Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

Journal of Clinical Immunology, Год журнала: 2022, Номер 42(7), С. 1473 - 1507

Опубликована: Июнь 24, 2022

Abstract We report the updated classification of inborn errors immunity, compiled by International Union Immunological Societies Expert Committee. This documents key clinical and laboratory features 55 novel monogenic gene defects, 1 phenocopy due to autoantibodies, that have either been discovered since previous update (published January 2020) or were characterized earlier but confirmed expanded in subsequent studies. While variants additional genes associated with immune diseases reported literature, this includes only those committee assessed reached necessary threshold represent immunity. There are now a total 485 These advances discovering genetic causes human continue significantly further our understanding molecular, cellular, immunological mechanisms disease pathogenesis, thereby simultaneously enhancing knowledge improving patient diagnosis management. is designed serve as resource for immunologists geneticists pursuing molecular individuals heritable disorders scientific dissection cellular underlying related diseases.

Язык: Английский

---

SARS-CoV-2 pathogenesis

Nature Reviews Microbiology, Год журнала: 2022, Номер 20(5), С. 270 - 284

Опубликована: Март 30, 2022

Язык: Английский

---

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Science Immunology, Год журнала: 2021, Номер 6(62)

Опубликована: Авг. 10, 2021

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found about 10% patients with critical COVID-19 pneumonia, but not subjects asymptomatic infections. We detect auto-Abs 100-fold lower, more physiological, (100 pg/mL, 1/10 dilutions plasma) 13.6% 3,595 COVID-19, including 21% 374 > 80 years, and 6.5% 522 severe COVID-19. These antibodies also detected 18% the 1,124 deceased (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% 0.9% have IFN-β. show, a sample 34,159 uninfected from general population, that present 0.18% individuals between 18 69 1.1% 79 3.4% >80 years. proportion carrying lower is greater subsample 10,778 individuals: 1% <70 2.3% 6.3% By contrast, IFN-β do become frequent age. Auto-Abs type I IFNs predate SARS-CoV-2 infection sharply increase prevalence after age They account for 20% both cases over-80s, total fatal cases.

Язык: Английский

---

Innate immunity: the first line of defense against SARS-CoV-2

Nature Immunology, Год журнала: 2022, Номер 23(2), С. 165 - 176

Опубликована: Фев. 1, 2022

Язык: Английский

---

TLR7 gain-of-function genetic variation causes human lupus

Nature, Год журнала: 2022, Номер 605(7909), С. 349 - 356

Опубликована: Апрель 27, 2022

Abstract Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease 1–7 , lupus-causing TLR7 gene variants is lacking. Here we describe lupus erythematosus caused by gain-of-function variant. sensor viral RNA 8 9 and binds to guanosine 10 – 12 . We identified de novo, previously undescribed missense Y264H variant in child with severe additional other patients lupus. The selectively increased sensing 2',3'-cGMP 10–12 was sufficient cause when introduced into mice. show that drives aberrant survival B cell (BCR)-activated cells, cell-intrinsic manner, accumulation CD11c + age-associated cells germinal centre cells. Follicular extrafollicular helper T were also but these phenotypes cell-extrinsic. Deficiency MyD88 (an adaptor protein downstream TLR7) rescued autoimmunity, survival, all cellular serological phenotypes. Despite prominent spontaneous germinal-centre formation Tlr7 mice, autoimmunity not ameliorated deficiency, suggesting an origin pathogenic establish the importance guanosine-containing self-ligands for pathogenesis, which paves way therapeutic or inhibition.

Язык: Английский

---

Human genetic and immunological determinants of critical COVID-19 pneumonia

Nature, Год журнала: 2022, Номер 603(7902), С. 587 - 598

Опубликована: Янв. 28, 2022

Язык: Английский

---

Whole-genome sequencing reveals host factors underlying critical COVID-19

Nature, Год журнала: 2022, Номер 607(7917), С. 97 - 103

Опубликована: Март 7, 2022

Abstract Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care 1 or hospitalization 2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics Mortality in Care) study enables comparison genomes from individuals who are critically ill those population controls to find underlying disease mechanisms. Here we use whole-genome sequencing 7,491 compared 48,400 discover and replicate 23 independent variants that significantly predispose COVID-19. We identify 16 new associations, including within genes involved interferon signalling ( IL10RB PLSCR1 ), leucocyte differentiation BCL11A ) blood-type antigen secretor status FUT2 ). Using transcriptome-wide association colocalization infer effect gene expression on severity, evidence implicates multiple genes—including reduced a membrane flippase ATP11A increased mucin MUC1 )—in disease. Mendelian randomization provides support causal roles for myeloid cell adhesion molecules SELE , ICAM5 CD209 coagulation factor F8 all which potentially druggable targets. Our results broadly consistent multi-component model pathophysiology, at least two distinct mechanisms can life-threatening disease: failure control viral replication; an enhanced tendency towards pulmonary inflammation intravascular coagulation. show between cases highly efficient detection therapeutically relevant

Язык: Английский

---

Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19

Science Translational Medicine, Год журнала: 2021, Номер 13(612)

Опубликована: Авг. 24, 2021

Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the caused by severe acute respiratory syndrome 2 (SARS-CoV-2). However, prevalence of these antibodies, their longitudinal dynamics across severity scale, and functional effects on circulating leukocytes remain unknown. Here, 284 COVID-19, we IFN–specific peripheral blood samples from 19% 6% disease. We no IFN individuals moderate Longitudinal profiling over 600,000 mononuclear cells using multiplexed single-cell epitope transcriptome sequencing 54 COVID-19 26 non–COVID-19 controls revealed a lack IFN–stimulated gene (ISG-I) responses myeloid This was especially evident dendritic cell populations isolated producing autoantibodies. Moreover, elevated expression inhibitory receptor leukocyte-associated immunoglobulin-like 1 (LAIR1) surface monocytes early course. LAIR1 is inversely correlated ISG-I response but not expressed healthy controls. The deficient observed without supports unifying model for pathogenesis involving suppression through convergent mechanisms.

Язык: Английский

---

Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19

Nature Medicine, Год журнала: 2022, Номер 28(5), С. 1050 - 1062

Опубликована: Фев. 17, 2022

Язык: Английский

---

SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations after recovery

Science Translational Medicine, Год журнала: 2022, Номер 14(664)

Опубликована: Июнь 7, 2022

The host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in prolonged pathologies collectively referred as post-acute sequalae of COVID-19 (PASC) or long COVID. To better understand the mechanism underlying COVID biology, we compared short- and long-term systemic responses golden hamster after either SARS-CoV-2 influenza A virus (IAV) infection. Results demonstrated that exceeded IAV its capacity cause permanent injury lung kidney uniquely affected olfactory bulb (OB) epithelium (OE). Despite a lack detectable infectious virus, OB OE myeloid T cell activation, proinflammatory cytokine production, an interferon correlated with behavioral changes extending month viral clearance. These sustained transcriptional could also be corroborated from tissue isolated individuals who recovered COVID-19. data highlight molecular for persistent symptomology provide small animal model explore future therapeutics.

Язык: Английский

---