Abstract
Primary immune deficiency diseases (PID) comprise 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, NK cells, as well as T and B lymphocytes. The study of these diseases has provided essential insights into the functioning of the immune system. Over 120 distinct genes have been identified, whose abnormalities account for more than 150 different forms of PID. The complexity of the genetic, immunological, 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 two years since 1970. In its last meeting in Jackson Hole, Wyoming, United States, following three days of intense scientific presentations and discussions, the Committee has updated the classification of PID as reported in this article.
Keywords: Primary Immunodeficiency diseases, T cells, B cells, phagocytes, complement, immune dysregulation syndromes, innate immunity
Following the original invitation by the World Health Organization in 1970, a Committee of experts in the field of Primary Immune Deficiencies (PID) has met every two 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 (IUIS), with support from the Jeffrey Modell Foundation and the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, took place in Jackson Hole, Wyoming, USA, in June 2007. In addition to members of the Experts Committee, the meeting gathered more than 30 speakers and over 150 participants from six 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 helper T 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 two different mechanisms (i.e., 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 syndrome1,2. 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)3 and Dick van Gent (DNA ligase 4 deficiency)4, while Fred Alt illustrated how these and other defects may lead to generalized genomic instability5 and contribute also 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 repair6.
John Ziegler reported on a recently identified form of PID, familial hepatic veno-occlusive disease and immunodeficiency (VODI), a combined immunodeficiency due to mutations of the SP110 gene, a component of PML nuclear bodies7. 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 signals8. Genevieve de Saint Basile discussed the basic mechanisms involved in cell-mediated cytotoxicity, and especially generation and trafficking of exocytic vescicles and cytolytic granules, as unraveled through the study of human models of impaired cytotoxicity9. Dale Umetsu reviewed the biology of Natural Killer T (NKT) cells, and Sylvain Latour described a novel form of X-linked lymphoproliferative disease, due to mutations of the XIAP (X-linked inhibitor of apoptosis) gene, in which impaired apoptosis is associated with a severe decrease of NKT cells in the periphery10.
Amos Etzioni reported on Leukocyte Adhesion Deficiency type 3 (LAD3), a disease characterized by impaired inside-out integrin signaling in leukocytes and platelets, due to mutations of the CALDAG-GEF1 gene11. The different requirement for T and B cell immunological memory by cytopathic vs. non cytopathic 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 disease12. Steven Holland reported that heterozygous mutations of STAT3 account for the more common autosomal dominant form of the disease, a previously unwknown finding also confirmed by the group of Karasuyama13. Two young investigators, Lilit Garibyan and Lalit Kumar, discussed the molecular mechanisms of TACI deficiency (providing evidence for intracellular pre-assembly of high-order multimers of the protein)14 and the phenotype of LRRC8 knock-out mice, respectively.
Exciting results have recently appeared on the molecular and cellular characterization of severe congenital neutropenia (SCN). Cristoph Klein reported on the identification of two such defects: mutations of p1415, an endosomal scaffold protein, and of HAX116, involved in control of apoptosis. The inflammasome was reviewed by Nunez, who showed that both gain-of-function and loss-of-function mutations of NOD-like receptors (NLR) may cause disease in humans. Nunez especially focused on the interplay between pathogens and molecules of the innate immunity system17. Jean-Laurent Casanova reported on an unusual phenotype associated with mutations of the CYBB gene (that usually cause chronic granulomatous disease), thus 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 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 disease18.
Immunodysregulatory disorders were introduced by Sasha Rudensky, who discussed the development and biology of regulatory T cells. Scott Snapper showed how mutations in WASP lead to inflammatory bowel disease in mice. Alberto Bosque presented novel data on Fas ligand (FasL) mutations in a subgroup of patients with autoimmune lymphoproliferative syndrome (ALPS), that result in impaired Bim expression and hence in decreased apoptosis19. Richard Siegel discussed the molecular mechanisms involved in TRAPS, and showed that retention of TRAPS-associated mutant TNF-receptor 1 (TNFR1) molecules in the endoplasmic retyculum results in ligand-independent signaling20.
