anti-IFNγ Autoantibodies Research Articles

Physiological Changes in the Levels of Anti-Cytokine Autoantibodies in Early Pregnancy Are Missing in Pregnant Women with Hashimoto's Thyroiditis.

T helper type 1 (Th1) and inflammatory cytokines play essential roles in early pregnancy and also in the pathogenesis of Hashimoto's thyroiditis (HT). Changes in the serum level of autoantibodies to cytokines, which may be able to modulate their availability and actions have been described in several autoimmune disorders. Yet, no data are available on anti-cytokine autoantibodies either during early pregnancy or in patients with HT. The aim of the study was to measure autoantibodies to inflammatory-, Th1- and Th22-cytokines in serum samples in healthy pregnancy (HP) and in pregnant women with HT (HTP). As pathological autoantibodies are hallmarks of HT, in addition we also measured anti-B-cell activator factor (BAFF) autoantibodies. The measurement was carried out with a Luminex multiplex assay and the Luminex MAGPIX Instrument, age-matched healthy women (HC) and women with HT (HT) were used as controls. In the first trimester of HP, anti-TNFα, anti-IL-8, and anti-IFNγ autoantibodies were significantly decreased, while autoantibodies to BAFF were significantly elevated compared to the HC. However, these alterations were not present in the HTP. Moreover, the levels of autoantibodies to IL-22 and TNFα were significantly increased in HTP compared to the HP. All differences in the levels of the investigated autoantibodies could be detected in the first trimester of pregnancies except for anti-IL-22 autoantibodies. According to our results we can conclude that alterations in the levels of autoantibodies to inflammatory and Th1 cytokines are physiological in the first trimester of pregnancy and their disturbance can be associated with autoimmune conditions such as HT.

NK Cell-Derived IFN-γ Protects against Nontuberculous Mycobacterial Lung Infection.

In developed countries, pulmonary nontuberculous mycobacteria (NTM) infections are more prevalent than Mycobacterium tuberculosis infections. Given the differences in the pathogenesis of NTM and M. tuberculosis infections, separate studies are needed to investigate the pathological effects of NTM pathogens. Our previous study showed that anti-IFN-γ autoantibodies are detected in NTM-infected patients. However, the role of NK cells and especially NK cell-derived IFN-γ in this context has not been studied in detail. In the current study, we show that NK1.1 cell depletion increases bacterial load and mortality in a mouse model of pulmonary NTM infection. NK1.1 cell depletion exacerbates NTM-induced pathogenesis by reducing macrophage phagocytosis, dendritic cell development, cytokine production, and lung granuloma formation. Similar pathological phenomena are observed in IFN-γ-deficient (IFN-γ-/-) mice following NTM infection, and adoptive transfer of wild-type NK cells into IFN-γ-/- mice considerably reduces NTM pathogenesis. Injection of rIFN-γ also prevents NTM-induced pathogenesis in IFN-γ-/- mice. We observed that NK cells represent the main producers of IFN-γ in the lungs and production starts as soon as 1 d postinfection. Accordingly, injection of rIFN-γ into IFN-γ-/- mice 1 d (but not 2 wk) postinfection significantly improves immunity against NTM infection. NK cells also stimulate mycobacterial killing and IL-12 production by macrophages. Our results therefore indicate that IFN-γ production by NK cells plays an important role in activating and enhancing innate and adaptive immune responses at early stages of pulmonary NTM infection.

Anticytokine autoantibodies in infection and inflammation: an update.

