis, and adult-onset immunodeficiency.

Adult-onset immunodeficiency syndrome (AOID) with anti-interferon (IFN)-γ autoantibodies is characterized by an AIDS-like illness with disruptive IFN-γ signaling. Patients generally present with recurrent and disseminated opportunistic infections along with neutrophilic dermatoses. Generalized pustular psoriasis (GPP; Online Mendelian Inheritance in Man #614204) is characterized by acute generalized erythema and scaling with numerous aseptic pustules. Mutations in SERPINA3 have been reported as predisposing risk factors for both AOID and GPP. Here, we report two unrelated patients, one with AOID and a pustular skin reaction and the other with GPP, who both carried the same heterozygous variant c.718G>A (p.Val240Met) in SERPINA1. Our observation of a shared mutation in SERPINA1 in AOID and GPP indicate possible pathobiological and disease mechanism similarities in these two disorders. Thus, variants in both SERPINA1, SERPINA3, and potentially other SERPIN family members may be associated with the etiology of GPP and AOID.

Neutralizing Activity of Anti-interferon-γ Autoantibodies in Adult-Onset Immunodeficiency Is Associated With Their Binding Domains.

Adult-onset immunodeficiency (AOID) with anti-interferon-γ (IFN-γ) autoantibodies (autoAbs) is an emerging immunodeficiency syndrome in Asian countries. The presence of neutralizing anti-IFN-γ autoAbs are significantly associated with severe disseminated opportunistic infections. However, the characteristics of the neutralizing antibodies in patients are poorly defined. To better understand the properties of the anti-IFN-γ autoAbs in patients with opportunistic infections, a simplified competitive-binding ELISA was developed. The domains recognized by anti-IFN-γ autoAbs were assessed based on their competition with commercial neutralizing mouse anti-IFN-γ monoclonal antibodies (mAbs). First, the binding affinity and neutralizing capacity of these mAbs (clones B27, B133.5, and MD-1) were characterized. Kinetic analysis and epitope binning using bio-layer interferometry showed the comparable binding affinity of these mAbs to full-length IFN-γ and to the adjacent binding region. These mAbs did not recognize the synthetic 20-mer peptides and inhibited IFN-γ-mediated functions differently. In a competitive-binding ELISA, the anti-IFN-γ autoAbs in AOID serum blocked B27, B133.5, and MD-1 mAb binding. This evidence suggested that the autoAbs that competed with neutralizing mouse anti-IFN-γ mAbs recognized a discontinuous epitope of homodimeric IFN-γ as these mAbs. The patient autoAbs that recognized the B27 epitope exhibited strong neutralizing activity that was determined by the functional analysis. Our results demonstrated the heterogeneity of the autoAbs against IFN-γ in AOID patients and the different patterns among individuals. These data expand upon the fundamental knowledge of neutralizing anti-IFN-γ autoAbs in AOID patients.

Disseminated Talaromyces marneffei and Mycobacterium abscessus in a Patient With Anti-Interferon-γ Autoantibodies.

Anti-interferon (IFN)-γ autoantibodies are increasingly recognized as a cause of adult-onset immunodeficiency and increased risk for infections with intracellular pathogens. We report on disseminated Talaromyces (Penicillium) marneffei and Mycobacterium abscessus infection in a 72-year-old, human immunodeficiency virus noninfected, Thai man with anti-IFN-γ autoantibody. The patient was successfully treated with antimicrobial therapy and rituximab to control B cell-derived autoantibodies.