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. While PID 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, PID have illustrated the multiple pathways (impaired negative selection, defective development/function of regulatory T cells, perturbed apoptosis of self-reacive lymphocytes in the periphery) that may cause autoimmunity. Much more than generation of artificial models in mice, the study of humans 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 IUIS Expert Committee met to update the classification of PID, as presented in Table 1–8.
Table I.
Combined T and B cell immunodeficiencies
| Disease | Circulating T cells | Circulating B cells | Serum Ig | Associated Features | Inheritance | Genetic defects/presumed pathogenesis |
|---|---|---|---|---|---|---|
| 1. T−B+ SCID* | ||||||
| (a) γc deficiency | Markedly decreased | Normal or increased | Decreased | Markedly decreased NK cells | XL | Defect in γ chain of receptors for IL-2, -4, -7, -9, -15, -21 |
| (b) JAK3 deficiency | Markedly decreased | Normal or increased | Decreased | Markedly decreased NK cells | AR | Defect in JAK3 signaling kinase |
| (c) IL7Rα deficiency | Markedly decreased | Normal or increased | Decreased | Normal NK cells | AR | Defect in IL-7 receptor α chain |
| (d) CD45 deficiency | Markedly decreased | Normal | Decreased | Normal γ/δ T cells | AR | Defect in CD45 |
| (e) CD3δ/CD3ε /CD3 ζ deficiency | Markedly Decreased | Normal | Decreased | Normal NK cells | AR | Defect in CD3δ CD3ε or CD3ζ chains of T cell antigen receptor |
| 2. T−B−SCID* | ||||||
| (a) RAG 1/2 deficiency | Markedly decreased | Markedly decreased | Decreased | Defective VDJ recombination | AR | Complete defect of recombinase activating gene (RAG) 1 or 2 |
| (b) DCLRE1C (Artemis) deficiency | Markedly decreased | Markedly decreased | Decreased | Defective VDJ recombination, radiation sensitivity | AR | Defect in Artemis DNA recombinase-repair protein |
| (c) Adenosine deaminase deficiency (ADA) | Absent from birth (null mutations) or progressive decrease | Absent from birth or progressive decrease | Progressive decrease | Costochondral junction flaring | AR | Absent ADA, elevated lymphotoxic metabolites (dATP, S-adenosyl homocysteine) |
| (d) Reticular dysgenesis | Markedly decreased | Decreased or normal | Decreased | Granulocytopenia, thrombocytopenia (deafness) | AR | Defective maturation of T, B and myeloid cells (stem cell defect) |
| 3. Omenn syndrome | Present; restricted heterogeneity | Normal or decreased | Decreased, except increased IgE | Erythroderma, eosinophilia, adenopathy, hepatosplenomegaly | AR | Missense mutations allowoing residual activity, usually in RAG1 or 2 genes but also in Artemis , IL-7Rα and RMRP genes |
| 4. DNA ligase IV | Decreased | Decreased | Decreased | Microcephaly, facial dystrophy, radiation sensitivity | AR | DNA ligase IV defect, impaired nonhomologous end joining (NHEJ) |
| 5. Cernunnos/XLF deficiency | Decreased | Decreased | Decreased | Microcephaly, in utero growth retardation, radiation sensitivity | AR | Cernunnos defect, impaired NHEJ) |
| 6. CD40 ligand deficiency | Normal | IgM and IgD B memory cells present, but others absent | IgM increased or normal, other isotypes decreased | Neutropenia, thrombocytopenia; hemolytic anemia, (biliary tract and liver disease, opportunistic infections) | XL | Defects in CD40 ligand (CD40L), defective B and dendritic cell signaling |
| 7. CD40 deficiency | Normal | IgM and IgD B cells present, other isotypes absent | IgM increased or normal, other isotypes decreased | Neutropenia, gastrointestinal and liver disease, opportunistic infections | AR | Defects in CD40, defective B and dendritic cell signaling |
