Primary immunodeficiency diseases: An update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee
2007; Elsevier BV; Volume: 120; Issue: 4 Linguagem: Inglês
10.1016/j.jaci.2007.08.053
ISSN1097-6825
AutoresRaif S. Geha, Luigi D. Notarangelo, Jean‐Laurent Casanova, Helen Chapel, Mary Ellen Conley, Alain Fischer, Lennart Hammarström, Shigeaki Nonoyama, Hans D. Ochs, Jennifer M. Puck, Chaim M. Roifman, Reinhard Seger, Josiah F. Wedgwood,
Tópico(s)Immune Cell Function and Interaction
ResumoPrimary immunodeficiency diseases (PIDs) are a genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system, such as neutrophils, macrophages, dendritic cells, complement proteins, natural killer cells, and T and B lymphocytes. The study of these diseases has provided essential insights into the functioning of the immune system. More than 120 distinct genes have been identified, whose abnormalities account for more than 150 different forms of PID. The complexity of the genetic, immunologic, and clinical features of PID has prompted the need for their classification, with the ultimate goal of facilitating diagnosis and treatment. To serve this goal, an international committee of experts has met every 2 years since 1970. In its last meeting in Jackson Hole, Wyo, after 3 days of intense scientific presentations and discussions, the committee has updated the classification of PID, as reported in this article. Primary immunodeficiency diseases (PIDs) are a genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system, such as neutrophils, macrophages, dendritic cells, complement proteins, natural killer cells, and T and B lymphocytes. The study of these diseases has provided essential insights into the functioning of the immune system. More than 120 distinct genes have been identified, whose abnormalities account for more than 150 different forms of PID. The complexity of the genetic, immunologic, and clinical features of PID has prompted the need for their classification, with the ultimate goal of facilitating diagnosis and treatment. To serve this goal, an international committee of experts has met every 2 years since 1970. In its last meeting in Jackson Hole, Wyo, after 3 days of intense scientific presentations and discussions, the committee has updated the classification of PID, as reported in this article. After the original invitation by the World Health Organization in 1970, a committee of experts in the field of primary immunodeficiency diseases (PIDs) has met every 2 years with the goal of classifying and defining this group of disorders. The most recent meeting, organized under the aegis of the International Union of Immunological Societies, with support from the Jeffrey Modell Foundation and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, took place in Jackson Hole, Wyo, in June 2007. In addition to members of the Experts Committee, the meeting gathered more than 30 speakers and more than 150 participants from 6 continents. Recent updates in the molecular and cellular pathophysiology of PID were reviewed and provided the basis for updating the classification of PID. After an opening lecture in which Tom Waldmann, a founding member of the committee, highlighted some of his most remarkable achievements in the fields of PID and tumor immunology, Kenneth Murphy reviewed the signals that govern TH cell development and differentiation into TH1, TH2, and TH17 cells. This paved the way to presentations by Bill Paul and Anna Villa, who illustrated how 2 different mechanisms (ie, homeostatic proliferation of CD4+ T cells in a lymphopenic host, and impaired central and peripheral tolerance in mice with hypomorphic defects of V[D]J recombination) may lead to similar phenotypic manifestations that mimic Omenn syndrome.1Marrella V. Poliani P.L. Casati A. Rucci F. Frascoli L. Gougeon M.L. et al.A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome.J Clin Invest. 