Inborn errors of immunity reveal molecular requirements for generation and maintenance of human CD4 IL-9-expressing cells.

Background: CD4 T cells play essential roles in adaptive immunity. Distinct CD4 T-cell subsets-T1, T2, T17, T22, T follicular helper, and regulatory T cells-have been identified, and their contributions to host defense and immune regulation are increasingly well defined. IL-9-producing T9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity.

Autoantibodies neutralizing GM-CSF in HIV-negative Colombian patients infected with Cryptococcus gattii and C. neoformans.

Background: Cryptococcosis is a life-threatening disease caused by or . Autoantibodies (auto-Abs) neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) in otherwise healthy adults with cryptococcal meningitis have been described since 2013. We searched for neutralizing auto-Abs in sera from Colombian patients with non-HIV related cryptococcosis in a retrospective national cohort collected from 1997 to 2016.

Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs), conferring a predisposition to life-threatening COVID-19 pneumonia. 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, p52/IκBδ).

Autoantibodies neutralizing type I IFNs underlie West Nile virus encephalitis in ∼40% of patients.

Mosquito-borne West Nile virus (WNV) infection is benign in most individuals but can cause encephalitis in <1% of infected individuals. We show that ∼35% of patients hospitalized for WNV disease (WNVD) in six independent cohorts from the EU and USA carry auto-Abs neutralizing IFN-α and/or -ω. The prevalence of these antibodies is highest in patients with encephalitis (∼40%), and that in individuals with silent WNV infection is as low as that in the general population.

Autoantibodies Neutralizing Type III Interferons Are Uncommon in Patients with Severe Coronavirus Disease 2019 Pneumonia.

Autoantibodies (AABs) neutralizing type I interferons (IFN) underlie about 15% of cases of critical coronavirus disease 2019 (COVID-19) pneumonia. The impact of autoimmunity toward type III IFNs remains unexplored. We included samples from 1,002 patients with COVID-19 (50% with severe disease) and 1,489 SARS-CoV-2-naive individuals.

No increased prevalence of autoantibodies neutralizing type I IFNs in idiopathic pulmonary fibrosis patients.

SARS-CoV2 infection has a poor prognosis in patients affected of idiopathic pulmonary fibrosis (IPF). Autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) are found in the blood of at least 15% of patients with life-threatening COVID-19 pneumonia. Because of the elevated prevalence of some auto-Abs in IPF patients, we hypothesize that the prevalence of auto-Abs neutralizing type I IFNs might be increased in the IPF population and then explained specific poor outcome after COVID-19.

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.

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.

Human autoantibodies underlying infectious diseases.

The vast interindividual clinical variability observed in any microbial infection-ranging from silent infection to lethal disease-is increasingly being explained by human genetic and immunological determinants. Autoantibodies neutralizing specific cytokines underlie the same infectious diseases as inborn errors of the corresponding cytokine or response pathway. Autoantibodies against type I IFNs underlie COVID-19 pneumonia and adverse reactions to the live attenuated yellow fever virus vaccine.

Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine.

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease.

A deep intronic splice mutation of underlies hyper IgE syndrome by negative dominance.

Heterozygous in-frame mutations in coding regions of human underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in recipient cells.

Deep dermatophytosis and inherited CARD9 deficiency.

Background: Deep dermatophytosis is a severe and sometimes life-threatening fungal infection caused by dermatophytes. It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection and has been reported in patients with no known immunodeficiency.

Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity.

Neomycin ototoxicity and electrode insertion trauma both involve activation of the mitogen activated protein kinase (MAPK)/c-Jun-N-terminal kinase (JNK) cell death signal cascade. This article discusses mechanisms of cell death on a cell biology level (e.g.