Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal alpha-toxin

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor kappa B signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor alpha-toxin. Naturally elicited antibodies against alpha-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to alpha-toxin in nonleukocytic cells.Peer reviewe

Partial IFN-?R2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation

PubMed ID: 23963039We report a molecular study of the two known patients with autosomal recessive, partial interferon-? receptor (IFN-?R)2 deficiency (homozygous for mutations R114C and G227R), and three novel, unrelated children, homozygous for S124F (P1) and G141R (P2 and P3). IFN-?R2 levels on the surface of the three latter patients' cells are slightly lower than those on control cells. The patients' cells also display impaired, but not abolished, response to IFN-?. Moreover, the R114C, S124F, G141R and G227R IFNGR2 hypomorphic alleles all encode misfolded proteins with abnormal N-glycosylation. The mutants are largely retained in the endoplasmic reticulum, although a small proportion reach and function at the cell surface. Strikingly, the IFN-? response of the patients' cells is enhanced by chemical modifiers of N-glycosylation, as previously shown for patients with gain-of-glysosylation T168N and misfolding 382-387dup null mutations. All four in-frame IFNGR2 hypomorphic mutant alleles encoding surface-expressed receptors are thus deleterious by a mechanism involving abnormal N-glycosylation and misfolding of the IFN-?R2 protein. The diagnosis of partial IFN-?R2 deficiency is clinically useful, as affected patients should be treated with IFN-, unlike patients with complete IFN-?R2 deficiency. Moreover, inhibitors of glycosylation might be beneficial in patients with complete or partial IFN-?R2 deficiency due to misfolding or gain-of-glycosylation receptors. © 2013 by The American Society of Hematology.Rockefeller Foundation Institut National de la Santé et de la Recherche Médicale, Inserm Agence Nationale de la Recherche, ANR: HEALTH-F3-2008-200732 National Center for Advancing Translational Sciences, NCATS Institut National de la Santé et de la Recherche Médicale, Inserm Rockefeller University Shanghai Educational Development Foundation Center for Clinical and Translational Science, Ohio State University, CCTS, OSU: 8UL1TR000043 St. Giles Foundation Université Paris Descartes National Center for Advancing Translational Sciences, NCATS National Center for Research Resources, NCRR AXA Research Fund, AXA Bill and Melinda Gates Foundation, BMGF National Council for Eurasian and East European Research, NCEEER: ERC-2010-AdG-268777 National Institute of Allergy and Infectious Diseases, NIAID: 1R01AI089970 Jeffrey Modell Foundation, JMF Stony Wold-Herbert FundThis study was conducted in accordance with the Helsinki Declaration, with written informed consent obtained from the patient family. Approval for this study was obtained from the Comité de Protection des Personnes and Institut National de la Santéet de la Recherche Médicale in France and the Rockefeller Institutional Review Board (New York, NY). -- This work was supported by grants from the European Research Council (ERC-2010-AdG-268777), Institut National de la Santé et de la Recherche Médicale, University Paris Descartes, French National Agency for Research (ANR), the EU-grant HOMITB (grant HEALTH-F3-2008-200732), the Bill and Melinda Gates Foundation, the St. Giles Foundation, the Jeffrey Modell Foundation,and Talecris Biotherapeutics, Rockefeller University Center for Clinical and Translational Science grant 8UL1TR000043 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), the Rockefeller University, and the National Institute of Allergy and Infectious Diseases (grant 1R01AI089970). R.M.-B. is supported by the EMBO Long Term Fellowship program. X.-F.K. is supported by the Stony Wold-Herbert Fund, Choh-Hao Li Memorial Fund Scholar award, and the Shanghai Educational Development Foundation, Y.I. was supported by the AXA Research Fund. V.L.B. was supported by the Stony Wold-Herbert Fund, and A.Y.K. was supported by the Fondation Médicale Medische Stichting Mathilde E. Horlait-Dapsens. -