2007; 117: 1260-1269Crossref PubMed Scopus (90) Google Scholar, 2Milner J.D. Ward J.M. Keane-Myers A. Paul W.E. Lymphopenic mice reconstituted with limited repertoire T cells develop severe, multiorgan, Th2-associated inflammatory disease.Proc Natl Acad Sci U S A. 2007; 104: 576-581Crossref PubMed Scopus (85) Google Scholar The expanding field of genes involved in V(D)J recombination, class switch recombination, and DNA repair was reviewed by Jean Pierre de Villartay (who has reported on Cernunnos deficiency)3Buck D. Malivert L. de Chasseval R. Barraud A. Fondaneche M.C. Sanal O. et al.Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly.Cell. 2006; 124: 287-299Abstract Full Text Full Text PDF PubMed Scopus (590) Google Scholar and Dick van Gent (DNA ligase 4 deficiency),4Van der Burg M. van Veelen L.R. Verkaik N.S. Wiegant W.W. Hartwig N.G. Barendregt B.H. et al.A new type of radiosensitive T−B−NK+ severe combined immunodeficiency caused by a LIG4 mutation.J Clin Invest. 2006; 116: 137-145Crossref PubMed Scopus (152) Google Scholar while Fred Alt illustrated how these and other defects may lead to generalized genomic instability5Zha S. Alt F.W. Cheng H.L. Brush J.W. Li G. Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficienct murine ES cells.Proc Natl Acad Sci U S A. 2007; 104: 4518-4523Crossref PubMed Scopus (93) Google Scholar and contribute to tumor development. Later in the meeting, Qiang Pan-Hammarström expanded on chromosome instability syndromes, and in particular on the role played by ATM, the gene mutated in Ataxia-Telangiectasia, in DNA repair.6Pan-Hammarstrom Q. Lahdesmaki A. Zhao Y. Du L. Zhao Z. Wen S. et al.Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation.J Exp Med. 2006; 203: 99-110Crossref PubMed Scopus (36) Google Scholar John Ziegler reported on a recently identified form of PID, familial hepatic veno-occlusive disease and immunodeficiency, a combined immunodeficiency caused by mutations of the SP110 gene, a component of PML nuclear bodies.7Roscioli T. Cliffe S.T. Bloch D.B. Bell C.G. Mullan G. Taylor P.J. et al.Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and veno-occlusive disease.Nat Genet. 2006; 38: 620-622Crossref PubMed Scopus (76) Google Scholar Stefan Feske presented his work on cloning of the ORAI1 gene, which encodes for an integral component of calcium channels, whose mutations lead to a severe combined immune deficiency in which T-cell development is not arrested but peripheral T cells are unresponsive to proliferative signals.8Feske S. Gwack Y. Prakriya M. Srikanth S. Puppel S.H. Tanasa B. et al.A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function.Nature. 2006; 441: 179-185Crossref PubMed Scopus (1879) Google Scholar Genevieve de Saint Basile discussed the basic mechanisms involved in cell-mediated cytotoxicity, and especially generation and trafficking of exocytic vesicles and cytolytic granules, as unraveled through the study of human models of impaired cytotoxicity.9Menager M.M. Menasche G. Romao M. Knapnougel P. Ho C.H. Garfa M. et al.Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4.Nat Immunol. 2007; 8: 257-267Crossref PubMed Scopus (217) Google Scholar Dale Umetsu reviewed the biology of natural killer (NK) T cells, and Sylvain Latour described a novel form of X-linked lymphoproliferative disease caused by mutations of the X-linked inhibitor of apoptosis gene, in which impaired apoptosis is associated with a severe decrease in NK T cells in the periphery.10Riagud S. Fontaneche M.C. Lambert N. Pasquier B. Mateo V. Soulas P. et al.XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.Nature. 2006; 444: 110-114Crossref PubMed Scopus (578) Google Scholar Amos Etzioni reported on leukocyte adhesion deficiency type 3, a disease characterized by impaired inside-out integrin signaling in leukocytes and platelets caused by mutations of the CALDAG-GEF1 gene.11Pasvolsky R. Feigelson S.W. Kilic S.S. Simon A.J. Tal-Lapidot G. Grabovsky V. et al.A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets.J Exp Med. 2007; 204: 1571-1582Crossref PubMed Scopus (138) Google Scholar The different requirements for T-cell and B-cell immunologic memory by cytopathic versus noncytopathic viruses, and the possible need for persistence/boosting with antigen in this process, were reviewed by Rolf Zinkernagel. In the last year, major advances have been achieved in the molecular and cellular characterization of hyper-IgE syndrome. Hajime Karasuyama gave an update on mutations of the TYK2 gene and abnormal cytokine-mediated signaling in an autosomal-recessive form of the disease.12Minegishi Y. Saito M. Morio T. Watanabe K. Agematsu K. Tsuchiya S. et al.Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.Immunity. 2006; 25: 745-755Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar Steven Holland reported that heterozygous mutations of signal transducer and activator of transcription (STAT)–3 account for the more common autosomal-dominant form of the disease, a previously unknown finding also confirmed by the group of Karasuyama.13Minegishi Y. Saito M. Tsuchiya S. Tsuge I. Takada H. Hara T. et al.Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome.Nature. 2007; (Aug 5 [epub ahead of print])Crossref Scopus (828) Google Scholar Two young investigators, Lilit Garibyan and Lalit Kumar, discussed the molecular mechanisms of transmembrane activator and CAML interactor (TACI) deficiency (providing evidence for intracellular preassembly of high-order multimers of the protein)14Garibyan L. Lobito A.A. Siegel R.M. Call M.E. Wucherpfennig K.W. Geha R.S. Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID).J Clin Invest. 2007; 117: 1550-1557Crossref PubMed Scopus (78) Google Scholar and the phenotype of LRRC8 knockout mice, respectively. Exciting results have recently appeared on the molecular and cellular characterization of severe congenital neutropenia. Cristoph Klein reported on the identification of 2 such defects: mutations of p14,15Bohn G. Allroth A. Brandes G. Thiel J. Glocker E. Schaffer A.A. et al.A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14.Nat Med. 2007; 13: 38-45Crossref PubMed Scopus (165) Google Scholar an endosomal scaffold protein, and of HCLS1-associated protein x1 (HAX1),16Klein C. Grudzien M. Appaswamy G. Germeshausen M. Sandrock I. Schaffer A.A. et al.HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease).Nat Genet. 2007; 39: 86-92Crossref PubMed Scopus (395) Google Scholar involved in control of apoptosis. The inflammasome was reviewed by Nunez, who showed that both gain-of-function and loss-of-function mutations of nucleotide-binding oligomerization domain (NOD)-like receptors may cause disease in human beings. Nunez especially focused on the interplay between pathogens and molecules of the innate immunity system.17Kanneganti T.D. Ozoren N. Body-Malapel M. Amer A. Park J.H. Franchi L. et al.Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3.Nature. 2006; 440: 233-236Crossref PubMed Scopus (928) Google Scholar Jean-Laurent Casanova reported on an unusual phenotype associated with mutations of the CYBB gene (which usually cause chronic granulomatous disease), further illustrating the importance of studying human patients to unravel novel molecules and functions within the immune system. The interplay between molecules of the immune system and pathogens was also discussed by Cox Terhorst, who reported on the role played by signaling lymphocyte activation molecule (SLAM) and SLAM family members in controlling bacterial infections. Michael Carroll illustrated the role played by complement in governing memory B-cell responses, whereas Peter Zipfel discussed how defects of the alternative pathway may lead to kidney disease.18Zipfel P.F. Edey M. Heinen S. Jozsi M. Richter H. Misselwitz J. et al.Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome.PloS Genet. 2007; 3: e41Crossref PubMed Scopus (268) Google Scholar Immunodysregulatory disorders were introduced by Sasha Rudensky, who discussed the development and biology of regulatory T cells. Scott Snapper showed how mutations in Wiskott-Aldrich syndrome protein (WASP) lead to inflammatory bowel disease in mice. Alberto Bosque presented novel data on Fas ligand mutations in a subgroup of patients with autoimmune lymphoproliferative syndrome that result in impaired Bcl2-interacting protein (Bim) expression and hence in decreased apoptosis.19Bosque A. Aguilo J.I. Alava M.A. Paz-Artal E. Naval J. Allende L.M. et al.The induction of Bim expression in human T-cell blasts is dependent on nonapoptotic Fas/CD95 signaling.Blood. 