Tick-borne encephalitis (TBE) virus (TBEV) is transmitted to humans via tick bites. Infection is benign in >90% of the cases but can cause mild (<5%), moderate (<4%), or severe (<1%) encephalitis. We show here that ∼10% of patients hospitalized for severe TBE in cohorts from Austria, Czech Republic, and France carry auto-Abs neutralizing IFN-α2, -β, and/or -ω at the onset of disease, contrasting with only ∼1% of patients with moderate and mild TBE. These auto-Abs were found in two of eight patients who died and none of 13 with silent infection. The odds ratios (OR) for severe TBE in individuals with these auto-Abs relative to those without them in the general population were 4.9 (95% CI: 1.5-15.9, P < 0.0001) for the neutralization of only 100 pg/ml IFN-α2 and/or -ω, and 20.8 (95% CI: 4.5-97.4, P < 0.0001) for the neutralization of 10 ng/ml IFN-α2 and -ω. Auto-Abs neutralizing type I IFNs accounted for ∼10% of severe TBE cases in these three European cohorts.
- MeSH
- autoprotilátky * imunologie MeSH
- dospělí MeSH
- interferon typ I * imunologie MeSH
- klíšťová encefalitida * imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- neutralizující protilátky * imunologie MeSH
- senioři MeSH
- viry klíšťové encefalitidy imunologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Rakousko MeSH
Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.
- MeSH
- aktivační mutace MeSH
- autoprotilátky * imunologie MeSH
- COVID-19 genetika imunologie MeSH
- epiteliální buňky štítné žlázy metabolismus patologie MeSH
- genetická predispozice k nemoci * MeSH
- heterozygot MeSH
- interferon typ I * antagonisté a inhibitory imunologie MeSH
- kinasa indukující NF-kappaB MeSH
- lidé MeSH
- mutace ztráty funkce MeSH
- NF-kappa B - podjednotka p52 nedostatek genetika MeSH
- NF-kappa B * nedostatek genetika MeSH
- protein AIRE MeSH
- proteiny I-kappa B nedostatek genetika MeSH
- thymus abnormality imunologie patologie MeSH
- virová pneumonie genetika imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
- MeSH
- autoimunita * MeSH
- autoprotilátky * krev MeSH
- COVID-19 * imunologie mortalita MeSH
- dospělí MeSH
- interferon typ I * imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- neutralizující protilátky * krev MeSH
- riziko MeSH
- SARS-CoV-2 * MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- věkové faktory MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.
- MeSH
- autoprotilátky krev imunologie MeSH
- COVID-19 imunologie mortalita MeSH
- dítě MeSH
- dospělí MeSH
- imunoglobulin G krev imunologie MeSH
- interferon alfa imunologie MeSH
- interferon typ I imunologie MeSH
- kojenec MeSH
- kritický stav MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- neutralizující protilátky krev imunologie MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
OBJECTIVES: A growing body of evidence highlights the persistent activation of the innate immune system and type I interferon (IFN) signature in the pathogenesis of rheumatoid arthritis (RA) and its association with disease activity. Since the recent study revealed heterogeneity in the IFN signature in RA, we investigated for the first time the heterogeneity in innate signature in RA. METHODS: The innate gene expression signature (10 TLRs, 7 IL1/IL1R family members, and CXCL8/IL8) was assessed in peripheral blood mononuclear cells from RA patients (n=67), both with active (DAS28≥3.2, n=32) and inactive disease (DAS28<3.2, n=35), and in healthy control subjects (n=55). RESULTS: Of the 13 deregulated innate genes (TLR2, TLR3, TLR4, TLR5, TLR8, TLR10, IL1B, IL1RN, IL18, IL18R1, IL1RAP, and SIGIRR/IL1R8) associated with RA, TLR10 and IL1RAP are being reported for the first time. Multivariate analysis based on utilising patient similarity networks revealed the existence of four patient's subsets (clusters) based on different TLR8 and IL1RN expression profiles, two in active and two in inactive RA. Moreover, neural network analysis identified two main gene sets describing active RA within an activity-related innate signature (TLR1, TLR2, TLR3, TLR7, TLR8, CXCL8/IL8, IL1RN, IL18R1). When comparing active and inactive RA, upregulated TLR2, TLR4, TLR6, and TLR8 and downregulated TLR10 (P<0.04) expression was associated with the disease activity. CONCLUSIONS: Our study on the comprehensive innate gene profiling together with multivariate analysis revealed a certain heterogeneity in innate signature within RA patients. Whether the heterogeneity of RA elucidated from diversity in innate signatures may impact the disease course and treatment response deserves future investigations.
