Advances in basic and clinical immunology in 2014
2015; Elsevier BV; Volume: 135; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2015.02.037
ISSN1097-6825
AutoresJavier Chinen, Luigi D. Notarangelo, William T. Shearer,
Tópico(s)Cystic Fibrosis Research Advances
ResumoGenetic identification of immunodeficiency syndromes has become more efficient with the availability of whole-exome sequencing, expediting the identification of relevant genes and complementing traditional linkage analysis and homozygosity mapping. New genes defects causing immunodeficiency include phophoglucomutase 3 (PGM3), cytidine 5′ triphosphate synthase 1 (CTPS1), nuclear factor κB–inducing kinase (NIK), cytotoxic T lymphocyte–associated antigen 4 (CTLA4), B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10), phosphoinositide-3 kinase regulatory subunit 1 (PIK3R1), IL21, and Jagunal homolog 1 (JAGN1). New case reports expanded the clinical spectrum of gene defects. For example, a specific recombination-activating gene 1 variant protein with partial recombinant activity might produce Omenn syndrome or a common variable immunodeficiency phenotype. Central and peripheral B-cell tolerance was investigated in patients with several primary immunodeficiencies, including common variable immunodeficiency and Wiskott-Aldrich syndrome, to explain the occurrence of autoimmunity and inflammatory disorders. The role of IL-12 and IL-15 in the enhancement of natural killer cell activity was reported. Newborn screening for T-cell deficiency is being implemented in more states and is achieving its goal of defining the true incidence of severe combined immunodeficiency and providing early treatment that offers the highest survival for these patients. Definitive treatment of severe immunodeficiency with both hematopoietic stem cell transplantation and gene therapy was reported to be successful, with increasing definition of conditions needed for optimal outcomes. Progress in HIV infection is directed toward the development of an effective vaccine and the eradication of hidden latent virus reservoirs. Genetic identification of immunodeficiency syndromes has become more efficient with the availability of whole-exome sequencing, expediting the identification of relevant genes and complementing traditional linkage analysis and homozygosity mapping. New genes defects causing immunodeficiency include phophoglucomutase 3 (PGM3), cytidine 5′ triphosphate synthase 1 (CTPS1), nuclear factor κB–inducing kinase (NIK), cytotoxic T lymphocyte–associated antigen 4 (CTLA4), B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10), phosphoinositide-3 kinase regulatory subunit 1 (PIK3R1), IL21, and Jagunal homolog 1 (JAGN1). New case reports expanded the clinical spectrum of gene defects. For example, a specific recombination-activating gene 1 variant protein with partial recombinant activity might produce Omenn syndrome or a common variable immunodeficiency phenotype. Central and peripheral B-cell tolerance was investigated in patients with several primary immunodeficiencies, including common variable immunodeficiency and Wiskott-Aldrich syndrome, to explain the occurrence of autoimmunity and inflammatory disorders. The role of IL-12 and IL-15 in the enhancement of natural killer cell activity was reported. Newborn screening for T-cell deficiency is being implemented in more states and is achieving its goal of defining the true incidence of severe combined immunodeficiency and providing early treatment that offers the highest survival for these patients. Definitive treatment of severe immunodeficiency with both hematopoietic stem cell transplantation and gene therapy was reported to be successful, with increasing definition of conditions needed for optimal outcomes. Progress in HIV infection is directed toward the development of an effective vaccine and the eradication of hidden latent virus reservoirs. In 2014, several reports studied immunodeficiency syndromes that have in common an impaired signal transduction needed for nuclear factor κB (NF-κB) activation. These molecular defects result in defective B- and T-cell function with variable clinical manifestations. Turvey et al1Turvey S.E. Durandy A. Fischer A. Fung S.Y. Geha R.S. Gewies A. et al.The CARD11-BCL10-MALT1 (CBM) signalosome complex: stepping into the limelight of human primary immunodeficiency.J Allergy Clin Immunol. 