2007; 109: 1627-1635Crossref PubMed Scopus (20) Google Scholar Richard Siegel discussed the molecular mechanisms involved in TNF receptor–associated periodic syndrome (TRAPS) and showed that retention of TRAPS-associated mutant TNF receptor 1 molecules in the endoplasmic reticulum results in ligand-independent signaling.20Lobito A.A. Kimberley F.C. Muppidi J.R. Komarow H. Jackson A.J. Hull K.M. et al.Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS).Blood. 2006; 108: 1320-1327Crossref PubMed Scopus (196) Google Scholar In his concluding remarks, Alain Fischer summarized the heuristic value of PID. He pointed out that a substantial number of immune genes have been discovered (even in recent years) through the study of patients with PID, whereas for many others, the function has been clarified (or revealed) through the careful study of human patients. Although PIDs have been traditionally viewed as predisposing to a broad range of infectious pathogens, more and more examples are being identified in which they cause selective susceptibility to single pathogens. Furthermore, PIDs have illustrated the multiple pathways (impaired negative selection, defective development/function of regulatory T cells, perturbed apoptosis of self-reactive lymphocytes in the periphery) that may cause autoimmunity. Much more than generation of artificial models in mice, the study of human beings with PID has demonstrated the variability of phenotypes that may associate with distinct mutations in the same gene. As Fischer emphasized, it is now time to look at novel approaches to therapy for PID based on the study of disease mechanisms. This is not restricted to gene therapy but also includes bypassing biochemical and/or cellular defects (as shown by the use of IFN-γ in familial mycobacteriosis) and exploiting the use of chemical compounds to allow reading-through nonsense mutations or correction of splice-site mutations. At the end of the meeting, the International Union of Immunological Societies Expert Committee met to update the classification of PID, as presented in Table I, Table II, Table III, Table IV, Table V, Table VI, Table VII, Table VIII.Table ICombined T-cell and B-cell immunodeficienciesDiseaseCirculating T cellsCirculating B cellsSerum immunoglobulinAssociated featuresInheritanceGene defects/presumed pathogenesis1. T−B+ SCID∗Atypical cases of SCID may present with T cells because of hypomorphic mutations or somatic mutations in T-cell precursors. (a) γc deficiencyMarkedly decreasedNormal or increasedDecreasedMarkedly decreased NK cellsXLDefect in γ chain of receptors for IL-2, -4, -7, -9, -15, -21 (b) JAK3 deficiencyMarkedly decreasedNormal or increasedDecreasedMarkedly decreased NK cellsARDefect in JAK3 signaling kinase (c) IL7Rα deficiencyMarkedly decreasedNormal or increasedDecreasedNormal NK cellsARDefect in IL-7 receptor α chain (d) CD45 deficiencyMarkedly decreasedNormalDecreasedNormal γ/δ T cellsARDefect in CD45 (e) CD3δ/CD3ɛ/CD3ζ deficiencyMarkedly decreasedNormalDecreasedNormal NK cellsARDefect in CD3δ CD3ɛ or CD3ζ chains of T-cell antigen receptor2. T−B− SCID∗Atypical cases of SCID may present with T cells because of hypomorphic mutations or somatic mutations in T-cell precursors. (a) RAG 1/2 deficiencyMarkedly decreasedMarkedly decreasedDecreasedDefective VDJ recombinationARComplete defect of RAG 1 or 2 (b) DCLRE1C (Artemis) deficiencyMarkedly decreasedMarkedly decreasedDecreasedDefective VDJ recombination, radiation sensitivityARDefect in Artemis DNA recombinase-repair protein (c) Adenosine deaminase deficiencyAbsent from birth (null mutations) or progressive decreaseAbsent from birth or progressive decreaseProgressive decreaseCostochondral junction flaringARAbsent ADA, elevated lymphotoxic metabolites (dATP, S-adenosyl homocysteine) (d) Reticular dysgenesisMarkedly decreasedDecreased or normalDecreasedGranulocytopenia, thrombocytopenia (deafness)ARDefective maturation of T, B, and myeloid cells (stem cell defect)3. Omenn syndromePresent; restricted heterogeneityNormal or decreasedDecreased, except increased IgEErythroderma, eosinophilia, adenopathy, hepatosplenomegalyARMissense mutations allowing residual activity, usually in RAG1 or 2 genes but also in