- MeSH
- interferon typ I * imunologie MeSH
- leukocyty mononukleární MeSH
- lidé MeSH
- multivariační analýza MeSH
- revmatoidní artritida * genetika imunologie metabolismus MeSH
- toll-like receptory * genetika imunologie metabolismus MeSH
- transkriptom MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2- BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.
- MeSH
- 9,10-dimethyl-1,2-benzanthracen MeSH
- analýza přežití MeSH
- experimentální nádory mléčných žláz chemicky indukované imunologie prevence a kontrola MeSH
- imunoterapie metody MeSH
- interferon typ I imunologie metabolismus MeSH
- karcinogeneze účinky léků imunologie MeSH
- lidé MeSH
- medroxyprogesteronacetát MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- nádory prsu imunologie metabolismus terapie MeSH
- niacinamid aplikace a dávkování MeSH
- progrese nemoci MeSH
- receptor erbB-2 imunologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Carp from breeding strains with different genetic background present diverse levels of resistance to viral pathogens. Carp strains of Asian origin, currently being treated as Cyprinus rubrofuscus L., especially Amur wild carp (AS), were proven to be more resistant to koi herpesvirus disease (KHVD; caused by cyprinid herpesvirus 3, CyHV-3) than strains originating from Europe and belonging to Cyprinus carpio L., like the Prerov scale carp (PS) or koi carp from a breed in the Czech Republic. We hypothesised that it can be associated with a higher magnitude of type I interferon (IFN) response as a first line of innate defence mechanisms against viral infections. To evaluate this hypothesis, four strains of common carp (AS, Rop, PS and koi) were challenged using two viral infection models: Rhabdovirus SVCV (spring viremia of carp virus) and alloherpesvirus CyHV-3. The infection with SVCV induced a low mortality rates and the most resistant was the Rop strain (no mortalities), whereas the PS strain was the most susceptible (survival rate of 78%). During CyHV-3 infection, Rop and AS strains performed better (survival rates of 78% and 53%, respectively) than PS and koi strains (survival rates of 35% and 10%, respectively). The evaluation of virus loads and virus replication showed significant differences between the carp strains, which correlated with the mortality rate. The evaluation of type I IFN responses showed that there were fundamental differences between the virus infection models. While responses to the SVCV were high, the CyHV-3 generally induced low responses. Furthermore, the results demonstrated that the magnitude of type I IFN responses did not correlate with a higher resistance in infected carp. In the case of a CyHV-3 infection, reduced type I IFN responses could be related to the potential ability of the virus to interfere with cellular sensing of foreign nucleic acids. Taken together, the results broaden our understanding of how common carp from different genetic strains interact with various viral pathogens.
- MeSH
- Herpesviridae fyziologie MeSH
- herpetické infekce imunologie veterinární MeSH
- infekce viry z čeledi Rhabdoviridae imunologie veterinární MeSH
- interferon typ I genetika imunologie MeSH
- kapři genetika imunologie MeSH
- nemoci ryb imunologie MeSH
- odolnost vůči nemocem genetika MeSH
- Rhabdoviridae fyziologie MeSH
- rybí proteiny genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- adaptivní imunita fyziologie MeSH
- alergie imunologie klasifikace MeSH
- cytokiny fyziologie imunologie klasifikace MeSH
- dendritické buňky fyziologie imunologie MeSH
- imunita * MeSH
- imunitní systém fyziologie imunologie MeSH
- imunoglobuliny analýza klasifikace MeSH
- interferon typ I analýza imunologie MeSH
- komplement analýza imunologie MeSH
- leukocyty fyziologie imunologie MeSH
- lidé MeSH
- lymfocyty fyziologie imunologie MeSH
- makrofágy fyziologie imunologie MeSH
- mastocyty imunologie MeSH
- přirozená imunita fyziologie MeSH
- revmatické nemoci * imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- autoimunitní nemoci nervového systému genetika imunologie MeSH
- autoimunitní nemoci * diagnóza genetika imunologie terapie MeSH
- dědičné zánětlivé autoimunitní nemoci diagnóza imunologie terapie MeSH
- dítě MeSH
- horečka genetika komplikace MeSH
- interferon typ I imunologie MeSH
- kožní manifestace MeSH
- kůže patologie MeSH
- lidé MeSH
- nemoci novorozenců epidemiologie imunologie MeSH
- novorozenec MeSH
- periodické syndromy asociované s kryopyrinem farmakoterapie genetika MeSH
- sideroblastická anemie genetika imunologie vrozené MeSH
- syndromy imunologické nedostatečnosti genetika MeSH
- vaskulární kalcifikace genetika imunologie MeSH
- vaskulitida genetika imunologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- novorozenec MeSH