2014; 134: 276-284Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar discussed the pathways in NF-κB activation by the caspase recruitment domain family (CARD11)–B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)–mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) signalosome complex. They also reviewed the features of CARD11-BCL10-MALT1 complex defect syndromes and postulated how the study of these gene defects has resulted in identification of novel potential pharmacologic targets for inflammatory diseases and lymphoreticular malignancies.An example of the diverse clinical presentation associated with genetic defects of NF-κB signaling is the report by McKinnon et al2McKinnon M. Rozmus J. Fung S.Y. Hirschsfield A. Del Bel K.I. Thomas L. et al.Combined immunodeficiency associated with homozygous MALT1 mutations.J Allergy Clin Immunol. 2014; 133 (1462.e1-7): 1458-1462Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar of a patient with eczema, skin infections, chronic cheilitis, inflammatory bowel disease, and osteoporosis in whom whole-exome sequencing (WES) revealed a missense mutation in MALT1. Findings included absent mitogen and antigen-induced T-cell responses, B-cell lymphopenia, increased IgE levels, and normal IgG levels and antibody responses.Hannah and Etzioni3Hannah S. Etzioni A. MHC class I and II deficiencies.J Allergy Clin Immunol. 2014; 134: 269-275Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar reviewed the molecular pathogenesis and clinical and immunologic features of the rare MHC class I and II deficiencies. MHC class II deficiencies commonly present as a combined immunodeficiency, whereas patients with MHC class I deficiency present with chronic lung disease, inflammatory skin disease, and vasculitis.Lessons in the study of natural killer (NK) cells included the demonstration by Simhadri et al4Simhadri V.R. Mariano M.L. Zemarruzabeitia O. Seroogy C.M. Holland S.M. Kuehn H.S. et al.Intact IL-12 signaling is necessary for the generation of human natural killer cells with enhanced effector function after restimulation.J Allergy Clin Immunol. 2014; 134: 1190-1193.e1Abstract Full Text Full Text PDF PubMed Google Scholar of the need for IL-12 in the generation of NK cells with enhanced function. Another regulator of NK cell activity reported was microRNA-150. Kim et al5Kim N. Kim M. Yun S. Doh J. Greenberg P.D. Kim T.D. et al.MicroRNA-150 regulates the cytotoxicity of natural killers by targeting perforin-1.J Allergy Clin Immunol. 2014; 134: 195-203Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar showed that microRNA-150 binds to the 3′ regions of both the mouse and human perforin-1 (PRF1) gene, inhibiting its transcription. IL-15 activation decreased production of microRNA-150, followed by increased perforin expression and NK cell lytic activity.Mechanisms of B-cell function and central and peripheral tolerance were the object of studies that took advantage of the availability of patients with monogenic diseases, providing explanations for the immune dysregulation that occurs in patients with primary immunodeficiencies (Table I).6Sic H. Kraus H. Madl J. Flittner K.A. von Muschow A.L. Pieper K. et al.Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia and multiple sclerosis.J Allergy Clin Immunol. 2014; 134: 420-428Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 7Hennig C. Ilginus C. Boztug K. Skokowa J. Marodi L. Szaflarska A. et al.High-content cytometry and transcriptomic biomarker profiling of human B-cell activation.J Allergy Clin Immunol. 