LE DEFICIT IMMUNITAIRE COMMUN VARIABLE (A PROPOS DE 6 CAS)

Common variable immunodeficiency (CVID) is a constitutional deficit in the antibody. It can be of transmission recessive, dominating or related to X. The CVID is the only being able to appear at the adulthood. The fundamental cause of this disorder remains unknown. The disease is characterized by the heterogeneity of the clinical picture and the immunological characteristic Our study’s goal is to present un discuss 6 cases of CVID hospitalized at the clinical Immunology Unit, of the Pediatry I department in the child hospital of Casablanca, between March 1998 and March 2004. The mean age at the first clinical symptoms is 11 years. Our six patients, suffered from recurrent pneumonias, the recurrent sinusitis, the chronic diarrhea with failure to thrive and granulomatous disease. They all had a hypogammaglobulinemia, the taking in charge consisted in an infections episode treatment as well as a nutrition rehabilitation with intravenous immunoglobulin antibiotic prophylaxis and a respiratory kinesitherapy. Our set was characterized by the severity of the clinical phenotype, especially by the therapeutic means insufficiency, and the delay of the diagnostic. A considerable effort should be achieved in order to make doctors more sensitive, tools of diagnosis and the hold in charge.Le déficit immunitaire commun variable (DICV) est un déficit primitif en anticorps, de transmission récessive, dominante ou liée à l’X, et qui peut se révéler à l’âge adulte. Son mécanisme moléculaire est encore inconnu. Le diagnostic est caractérisé par une hétérogénéité du tableau clinique et immunologique. L’objectif de notre travail est de présenter et discuter 6 cas de DICV, hospitalisés à l’unité d’immunologie clinique de la Pédiatrie I à l’hôpital d’Enfants de Casablanca, sur 6 ans (1998 – 2004). L’âge moyen de début des symptômes est de 11 ans. Nos 6 malades avaient présenté des broncho-pneumopathies à répétitions, des infections ORL, des diarrhées chroniques avec retentissement staturo-pondéral, et un cas de sarcoïdose. Ils avaient présenté tous une hypogammaglobulinémie globale. La prise en charge a consisté en un traitement des épisodes infectieux, une perfusion des immunoglobulines, une antibioprophylaxie et une kinésithérapie respiratoire. Le tableau clinique de nos malades reste sévère du fait du retard du diagnostic et de l’insuffisance des moyens thérapeutiques ; c’est pourquoi un effort doit être réalisé, afin de sensibiliser les médecins, pour établir un diagnostic précoce et une prise en charge adéquate

Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification.

Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI

A partial form of inherited human USP18 deficiency underlies infection and inflammation

International audienceHuman USP18 is an interferon (IFN)-stimulated gene product and a negative regulator of type I IFN (IFN-I) signaling. It also removes covalently linked ISG15 from proteins, in a process called deISGylation. In turn, ISG15 prevents USP18 from being degraded by the proteasome. Autosomal recessive complete USP18 deficiency is life-threatening in infancy owing to uncontrolled IFN-I–mediated autoinflammation. We report three Moroccan siblings with autoinflammation and mycobacterial disease who are homozygous for a new USP18 variant. We demonstrate that the mutant USP18 (p.I60N) is normally stabilized by ISG15 and efficient for deISGylation but interacts poorly with the receptor-anchoring STAT2 and is impaired in negative regulation of IFN-I signaling. We also show that IFN-γ–dependent induction of IL-12 and IL-23 is reduced owing to IFN-I–mediated impairment of myeloid cells to produce both cytokines. Thus, insufficient negative regulation of IFN-I signaling by USP18-I60N underlies a specific type I interferonopathy, which impairs IL-12 and IL-23 production by myeloid cells, thereby explaining predisposition to mycobacterial disease

The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies

Since the 1990s, the International Union of Immunological Societies (IUIS) PID expert committee (EC), now called Inborn Errors of Immunity Committee, has published every other year a classification of the inborn errors of immunity. This complete catalog serves as a reference for immunologists and researchers worldwide. However, it was unadapted for clinicians at the bedside. For those, the IUIS PID EC is now publishing a phenotypical classification since 2013, which proved to be more user-friendly. There are now 320 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. We herein propose the revised 2017 phenotypic classification, based on the accompanying 2017 IUIS Inborn Errors of Immunity Committee classification

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity.

Heterozygosity for human () dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the promoter. The patients\u27 cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with DN mutations, ZNF341-deficient patients lack T helper 17 (T17) cells, have an excess of T2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the transcription-dependent autoinduction and sustained activity of STAT3

A novel homozygous p.R1105X mutation of the AP4E1 gene in twins with hereditary spastic paraplegia and mycobacterial disease.

We report identical twins with intellectual disability, progressive spastic paraplegia and short stature, born to a consanguineous family. Intriguingly, both children presented with lymphadenitis caused by the live Bacillus Calmette-Guérin (BCG) vaccine. Two syndromes - hereditary spastic paraplegia (HSP) and mycobacterial disease - thus occurred simultaneously. Whole-exome sequencing (WES) revealed a homozygous nonsense mutation (p.R1105X) of the AP4E1 gene, which was confirmed by Sanger sequencing. The p.R1105X mutation has no effect on AP4E1 mRNA levels, but results in lower levels of AP-4ε protein and of the other components of the AP-4 complex, as shown by western blotting, immunoprecipitation and immunofluorescence. Thus, the C-terminal part of the AP-4ε subunit plays an important role in maintaining the integrity of the AP-4 complex. No abnormalities of the IL-12/IFN-γ axis or oxidative burst pathways were identified. In conclusion, we identified twins with autosomal recessive AP-4 deficiency associated with HSP and mycobacterial disease, suggesting that AP-4 may play important role in the neurological and immunological systems