2. Update on primary immunodeficiency diseases
2006; Elsevier BV; Volume: 117; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2005.09.051
ISSN1097-6825
AutoresFrancisco A. Bonilla, R S Geha,
Tópico(s)Congenital heart defects research
ResumoThe pace of discovery in primary immunodeficiency continues to accelerate. In particular, lymphocyte defects have been the source of the most impressive expansion in recent years. Novel forms of agammaglobulinemia, class-switch defects, and T-B+ severe combined immunodeficiency have been described. Little by little, the genetic heterogeneity of the common variable immunodeficiency and IgA deficiency phenotypes continues to be unraveled as new molecular defects have been reported in these patients as well. The phenotypic spectrum of DiGeorge syndrome has been further developed, along with promising advances in therapy. Defects of nuclear factor κB regulation and Toll-like receptor signaling have been described, along with defects of chemokine receptors and cytoplasmic proteases. Clinically defined immunodeficiencies, such as hyper-IgE syndrome and idiopathic CD4 lymphocytopenia, are also discussed. Finally, significant adverse effects in some patients have tempered initial enthusiasm for gene therapy. The pace of discovery in primary immunodeficiency continues to accelerate. In particular, lymphocyte defects have been the source of the most impressive expansion in recent years. Novel forms of agammaglobulinemia, class-switch defects, and T-B+ severe combined immunodeficiency have been described. Little by little, the genetic heterogeneity of the common variable immunodeficiency and IgA deficiency phenotypes continues to be unraveled as new molecular defects have been reported in these patients as well. The phenotypic spectrum of DiGeorge syndrome has been further developed, along with promising advances in therapy. Defects of nuclear factor κB regulation and Toll-like receptor signaling have been described, along with defects of chemokine receptors and cytoplasmic proteases. Clinically defined immunodeficiencies, such as hyper-IgE syndrome and idiopathic CD4 lymphocytopenia, are also discussed. Finally, significant adverse effects in some patients have tempered initial enthusiasm for gene therapy. This updated chapter on primary immunodeficiency serves as a companion to the chapter published in the most recent edition of the full Primer on Allergic and Immunologic Diseases.1Bonilla F.A. Geha R.S. Primary immunodeficiency diseases.J Allergy Clin Immunol. 2003; 111: S571-S581Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar This update contains important new material, as well as useful information that was not included in the original chapter because of space constraints. Potential new literature sources for this update were collected through a PubMed search using the MeSH major topic "immunologic deficiency syndromes" with the Boolean operator "NOT" linked to HIV and AIDS. Changes have been made to all of the tables, and they are included here in their entirety. Table I describes the major classes of infectious susceptibilities associated with each of the principal categories of immunodeficiency (lymphocyte defects resulting in antibody deficiencies, cellular immune deficiencies, and combined deficiencies, as well as phagocyte and complement defects). Table II contains a listing and classification of selected molecular defects associated with primary immunodeficiency. Table III indicates the alterations in the major subpopulations of peripheral blood lymphocytes in several forms of severe combined immunodeficiency (SCID). A more detailed treatment of diagnosis and management of primary immunodeficiency can be found in a recently published practice parameter.2Bonilla F.A. Bernstein I.L. Khan D.A. Ballas Z.K. Chinen J. Frank M.M. et al.Practice parameter for the diagnosis and management of primary immunodeficiency.Ann Allergy Asthma Immunol. 