2014; 133: 172-180Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 8Horiuchi K. Imai K. Mitsui-Sekinaka K. Yeh T.W. Ochs H. Durandy A. et al.Analysis of somatic hypermutation in the IgM switch region in human B cells.J Allergy Clin Immunol. 2014; 134: 411-419Abstract Full Text Full Text PDF PubMed Google Scholar, 9Van Zelm M.C. Bartol S.J. Driessen G.J. Mascart F. Reisli I. Franco J.L. et al.Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation.J Allergy Clin Immunol. 2014; 134: 135-144Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 10Yu X. Almeida J.R. Darko S. van der Burg M. Ravin S.S. Malech H. et al.Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development.J Allergy Clin Immunol. 2014; 133: 1109-1115Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 11Simon K. Anderson A.M. Garabedian E.K. Moratto D. Sokolic R.A. Candotti F. Molecular and phenotypic abnormalities of B lymphocytes in patients with Wiskott-Aldrich syndrome.J Allergy Clin Immunol. 2014; 134: 896-899Abstract Full Text Full Text PDF Scopus (2) Google Scholar, 12Legresle-Peyrou C. Millili M. Luce S. Boned A. Sadek H. Roullir J. et al.The BLNK adaptor protein has a nonredundant role in human B-cell differentiation.J Allergy Clin Immunol. 2014; 134: 145-154Abstract Full Text Full Text PDF PubMed Google Scholar, 13Menard L. Caekert T. Chamberlain N. Tangye S.G. Riminton S. Church J.A. et al.Signaling lymphocyte activation molecule associated protein (SAP) pathway regulates human B cell tolerance.J Allergy Clin Immunol. 2014; 133: 1149-1161Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 14Janssen E. Morbach H. Ullas S. Bannock J.M. Massad C. Menard L. et al.Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells.J Allergy Clin Immunol. 2014; 134: 1365-1374Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 15Visentine M. Marrapodi R. Conti V. Mitrevski M. Camponeschi A. Lazzeri C. et al.Dysregulated extracellular signal-regulated kinase signaling associated with impaired B-cell receptor endocytosis in patients with common variable immunodeficiency.J Allergy Clin Immunol. 2014; 134: 401-410Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 16Pieper K. Rizzi M. Spelatas M. Smulski C. Sic H. Kraus H. et al.A common single nucleotide polymorphism impairs B-cell activating factor receptor's multimerization, contributing to common variable immunodeficiency.J Allergy Clin Immunol. 2014; 133: 1222-1225Abstract Full Text Full Text PDF PubMed Scopus (8) Google ScholarTable ISelected advances in B-cell function and immunologic tolerance•Sphingosine-1-phosphate receptors in human B cells regulate lymphocyte traffic and migration and are modulated by WASP, LRBA, and DOCK8 proteins.6Sic H. Kraus H. Madl J. Flittner K.A. von Muschow A.L. Pieper K. et al.Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia and multiple sclerosis.J Allergy Clin Immunol. 2014; 134: 420-428Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar•Kinetics of CD40L/IL-21 activation of B cells was modeled by using chip cytometry and RNA microarray, integrating membrane receptors, signal transduction, class-switch recombination, DNA repair, and cell cycle–related genes.7Hennig C. Ilginus C. Boztug K. Skokowa J. Marodi L. Szaflarska A. et al.High-content cytometry and transcriptomic biomarker profiling of human B-cell activation.J Allergy Clin Immunol. 2014; 133: 172-180Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar•Somatic hypermutation in the S region occurs before class-switch recombination and depends on CD40L, uracil-DNA glycosylase, and activation-induced deaminase.8Horiuchi K. Imai K. Mitsui-Sekinaka K. Yeh T.W. Ochs H. Durandy A. et al.Analysis of somatic hypermutation in the IgM switch region in human B cells.J Allergy Clin Immunol. 2014; 134: 411-419Abstract Full Text Full Text PDF PubMed Google Scholar•CD40L and BCR signaling pathways are complementary to eliminate autoreactive clones and provide a balanced B-cell repertoire.9Van Zelm M.C. Bartol S.J. Driessen G.J. Mascart F. Reisli I. Franco J.L. et al.Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation.J Allergy Clin Immunol. 2014; 134: 135-144Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar•BLNK plays an essential role in pre-B cell differentiation and normal use of IgVk genes.10Yu X. Almeida J.R. Darko S. van der Burg M. Ravin S.S. Malech H. et al.Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development.J Allergy Clin Immunol. 2014; 133: 1109-1115Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar•CDR3 and junctional diversity were less in patients with Omenn syndrome because of RAG mutations than in patients with atypical DiGeorge syndrome or ZAP70.11Simon K. Anderson A.M. Garabedian E.K. Moratto D. Sokolic R.A. Candotti F. Molecular and phenotypic abnormalities of B lymphocytes in patients with Wiskott-Aldrich syndrome.J Allergy Clin Immunol. 2014; 134: 896-899Abstract Full Text Full Text PDF Scopus (2) Google Scholar•Patients with WAS show an expansion of naive-like CD19hi21lo B cells thought to be autoreactive cells and a decreased proportion of memory CD27+ B cells that are more pronounced in those with autoimmunity.12Legresle-Peyrou C. Millili M. Luce S. Boned A. Sadek H. Roullir J. et al.The BLNK adaptor protein has a nonredundant role in human B-cell differentiation.J Allergy Clin Immunol. 2014; 134: 145-154Abstract Full Text Full Text PDF PubMed Google Scholar•B cells from patients with X-linked lymphoproliferative disease are enriched in autoreactive clones.13Menard L. Caekert T. Chamberlain N. Tangye S.G. Riminton S. Church J.A. et al.Signaling lymphocyte activation molecule associated protein (SAP) pathway regulates human B cell tolerance.J Allergy Clin Immunol. 2014; 133: 1149-1161Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar•Defective B-cell tolerance and Treg cells were also described in DOCK8-deficient patients with increased autoantibody levels.14Janssen E. Morbach H. Ullas S. Bannock J.M. Massad C. Menard L. et al.Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells.J Allergy Clin Immunol. 2014; 134: 1365-1374Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar•B cells in patients with CVID showed high constitutive extracellular signal-regulated kinase phosphorylation with defective BCR responses, which is in agreement with the anergic nature of B cells.15Visentine M. Marrapodi R. Conti V. Mitrevski M. Camponeschi A. Lazzeri C. et al.Dysregulated extracellular signal-regulated kinase signaling associated with impaired B-cell receptor endocytosis in patients with common variable immunodeficiency.J Allergy Clin Immunol. 2014; 134: 401-410Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar•A BAFFR variant with less affinity is present in 10% of patients with CVID, suggesting it might be a risk factor for the condition.16Pieper K. Rizzi M. Spelatas M. Smulski C. Sic H. Kraus H. et al.A common single nucleotide polymorphism impairs B-cell activating factor receptor's multimerization, contributing to common variable immunodeficiency.J Allergy Clin Immunol. 2014; 133: 1222-1225Abstract Full Text Full Text PDF PubMed Scopus (8) Google ScholarBAFFR, B cell–activating factor receptor; BCR, B-cell receptor; BLNK, B-cell linker; CD40L, CD40 ligand; LRBA, LPS-responsive, beige-like anchor protein; WAS, Wiskott-Aldrich syndrome; WASP, Wiskott-Aldrich protein; ZAP70, ζ Chain–associated protein of 70 kDa. Open table in a new tab Dhanju et al17Dhanju R. Min W. Ackerley C. Cimpean L. Palaniyar N. Roifman C.M. et al.Pulmonary alveolar proteinosis in adenosine-deaminase-deficient mice.J Allergy Clin Immunol. 2014; 133: 1467-1471Abstract Full Text Full Text PDF PubMed Google Scholar established a mouse model of adenosine deaminase (ADA) deficiency to study pulmonary alveolar proteinosis (PAP). PAP was detected early in these mice, and autoantibodies were ruled out as a cause. There was increased apoptosis of alveolar macrophages and impaired surfactant clearance. ADA enzyme supplementation prevented the development of PAP.Buckner et al18Buckner C.M. Moir S. Kardava L. Ho J. Santich B.H. Kim L.J. et al.CXCR4/IgG-expressing plasma cells are associated with human gastrointestinal tissue inflammation.J Allergy Clin Immunol. 