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  • 1. • Basic and Clinical Immunology jaci.2004.06.044 Primary immunodeficiency diseases: An update Luigi Notarangelo, MD a [MEDLINE • Previous article in Issue LOOKUP] • Next article in Issue Jean-Laurent Casanova, MD b • View print version (PDF) [MEDLINE LOOKUP] Alain Fischer, MD b [MEDLINE • Drug links from Mosby's DrugConsult LOOKUP] • Genetic information from OMIM Jennifer Puck, MD c [MEDLINE • Citation of this Article LOOKUP] • View on PubMed Fred Rosen, MD d [MEDLINE LOOKUP] • Download in citation manager format Reinhard Seger, MD e [MEDLINE • Download in Medlars format LOOKUP] • Related articles in PubMed Raif Geha, MD f * [MEDLINE LOOKUP] For the International Union of Immunological Societies Primary Immunodeficiency diseases classification committee * [MEDLINE LOOKUP] Sections • Abstract • Acknowledgements • References • Publishing and Reprint Information TOP Although relatively rare, primary immune deficiency diseases (PIDs) provide an excellent window into the functioning of the immune system. In the late 1960s, observations on these diseases, with their associated infections and genetics, bisected the immune system into humoral immunity and cell-mediated immunity. These diseases also represent a challenge in their diagnosis and treatment. Beginning in 1970, a unified nomenclature for the then-known primary immunodeficiency diseases was created by a committee convened by the World Health Organization. Since then, and later under the aegis of the International Union of Immunological Societies, an international committee of experts has met every 2 to 3 years to update the classification of PIDs. During the past 15 years, the molecular basis of more than 100 PIDs has been elucidated. This update results from the latest meeting of this committee in Sintra, Portugal, June 2003, which followed 2½ days of scientific discussions. Abbreviations used PID Primary immunodeficiency disease WHO World Health Organization (Click on a term to search this journal for other articles containing that term.) Key words Primary immunodeficiency diseases, T cells, B cells, phagocytes, complement,
  • 2. immune dysregulation syndromes, innate immunity In 1970, the World Health Organization (WHO) convened a committee the task of which was to classify and define the primary immunodeficiency diseases (PIDs). This expert committee met at the WHO headquarters in Geneva, Switzerland, and accomplished its task of creating a unified nomenclature for the then-known primary immunodeficiency diseases. Fourteen different entities were identified. A report was drafted that described the genetics, clinical phenotype, diagnostic tests, and therapy of the primary immunodeficiency diseases. The committee members were Hugh Fudenberg, Robert Good, Walter Hitzig, Henry Kunkel, Ivan Roitt, Fred Rosen, David Rowe, Maxim Seligmann, and John Soothill. A summary of their report was published in the New England Journal of Medicine,1 and the full-length report appeared in Pediatrics.2 The classification was amended during a meeting of the committee in St Petersburg, Florida, in 1973, and a summary of the report was again published in the New England Journal of Medicine.3 The expert committee met just once more in Geneva in 1977 to update the nomenclature and classification of the PIDs. After the meeting in Geneva in 1977, the WHO sponsored biennial or triennial meetings of the Committee on Primary Immunodeficiency Diseases. These meetings served as a vehicle for scientific presentations on advances in our knowledge of PIDs and related subjects. After each meeting, the report was updated to include new entities and further refinements in the definition of the PIDs. These meetings were held in Royaumont, France (1980); Orcas Island, Washington (1982); Gmunden, Austria (1985); Woods Hole, Massachusetts (1988); Tomamu, Japan (1991); Orvieto, Italy (1994); and Bristol, England (1996). After that, the sponsorship of the Committee was assumed by the International Union of Immunology Societies and the Jeffrey Modell Foundation. Meetings were held in Baden bei Wien, Austria (1999); Luzern, Switzerland (2001); and Sintra, Portugal (2003). This update issues from this last meeting. During the intervening 2 years between the previous meeting held in Luzern, Switzerland. in 20014 and the Sintra meeting, the molecular basis of a number of PIDs was elucidated. These diseases include previously known types, as well as those that are newly recognized (Tables I-VIII). We have also classified autoimmune lymphoproliferative syndromes and defects of innate immunity in separate tables (Tables IV and VI), introduced a new table for genetically inherited autoinflammatory disorders (Table VII), and reintroduced and updated the table on complement deficiencies (Table VIII).