Artemis, IL-7Rα, and RMRP genes4. DNA ligase IVDecreasedDecreasedDecreasedMicrocephaly, facial dystrophy, radiation sensitivityARDNA ligase IV defect, impaired NHEJ5. Cernunnos/XLF deficiencyDecreasedDecreasedDecreasedMicrocephaly, in utero growth retardation, radiation sensitivityARCernunnos defect, impaired NHEJ6. CD40 ligand deficiencyNormalIgM+ and IgD+ B cells present, but others absentIgM increased or normal, other isotypes decreasedNeutropenia, thrombocytopenia; hemolytic anemia, (biliary tract and liver disease, opportunistic infections)XLDefects in CD40 ligand (CD40L), defective B-cell and dendritic cell signaling7. CD40 deficiencyNormalIgM+ and IgD+ B cells present, other isotypes absentIgM increased or normal, other isotypes decreasedNeutropenia, gastrointestinal and liver disease, opportunistic infectionsARDefects in CD40, defective B-cell and dendritic cell signaling8. PNP deficiencyProgressive decreaseNormalNormal or decreasedAutoimmune hemolytic anemia, neurological impairmentARAbsent PNP, T-cell and neurologic defects from elevated toxic metabolites (eg, dGTP)9. CD3γ deficiencyNormal (reduced TCR expression)NormalNormalARDefect in CD3γ chain10. CD8 deficiencyAbsent CD8, normal CD4 cellsNormalNormalARDefects of CD8 α chain11. ZAP-70 deficiencyDecreased CD8, normal CD4 cellsNormalNormalARDefects in ZAP-70 signaling kinase12. Ca++ channel deficiencyNormal counts, defective TCR mediated activationNormal countsNormalAutoimmunity, anhydrotic ectodermic dysplasia, nonprogressive myopathyARDefect in Orai-1, a Ca++ channel component13. MHC class I deficiencyDecreased CD8, normal CD4NormalNormalVasculitisARMutations in TAP1, TAP2 or TAPBP (tapasin) genes giving MHC class I deficiency14. MHC class II deficiencyNormal number, decreased CD4 cellsNormalNormal or decreasedARMutation in transcription factors for MHC class II proteins (C2TA, RFX5, RFXAP, RFXANK genes)15. Winged helix deficiency (nude)Markedly decreasedNormalDecreasedAlopecia, abnormal thymic epithelium (resembles nude mouse)ARDefects in forkhead box N1 transcription factor encoded by FOXN1, the gene mutated in nude mice16. CD25 deficiencyNormal to modestly decreasedNormalNormalLymphoproliferation (lymphadenopathy, hepatosplenomegaly), autoimmunity (may resemble IPEX syndrome), impaired T-cell proliferationARDefects in IL-2R α chain17. STAT5b deficiencyModestly decreasedNormalNormalGrowth hormone–insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitisARDefects of STAT5B gene, impaired development and function of γδ T cells, T-regulatory and NK cells, impaired T-cell proliferationADA, Adenosine deaminase; DCLRE, DNA cross-link repair protein 1C; dATP, deoxyadenosine triphosphate; dGTP, deoxyguanosin triphosphate; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; AR, autosomal recessive inheritance; JAK3, Janus kinase 3; NHEJ, nonhomologous end joining; PNP, purine nucleoside phosphorylase; RAG, recombinase activating gene; RMRP, RNA of mitochondrial RNA-processing endoribonuclease; SCID, severe combined immune deficiency; TAP, transporter associated with antigen processing; TAPBP, TAP binding protein; TCR, T-cell receptor; XL, X-linked inheritance; XLF, XRCC4-like factor.∗ Atypical cases of SCID may present with T cells because of hypomorphic mutations or somatic mutations in T-cell precursors. Open table in a new tab Table IIPredominantly antibody deficienciesDiseaseSerum immunoglobulinAssociated featuresInheritanceGene defects/presumed pathogenesis1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells (a) Btk deficiencyAll isotypes decreasedSevere bacterial infections; normal numbers of pro-B cellsXLMutations in Burton tyrosine kinase (b) μ Heavy chain deficiencyAll isotypes decreasedSevere bacterial infections; normal numbers of pro-B cellsARMutations in μ heavy chain (c) λ5 DeficiencyAll isotypes decreasedSevere bacterial infections; normal numbers of pro-B cellsARMutations in λ5 (d) Igα deficiencyAll isotypes decreasedSevere bacterial infections; normal numbers of pro-B cellsARMutations in Igα (e) Igβ deficiencyAll isotypes decreasedSevere bacterial infections; normal numbers of pro-B cellsARMutations in Igβ (f) BLNK deficiencyAll isotypes