2005; 94: S1-S63Abstract Full Text PDF PubMed Scopus (450) Google ScholarTable IInfectious organisms frequently associated with or characteristic of major categories of immune deficiencyOrganismAntibody deficiencyCellular deficiencyCombined deficiencyPhagocyte defectComplement deficiencyVirusesEnterovirusesHerpesvirusesAllNoNoBacteriaStreptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa, Campylobacter fetus, Neisseria meningitidis, Mycoplasma hominis, Ureaplasma urealyticumSalmonella typhiAs for antibody deficiency and cellular deficiency, also: Listeria monocytogenes, enteric floraS aureus, enteric flora, P aeruginosa, S typhi, Nocardia asteroidesAs for antibody deficiency, also N meningitidis (terminal pathway defect)MycobacteriaNoAll, including BCGAll, including BCGAll, including BCGNoFungiNoCandida albicans, Coccidioides immitis, Histoplasma capsulatum, Aspergillus fumigatusC albicans, Cryptococcus neoformans, Pneumocystis jiroveciAspergillus fumigatus, C albicans, P jiroveciNoProtozoaGiardia lambliaToxoplasma gondiiNo Open table in a new tab Table IISome immunodeficiencies associated with known molecular defectsDisordersMoleculesAntibody deficiencies The agammaglobulinemias X-linkedBruton's tyrosine kinase (BTK) Autosomal recessiveIgM heavy chain, Ig-α, surrogate light chain, B cell–linker protein (BLNK), LRRC8 Hyper-IgM syndrome, autosomal recessiveAID, UNG ICF syndromeDNA methyltransferase 3B CVIDTACI, ICOSCellular deficiencies IFN-γ/IL-12 axisIFN-γ receptor α and β chains, IL-12 p40 subunit, IL-12 receptor α chain, signal transducer and activator of transcription 1 (STAT-1) Autoimmune polyglandular syndrome type 1Autoimmune regulator (AIRE) Defective NK function (CD16 deficiency)FcγRIIICombined deficiencies SCID Defective cytokine signaling X-linkedCytokine receptor common γ chain Autosomal recessiveIL-2 receptor α chain, IL-7 receptor α chain, Janus kinase 3 (JAK3) Defective T-cell receptor signalingCD45, CD3γ, CD3δ, CD3ɛ Defective receptor gene recombinationRAG1, RAG2, DNA cross-link repair 1C (DCLRE1C, ARTEMIS) Defective nucleotide salvage pathwayAdenosine deaminase, purine nucleoside phosphorylase Defective MHC class I expressionTransporter of antigenic peptides 1 and 2 (TAP1, TAP2), TAP-binding protein Defective MHC class II transcription complementation groups A-DFour components of the MHC class II gene transcription complex: CIITA, RFXANK, RFX5, and RFXAP OtherWinged-helix nude transcription factor Wiskott-Aldrich syndromeWiskott-Aldrich syndrome protein (WASP) Ataxia-telangiectasia groupAtaxia-telangiectasia mutated (ATM), nibrin DGSChromosome 22q11 deletion, T box-1 transcription factor (TBX1) Hyper-IgM syndrome X-linkedCD40 ligand Autosomal recessiveCD40 X-linked lymphoproliferative syndromeSLAM-associated protein (SAP) Defects of NF-κB regulationNF-κB essential modulator (NEMO), IκB kinase α chain Defects of Toll-like receptor signalingIL-1 receptor associated kinase 4 (IRAK-4) WHIM syndromeCXC chemokine receptor 4 (CXCR4) Caspase 8 deficiencyCaspase 8Phagocyte defects Chronic granulomatous disease X-linkedCytochrome b558 α chain (gp91phox) Autosomal recessiveCytochrome b558 β chain (p22phox), neutrophil cytosolic factors 1 (p47phox) and 2 (p67phox), ras-related C3 botulinum toxin substrate 2 (RAC2) Chediak-Higashi syndromeLysosomal trafficking regulator (LYST) Leukocyte adhesion deficiency 1, 2β2 integrin (CD18), fucose transporter (solute carrier family 35, member C1) Neutrophil-specific granule deficiencyCCAAT/enhancer binding protein (C/EBP)-ɛ Cyclic neutropenia, Kostmann's syndromeElastase 2 X-linked neutropeniaWiskott-Aldrich syndrome proteinComplement defectsAll soluble complement components except factor BICF, Immunodeficiency, centromeric instability, and facial anomalies; WHIM, warts, hypogammaglobulinemia, infection, myelokathexis. Open table in a new tab Table IIILymphocyte phenotypes characteristically associated with particular