  • 3. Table I. T- and B-cell immunodeficiencies Disease Circulating T Circulating Serum Ig Associated features Inheritance Genetic cells B cells defects– presumed pathogenesis 1. T-B+ SCID* a. c Markedly Normal or Decreased Markedly decreased XL Mutations in deficiency decreased increased NK chain of IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors b. Jak3 Markedly Normal or Decreased Markedly decreased AR Mutation in deficiency* decreased increased NK Jak3 c. IL7R Markedly Normal or Decreased Normal NK AR Mutation in deficiency decreased increased IL7RA gene d. CD45 Markedly Normal Decreased Normal / T cells AR Mutation in deficiency decreased CD45 gene e. CD3 Decreased Normal Decreased AR mutation is deficiency CD3D gene 2. T-B– SCID a. RAG 1/2 Markedly Markedly Decreased Defective VDJ AR Mutation in deficiency decreased decreased recombination RAG1 or RAG2 genes b. Artemis Decreased Decreased Decreased Defective VDJ AR Mutation in deficiency recombinationRadiation Artemis gene sensitivity c. ADA Progressive Progressive Decreased AR Mutation in deficiency decrease decrease ADA gene T- cell and B-cell defects from toxic metabolites (eg, dATP, S- adenosyl homocysteine) caused by enzyme deficiency d. Reticular Markedly Markedly Decreased Granulocytopenia; AR Defective dysgenesis decreased decreased thrombocytopenia maturation of deafness T and B cells and myeloid cells (stem cell defect) 3. Omenn Present; Normal or Decreased; Erythroderma; AR Missense syndrome restricted decreased increased eosinophilia; mutations in
  • 4. heterogeneity IgE hepatosplenomegaly RAG1 or RAG2 genes 4. DNA Decreased Decreased Decreased Microcephaly facial AR DNA ligase ligase IV dystrophy, radiation IV:Defective sensitivity NHEJ DNA repair 5. X-linked Normal IgM- and IgM Neutropenia; XL Mutations in hyper-IgM IgD-bearing increased thrombocytopenia; CD40 ligand syndrome cells or normal; hemolytic anemia; gene, present but other gastrointestinal and defective B- others isotypes liver involvement; cell/DC absent decreased opportunistic infections signaling 6. CD40 Normal IgM- and IgM Neutropenia; AR Mutations in deficiency IgD-bearing increased gastrointestinal and CD40 gene, cells or normal; liver involvement; defective B- present but other opportunistic infections cell/DC others isotypes signaling absent decreased 7. PNP Progressive Normal Normal or Autoimmune hemolytic AR Mutation in NP deficiency decrease decreased anemia: neurologic gene T-cell symptoms defect from toxic metabolites (eg, dGTP) caused by enzyme deficiency 8. MHC Normal, Normal Normal or AR Mutation in class II decreased decreased transcription deficiency CD4 numbers factors (CIITA or RFX5, RFXAP, and RFXANK genes) for MHC class II molecules 9. CD3 Normal Normal Normal AR CD3D and and CD3 CD3E: deficiency Defective transcription of CD3 or CD3 chain 10. CD8 Absent CD8, Normal Normal AR Mutations of deficiency normal CD4 CD8A gene 11. ZAP-70 Decreased Normal Normal AR Mutations in deficiency CD8, normal ZAP-70 kinase CD4 gene 12. TAP-1 Decreased Normal Normal Vasculitis AR Mutations in deficiency CD8, normal TAP1 gene: CD4 MHC class I deficiency 13. TAP-2 Decreased Normal Normal Vasculitis AR Mutations in
  • 5. deficiency CD8, normal TAP2 gene: CD4 MHC class I deficiency 14. WHN Markedly Normal Decreased Alopecia; thymic AR Mutation in deficiency decreased epithelium abnormal WHN gene SCID, Severe combined immune deficiency; NK, natural killer cells; XL, X-linked inheritance; AR, autosomal recessive inheritance; RAG, recombinase activation gene; ADA, adenosine deaminase; dATP, deoxyadenosine triphosphate; NHEJ, non-homologous end joining; DC, dendritic cell; PNP, purine nucleoside phosphorylase; dGTP, deoxyguanosine triphosphate; ZAP, zeta associated protein; TAP, transporter associated protein; WHN, winged helix nude * Atypical cases of c or Jak3 deficiency might present with T cells.