| 8. Purine nucleoside phosphorylase deficiency(PNP) | Progressive decrease | Normal | Normal or decreased | Autoimmune haemolytic anaemia, neurological impairment | AR | Absent PNP, T-cell and neurologic defects from elevated toxic metabolites (e.g. dGTP) |
| 9. CD3γ deficiency | Normal (reduced TCR expression) | Normal | Normal | AR | Defect in CD3 γ | |
| 10. CD8 deficiency | Absent CD8, normal CD4 cells | Normal | Normal | AR | Defects of CD8 α chain | |
| 11. ZAP-70 deficiency | Decreased CD8, normal CD4 cells | Normal | Normal | AR | Defects in ZAP-70 signaling kinase | |
| 12. Ca++ channel deficiency | Normal counts, defective TCR mediated activation | Normal counts | Normal | Autoimmunity , anhydrotic ectodermic dysplasia, non progressive myopathy | AR | Defect in Orai-1, a Ca++ channel component |
| 13. MHC class I deficiency | Decreased CD8, normal CD4 | Normal | Normal | Vasculitis | AR | Mutations in TAP1, TAP2 or TAPBP (tapasin) genes giving MHC class I deficiency |
| 14. MHC class II deficiency | Normal number, decreased CD4 cells | Normal | Normal or decreased | AR | Mutation in transcription factors for MHC class II proteins (C2TA, RFX5, RFXAP, RFXANK genes) | |
| 15. Winged helix deficiency (Nude) | Markedly decreased | Normal | Decreased | Alopecia, abnormal thymic epithelium (resembles nude mouse) | AR | Defects in forkhead box N1 transcription factor encoded by FOXN1, the gene mutated in nude mice |
| 16. CD25 deficiency | Normal to modestly decreased | Normal | Normal | Lymphoproliferation (lymphadenopathy, hepatosplenomegaly), autoimmunity (may resemble IPEX syndrome), impaired T-cell proliferation | AR | Defects in IL-2R α chain |
| 17. STAT5b deficiency | Modestly decreased | Normal | Normal | Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstital pneumonitis | AR | Defects of STAT5B gene, impaired development and function of γδT cells, Treg and NK cells, impaired T-cell proliferation |
Abbreviations: SCID, severe combined immune deficiencies; XL, X-linked inheritance; AR, autosomal recessive inheritance; NK, natural killer cells.
Atypical cases of SCID may present with T cells because of hypomorphic mutations or somatic mutations in T cell precursors.
Table VIII.
Complement deficiencies
| Disease | Functional Defect | Associated Features | Inheritance | Gene Defects |
|---|---|---|---|---|
| C1q deficiency | -Absent C hemolytic activity, Defective MAC * -Faulty dissolution of immune complexes -Faulty clearance of apoptotic cells |
SLE–like syndrome, rheumatoid disease, infections | AR | C1q |
| C1r deficiency* | -Absent C hemolytic activity, Defective MAC -Faulty dissolution of immune complexes |
SLE–like syndrome, rheumatoid disease, infections | AR | C1r* |
| C1s deficiency | -Absent C hemolytic activity | SLE-like syndrome; multiple autoimmune diseases | AR | C1s* |
| C4 deficiency | -Absent C hemolytic activity, Defective MAC -Faulty dissolution of immune complexes -Defective humoral immune response |
SLE–like syndrome, rheumatoid disease, infections | AR | C4A and C4B§ |
| C2 deficiency ** | -Absent C hemolytic activity, Defective MAC -Faulty dissolution of immune complexes |
SLE–like syndrome, vasculitis, polymyositis, pyogenic infections | AR | C2** |
| C3 deficiency | -Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity -Defective humoral immune response |
Recurrent pyogenic infections | AR | C3 |
| C5 deficiency | -Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity |
Neisserial infections, SLE | AR | C5 |