decreasedSevere bacterial infections; normal numbers of pro-B cellsARMutations in BLNK (g) Thymoma with immunodeficiencyAll isotypes decreasedInfections; decreased numbers of pro-B cellsNoneUnknown (h) MyelodysplasiaAll isotypes decreasedInfections; decreased numbers of pro-B cellsVariableMay have monosomy 7, trisomy 8 or dyskeratosis congenita2. Severe reduction in serum IgG and IgA with normal, low or very low numbers of B cellsCommon variable immunodeficiency disorders∗There are several different clinical phenotypes, probably representing distinguishable diseases with differing immunopathogeneses; alterations in TACI, BAFFR and Msh5 sequences may represent contributing polymorphisms or disease-modifying alterations.Low IgG and IgA; variable IgMAll have recurrent bacterial infections. Clinical phenotypes vary: autoimmune, lymphoproliferative and/or granulomatous diseaseApproximately 10% have a positive family history (AR or autosomal-dominant)Alterations in TACI, BAFFR, Msh5 may act as contributing polymorphisms†A disease-causing effect has been identified for homozygous C140R, S144X, and A181E TACI mutations. (a) ICOS deficiencyLow IgG and IgA; normal IgM—ARMutations in ICOS (b) CD19 deficiencyLow IgG, IgA and IgM—ARMutations in CD19 (c) X-linked lymphoproliferative syndrome 1‡XLP1 (X-linked lymphoproliferative syndrome) is also included in Table IV.All isotypes may be lowSome patients have antibody deficiency, although most present with fulminant EBV infection or lymphomaXLMutations in SH2D1A3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells (a) CD40L deficiency§CD40L deficiency (X-linked hyper IgM syndrome) and CD40 deficiency are also included in Table I.IgG and IgA decreased; IgM may be normal or increased; B cell numbers may be normal or increasedOpportunistic infections, neutropenia, autoimmune diseaseXLMutations in CD40L (also called TNFSF5 or CD154) (b) CD40 deficiency§Low IgG and IgA; normal or raised IgMOpportunistic infections, neutropeniaARMutations in CD40 (also called TNFRSF5) (c) Activation-induced cytidine deaminase deficiencyIgG and IgA decreased; IgM increasedEnlarged lymph nodes and germinal centresARMutations in AICDA gene (d) UNG deficiencyIgG and IgA decreased; IgM increasedEnlarged lymph nodes and germinal centersARMutations in UNG gene4. Isotype or light chain deficiencies with normal numbers of B cells (a) Ig heavy chain deletionsOne or more IgG and/or IgA subclasses as well as IgE may be absentMay be asymptomaticARChromosomal deletion at 14q32 (b) κ chain deficiencyAll immunoglobulins have λ light chainAsymptomaticARMutations in κ constant gene (c) Isolated IgG subclass deficiencyReduction in 1 or more IgG subclassUsually asymptomatic; may have recurrent viral/bacterial infectionsVariableUnknown (d) IgA deficiency associated with IgG subclass deficiencyReduced IgA with decrease in 1 or more IgG subclassRecurrent bacterial infections in majorityVariableUnknown (e) Selective IgA deficiencyIgA decreased/absentUsually asymptomatic; may have recurrent infections with poor antibody responses to carbohydrate antigens; may have allergies or autoimmune diseases; a few cases progress to CVID; others coexist with CVID in the same familyVariableUnknown5. Specific antibody deficiency with normal Ig concentrations and normal numbers of B cellsNormalInability to make antibodies to specific antigensVariableUnknown6. Transient hypogammaglobulinemia of infancy with normal numbers of B cellsIgG and IgA decreasedRecurrent moderate bacterial infectionsVariableUnknownAR, Autosomal-recessive inheritance; BAFFR, B-cell–activating factor receptor; BLNK, B-cell linker protein; CVID, common variable immune deficiency; ICOS, inducible costimulator; Msh5, homolog of E. coli MutS; UNG, uracil-DNA glycosylase; XL, X-linked inheritance.∗ There are several different clinical phenotypes, probably representing distinguishable diseases with differing immunopathogeneses; alterations in TACI, BAFFR and Msh5 sequences may represent contributing polymorphisms or disease-modifying alterations.† A disease-causing effect has been identified for homozygous C140R, S144X, and A181E TACI mutations.