  • 6. Table II. Predominantly antibody deficiencies Disease Circulating Serum Ig Associated Inheritance Genetic B cells features defects– presumed pathogenesis 1. X-linked Profoundly All isotypes Severe XL Mutations in agammaglobulinemia decreased decreased bacterial BTK infections 2. Autosomal recessive Profoundly All isotypes Severe AR Mutations in µ, agammaglobulinemia decreased decreased bacterial Ig , 5 genes, infections BLNK or LRRC8 genes 3. Ig heavy-chain gene Normal or IgG1 or Not always AR Chromosomal deletions decreased IgG2, IgG4 symptomatic deletion at absent and 14q32 in some cases IgE and IgA1 or IgA2 absent 4. Chain deficiency Normal or Ig( ) — AR Point mutations decreased decreased: at chromosome -bearing antibody 2p11 in some cells response patients normal or decreased 5. AID deficiency* Normal IgG and IgA Enlarged AR Mutation in AID decreased lymph nodes gene and germinal centers 6. UNG deficiency* Normal IgG and IgA Enlarged AR Mutation in decreased lymph nodes UNG gene and germinal centers 7. ICOS deficiency Decreased All isotypes Recurrent AR Mutation in decreased bacterial ICOS gene infections 8. Common variable Normal or Decrease in Variable Variable; immunodeficiency† decreased IgG and undetermined usually IgA ± IgM 9. Selective Ig deficiency a. IgG subclass Normal or Decrease in Not always Unknown Defects of deficiency immature one or more symptomatic isotype IgG isotypes differentiation b. IgA deficiency Normal or Decrease in Autoimmune Variable Failure of decreased IgA1 and or allergic terminal sIgA+cells IgA2 disorders; differentiation in some have IgA-positive B infections cells
  • 7. 10. Specific antibody Normal Normal Inability to Unknown Unknown deficiency make antibody to specific antigens 11. Transient Normal IgG and IgA Unknown Differentiation hypogammaglobulinemia decreased defect: delayed of infancy maturation of helper function XL, X-linked inheritance; AR, autosomal recessive inheritance; AID, activation-induced cytidine deaminase; UNG, uracil-DNA glycosylase; ICOS, inducible costimulator; Ig( ), immunoglobulin of light-chain type; BTK, Bruton tyrosine kinase. * Deficiency of activation-induced cytidine deaminase (AID) or uracil-DNA glycosylase (UNG) is present as forms of the hyper-IgM syndrome but differs from CD40L and CD40 deficiencies in that the patients have large lymph nodes with germinal centers and are not susceptible to opportunistic infections. † Common variable immunodeficiency: there are several different clinical phenotypes, probably representing distinguishable diseases with differing immunopathogeneses.
