Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee

Опубликована: Апрель 15, 2025

This report provides an updated classification of inborn errors immunity (IEIs) involving 508 different genes and 17 phenocopies. Of these, we 67 novel monogenic defects 2 phenocopies due to neutralizing anti-cytokine autoantibodies or somatic mutations, which either have been discovered since the previous update (published June 2022) were reported earlier but recently confirmed and/or expanded. The new additions made after rigorous review genetic descriptions IEIs by International Union Immunological Societies (IUIS) Expert Committee using criteria established define IEI. Although similar pathogenic variants in one gene, terms both classes mutation (missense, nonsense, etc.) impact on protein function, can result a spectrum phenotypic manifestations, they are herein classified according most consistently phenotype. In addition, because single gene recognizable diseases gain loss such cases their clinical manifestations as distinct entry same table depending associated will serve valuable resource for immunologists geneticists involved molecular diagnosis individuals with heritable acquired immunological disorders. Moreover, expect this also all disciplines medicine, patients may be first seen rheumatologists, hematologists, allergists, dermatologists, neurologists, gastroenterologists, pulmonologists, upon presenting features. Finally, expanding known related causes human immune requires dissection underlying cellular mechanisms, reveals fundamental requirements specific genes, pathways, processes, even cell types. Such knowledge not only contribute improved patient management pave way development implementation therapies that target cause—rather than symptoms—of these conditions.

Язык: Английский

---

Autoinflammatory encephalopathy due to PTPN1 haploinsufficiency: a case series

The Lancet Neurology, Год журнала: 2025, Номер 24(3), С. 218 - 229

Опубликована: Фев. 19, 2025

Through the agnostic screening of patients with uncharacterised disease phenotypes for an upregulation type I interferon (IFN) signalling, we identified a cohort individuals heterozygous mutations in PTPN1, encoding protein-tyrosine phosphatase 1B (PTP1B). We aimed to describe clinical phenotype and molecular cellular pathology this new disease. In case series, collected neuroradiological data through collaboration paediatric neurology genetics colleagues across Europe (Czechia, France, Germany, Italy, Slovenia, UK) Israel. Variants PTPN1 were by exome directed Sanger sequencing. The expression IFN-stimulated genes was determined quantitative (q) PCR or NanoString technology. Experiments assess RNA protein investigate 1 IFN signalling undertaken patient fibroblasts, hTERT-immortalised BJ-5ta RPE-1 cells using CRISPR-Cas9 editing standard cell biology techniques. Between Dec 20, 2013, Jan 11, 2023, 12 from 11 families who PTPN1. found ten novel very rare variants (frequency on gnomAD version 4.1.0 <1·25 × 10:sup>-6). Six predicted as STOP mutations, two involved canonical splice-site nucleotides, missense substitutions. three patients, variant occurred de novo, whereas nine affected individuals, inherited asymptomatic parent. characterised subacute onset (age range 1-8 years) loss motor language skills absence seizures after initially normal development, leading spastic dystonia bulbar involvement. Neuroimaging variably demonstrated cerebral atrophy (sometimes unilateral initially) high T2 white matter signal. Neopterin CSF elevated all tested, probands whole blood. Although stabilisation improvement seen both treated untreated six eight high-dose corticosteroids judged clinically result neurological status. Of four parents blood (three patients) minimally (one patient). Analysis fibroblasts showed that tested led reduced levels mRNA PTP1B protein, in-vitro assays function associated impaired negative regulation signalling. haploinsufficiency causes IFN-driven autoinflammatory encephalopathy. Notably, some stabilisation, even recovery, treatment, others, appeared be responsive immune suppression. Prospective studies are needed safety efficacy specific suppression approaches population. UK Medical Research Council, European Agence Nationale la Recherche.