forms of SCIDT cellsForm of SCIDCD3CD4CD8B cellsNK cellsCommon γ chain, JAK3, IL-2R α chain, CD45↓↓↓NL↓IL-7R α chain, CD3δ↓↓↓NLNLRAG1, RAG2↓↓↓↓NLAdenosine deaminase↓↓↓↓↓MHC class IINL↓NLNLNLZAP70, MHC class INLNL↓NLNL↓, Decreased; NL, normal; ZAP70, ζ-associated protein, 70 kd. Open table in a new tab ICF, Immunodeficiency, centromeric instability, and facial anomalies; WHIM, warts, hypogammaglobulinemia, infection, myelokathexis. ↓, Decreased; NL, normal; ZAP70, ζ-associated protein, 70 kd. A form of agammaglobulinemia with absent B cells in a girl with abnormal facies has been ascribed to alteration of the leucine-rich repeat–containing 8 gene (LRRC8).3Sawada A. Takihara Y. Kim J.Y. Matsuda-Hashii Y. Tokimasa S. Fujisaki H. et al.A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans.J Clin Invest. 2003; 112: 1707-1713PubMed Google Scholar LRRC8 belongs to a family of leucine-rich proteins of unknown function.4Kubota K. Kim J.Y. Sawada A. Tokimasa S. Fujisaki H. Matsuda-Hashii Y. et al.LRRC8 involved in B cell development belongs to a novel family of leucine-rich repeat proteins.FEBS Lett. 2004; 564: 147-152Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar In the single patient described, a balanced chromosomal translocation permitted expression of a truncated molecule that exhibited dominant negative activity. B-cell development was arrested in the bone marrow, as in other forms of agammaglobulinemia.5Conley M.E. Broides A. Hernandez-Trujillo V. Howard V. Kanegane H. Miyawaki T. et al.Genetic analysis of patients with defects in early B-cell development.Immunol Rev. 2005; 203: 216-234Crossref PubMed Scopus (155) Google Scholar However, the role of LRRC8 in B-cell development requires clarification. Uracil nucleoside glycosylase (UNG) deficiency leads to a form of hyper-IgM syndrome (low IgG and IgA levels with normal or increased IgM levels) highly similar to that associated with lack of activation-induced cytidine deaminase (AID).6Imai K. Slupphaug G. Lee W.I. Revy P. Nonoyama S. Catalan N. et al.Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination.Nat Immunol. 2003; 4: 1023-1028Crossref PubMed Scopus (544) Google Scholar Both AID and UNG are nucleotide-modifying enzymes expressed only in B cells and operate on sequential steps in the processes of class-switching and somatic hypermutation of immunoglobulin genes.7Longerich S. Storb U. The contested role of uracil DNA glycosylase in immunoglobulin gene diversification.Trends Genet. 2005; 21: 253-256Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 8Durandy A. Revy P. Imai K. Fischer A. Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects.Immunol Rev. 2005; 203: 67-79Crossref PubMed Scopus (74) Google Scholar AID and UNG defects have no effect on T-cell function, and patients with these diseases do not have the associated cellular immunodeficiency that is seen with defects of CD40L (CD40 ligand or CD154, X-linked hyper-IgM syndrome) and CD40 (another autosomal recessive form of hyper-IgM syndrome).9Lougaris V. Badolato R. Ferrari S. Plebani A. Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features.Immunol Rev. 2005; 203: 48-66Crossref PubMed Scopus (140) Google Scholar Some patients initially given diagnoses of common variable immunodeficiency (CVID) have been found to have mutations in the inducible T-cell costimulator gene (ICOS).10Salzer U. Maul-Pavicic A. Cunningham-Rundles C. Urschel S. Belohradsky B.H. Litzman J. et al.ICOS deficiency in patients with common variable immunodeficiency.Clin Immunol. 2004; 113: 234-240Crossref PubMed Scopus (162) Google Scholar This molecule is expressed on the surface of activated T cells and interacts with ICOS ligand expressed on B cells. This interaction clearly is important for the development of antibody responses, as evidenced by the panhypogammaglobulinemia and poor antibody formation in those who lack it. One interesting unexplained feature of this disease is that the onset of clinical symptoms does not occur until late childhood or adulthood. Only 9 in 226 patients with CVID screened thus far have been found to have ICOS mutations.10Salzer U. Maul-Pavicic A. Cunningham-Rundles C. Urschel S. Belohradsky B.H. Litzman J. et al.ICOS deficiency in patients with common variable immunodeficiency.Clin Immunol. 