  • 8. Table III. Other well-defined immunodeficiency syndromes Disease Circulating Circulating Serum Ig Associated Inheritance Genetic T cells B cells features defects– presumed pathogenesis 1. Wiskott- Progressive Normal Decreased IgM: Thrombocytopenia; XL Mutations in Aldrich decrease antibody to small defective WASP gene; syndrome polysaccharides platelets; eczema; cytoskeletal particularly lymphomas; defect decreased; autoimmune disease affecting often increased hematopoietic IgA and IgE stem cell derivatives 2. DNA repair defects a. Ataxia- Decreased Normal Often Ataxia; AR Mutation in telangiectasia decreased IgA, telangiectasia; ATM; disorder IgE and IgG increased of cell cycle subclasses; fetoprotein; check-point increased IgM lymphoreticular and pathway monomers; other malignancies; leading to antibodies increased x-ray chromosomal variably sensitivity instability decreased b. Ataxia-like Decreased Normal Often Moderate ataxia; AR Mutation in syndrome decreased IgA, severely increased Mre 11 IgE and IgG radiosensitivity subclasses; increased IgM monomers; antibodies variably decreased c. Nijmegen Decreased Normal Often Microcephaly AR Mutation in breakage decreased IgA, lymphomas, ionizing NBS1 (Nibrin); syndrome IgE and IgG radiation sensitivity, disorder of cell subclasses; chromosomal cycle increased IgM instability checkpoint monomers; and DNA antibodies double- strand variably break repair decreased d. Artemis Decreased Decreased Decreased Radiation sensitivity AR Mutations in deficiency Artemis Defective VDJ recombination e. DNA ligase Decreased Decreased Decreased Microcephaly facial AR Mutation in IV dystrophy, radiation DNA ligase: IV sensitivity Defective NHEJ DNA repair
  • 9. f. Bloom Normal Normal Reduced Chromosomal AR Mutation in Syndrome instability, marrow Helicase failure, leukemia,lymphoma, short stature, bird- like face, sensitivity to the sun telangiectasias 3. Thymic defects a. DiGeorge Decreased Normal Normal or Hypoparathyroidism, De novo Contiguous anomaly or normal decreased conotruncal defect or gene defect in malformation; AD 90%, affecting abnormal facies; thymic partial monosomy of development 22q11-pter or 10p in some patients b. Winged Markedly Normal Decreased Alopecia; thymic AR Mutation in helix nude decreased epithelium abnormal WHN gene deficiency XL, X-linked inheritance; AR, autosomal recessive inheritance; NHEJ, non-homologous end joining; WHN, winged helix nude.
  • 10. Table IV. Disease of immune dysregulation Disease Circulating Circulating Serum Ig Associated Inheritance Genetic T cells B cells features defects– presumed pathogenesis 1. Immunodeficiency with albinism a. Chediak Higashi Normal Normal Normal Partial albinism; AR LYST: syndrome acute-phase impaired reaction; low NK lysosomal and CTL trafficking activities; giant lysosomes; encephalopathic accelerated phase b. Griscelli Normal Normal Normal Partial albinism; AR RAB27A: syndrome type 2 acute-phase secretory reaction; low NK vescicle and CTL GTPase activities; progressive encephalopathy in severe cases 2. Familial hemophagocytic lymphohistiocytosis a. Perforin Normal Normal Normal Decreased NK AR PRF1: deficiency and CTL perforin, major activities cytolytic protein b. Munc deficiency Normal Normal Normal Decreased NK AR MUNC13-4: and CTL Unc-like activities priming of vescicles for fusion 3. XLP Normal Normal or Normal, rarely Clinical and XL SAP/SH2D1A: reduced hypogammaglobulinemia immunologic adaptor manifestations protein induced by EBV regulating infection; intracellular hepatitis; signals aplastic anemia; lymphomas 4. Syndromes with autoimmunity a. ALPS i. CD95 (Fas) Normal, Normal Normal or increased Adenopathy, AR TNFRSF6:
  • 11. defects, type 1a increased splenomegaly; cell-surface CD4- CD8- defective apoptosis T cells, lymphocyte receptor activated apoptosis; phenotype autoimmune blood cytopenias; increased lymphoma risk ii. CD95L (Fas Normal, Normal Normal Adenopathy, AR TNFSF6: ligand) defects, increased defective Fas ligand for ALPS type 1b CD4- CD8- ligand mediated CD95 T cells apoptosis, apoptosis autoimmunity, eceptor lupus iii. Caspase 10 Normal, Normal Normal Adenopathy, AR CASP10: defects, ALPS type increased splenomegaly, intracellular 2a CD4- CD8- increased apoptosis T cells dendritic cells; pathway defective lymphocyte apoptosis; autoimmune disease iv. Caspase 8 Normal, Normal Normal or decreased Adenopathy, AR CASP8: defects, ALPS type slightly splenomegaly; intracellular 2b increased defective apoptosis and CD4- CD8- lymphocyte activation T cells apoptosis and pathways activation; recurrent bacterial and viral infections XL, X-linked inheritance; AR, autosomal recessive inheritance; CTL, cutaneous lymphocyte; XLP, X-linked lymphoproliferative syndrome; ALPS, autoimmune lymphoproliferative syndrome.