| C6 deficiency | -Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity |
Neisserial infections, SLE | AR | C6 |
| C7 deficiency | -Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity |
Neisserial infections, SLE, vasculitis | AR | C7 |
| C8a deficiency *** | -Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity |
Neisserial infections, SLE | AR | C8α |
| C8b deficiency | -Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity |
Neisserial infections, SLE | AR | C8β |
| C9 deficiency | -Reduced C hemolytic activity, Defective MAC -Defective Bactericidal activity |
Neisserial infections**** | AR | C9 |
| C1 inhibitor deficiency | -Spontaneous activation of the complement pathway with consumption of C4/C2 -Spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen |
Hereditary angioedema | AD | C1 inhibitor |
| Factor I deficiency | -Spontaneous activation of the alternative complement pathway with consumption of C3 | Recurrent pyogenic infections, glomerulonephritis, hemolytic-uremic syndrome | AR | Factor I |
| Factor H deficiency | -Spontaneous activation of the alternative complement pathway with consumption of C3 | Hemolytic-uremic syndrome, membranoproliferative glomerulonephritis | AR | Factor H |
| Factor D deficiency | -Absent hemolytic activity by the alternate pathway | Neisserial infection | AR | Factor D |
| Properdin deficiency | -Absent hemolytic activity by the alternate pathway | Neisserial infection | XL | Properdin |
| MBP deficiency ***** | -Defective mannose recognition -Defective hemolytic activity by the lectin pathway. |
Pyogenic infections with very low penetrance mostly asymptamatic | AR | MBP ***** |
| MASP2 deficiency****** | -Absent hemolytic activity by the lectin pathway | SLE syndrome, pyogenic infection | AR | MASP2 |
| Complement Receptor 3 (CR3) deficiency | -see LAD1 in Table V, above | AR | INTGB2 | |
| Membrane Cofactor Protein (CD46) deficiency | -Inhibitor of complement alternate pathway, decreased C3b binding | Glomerulonephritis, atypical hemolytic uremic syndrome | AD | MCP |
| Membrane Attack Complex Inhibitor (CD59) deficiency | -Erythrocytes highly susceptible to complement-mediated lysis | Hemolytic anemia, thrombosis | AR | CD59 |
| Paroxysmal nocturnal hemoglobinuria | -Complement-mediated hemolysis | Recurrent hemolysis | Acquired X-linked mutation | PIGA |
The C1r and C1s genes are located within 9.5 kb of each other. In many cases of C1r deficiency, C1s is also deficient.
Gene duplication has resulted in two active C4A genes located within 10 kb. C4 deficiency requires abnormalities in both genes, usually the result of deletions.
Type 1 C2 deficiency is in linkage disequilibrium with HLA-A25, B18 and -DR2 and complotype, SO42 (slow variant of Factor B, absent C2, type 4 C4A, type 2 C4B) and is common in Caucasians (about 1 per 10,000). It results from a 28-bp deletion resulting in a premature stop codon in the C2 gene; C2 mRNA is not produced. Type 2 C2 deficiency is very rare and involves amino acid substitutions which result in C2 secretory block.
C8alpha deficiency is always associated with C8gamma deficiency. The gene encoding C8gamma maps to chromosome 9 and is normal. C8gamma is covalently bound to C8alpha.
Association is weaker than with C5, C6, C7 and C8 deficiencies. C9 deficiency occurs in about 1 per 1,000 Japanese.
Population studies reveal no detectable increase in infections in MBP deficient adults.
A single patient.
Abbreviations: MAC= Membrane attack complex SLE: systemic lupus erythematosus; MBP: Mannose binding Protein; MASP-2: MBP associated serine protease 2.
Table II.