‡ XLP1 (X-linked lymphoproliferative syndrome) is also included in Table IV.§ CD40L deficiency (X-linked hyper IgM syndrome) and CD40 deficiency are also included in Table I. Open table in a new tab Table IIIOther well defined immunodeficiency syndromesDiseaseCirculating T cellsCirculating B cellsSerum immunoglobulinAssociated featuresInheritanceGene defects/presumed pathogenesis1. WASProgressive decreaseNormalDecreased IgM: antibody to polysaccharides particularly decreased; often increased IgA and IgEThrombocytopenia with small platelets; eczema; lymphomas; autoimmune disease; IgA nephropathy; bacterial and viral infections. XL thrombocytopenia is a mild form of WAS, and XL neutropenia is caused by missense mutations in the GTPase binding domain of WASPXLMutations in WASP; cytoskeletal defect affecting hematopoietic stem cell derivatives2. DNA repair defects (other than those in Table I) (a) Ataxia-telangiectasiaProgressive decreaseNormalOften decreased IgA, IgE and IgG subclasses; increased IgM monomers; antibodies variably decreasedAtaxia; telangiectasia; increased α fetoprotein; lympho-reticular and other malignancies; increased X-ray sensitivity; chromosomal instabilityARMutation in ATM; disorder of cell cycle check-point and of DNA double-strand break repair (b) Ataxia-telangiectasia-like diseaseProgressive decreaseNormalOften decreased IgA, IgE and IgG subclasses; increased IgM monomers; antibodies variably decreasedModerate ataxia; severely increased radiosensitivityARHypomorphic mutation in MRE11; disorder of cell cycle checkpoint and of DNA double-strand break repair (c) Nijmegen breakage syndromeProgressive decreaseNormalOften decreased IgA, IgE and IgG subclasses; increased IgM monomers; antibodies variably decreasedMicrocephaly; birdlike face; lymphomas; ionizing radiation sensitivity; chromosomal instabilityARHypomorphic mutation in NBS1 (Nibrin); disorder of cell cycle checkpoint and of DNA double-strand break repair (d) Bloom syndromeNormalNormalReducedChromosomal instability; marrow failure; leukemia; lymphoma; short stature; birdlike face; sensitivity to the sun telangiectasiasARMutation in BLM, a RecQ-like helicase3. Thymic defectsDiGeorge anomalyDecreased or normal; often progressive normalizationNormalNormal or decreasedHypoparathyroidism; conotruncal heart defects; abnormal facies; interstitial deletion of 22q11-pter (or 10p) in some patientsDe novo defect or ADContiguous gene defect in 90% affecting thymic development; mutation in transcription factor TBX14. Immuno-osseous dysplasias (a) Cartilage hair hypoplasiaDecreased or normal∗Patients with cartilage-hair hypoplasia can also present also with typical severe combined immune deficiency or with Omenn syndrome.NormalNormal or reduced; antibodies variably decreasedShort-limbed dwarfism with metaphyseal dysostosis; sparse hair; anemia; neutropenia; susceptibility to lymphoma and other cancers; impaired spermatogenesis; neuronal dysplasia of the intestineARMutation in RMRP (RNase MRP RNA) (b) Schimke syndromeDecreasedNormalNormalShort stature; spondyloepiphyseal dysplasia; intrauterine growth retardation; nephropathyARMutation in SMARCAL15. Hyper-IgE syndromes (HIES) (a) Job syndrome (AD HIES)NormalNormalElevated IgERecurrent skin boils and pneumonia often caused by Staphylococcus aureus; pneumatoceles; eczema, nail candidiasis; distinctive facial features (thickened skin, broad nasal tip); failure/delay of shedding primary teeth; hyperextensible jointsAD, many de novo mutationsMutation in STAT3 (b) AR HIES with mycobacterial and viral infectionsNormalNormalElevated IgESusceptibility to intracellular bacteria (mycobacteria, Salmonella), fungi, and viruses; eczemaARMutation in TYK2,No skeletal or connective tissue abnormalities i) CNS hemorrhage, fungal and viral infectionsUnknown (c) AR HIES with viral infections and CNS vasculitis/hemorrhageNormalNormalElevated IgESusceptibility to bacterial, viral and fungal infections; eczema; vasculitis; CNS hemorrhage; no skeletal or connective tissue abnormalitiesARUnknown6. Chronic mucocutaneous candidiasisNormalNormalNormalChronic mucocutaneous candidiasis; impaired delayed-type hypersensi
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