  • 12. Table V. Congenital defects of phagocyte number, function, or both Disease Affected Affected Associated Inheritance Gene defects– cells function features presumed pathogenesis Severe congenital N Myeloid Subgroup with AD ELA2: neutropenias Kostmann Differentiation myelodysplasia mistrafficking of elastase N Myeloid B/T lymphopenia AD GFI1: repression Differentiation of elastase Cyclic neutropenia N ? Oscillations of AD ELA2: other leukocytes mistrafficking of and platelets elastase X-linked N+M ? — XL WASP: Regulator neutropenia/myelodysplasia of actin cytoskeleton (loss of autoinhibition) Leukocyte adhesion N+M Adherence Delayed cord AR INTG2: Adhesion deficiency type 1 L+NK Chemotaxis separation Skin protein EndocytosisT/NK ulcers cytotoxicity Periodontitis Leukocytosis Leukocyte adhesion N +M Rolling LAD type 1 AR FUCT1 GDP- deficiency type 2 Chemotaxis features plus hh- Fucose transporter blood group and mental retardation Leukocyte adhesion N+M Adherence LAD type 1 plus AR ? Rap1-activation deficiency type 3 L+NK Bleeding tendency of integrins Rac 2 deficiency N Adherence Poor wound AD RAC2:Regulation ChemotaxisO2- healing of actin production Leukocytosis cytoskeleton -actin deficiency N+M Motility Mental retardation AD ACTB:Cytoplasmic Short stature Actin Localized juvenile N Formylpeptide Periodontitis only AR FPR1:Chemokine Periodontitis induced receptor chemotaxis Papillon-Lefèvre Syndrome N+M Chemotaxis Periodontitis AR CTSC:Cathepsin C Palmoplantar activation of serine hyperkeratosis proteases Specific granule deficiency N Chemotaxis N with bilobed AR C/EBPE:myeloid nuclei Transcription factor Shwachman-Diamond N Chemotaxis Pancytopenia AR SBDS Syndrome Exocrine pancreatic insufficiency Chondrodysplasia Chronic granulomatous N+M Killing (faulty O2- Subgroup:McLeod XLAR CyBA:Electron diseases X-linked CGD N+M production) phenotype transport protein
  • 13. Autosomal CGD's Killing (faulty O2- (gp91phox) CYBB production) Electron transport protein (p22phox) NCF1 Adapter protein (p47phox) NCF2 Activating protein (p67phox) Neutrophil G-6PD N+M Killing (faulty O2- Hemolytic anemia XL G-6PD:NADPH deficiency production) generation Myeloperoxidase deficiency N Candida killing Found in normal AR MPO:Antioxidative people Protection of Cathepsin G and Elastase IL-12 and IL-23 receptor L+NK IFN- secretion Susceptibility to AR IL-12R 1:IL12 and deficiency Mycobacteria and IL23 receptor 1 Salmonella chain IL-12p40 deficiency M IFN- secretion Susceptibility to AR IL-12p40 subunit Mycobacteria and of IL12/IL23: Salmonella IL12/IL23 production IFN- receptor deficiencies M+L IFN- binding or Susceptibility to AR, AD* AR IFN- R1: IFN- R signaling Mycobacteria and binding chain IFN- Salmonella R2: IFN- R signaling chain STAT1 deficiency(2 forms) M+L -IFN / / Susceptibility to AR AD* STAT1: STAT1 signaling IFN- Mycobacteria, signaling Salmonella, and viruses Susceptibility to Mycobacteria and Salmonella AD, Inherited form of IFN-R 1 deficiency or of STAT1 deficiency is due to dominant negative mutations; XL, X- linked inheritance; AR, autosomal recessive inheritance; N, neutrophils; M, monocyets-macrophages; L, lymphocytes; NK, natural killer cells; STAT1, signal transducer and activator of transcription 1.