Predominantly antibody deficiencies
| Disease | Serum Ig | Associated features | Inheritance | Genetic defects/presumed pathogenesis |
|---|---|---|---|---|
| 1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells | ||||
| a) Btk deficiency | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | XL | Mutations in BTK |
| b) μ heavy chain deficiency | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in μ heavy chain |
| c) λ5 deficiency | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in λ5 |
| d) Igα Deficiency | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in Igα |
| e) Igβ Deficiency | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in Igβ |
| f) BLNK deficiency | All isotypes decreased | Severe bacterial infections; normal numbers of pro-B cells | AR | Mutations in BLNK |
| g) Thymoma with immunodeficiency | All isotypes decreased | Infections; decreased numbers of pro-B cells | None | Unknown |
| h) Myelodysplasia | All isotypes decreased | Infections; decreased numbers of pro-B cells | Variable | May have monosomy 7, trisomy 8 or dyskeratosis congenita |
| 2. Severe reduction in serum IgG and IgA with normal, low or very low numbers of B cells | ||||
| Common variable immunodeficiency disorders* | Low IgG and IgA; variable IgM | All have recurrent bacterial infections. Clinical phenotypes vary: autoimmune, lymphoproliferative and/or granulomatous disease | Approximately 10% have a positive family history (AR or AD) | Alterations in TACI, BAFFR, Msh5 may act as contributing polymorphisms** |
| a) ICOS deficiency | Low IgG and IgA; normal IgM | - | AR | Mutations in ICOS |
| b) CD19 deficiency | Low IgG, IgA and IgM | - | AR | Mutations in CD19 |
| c) XLP1*** | All isotypes may be low | Some patients have antibody deficiency though most present with fulminant Epstein Barr Virus infection or Lymphoma | XL | Mutations in SH2D1A |
| 3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells | ||||
| a) CD40L deficiency**** | IgG and IgA decreased; IgM may be normal or increased; B cell numbers may be normal or increased | Opportunistic infections, neutropenia, autoimmune disease | XL | Mutations in CD40L (also called TNFSF5 or CD154) |
| b) CD40 deficiency**** | Low IgG and IgA; normal or raised IgM | Opportunistic infections, neutropenia | AR | Mutations in CD40 (also called TNFRSF5) |
| c) AID deficiency | IgG and IgA decreased; IgM increased | Enlarged lymph nodes and germinal centres | AR | Mutations in AICDA gene |
| d) UNG deficiency | IgG and IgA decreased; IgM increased | Enlarged lymph nodes and germinal centres | AR | Mutations in UNG gene |
| 4. Isotype or light chain deficiencies with normal numbers of B cells | ||||
| a) Ig heavy chain deletions | One or more IgG and/or IgA subclasses as well as IgE may be absent | May be asymptomatic | AR | Chromosomal deletion at 14q32 |
| b) k chain deficiency | All immunoglobulins have lambda light chain | Asymptomatic | AR | Mutations in kappa constant gene |
| c) Isolated IgG subclass deficiency | Reduction in one or more IgG subclass | Usually asymptomatic; may have recurrent viral/bacterial infections | Variable | Unknown |
| d) IgA deficiency associated with IgG subclass deficiency | Reduced IgA with decrease in one or more IgG subclass | Recurrent bacterial infections in majority | Variable | Unknown |
| e) Selective IgA deficiency | IgA decreased/absent | Usually asymptomatic; may have recurrent infections with poor antibody responses to carbohydrate antigens; may have allergies or autoimmune diseases. | Variable | Unknown |
| A few cases progress to CVID, others coexist with CVID in the same family. | ||||
| 5. Specific antibody deficiency with normal Ig concentrations and normal numbers of B cells | Normal | Inability to make antibodies to specific antigens | Variable | Unknown |
| 6. Transient hypogammaglobulinemia of infancy with normal numbers of B cells | IgG and IgA decreased | Recurrent moderate bacterial infections | Variable | Unknown |
XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; BTK, Burton tyrosine kinase; BLNK, B cell linker protein; AID, activation-induced cytidine deaminase; UNG, uracil-DNA glycosylase; ICOS, inducible costimulator; Ig(κ), immunoglobulin of κ light-chain type.