Partial IFN-gamma R2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation

WOS: 000326078200022PubMed ID: 23963039We report a molecular study of the two known patients with autosomal recessive, partial interferon-gamma receptor (IFN-gamma R)2 deficiency (homozygous for mutations R114C and G227R), and three novel, unrelated children, homozygous for S124F (P1) and G141R (P2 and P3). IFN-gamma R2 levels on the surface of the three latter patients' cells are slightly lower than those on control cells. The patients' cells also display impaired, but not abolished, response to IFN-gamma. Moreover, the R114C, S124F, G141R and G227R IFNGR2 hypomorphic alleles all encode misfolded proteins with abnormal N-glycosylation. The mutants are largely retained in the endoplasmic reticulum, although a small proportion reach and function at the cell surface. Strikingly, the IFN-gamma response of the patients' cells is enhanced by chemical modifiers of N-glycosylation, as previously shown for patients with gain-of-glysosylation T168N and misfolding 382-387dup null mutations. All four in-frame IFNGR2 hypomorphic mutant alleles encoding surface-expressed receptors are thus deleterious by a mechanism involving abnormal N-glycosylation and misfolding of the IFN-gamma R2 protein. The diagnosis of partial IFN-gamma R2 deficiency is clinically useful, as affected patients should be treated with IFN-, unlike patients with complete IFN-gamma R2 deficiency. Moreover, inhibitors of glycosylation might be beneficial in patients with complete or partial IFN-gamma R2 deficiency due to misfolding or gain-of-glycosylation receptors.European Research CouncilEuropean Research Council (ERC) [ERC-2010-AdG-268777]; Institut National de la Sante et de la Recherche Medicale, University Paris Descartes, French National Agency for Research (ANR)French National Research Agency (ANR); EUEuropean Union (EU) [HEALTH-F3-2008-200732]; Bill and Melinda Gates FoundationGates Foundation; St. Giles Foundation; Jeffrey Modell Foundation; Talecris Biotherapeutics; Rockefeller University Center for Clinical and Translational Science from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS) [8UL1TR000043]; Rockefeller University; National Institute of Allergy and Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [1R01AI089970]; EMBO Long Term Fellowship program; Stony Wold-Herbert Fund; Choh-Hao Li Memorial Fund Scholar award; Shanghai Educational Development Foundation; AXA Research Fund; Fondation Medicale Medische Stichting Mathilde E. Horlait-DapsensThis work was supported by grants from the European Research Council (ERC-2010-AdG-268777), Institut National de la Sante et de la Recherche Medicale, University Paris Descartes, French National Agency for Research (ANR), the EU-grant HOMITB (grant HEALTH-F3-2008-200732), the Bill and Melinda Gates Foundation, the St. Giles Foundation, the Jeffrey Modell Foundation, and Talecris Biotherapeutics, Rockefeller University Center for Clinical and Translational Science grant 8UL1TR000043 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), the Rockefeller University, and the National Institute of Allergy and Infectious Diseases (grant 1R01AI089970). R.M.-B. is supported by the EMBO Long Term Fellowship program. X.-F.K. is supported by the Stony Wold-Herbert Fund, Choh-Hao Li Memorial Fund Scholar award, and the Shanghai Educational Development Foundation, Y.I. was supported by the AXA Research Fund. V.L.B. was supported by the Stony Wold-Herbert Fund, and A.Y.K. was supported by the Fondation Medicale Medische Stichting Mathilde E. Horlait-Dapsens

Avarietyofalu-mediated copy number variations can underlie il-12rβ1 deficiency

Purpose Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rβ1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rβ1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rβ1 deficiency due to CNVs. Methods We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variations by IL12RB1-targeted next-generation sequencing (NGS). Results We identified six new IL-12Rβ1-deficient patients with a complete loss of IL-12Rβ1 expression on phytohemagglutinin-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL-12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, either in the homozygous state (n =1)orintrans (n = 4) with a single-nucleotide variation (n = 3) or a small indel (n = 1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%). Conclusion The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rβ1 deficiency. © �Springer Science+Business Media, LLC, part of Springer Nature 2018

Hematologically important mutations: The autosomal forms of chronic granulomatous disease (third update)

Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe, recurrent bacterial and fungal infections. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is subsequently metabolized to hydrogen peroxide and other reactive oxygen species (ROS). These products are essential for intracellular killing of pathogens by phagocytic leukocytes (neutrophils, eosinophils, monocytes and macrophages). The leukocyte NADPH oxidase is composed of five subunits, four of which are encoded by autosomal genes. These are CYBA, encoding p22(phox), NCF1, encoding p47(phox), NCF2, encoding p67(phox) and NCF4, encoding p40(phox). This article lists all mutations identified in these genes in CGD patients. In addition, cytochrome b(558) chaperone-1 (CYBC1), recently recognized as an essential chaperone protein for the expression of the X-linked NADPH oxidase component gp91(phox) (also called Nox2), is encoded by the autosomal gene CYBC1. Mutations in this gene also lead to CGD. Finally, RAC2, a small GTPase of the Rho family, is needed for activation of the NADPH oxidase, and mutations in the RAC2 gene therefore also induce CGD-like symptoms. Mutations in these last two genes are also listed in this article

Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases

PubMed ID: 26936803Background Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. Objective Our objective was to assess the effect of mycobacterial disease in patients with CGD. Methods We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. Results Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. Conclusion Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD. © 2016 American Academy of Allergy, Asthma & Immunolog