2004; 113: 234-240Crossref PubMed Scopus (162) Google Scholar All have origins in the Black Forest region of Germany and have the same genetic deletion, which is indicative of a founder mutation. More recently, mutations of TNFRSF13B encoding the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) have been described in patients with CVID (17 of a total 181 screened) and IgA deficiency (1/16).11Castigli E. Wilson S.A. Garibyan L. Rachid R. Bonilla F. Schneider L. et al.TACI is mutant in common variable immunodeficiency and IgA deficiency.Nat Genet. 2005; 37: 829-834Crossref PubMed Scopus (584) Google Scholar, 12Salzer U. Chapel H.M. Webster A.D. Pan-Hammarstrom Q. Schmitt-Graeff A. Schlesier M. et al.Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.Nat Genet. 2005; 37: 820-828Crossref PubMed Scopus (554) Google Scholar TACI is expressed on B cells and interacts with the ligands BAFF (B-cell activating factor, TNFSF13B) and APRIL (a proliferation-inducing ligand, TNFSF13) expressed on macrophages and dendritic cells. These interactions have important roles in B-cell activation and immunoglobulin class switching. Most patients are heterozygous for a TACI mutation, although some homozygotes have been found.12Salzer U. Chapel H.M. Webster A.D. Pan-Hammarstrom Q. Schmitt-Graeff A. Schlesier M. et al.Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.Nat Genet. 2005; 37: 820-828Crossref PubMed Scopus (554) Google Scholar Disease severity varies widely. With the exception of the single patient with IgA deficiency, all patients exhibit hypogammaglobulinemia. Additional manifestations include autoimmune disease, lymphoproliferation and hepatosplenomegaly, and malignancy. As expected, patients exhibit impaired antibody responses to immunization-infection. They also have reductions in peripheral blood switched memory B cells, which is also seen in a majority of patients with CVID (most of who probably do not have a TACI mutation).13Warnatz K. Denz A. Drager R. Braun M. Groth C. Wolff-Vorbeck G. et al.Severe deficiency of switched memory B cells (CD27(+)IgM(-)IgD(-)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease.Blood. 2002; 99: 1544-1551Crossref PubMed Scopus (512) Google Scholar There are additional reports of patients with phenotypes consistent with CVID ultimately found to have mutations in genes associated with distinct immunodeficiencies. These include BTK (mutated in X-linked agammaglobulinemia)14Stewart D.M. Tian L. Nelson D.L. A case of x-linked agammaglobulinemia diagnosed in adulthood.Clin Immunol. 2001; 99: 94-99Crossref PubMed Scopus (33) Google Scholar, 15Kanegane H. Tsukada S. Iwata T. Futatani T. Nomura K. Yamamoto J. et al.Detection of Bruton's tyrosine kinase mutations in hypogammaglobulinaemic males registered as common variable immunodeficiency (CVID) in the Japanese Immunodeficiency Registry.Clin Exp Immunol. 2000; 120: 512-517Crossref PubMed Scopus (70) Google Scholar and SH2D1A (SLAM-associated protein, mutated in X-linked lymphoproliferative disorder).16Morra M. Silander O. Calpe S. Choi M. Oettgen H. Myers L. et al.Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome.Blood. 2001; 98: 1321-1325Crossref PubMed Scopus (105) Google Scholar In a recent review of 127 cases of IgA deficiency, 50% had recurrent infections (predominantly involving the respiratory tract), 28% had autoimmune disease, and 13% exhibited asthma and allergies.17Edwards E. Razvi S. Cunningham-Rundles C. IgA deficiency: clinical correlates and responses to pneumococcal vaccine.Clin Immunol. 