Common 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.
A disease-causing effect has been identified for homozygous C140R 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.
Table III.
Other well-defined immunodeficiency syndromes.
| Disease | Circulating T cells | Circulating B cells | Serum Ig | Associated features | Inheritance | Genetic defects/Presumed Pathogenesis |
|---|---|---|---|---|---|---|
| 1. Wiskott-Aldrich syndrome (WAS) | Progressive decrease | Normal | Decreased IgM: antibody to polysaccharides particularly decreased; often increased IgA and IgE | Thrombocytopenia 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 WASP | XL | Mutations in WASP; cytoskeletal defect affecting haematopoietic stem cell derivatives |
| 2. DNA repair defects (other than those in Table 1) | ||||||
| (a) Ataxia-telangiectasia | Progressive decrease | Normal | Often decreased IgA, IgE and IgG subclasses; increased IgM monomers; antibodies variably decreased | Ataxia; telangiectasia; increased alpha fetoprotein; lympho-reticular and other malignancies; increased X-ray sensitivity; chromosomal instability | AR | Mutation in ATM; disorder of cell cycle check-point and of DNA double- strand break repair |
| (b) Ataxia- telangiectasia-like disease (ATLD) | Progressive decrease | Normal | Often decreased IgA, IgE and IgG subclasses; increased IgM monomers; antibodies variably decreased | Moderate ataxia; severely increased radiosensitivity | AR | Hypomorphic mutation in MRE11; disorder of cell cycle checkpoint and of DNA double- strand break repair |
| (c) Nijmegen breakage syndrome | Progressive decrease | Normal | Often decreased IgA, IgE and IgG subclasses; increased IgM monomers; antibodies variably decreased | Microcephaly; bird-like face; lymphomas; ionizing radiation sensitivity; chromosomal instability | AR | Hypomorphic mutation in NBS1 (Nibrin); disorder of cell cycle checkpoint and of DNA double- strand break repair |
| (d) Bloom Syndrome | Normal | Normal | Reduced | Chromosomal instability; marrow failure; leukemia; lymphoma; short stature; bird like face; sensitivity to the sun telangiectasias | AR | Mutation in BLM, a RecQ-like helicase |
| 3. Thymic defects | ||||||
| DiGeorge anomaly | Decreased or Normal; often progressive normalization | Normal | Normal or decreased | Hypoparathyroidism; conotruncal heart defects; abnormal facies; interstitial deletion of 22q11-pter (or 10p) in some patients | De novo defect or AD | Contiguous gene defect in 90% affecting thymic development; mutation in transcription factorTBX1 |
| 4. Immuno-osseous dysplasias | ||||||
| (a) Cartilage hair hypoplasia | Decreased or Normal* | Normal | Normal or reduced. Antibodies variably decreased | Short-limbed dwarfism with metaphyseal dysostosis; sparse hair; anemia; neutropenia; susceptibility to lymphoma and other cancers; impaired spermatogenesis; neuronal dysplasia of the intestine | AR | Mutation in RMRP (RNase MRP RNA) |
| (b) Schimke syndrome | Decreased | Normal | Normal | Short stature; spondiloepiphyseal dysplasia; intrauterine growth retardation; nephropathy | AR | Mutation in SMARCAL1 |
| 5. Hyper-IgE syndromes | ||||||
| (a) Job Syndrome (autosomal dominant HIES) | Normal | Normal | Elevated IgE | Recurrent skin boils and pneumonia often due to Staphylococcus aureus; pneumoatoceles; eczema, nail candidiasis; distinctive facial features (thickened skin, broad nasal tip); failure/delay of shedding primary teeth; hyperextensible joints | AD , many de novo mutations | Mutation in STAT 3 |