  • 14. Table VI. Defects in innate immunity Disease Affected cell Functional defect Associated features Inheritance G d Anhidrotic ectodermal Lymphocytes+monocytes NF B signaling Anhidrotic ectodermal XR N dysplasia with pathway dysplasia+specific immunodeficiency (EDA- antibody deficiency (lack ID) of antibody response to polysaccharides)+various infections (Mycobacteria and pyogens) Anhidrotic ectodermal Lymphocytes+monocytes NF B signaling Anhidrotic ectodermal AD IK dysplasia with pathway dysplasia+T-cell immunodeficiency (EDA- defect+various infections ID) IL-1 receptor associated Lymphocytes+monocytes TIR-IRAK signaling Bacterial infections AR IR kinase 4 (IRAK4) pathway (pyogens) deficiency WHIM (warts, Granulocytes+? Increased response of Hypogammaglobulinemia, AD C hypogammaglobulinemia lymphocytes the CXCR4 chemokine reduced B-cell number, infections, receptor to its ligand severe reduction of myelokathexis) CXCL12 (SDF-1) neutrophil count, syndrome warts/HPV infection Epidermodysplasia Keratinocytes ? HPV (group B1) infections AR E verruciformis and cancer of the skin E Mannose binding protein Monocytes - Mannose recognition- Bacterial infections AR M (MBP) deficiency Complement (pyogens)+very low activation/opsonization penetrance MASP 2 deficiency (MBP Monocytes - Binds MBP- SLE syndrome AR M associated serine Enhances complement protease 2) activation and opsonization by MBP NF B, Nuclear factor B; TIR, toll and IL-1R; HPV, human papilloma virus; MBP, mannose binding protein; SLE, system lupus erythematosus.
  • 15. Table VII. Autoinflammatory disorders Disease Affected cells Functional Associated Inheritance Genetic defects features defects Familial Mature Decreased Recurrent fever, AR MEFV Mediterranean granulocytes, production of serositis and fever cytokine- pyrin permits inflammation activated ASC-induced responsive to monocytes IL-1 processing colchicine. and inflammation Predisoposes to after subclinical vasculitis and serosal injury; inflammatory macrophage bowel disease. apoptosis decreased TNF receptor- PMNs, Mutations of 55- Recurrent fever, AD TNFRSF1A associated periodic monocytes kD TNF receptor serositis, rash, syndrome (TRAPS) leading to and ocular or diminished joint inflammation soluble cytokine receptor available to bind TNF Hyper-IgD Mevalonate Periodic fever AR MVK syndrome kinase deficiency and leukocytosis affecting with high IgD cholesterol levels synthesis; pathogenesis of disease unclear Muckle-Wells Peripheral Defect in Urticaria, SNHL, AD CIAS1 (also syndrome* blood cryopyrin, amyloidosis called leukocytes involved in PYPAF1 or leukocyte NALP3) apoptosis and NF B signaling and IL-1 processing Familial cold PMNs, Same as above Nonpruritic AD CIAS1 autoinflammatory monocytes urticaria, arthritis, syndrome* chills, fever and leukocytosis after cold exposure Neonatal onset PMNs, Same as above Neonatal onset AD CIAS1 multisystem chondrocytes rash, chronic inflammatory meningitis, and disease (NOMID) arthropathy with or chronic infantile fever and neurologic inflammation cutaneous and responsive to articular syndrome IL-1R antagonist (CINCA)* (anakinra)
  • 16. Pyogenic sterile hematopoietic Disordered actin Destructive AD PSTPIP1, arthritis, pyoderma tissues, reorganization arthritis, also called gangrenosum, upregulated in leading to inflammatory skin C2BP1 acne (PAPA) activated T- compromised rash, myositis syndrome cells physiologic signaling during inflammatory response Blau syndrome Monocytes Mutations in uveitis, AD NOD2 (also nucleotide granulomatous called binding site of synovitis, CARD15) CARD15, camptodactyly, possibly rash and cranial disrupting neuropathies, interactions with 30% develop LPSs and NF B Crohn disease signaling ASC, Apoptosis-associated speck-like protein with a caspase recruitment domain; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; NF B, nuclear factor B; CIAS1, cold- induced autoinflammatory syndrome 1; PSTPIP1, proline/serine/threonine phosphatase-interacting protein 1; CARD, caspase recruitment domain; CD2BP1, CD2 binding protein 1. * All 3 syndromes are associated with similar CIAS1 mutations; disease phenotype in any individual appears to depend on modifying effects of other genes and environmental factors.