2014; 133: 1676-1685Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar investigated plasma cells (PCs) in blood and the colon in patients with conditions that commonly present with noninfectious organ inflammation, such as Crohn disease. Although IgA-secreting PCs were predominant in the gut of healthy subjects, numbers of IgG-secreting PCs were increased in those with intestinal inflammation. The chemokine CXCR4 was strongly expressed in these cells. The authors suggest that CXCR4+ IgG-secreting PCs might be markers of intestinal inflammation.Dijkstra et al19Dijkstra K.K. Hoeks S.B. Prokken B.J. deRoeck S. TH17 differentiation capacity develops within the first 3 months of life.J Allergy Clin Immunol. 2014; 133: 891-894.e5Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar studied lymphocytes from cord blood and from infants up to 1 year of age. They showed that regulatory T (Treg) cells can be induced at any age and that TH17 cells can be induced starting at age 3 months. These findings suggest that development of tolerance and autoimmunity starts at an early age.The effect of thymectomy in infants undergoing heart defect repair was explored by Schadenberg et al.20Schadenberg A.W. van den Broek T. Siemelink M.A. Algra S.O. de Jong P.R. Jansen N.J.G. et al.Differential homeostatic dynamics of human regulatory T cell subsets following neonatal thymectomy.J Allergy Clin Immunol. 2014; 133 (e1-6): 277-280Abstract Full Text Full Text PDF PubMed Google Scholar In agreement with previous reports, they found decreased absolute CD4 T-cell subset counts compared with those in age-matched healthy control subjects. Activated Treg cell counts (CD45RO+FoxP3high) were increased, whereas naive Treg cell counts (CD45RO−FoxP3low) were decreased. Increased Ki-67 expression in Treg cells indicated increased proliferation, compensating for loss of thymic output. Similar changes in Treg cell counts have been associated with autoimmunity, and therefore the authors recommended long-term evaluation of thymectomized patients and preservation of thymic tissue when feasible.Apolipoprotein E (ApoE) is expressed in monocytes and macrophages and involved in serum lipoprotein metabolism. There are 3 human isoforms: ApoE2, ApoE3, and ApoE4. ApoE4 has been associated with cardiovascular disease, Alzheimer disease, and inflammatory disorders. Gale et al21Gale S.C. Gao L. Mikacenic C. Coyle S.M. Rafaels N. Murray Dudenkov T. et al.APOe4 is associated with human enhanced in vivo innate immune responses in human subjects.J Allergy Clin Immunol. 2014; 134: 127-134Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar performed in vitro experiments demonstrating that leukocytes from subjects carrying the ApoE3/ApoE4 phenotype expressed higher cytokines levels after stimulation with Toll-like receptor (TLR) 2, TLR4, and TLR5 agonists compared with cells from subjects carrying the ApoE3/ApoE3 phenotype. In a related observation monocyte-derived dendritic cells from Bruton tyrosine kinase–deficient patients showed differential responses to TLR agonists. Lougaris et al22Lougaris V. Baronio M. Vitali M. Tampella G. Cattalini M. Tassone L. et al.Bruton's tyrosine kinase mediates TLR9-dependent human dendritic cell activation.J Allergy Clin Immunol. 2014; 133: 1644-1650Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar showed impaired expression of activation markers and decreased secretion of IL-6, IL-12, and TNF-α in dendritic cells on stimulation with the TLR9 agonist CpG but not LPS.New primary immunodeficiency genesFor further information on new primary immunodeficiency genes, see Table II.23Zhang Y. Yu X. Ichikawa M. Lyons J.J. Datta S. Lamborn I.T. Jing H. et al.Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment.J Allergy Clin Immunol. 