| (b) Autosomal recessive HIES with mycobacterial And viral infections | Normal | Normal | Elevated IgE | Susceptibility to intracellular bacteria (Mycobacteria, Salmonella), fungi and viruses; eczema. No skeletal or connective tissue abnormalities | AR | Mutation in TYK2, |
| i) CNS hemorrhage, fungal, and viral infections | Unknown | |||||
| (c) Autosomal recessive HIES with viral infections and CNS vasculitis/hemorrhage | Normal | Normal | Elevated IgE | Susceptibility to bacterial, viral and fungal infections; eczema; vasculitis; CNS hemorrhage. No skeletal or connective tissue abnormalities | AR | Unknown |
| 6. Chronic mucocutaneous candidiasis | Normal | Normal | Normal | Chronic mucocutaneous candidiasis; impaired delayed-type hypersensitivity to candida antigens; autoimmunity; no ectodermal dysplasia | AD, AR, sporadic | Unknown |
| 7. Hepatic venoocculusive disease with immunodeficiency (VODI) | Normal (Decreased memory T cells) | Normal (Decreased memory B cells) | Decreased IgG, IgA, IgM | Hepatic veno-occulusive disease; Pneumocystis jiroveci pneumonia; thrombocytopenia, hepatosplenomegaly | AR | Mutation in SP110 |
| 8. Hoyeraal-Hreidarsson syndrome | Progressive decrease | Progressive decrease | Variable | Intrauterine growth retardation, microcephaly, digestive tract involvement, pancytopenia, reduced number and function of NK cells | XL | Mutation in Dyskerin |
Patients with cartilage-hair hypoplasia can present also with typical SCID or with Omenn syndrome
HIES: hyper-IgE syndrome; CNS: central nervous system
Table IV.
Diseases of immune Dysregulaton
| Disease | Circulating T Cells | Circulating B cells | Serum Ig | Associated Features | Inheritance | Genetic defects, Presumed Pathogenesis |
|---|---|---|---|---|---|---|
| 1. Immuno-deficiency with hypopigmentation | ||||||
| (a) Chediak-Higashi syndrome | Normal | Normal | Normal | Partial albinism, giant lysosomes, low NK and CTL activities, heightened acute-phase reaction, encephalopathic accelerated phase | AR | Defects in LYST, impaired lysosomal trafficking |
| (b) Griscelli Syndrome, type 2 | Normal | Normal | Normal | Partial albinism, low NK and CTL activities, heightened acute phase reaction, encephalopathy in some patients | AR | Defects in RAB27A encoding a GTPase in secretory vescicles |
| (c) Hermansky-Pudlak syndrome, type 2 | Normal | Normal | Normal | Partial albinism, neutropenia, low NK and CTL activity, increased bleeding | AR | Mutations of AP3B1 gene, encoding for the β subunit of the AP-3 complex |
| 2. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes | ||||||
| (a) Perforin deficiency | Normal | Normal | Normal | Severe inflammation, fever, decreased NK and CTL activities | AR | Defects in PRF1; perforin, a major cytolytic protein |
| (b) Munc 13-D deficiency | Normal | Normal | Normal | Severe inflammation, fever, decreased NK and CTL activities | AR | Defects in MUNC13D required to prime vescicles for fusion |
| (c) Syntaxin 11 deficiency | Normal | Normal | Normal | Severe inflammation, fever, decreased NK and CTL activities | AR | Defects in STX11, involved in vescicle trafficking and fusion |
| 3. X-linked lymphoproliferative syndrome (XLP) | ||||||
| (a) XLP1 | Normal | Normal or reduced | Normal or low immunoglobulins | Clinical and immunologic abnormalities triggered by EBV infection, including hepatitis, aplastic anaemia, lymphoma | XL | Defects in SH2D1A encoding an adaptor protein regulating intracellular signals |