  • 17. Table VIII. Complement deficiencies Disease Functional defect Associated features Inheritance Genetic defects C1q -Absent C hematolic activity- SLE like syndrome, AR C1q deficiency Faulty dissolution of immune rheumatoid disease, complexes infection C1r -Absent C hemolytic activity- SLE like syndrome, AR C1r* deficiency* Faulty dissolution of immune rheumatoid disease, complexes infection C4 deficiency -Absent C hemolytic activity- SLE like syndrome, AR C4 Faulty dissolution of immune rheumatoid disease, complexes infection C2 deficiency† -Absent C hemolytic activity- SLE like syndrome, AR C2† Faulty dissolution of immune vasculitis, polymyositis, complexes pyogenic infection C3 deficiency -Absent C hemolytic activity- Recurrent pyogenic AR C3 Defective Bactericidal activity infections C5 deficiency -Absent C hemolytic activity- Neisserial infection, AR C5 Defective Bactericidal activity SLE C6 deficiency -Absent C hemolytic activity- Neisserial infection, AR C6 Defective Bactericidal activity SLE C7 deficiency -Absent C hemolytic activity- Neisserial infection, AR C7 Defective Bactericidal activity SLE, vasculitis ‡ C8 -Absent C hemolytic activity- Neisserial infection, AR C8 deficiency‡ Defective Bactericidal activity SLE C8 -Absent C hemolytic activity- Neisserial infection, AR C8 deficiency Defective Bactericidal activity SLE C deficiency -Absent C hemolytic activity- Neisserial infection AR C9 Defective Bactericidal activity C1 inhibitor -Spontaneous activation of the Hereditary angioedema AD C1 deficiency complement pathway with consumption of C4/C2 alternate pathway Factor I -Spontaneous activation of the Recurrent pyogenic AR Factor I deficiency complement pathway with infections consumption of C3 alternate pathway Factor H -Spontaneous activation of the Recurrent pyogenic AR Factor H deficiency complement pathway with infections consumption of C3 alternate pathway Factor D -Absent hemolytic activity by Neisserial infection AR Factor D deficiency the alternate pathway Properdin -Absent hemolytic activity by Neisserial infection XL Properdin deficiency the alternate pathway MBP -Defective mannose Pyogenic infections with AR MBP§ deficiency recognition-Defective hemolytic very low penetrance
  • 18. activity by the lectin pathway. MASP2 -Absent hemolytic activity by SLE syndrome, AR MASP2 deficiency the lectin pathway pyogenic infection SLE, Systemic lupus erythematosus; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; XL, X-linked inheritance; MBP, mannose binding protein; MASP-2, MBP-associated serine protease 2. * C1r deficiency in most cases is associated with C1s deficiency. The gene for C1s also maps to chromosome 12 pter. † Type 1 C2 deficiency is in linkage disequilibrium with HLA-A25, B18, and HLA-DR2 and complotype SO42 (slow variant of factor B, absent C2, type 4 C4A, type 2 C4B) and is common in white subjects. It results from a 28-bp deletion in the gene encoding C2. C2 is synthesized but not secreted. Type 2 C2 deficiency is very rare and involves gene defects other than that found in type 1 C2 deficiency and a failure of C2 synthesis. ‡ C8 deficiency is always associated with C8 deficiency. The gene encoding C8 maps to chromosome 9 and is normal but C8 covalently binds to C8 . § Population studies reveal no detectable increase to infections in MBP-deficient adults. The changes are summarized below: 1. DNA ligase IV and CD3 deficiencies as a cause of severe combined immunodeficiency (Table