2004; 111: 93-97Crossref PubMed Scopus (114) Google Scholar In this group of patients, poor responses to pneumococcal polysaccharide vaccines correlated with low serum IgG2 levels (found in 8%), although, interestingly, not with respiratory infections. Low levels of IgG3 and IgG4 were found in 29% and 2% of patients, respectively; these did not correlate with other clinical or laboratory features. Approximately 75% of cases of immunodeficiency, centromeric instability, and facial anomalies syndrome result from mutation of DNMT3B (DNA methyltransferase 3B).18Ehrlich M. The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease.Clin Immunol. 2003; 109: 17-28Crossref PubMed Scopus (161) Google Scholar, 19De Ravel T.J. Deckers E. Alliet P.L. Petit P. Fryns J.P. The ICF syndrome: new case and update.Genet Couns. 2001; 12: 379-385PubMed Google Scholar Most have a variable hypogammaglobulinemia, and a few have minor in vitro abnormalities of T-cell function. About two thirds have recurrent respiratory tract bacterial infections. A similar proportion has abnormal facies, consisting of flat nasal bridge and hypertelorism with epicanthal folds. The disorder can be diagnosed on the basis of the pathognomonic karyotypic finding of abnormal structures of chromosomes 1, 9, and 16. Idiopathic CD4 lymphocytopenia is a rare immunodeficiency of unknown cause that clinically closely resembles HIV infection, but the absence of this and related viruses by means of all serologic and molecular methods of detection is a crucial element of the case definition.20Tanaka S. Teraguchi M. Hasui M. Taniuchi S. Ikemoto Y. Kobayashi Y. Idiopathic CD4+ T-lymphocytopenia in a boy with Down syndrome. Report of a patient and a review of the literature.Eur J Pediatr. 2004; 163: 122-123Crossref PubMed Scopus (13) Google Scholar Patients have persistently low CD4 T-cell counts ( 500 cells/mm3 and adequate response to polyclonal mitogens, not further specified).31Moylett E.H. Wasan A.N. Noroski L.M. Shearer W.T. Live viral vaccines in patients with partial DiGeorge syndrome: clinical experience and cellular immunity.Clin Immunol. 2004; 112: 106-112Crossref PubMed Scopus (55) Google Scholar However, in both studies, some patients with lower CD4 T-cell counts received these vaccines without serious adverse events. Some patients with complete DGS might have oligoclonal populations of T cells that do not function normally. These T cells might generate an autoimmune inflammatory response very similar to Omenn's syndrome (SCID with erythrodermia, hepatosplenomegaly and lymphadenopathy with histiocytic tissue infiltration, eosinophilia and IgE production with oligoclonal expansion of T cells expressing activation markers), which is characteristically associated with recombinase-activating gene (RAG1/RAG2) mutations.32Markert M.L. Alexieff M.J. Li J. Sarzotti M. Ozaki D.A. Devlin B.H. et al.Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome.Blood. 2004; 104: 2574-2581Crossref PubMed Scopus (79) Google Scholar, 33Scheimberg I. Hoeger P.H. Harper J.I. Lake B. Malone M. Omenn's syndrome: differential diagnosis in infants with erythroderma and immunodeficiency.Pediatr Dev Pathol. 2001; 4: 237-245Crossref PubMed Scopus (35) Google Scholar Complete DGS is a SCID phenotype and is fatal without immunoreconstitution. Although broader experience and longer follow-up are still required for complete knowledge regarding outcomes, thymus transplantation is emerging as a reproducible means for restoring T-cell function in patients with complete DGS, with or without the Omenn's syndrome phenotype.28Markert M.L. Sarzotti M. Ozaki D.A. Sempowski G.D. Rhein M.E. Hale L.P. et al.Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients.Blood. 2003; 102: 1121-1130Crossref PubMed Scopus (113) Google Scholar, 32Markert M.L. Alexieff M.J. Li J. Sarzotti M. Ozaki D.A. Devlin B.H. et al.Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome.Blood. 