2014; 133: 1400-1409Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 24Stray-Pedersen A. Backe P.H. Sorte H.S. Mørkrid L. Chokshi N.Y. Erichsen H.C. et al.PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia.Am J Hum Genet. 2014; 95: 96-107Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 25Sassi A. Lazaroski S. Wu G. Haslam S.M. Fliegauf M. Mellouli F. et al.Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels.J Allergy Clin Immunol. 2014; 133: 1410-1419Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 26Salzer E. Kansu A. Sic H. Majek P. Ikinciogullari A. Dogu F.E. et al.Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency.J Allergy Clin Immunol. 2014; 133: 1651-1659.e12Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 27Schubert D. Bode C. Kenefeck R. Hou T.Z. Wing J.B. Kennedy A. et al.Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.Nat Med. 2014; 20: 1410-1416Crossref PubMed Scopus (5) Google Scholar, 28Kuehn H.S. Ouyang W. Lo B. Deenick E.K. Niemela J.E. Avery D.T. et al.Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.Science. 2014; 345: 1623-1627Crossref PubMed Scopus (11) Google Scholar, 29Deau M.C. Heurtier L. Frange P. Suarez F. Bole-Feysot C. Nitschke P. et al.A human immunodeficiency caused by mutations in the PIK3R1 gene.J Clin Invest. 2014; 124: 3923-3928Crossref PubMed Scopus (6) Google Scholar, 30Lucas C.L. Zhang Y. Venida A. Wang Y. Hughes J. McElwee J. et al.Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.J Exp Med. 2014; 211: 2537-2547Crossref PubMed Google Scholar, 31Willmann K.L. Klaver S. Doğu F. Santos-Valente E. Garncarz W. Bilic I. et al.Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity.Nat Commun. 2014; 5: 5360Crossref PubMed Google Scholar, 32Torres J.M. Martinez-Barricarte R. García-Gómez S. Mazariegos M.S. Itan Y. Boisson B. et al.Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity.J Clin Invest. 2014; 124: 5239-5248Crossref PubMed Google Scholar, 33Martin E. Palmic N. Sanquer S. Lenoir C. Hauck F. Mongellaz C. et al.CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation.Nature. 2014; 510: 288-292Crossref PubMed Scopus (3) Google Scholar, 34Boztug K. Järvinen P.M. Salzer E. Racek T. Mönch S. Garncarz W. et al.JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia.Nat Genet. 2014; 46: 1021-1027Crossref PubMed Scopus (1) Google Scholar, 35Liu Y. Jesus A.A. Marrero B. Yang D. Ramsey S.E. Montealegre Sanchez G.A. et al.Activated STING in a vascular and pulmonary syndrome.N Engl J Med. 2014; 371: 507-518Crossref PubMed Scopus (25) Google Scholar, 36Kitamura A. Sasaki Y. Abe T. Kano H. Yasutomo K. An inherited mutation in NLRC4 causes autoinflammation in human and mice.J Exp Med. 2014; 211: 2385-2396Crossref PubMed Scopus (6) Google Scholar, 37Romberg N. Al Moussawi K. Nelson-Williams C. Stiegler A.L. Loring E. Choi M. et al.Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation.Nat Genet. 2014; 46: 1135-1139Crossref PubMed Scopus (13) Google Scholar, 38Canna S.W. de Jesus A.A. Gouni S. Brooks S.R. Marrero B. Liu Y. et al.An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.Nat Genet. 2014; 46: 1140-1146Crossref PubMed Scopus (12) Google Scholar, 39Zhou Q. Yang D. Ombrello A.K. Zavialov A.V. Toro C. Zavialov A.V. et al.Early-onset stroke and vasculopathy associated with mutations in ADA2.N Engl J Med. 2014; 370: 911-920Crossref PubMed Scopus (25) Google Scholar, 40Navon-Elkan P. Pierce S.B. Segel R. Walsh T. Barash J. Padeh S. et al.Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.N Engl J Med. 2014; 370: 921-931Crossref PubMed Scopus (21) Google Scholar, 41Bras J. Guerreiro R. Santo G.C. Mutant ADA2 in vasculopathies.N Engl J Med. 2014; 371: 479-480Google Scholar, 42Chakraborty P.K. Schmitz-Abe K. Kennedy E.K. Mamady H. Naas T. Durie D. et al.Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD).Blood. 