I); 2. UNG deficiency as a cause of hyper-IgM syndrome and ICOS deficiency as a cause of common variable immunodeficiency (Table II); 3. helicase deficiency as a cause of Bloom syndrome (Table III); 4. inclusion of diseases of immunoregulation in a new table (Table IV); 5. inclusion of a number of novel defects of phagocytic disorders (Table V); 6. inclusion of defects in innate immunity in a new table (Table VI); 7. inclusion of genetically inherited autoinflammatory disorders in a new table (Table VII); and 8. inclusion of a novel complement abnormality, MASP2 deficiency, in Table VIII. In addition, we have reconfigured the headings of the tables to make them uniform. This update continues to illustrate the fact that many developments in basic immunology have been suggested by newly described PIDs. Conversely, immune defects in mice with targeted gene disruption are important drivers for the discovery of novel human PIDs. The ever-expanding list of knockout mice with immune defects, accessible through the Web from a number of databases (eg,, strongly suggests that the quest for novel PIDs will continue to be fruitful for years to come. The next meeting of the International Union of Immunological Societies Scientific Committee for PID is to be held in the summer of 2005 in Budapest, Hungary. We can look forward to increased knowledge of immune pathways and the discovery of new genes that play important roles in immunity alongside the discovery of novel forms of PIDs. These advances uniformly lead to better diagnosis and treatment for PIDs. The field of primary immunodeficiency will continue to generate exciting discoveries for a long time.
  • 19. Acknowledgements TOP We thank Dr Rob Sundel (Children's Hospital, Boston, Mass) for contribution of Table VII and Ms Sayde El-Hachem for invaluable assistance in constructing the tables. References TOP 1. Fudenberg HH, Good RA, Hitzig W, Kunkel HG, Roitt IM, Rosen FS. Classification of the primary immune deficiencies: WHO recommendation N Engl J Med 1970;283:656-657. MEDLINE 2. Fudenberg H, Good RA, Goodman HC, Hitzig W, Kunkel HG, Roitt IM. Primary immunodeficiencies. Report of a World Health Organization Committee Pediatrics 1971;47:927-946. MEDLINE 3. Cooper MD, Faulk WP, Fudenberg HH, Good RA, Hitzig W, Kunkel H. Classification of primary immunodeficiencies N Engl J Med 1973;288:966-967. MEDLINE 4. International Union of Immunological Societies report on immunodeficiency disease: an update Clin Exp Immunol 2003;132:9-15. MEDLINE Publishing and Reprint Information TOP • a From the Department of Pediatrics, University of Brescia Spedali Civili, Brescia; • b Hopital Necker Enfants Malades, Paris; • c the National Institutes of Health, Bethesda; • d the Center for Blood Research, Harvard Medical School, Boston; • e Universitas-Kinderklinik, Zurich; and • f the Division of Immunology, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston. • * International Union of Immunological Societies Primary Immunodeficiency Disease Classification Committee: R. Geha and L. Notarangelo (Co-chairs) J-L. Casanova, H. Chapel, M.E. Conley, A. Fischer, S. Nonoyama, H. Ochs, J. Puck, F. Rosen, R. Seger and R. Geha. • * Reprint requests: Raif S. Geha, MD, Division of Immunology, 300 Longwood Ave, Boston, MA 02115. • Email address: (Raif Geha) • • • Copyright © by American Academy of Allergy, Asthma and Immunology • doi: 10.1016/j.jaci.2004.06.044 ________________________________________________