2004; 104: 2574-2581Crossref PubMed Scopus (79) Google Scholar As mentioned above, the Omenn's syndrome phenotype was described initially in patients with RAG1/RAG2 mutations.33Scheimberg I. Hoeger P.H. Harper J.I. Lake B. Malone M. Omenn's syndrome: differential diagnosis in infants with erythroderma and immunodeficiency.Pediatr Dev Pathol. 2001; 4: 237-245Crossref PubMed Scopus (35) Google Scholar In addition to its possible association with complete DGS, the Omenn's syndrome phenotype has also been associated with defects of ARTEMIS (gene designation DCLRE1C).34Ege M. Ma Y. Manfras B. Kalwak K. Lu H. Lieber M.R. et al.Omenn syndrome due to ARTEMIS mutations.Blood. 2005; 105: 4179-4186Crossref PubMed Scopus (185) Google Scholar Defects of NEMO (IKBKG mutation, X-linked) were initially described in male patients with hypohidrotic ectodermal dysplasia and combined immunodeficiency.35Orange J.S. Levy O. Geha R.S. Human disease resulting from gene mutations that interfere with appropriate nuclear factor-κB activation.Immunol Rev. 2005; 203: 21-37Crossref PubMed Scopus (97) Google Scholar, 36Ku C.L. Yang K. Bustamante J. Puel A. von Bernuth H. Santos O.F. et al.Inherited disorders of human Toll-like receptor signaling: immunological implications.Immunol Rev. 2005; 203: 10-20Crossref PubMed Scopus (111) Google Scholar One patient with this phenotype has been found to have an activating mutation in the IKBA gene (encoding the IκB α chain), leading to reduced NF-κB activity.37Courtois G. Smahi A. Reichenbach J. Doffinger R. Cancrini C. Bonnet M. et al.A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency.J Clin Invest. 2003; 112: 1108-1115Crossref PubMed Scopus (307) Google Scholar Recently, 2 patients have been reported to have immunodeficiency caused by NEMO mutation but without ectodermal dysplasia.38Orange J.S. Levy O. Brodeur S.R. Krzewski K. Roy R.M. Niemela J.E. et al.Human nuclear factor κB essential modulator mutation can result in immunodeficiency without ectodermal dysplasia.J Allergy Clin Immunol. 2004; 114: 650-656Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 39Niehues T. Reichenbach J. Neubert J. Gudowius S. Puel A. Horneff G. et al.Nuclear factor κB essential modulator-deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia.J Allergy Clin Immunol. 2004; 114: 1456-1462Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar IL-1 receptor–associated kinase 4 is a kinase critical for signaling by the majority of Toll-like receptors. Defects of the IRAK4 gene have been found in a few patients with extreme susceptibility to serious infections mainly caused by encapsulated gram-positive bacteria.40Picard C. Puel A. Bonnet M. Ku C.L. Bustamante J. Yang K. et al.Pyogenic bacterial infections in humans with IRAK-4 deficiency.Science. 2003; 299: 2076-2079Crossref PubMed Scopus (789) Google Scholar The results of standard screening tests of immune function are generally normal in these patients. The warts, hypogammaglobulinemia, infections, myelokathexis syndrome is the first described clinical immunodeficiency caused by mutation of a gene encoding a chemokine receptor (CXCR4).41Hernandez P.A. Gorlin R.J. Lukens J.N. Taniuchi S. Bohinjec J. Francois F. et al.Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease.Nat Genet. 2003; 34: 70-74Crossref PubMed Scopus (547) Google Scholar, 42Diaz G.A. CXCR4 mutations in WHIM syndrome: a misguided immune system?.Immunol Rev. 2005; 203: 235-243Crossref PubMed Scopus (72) Google Scholar These patients have diffuse warts, hypogammaglobulinemia, and neutropenia caused by retention of neutrophils in the bone marrow (myelokathexis). Caspases are a family (>10 members) of cytoplasmic cysteine proteases that have roles in cellular apoptosis (programmed cell death) in a variety of tissues or cell types.43Wang Z.B. Liu Y.Q. Cui Y.F. Pathways to caspase activation.Cell Biol Int. 2005; 29: 489-496Crossref PubMed Scopus (187) Google Scholar Caspase 8 deficiency (CASP8 mutation) leads to growth retardation, lymphadenopathy and hepatosplenomegaly, bacterial respiratory tract infections, and herpesvirus infections.44Chun H.J. Zheng L. Ahmad M. Wang J. Speirs C.K. Siegel R.M. et al.Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency.Nature. 2002; 419: 395-399Crossref PubMed Scopus (581) Google Scholar Laboratory immunologic abnormalities can include poor pneumococcal polysaccharide vaccine responses and selective CD4 lymphocytopenia. It is now clear that both cyclic neutropenia and a subset of Kostmann's syndrome, or congenital agranulocytosis, can result from deficiency of elastase 2.45Zeidler C. Welte K. Kostmann syndrome and severe congenital neutropenia.Semin Hematol. 2002; 39: 82-88Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Mutations in the granulocyte colony-stimulating factor receptor (CSF3R gene) that had previously been identified in patients with Kostmann's syndrome were found to have been acquired, possibly because of an underlying genetic instability in this disorder. Note that X-linked neutropenia has been associated with particular mutations of the WASP gene responsible for Wiskott-Aldrich syndrome.46Devriendt K. Kim A.S. Mathijs G. Frints S.G. Schwartz M. Van Den Oord J.J. et al.Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia.Nat Genet. 2001; 27: 313-317Crossref PubMed Scopus (358) Google Scholar This should be sought in male patients with chronic neutropenia who do not have elastase 2 deficiency. A novel form of hyper-IgE syndrome with autosomal recessive inheritance has been described; the gene defect is unknown.47Renner E.D. Puck J.M. Holland S.M. Schmitt M. Weiss M. Frosch M. et al.Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity.J Pediatr. 2004; 144: 93-99Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar, 48Grimbacher B. Holland S.M. Puck J.M. Hyper-IgE syndromes.Immunol Rev. 2005; 203: 244-250Crossref PubMed Scopus (213) Google Scholar In common with the autosomal dominant form, these patients have increased serum IgE levels, a chronic eczematous dermatitis with frequent staphylococcal superinfection, and lung infections with Aspergillus species. Patients with the autosomal recessive form have more severe viral illnesses (eg, molluscum contagiosum), do not have skeletal or dental abnormalities, and do not tend to form pneumatoceles with lung infections. Several have a novel feature: vasculitis with central nervous system involvement. Additional variants of hyper-IgE syndrome might exist.48Grimbacher B. Holland S.M. Puck J.M. Hyper-IgE syndromes.Immunol Rev. 2005; 203: 244-250Crossref PubMed Scopus (213) Google Scholar Two forms of SCID have been treated successfully with gene therapy: X-linked SCID (IL2RG mutation) and adenosine deaminase deficiency.49Gaspar H.B. Parsley K.L. Howe S. King D. Gilmour K.C. Sinclair J. et al.Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector.Lancet. 2004; 364: 2181-2187Abstract Full Text Full Text PDF PubMed Scopus (595) Google Scholar, 50Aiuti A. Slavin S. Aker M. Ficara F. Deola S. Mortellaro A. et al.Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning.Science. 2002; 296: 2410-2413Crossref PubMed Scopus (998) Google Scholar Approximately 20 patients in France, the United Kingdom, and the United States have been treated this way. Unfortunately, leukemia has developed in 3 patients thus far, apparently because of integration of the vector in a sensitive site for regulation of cell division (the LMO2 gene).51Check E. Gene-therapy trials to restart following cancer risk review.Nature. 2005; 434: 127Crossref PubMed Scopus (13) Google Scholar For this reason, gene therapy trials are currently under review. Continuing Medical Education examination: Update on primary immunodeficiency diseasesJournal of Allergy and Clinical ImmunologyVol. 117Issue 2Preview Full-Text PDF
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