Concise overview of the field of anticytokine autoantibodies with a focus on recent developments. Advances in particular in the analysis of autoantibodies to IFNγ, granulocyte-macrophage colony-stimulating factor (GM-CSF) and type I IFN are presented. The target epitope for anti-IFNγ autoantibodies has been found to have high homology to a protein from Aspergillus suggesting molecular mimicry as a mechanism of breaking self-tolerance. A treatment strategy using a recombinant, epitope-depleted version of IFNγ is suggested. Autoantibodies to GM-CSF are associated with disseminated Crytococcus and Nocardia infections thus expanding the spectrum of associated diseases beyond pulmonary alveolar proteinosis. Detailed analysis of anti-GM-CSF autoantibody clones derived from pulmonary alveolar proteinosis patients show evidence of high somatic mutation suggesting T cell-dependent affinity maturation; full GM-CSF neutralization is achieved by synergistic binding of antibodies targeting various distinct noncross-reactive epitopes and leading to antigen sequestration and Fc-mediated clearance. Single mAbs in contrast may lead to higher GM-CSF bioavailability. Anti type I IFN-specific autoantibodies derived from autoimmune polyglandular syndrome type I patients are of extreme high affinity and negatively correlate with the incidence of type I diabetes and may be thus considered to be protective. Hypomorphic severe combined immune deficiency may be associated with complex anticytokine patterns and the emergence of anti type I IFN autoantibodies correlates with severe viral infection histories. Anticytokine autoantibodies may cause susceptibility to infections. In autoimmune/autoinflammatory conditions, anticytokine autoantibodies may be protective or promote disease.

Anti–IFN-γ autoantibodies are strongly associated with HLA-DR*15:02/16:02 and HLA-DQ*05:01/05:02 across Southeast Asia

Anti–IFN-γ autoantibodies are strongly associated with HLA-DR*15:02/16:02 and HLA-DQ*05:01/05:02 across Southeast Asia

Anti–IFN-γ autoantibodies in adults with disseminated nontuberculous mycobacterial infections are associated with HLA-DRB1*16:02 and HLA-DQB1*05:02 and the reactivation of latent varicella-zoster virus infection

AbstractAdult patients with disseminated nontuberculous mycobacterial (dNTM) infections usually have severe immune system defects. Recently, several studies have shown that anti–IFN-γ autoantibodies may play an important role in the pathogenicity of dNTM infections. A considerable proportion of reported cases of anti–IFN-γ autoantibodies show either clinical or laboratory evidence of autoimmune disease. In the present study, we identified 19 formerly healthy adults who later developed dNTM infections, of whom 17 were further investigated immunologically. High-titer anti–IFN-γ autoantibodies capable of inhibiting IL-12 production in vitro were found in the plasma of all of these patients. In addition to dNTM infection, 35% and 71% of our patients also suffered from salmonellosis and herpes zoster, respectively. This observation suggests that IFN-γ may be crucial in controlling salmonella infection and reactivating latent varicella-zoster virus infection in humans. 2 HLA alleles, DRB1*16:02 DQB1*05:02 (odds ratio = 8.68; 95% confidence interval, 3.47-21.90; P = 1.1 × 10−6; Pc = 3.08 × 10−5 and odds ratio = 7.16; 95% confidence interval, 3.02-17.05; P = 1 × 10−7; Pc = 1.4 × 10−6, respectively), were found in 82% (14 of 17) of our patients. In conclusion, our data suggest that anti–IFN-γ autoantibodies may play a critical role in the pathogenesis of dNTM infections and reactivation of latent varicella-zoster virus infection and are associated with HLA-DRB1*16:02 and HLA-DQB1*05:02.

Anti-CD20 (rituximab) therapy for anti–IFN-γ autoantibody–associated nontuberculous mycobacterial infection

AbstractPatients with anti–IFN-γ autoantibodies have impaired IFN-γ signaling, leading to severe disseminated infections with intracellular pathogens, especially nontuberculous mycobacteria. Disease may be severe and progressive, despite aggressive treatment. To address the underlying pathogenic IFN-γ autoantibodies we used the therapeutic monoclonal rituximab (anti-CD20) to target patient B cells. All subjects received between 8 and 12 doses of rituximab within the first year to maintain disease remission. Subsequent doses were given for relapsed infection. We report 4 patients with refractory disease treated with rituximab who had clinical and laboratory evidence of therapeutic response as determined by clearance of infection, resolution of inflammation, reduction of anti–IFN-γ autoantibody levels, and improved IFN-γ signaling.