Язык: Английский

---

Case report: JAK inhibitor treatment of immune dysregulation symptoms in a patient with PTPN2 deficiency

Frontiers in Immunology, Год журнала: 2025, Номер 15

Опубликована: Янв. 31, 2025

A heterozygous mutation in the PTPN2 gene has recently been described several patients exhibiting symptoms of immune dysregulation. The encodes a ubiquitous non-receptor T-cell protein tyrosine phosphatase that exerts negative feedback on JAK-STAT pathway. Limited clinical data are available advocating use JAK inhibitors as an effective treatment for autoimmune complications deficiency. However, mechanism pathogenesis these suggests this possibility. We report 32-year-old male patient with interstitial lung disease, cytopenia, and lymphadenopathy accompanied by de-novo deletion PTPN2. receiving systemic steroid decades, which resulted hormone dependence well therapy-related adverse side effects. After diagnosis deficiency, inhibitor ruxolitinib was initiated at dose 15 mg per day, escalated to 30 daily after 1 month. discontinued within 3 months. At 9- 16-month checkpoint, 6 13 months correspondingly monotherapy dosage had stable blood counts, decreased, disease improved. Thus, according our experience, able alleviate deficiency symptoms, including hematological changes damage.

Язык: Английский

---

Maladies auto-inflammatoires : aspects physiopathologiques

Bulletin de l Académie Nationale de Médecine, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

---

Protein phosphatases in systemic autoimmunity

Immunometabolism, Год журнала: 2025, Номер 7(1), С. e00056 - e00056

Опубликована: Янв. 1, 2025

Protein phosphatases play a critical role in maintaining immune homeostasis by regulating various signaling pathways involved cell activation, differentiation, and function. In the context of systemic autoimmune diseases, dysregulation phosphatase activity contributes to aberrant responses, leading chronic inflammation tissue damage. This review explores key from protein serine/threonine tyrosine families that are implicated autoimmunity. We discuss their diverse roles subsets, mechanisms which drives pathogenesis, therapeutic potential targeting these enzymes.

Язык: Английский

---

How (Ultra‐)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases

ACR Open Rheumatology, Год журнала: 2025, Номер 7(2)

Опубликована: Фев. 1, 2025

The aim of this study was to explore the impact rare and ultra‐rare genetic variants on understanding treatment autoimmune autoinflammatory diseases with a focus systemic lupus erythematosus (SLE) Behçet syndrome. This review summarizes current research monogenic causes SLE syndrome, highlighting various pathways that can be responsible for these unique phenotypes. In SLE, identification complement DNASE1L3 deficiencies has elucidated mechanisms apoptotic body accumulation extracellular nucleic acid sensing. Type I interferonopathies underline specific role DNA/RNA sensing interferon overexpression in development autoimmunity. Other significant defects include Toll‐like receptor hypersignaling JAK/STATopathies, which contribute breakdown immune tolerance. To date, directly affecting B T cell biology only account minority identified lupus, importance tight regulation mechanistic target rapamycin RAS (Rat sarcoma GTPase)/MAPK (mitogen‐activated protein kinase) signaling lupus. TNFAIP3, RELA , NFKB1 genes have been identified, underscoring NF‐κB overactivation. Additional such as ELF4, WDR1 mutations trisomy 8 further illustrate complexity condition. Observations from studies syndrome highlight inflammatory distinct molecular caused by single‐gene promote or syndromes, often unrecognizable their genetically complex “classical” forms. Insights gained studying enhance our function health disease, paving way targeted therapies personalized medicine.

Язык: Английский

---

Insights from the 2024 pediatric rheumatology basic/translational years in review

Pediatric Rheumatology, Год журнала: 2025, Номер 23(1)

Опубликована: Май 23, 2025

Язык: Английский

---

Contribution of gut-derived T cells to extraintestinal autoimmune diseases

Trends in Immunology, Год журнала: 2024, Номер 45(9), С. 639 - 648

Опубликована: Авг. 23, 2024

Язык: Английский

---

PTPN2 deficiency: Amping up JAK/STAT

The Journal of Experimental Medicine, Год журнала: 2024, Номер 221(9)

Опубликована: Июль 19, 2024

Identification of monogenic causes immune dysregulation provides insight into human response and signaling pathways associated with autoimmunity. Here, Jeanpierre et al. (https://doi.org/10.1084/jem.20232337) identify new germline variants in the gene encoding PTPN2 loss regulatory function, enhanced JAK/STAT signaling, early-onset

Язык: Английский

---

Evans syndrome in conjunction with rheumatoid arthritis and SLE: A unique case of autoimmune intersection

Radiology Case Reports, Год журнала: 2024, Номер 19(12), С. 6323 - 6327

Опубликована: Сен. 25, 2024

Язык: Английский

---