Publications by authors named "J-L Beziat"

Autosomal recessive deficiency of the IFNAR1 or IFNAR2 chain of the human type I IFN receptor abolishes cellular responses to IFN-α, -β, and -ω, underlies severe viral diseases, and is globally very rare, except for IFNAR1 and IFNAR2 deficiency in Western Polynesia and the Arctic, respectively. We report 11 human IFNAR1 alleles, the products of which impair but do not abolish responses to IFN-α and -ω without affecting responses to IFN-β. Ten of these alleles are rare in all populations studied, but the remaining allele (P335del) is common in Southern China (minor allele frequency ≈2%).

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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.

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Article Synopsis
  • Inborn errors or autoantibodies (auto-Abs) against type I interferons (IFNs) can lead to severe viral infections.
  • Researchers developed a straightforward blood test that can identify these conditions by stimulating blood with glycosylated IFN-α2, -β, or -ω and measuring IP-10 levels.
  • The study found that IP-10 levels in patients with inherited deficiencies only increase with type II IFN (IFN-γ), while those with auto-Abs can still respond to non-neutralized type I IFNs.
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FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors.

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Article Synopsis
  • The study discusses a rare lung disease in nine children linked to a genetic deficiency of the CCR2 receptor, leading to conditions like pulmonary alveolar proteinosis (PAP) and increased vulnerability to infections.
  • This deficiency is characterized by loss-of-function variants, affecting the migration and signaling of immune cells, particularly monocytes, due to a lack of response to CCL-2, a chemokine essential for these processes.
  • Elevated levels of CCL-2 in the blood serve as a diagnostic marker for identifying children with unexplained respiratory issues or recurrent infections, indicating the importance of CCR2 in lung health and immune response.
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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).

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Article Synopsis
  • * This deficiency results in the impaired translation of important proteins like JAK2, affecting cellular responses to specific cytokines such as IL-23 and IL-12, particularly in T lymphocytes and phagocytes.
  • * The impaired response to IL-23 reduces the production of IFN-γ by certain immune cells during mycobacterial infections, highlighting a crucial link between MCTS1 deficiency and mycobacterial disease susceptibility.
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  • Inborn errors affecting the immune response to IFN-γ lead to mycobacterial diseases, while errors in IFN-α/β impact defense against viral infections.
  • A study of children with complete IRF1 deficiency showed they suffered from severe mycobacterial infections but displayed normal responses to various viruses, including SARS-CoV-2.
  • IRF1 plays a crucial role in the immune response to mycobacteria, enhancing IFN-γ responses, while its absence does not significantly hinder antiviral defenses associated with IFN-α/β.
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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.

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Background: Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the causes of multisystem inflammatory syndrome in children (MIS-C) remain elusive.

Objectives: To detect causal genetic variants in very rare cases with concomitant critical COVID-19 pneumonia and MIS-C.

Methods: Whole exome sequencing was performed, and the impact of candidate gene variants was investigated.

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Human papillomavirus (HPV) infections can cause common warts, which usually resolve spontaneously or become recalcitrant, resistant to multiple treatments. In rare cases, they transform into cutaneous giant horns resulting in the tree-man syndrome (TMS). Defective β-HPVs can cause flat warts in epidermodysplasia verruciformis (EV), a genetic disorder.

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Article Synopsis
  • The study looks at a patient and their relatives who have unusual skin growths caused by human papilloma virus (HPV).
  • The patients have a specific genetic change that makes a part of their immune cells (T cells) not work properly, which affects how their body fights off HPV.
  • Even though their T cells don’t respond well to HPV, the patients can still make antibodies against the viruses, showing that they can fight infections differently than expected.
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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.

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Background: Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown.

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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.

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