Novel Defects in Host Defense Evinced As Nontuberculous Mycobacterial and Dimorphic Mold Infections: GATA2 Deficiency, STAT1 Mutations, Anticytokine Autoantibodies

Abstract SCI-20Nontuberculous mycobacteria are relatively ubiquitous organisms of low virulence, disseminated infection with which suggests an underlying defect in host defense. Dimorphic molds (e.g., histoplasmosis, coccidioidomycosis, penicilliosis) are regionally limited and cause severe infections only in the immune compromised. We have focused on severe cases of these infections to identify genetic and acquired syndromes of immune deficiency that have not been previously recognized. 1. The syndrome of monocytopenia, NK, and B cell lymphopenia and lack of circulating dendritic cells is associated with severe infections with mycobacteria, dimorphic molds, human papilloma virus, and molluscum cantagiosum. These patients also develop myelodysplasia and pulmonary alveolar proteinosis and may progress to frank leukemia. Mutations in GATA2 are responsible for the syndrome (monoMAC for monocytopenia and M. avium complex infection). Hematopathologically, patients have micromegakaryocytes and cytogenetic abnormalities, most commonly monosomy 7 and trisomy 8. Both protein-positive and protein-negative heterozygous mutations have been identified, suggesting that haploinsufficiency is a unifying cause of disease. The spectrum of pathologic mutations is broad and likely extends into phenotypes that are distinct from those recognized initially. 2. Mutations in STAT1 have been associated with mycobacterial disease (dominant negative inhibitory), fatal viral and bacterial disease (recessive), and mucocutaneous candidiasis (dominant gain of function). We have identified distinct and independent STAT1 mutations in three patients that have led to severe, refractory disseminated coccidioidomycosis or histoplasmosis. These mutations lead to hypomethylation of STAT1, which leads to its persistent hyperphosphorylation, and impairment of restimulation activity. These mutations are important because they lie in the same plane of the molecule and cause severe invasive dimorphic yeast infections. 3. Autoantibodies are common, especially in adult women. We have previously recognized East Asia-born adult women living in the United States who have high titer autoantibodies to interferon gamma (IFNγ). We have recently recognized large cohorts of similar patients in Thailand and Taiwan and conducted a prospective trial of their phenotype and the presence and type of anti-IFNγ autoantibodies. We found a significant population of patients with disseminated nontuberculous mycobacterial infections (but not tuberculosis), salmonella, cryptococcosis, histoplasmosis, or varicella zoster in Asia whose sole identifiable risk factor was extremely elevated anti-IFNγ autoantibodies. We have characterized the severity of the blockade and the subclass of the antibodies and explored the rate in several control populations as well. These apparently adult-onset acquired autoantibodies profoundly inhibit IFNγ signaling, leading to infections with IFNγ-responsive organisms. These emerging syndromes cross the lines of infectious disease, cancer, and rheumatology. Disclosures:No relevant conflicts of interest to declare.

Naturally occurring anti–IFN-γ autoantibody and severe infections with Mycobacterium cheloneae and Burkholderia cocovenenans

AbstractRecently various genetic defects in immunity mediated by interferon γ (IFN-γ) have been described, including mutations in the IFN-γ receptor 1 (IFN-γR1) and receptor 2 (IFN-γR2), signal transducer and activator of transcription 1 (STAT 1), and interleukin 12 receptor β 1 (IL-12Rβ1), and IL-12 p40 genes. These mutations are associated with the occurrence of severe infections with intracellular pathogens especially nontuberculous mycobacteria and vaccine-associated bacilli Calmette-Guérin (BCG). Here we report data on a previously healthy adult patient primarily presenting with severe infections with Burkholderia cocovenenans and subsequently Mycobacterium cheloneae. We found a strong inhibitory anti–IFN-γ activity in the patient’s plasma and identified a highaffinity neutralizing anti–IFN-γ autoantibody. Unfortunately, the patient died due to severe sepsis before we knew the nature of the inhibitory activity. The application of alternative therapeutic approaches such as intravenous immunoglobulin or immunoadsorption may have been beneficial in this case. Screening for neutralizing anti–IFN-γ autoantibodies should supplement testing for IFN-γ and IL-12 pathway defects in patients with recurrent infections with intracellular pathogens, especially with nontuberculous mycobacteria.