2014; 124: 2867-2871Crossref PubMed Scopus (3) Google ScholarTable IINovel gene defects as a cause of primary immunodeficienciesGeneInheritanceImmunodeficiency syndromeReferencesPGM3Autosomal recessiveAtopy, autoimmunity, frequent infection, developmental delayZhang et al,23Zhang Y. Yu X. Ichikawa M. Lyons J.J. Datta S. Lamborn I.T. Jing H. et al.Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment.J Allergy Clin Immunol. 2014; 133: 1400-1409Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Stray-Pedersen et al,24Stray-Pedersen A. Backe P.H. Sorte H.S. Mørkrid L. Chokshi N.Y. Erichsen H.C. et al.PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia.Am J Hum Genet. 2014; 95: 96-107Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Sassi et al25Sassi A. Lazaroski S. Wu G. Haslam S.M. Fliegauf M. Mellouli F. et al.Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels.J Allergy Clin Immunol. 2014; 133: 1410-1419Abstract Full Text Full Text PDF PubMed Scopus (8) Google ScholarIL21Autosomal recessiveInflammatory bowel disease, hypogammaglobulinemiaSalzer et al26Salzer E. Kansu A. Sic H. Majek P. Ikinciogullari A. Dogu F.E. et al.Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency.J Allergy Clin Immunol. 2014; 133: 1651-1659.e12Abstract Full Text Full Text PDF PubMed Scopus (8) Google ScholarCTLA4Autosomal dominantCVID, ALPSSchubert et al,27Schubert D. Bode C. Kenefeck R. Hou T.Z. Wing J.B. Kennedy A. et al.Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.Nat Med. 2014; 20: 1410-1416Crossref PubMed Scopus (5) Google Scholar Kuehn et al28Kuehn H.S. Ouyang W. Lo B. Deenick E.K. Niemela J.E. Avery D.T. et al.Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.Science. 2014; 345: 1623-1627Crossref PubMed Scopus (11) Google ScholarPIK3R1Autosomal recessiveHypogammaglobulinemia, frequent infectionsDeau et al,29Deau M.C. Heurtier L. Frange P. Suarez F. Bole-Feysot C. Nitschke P. et al.A human immunodeficiency caused by mutations in the PIK3R1 gene.J Clin Invest. 2014; 124: 3923-3928Crossref PubMed Scopus (6) Google Scholar Lucas et al30Lucas C.L. Zhang Y. Venida A. Wang Y. Hughes J. McElwee J. et al.Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.J Exp Med. 2014; 211: 2537-2547Crossref PubMed Google ScholarMAP3K14Autosomal recessiveCombined immunodeficiencyWillmann et al31Willmann K.L. Klaver S. Doğu F. Santos-Valente E. Garncarz W. Bilic I. et al.Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity.Nat Commun. 2014; 5: 5360Crossref PubMed Google ScholarBCL10Autosomal recessiveCombined immunodeficiencyTorres et al32Torres J.M. Martinez-Barricarte R. García-Gómez S. Mazariegos M.S. Itan Y. Boisson B. et al.Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity.J Clin Invest. 2014; 124: 5239-5248Crossref PubMed Google ScholarCTPS1Autosomal recessiveCombined immunodeficiencyMartin et al33Martin E. Palmic N. Sanquer S. Lenoir C. Hauck F. Mongellaz C. et al.CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation.Nature. 2014; 510: 288-292Crossref PubMed Scopus (3) Google ScholarJAGN1Autosomal recessiveCongenital neutropeniaBoztug et al34Boztug K. Järvinen P.M. Salzer E. Racek T. Mönch S. Garncarz W. et al.JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia.Nat Genet. 2014; 46: 1021-1027Crossref PubMed Scopus (1) Google ScholarTMEM173Autosomal dominantSkin and pulmonary vasculopathy, early-onset inflammationLiu et al35Liu Y. Jesus A.A. Marrero B. Yang D. Ramsey S.E. Montealegre Sanchez G.A. et al.Activated STING in a vascular and pulmonary syndrome.N Engl J Med. 2014; 371: 507-518Crossref PubMed Scopus (25) Google ScholarNLRC4Autosomal dominantFever, rash, arthralgia induced by coldPeriodic fever, macrophage activation syndromeKitamura et al36Kitamura A. Sasaki Y. Abe T. Kano H. Yasutomo K. An inherited mutation in NLRC4 causes autoinflammation in human and mice.J Exp Med. 2014; 211: 2385-2396Crossref PubMed Scopus (6) Google ScholarRomberg et al,37Romberg N. Al Moussawi K. Nelson-Williams C. Stiegler A.L. Loring E. Choi M. et al.Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation.Nat Genet. 2014; 46: 1135-1139Crossref
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