| (b) XLP2 | Normal | Normal or reduced | Normal or low immunoglobulins | Clinical and immunologic abnormalities triggered by EBV infection, including splenomegaly, hepatitis, hemophagocytic syndrome, lymphoma | XL | Defects in XIAP encoding an inhibitor of apoptosis |
| 4. Syndromes with autoimmunity | ||||||
| (a) Autoimmune lymphoproliferative syndrome (ALPS) | ||||||
| (i) CD95 (Fas) defects, ALPS type 1a | Increased double-negative (CD4− CD8−) T cells | Normal | Normal or increased | Splenomegaly, adenopathy, autoimmune blood cytopenias, defective lymphocyte apoptosis increased lymphoma risk | AD (rare severe AR cases) | Defects in TNFRSF6, cell surface apoptosis receptor; in addition to germline mutations, somatic mutations cause similar phenotype, ALPS 1a (somatic) |
| (ii) CD95L (Fas ligand) defects, ALPS type 1b | Increased double-negative (CD4− CD8−) T cells | Normal | Normal | Splenomegaly, adenopathy, autoimmune blood cytopenias, defective lymphocyte apoptosis, lupus | AD AR |
Defects in TNFSF6, ligand for CD95 apoptosis receptor |
| (iii) Caspase 10 defects, ALPS type 2a | Increased CD4− CD8− T cells | Normal | Normal | Adenopathy, splenomegaly, autoimmune disease, defective lymphocyte apoptosis | AD | Defects in CASP10, intracellular apoptosis pathway |
| (iv) Caspase 8 defects, ALPS type 2b | Slightly increased CD4− CD8− T cells | Normal | Normal or decreased | Adenopathy, splenomegaly, recurrent bacterial and viral infections, defective lymphocyte apoptosis and activation; | AD | Defects in CASP8, intracellular apoptosis and activation pathways |
| (v) Activating N-Ras defect, N-Ras ALPS | Increased CD4− CD8− T cells | Elevation of CD5 B cells | Normal | Adenopathy, splenomegaly, leukemia, lymphoma, defective lymphocyte apoptosis following IL-2 withdrawal | AD | Defect in NRAS encoding a GTP binding protein with diverse signaling functions, activating mutations impair mitochondrial apoptosis |
| (b) APECED, autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy | Elevated CD4+ cells | Normal | Normal | Autoimmune disease, particularly of parathyroid, adrenal and other endocrine organs plus candidiasis, dental enamel hypoplasia and other abnormalities | AR | Defects in AIRE, encoding a transcription regulator needed to establish thymic self-tolerance |
| (c) IPEX, immune dysregulation, polyendocrinopathy, enteropathy (X-linked) | Lack of CD4+ CD25+ FOXP3+ regulatory T cells | Normal | Elevated IgA, IgE | Autoimmune diarrhea, early onset diabetes, thyroiditis, hemolytic anemia, thrombocytopenia, eczema | XL | Defects in FOXP3, encoding a T cell transcription factor |
Table V.
Congenital defects of phagocyte number, function, or both
| Disease | Affected cells | Affected function | Associated features | Inheritance | Gene defects-presumed pathogenesis | |
|---|---|---|---|---|---|---|
| 1.–3. | Severe congenital neutropenias | N | Myeloid Differentiation | Subgroup with myelodysplasia | AD | ELA2: mistrafficking of elastase |
| N | Myeloid Differentiation | B/T lymphopenia | AD | GFI1: repression of elastase | ||
| N | Myeloid Differentiation | G-CSF refractory neutropenia | AD | G-CSFR | ||
| 4. | Kostmann Disease | N | Myeloid Differentiation | AR | HAX1:control of apoptosis | |
| 5. | Cyclic neutropenia | N | ? | Oscillations of other leukocytes and platelets | AD | ELA2: mistrafficking of elastase |
| 6. | X-linked neutropenia/myelodysplasia | N + M | ? | Monocytopenia | XL | WASP: Regulator of actin cytoskeleton (loss of autoinhibition) |
| 7. | P14 deficiency | N+L | Endosome biogenesis | Neutropenia | AR | MAPBPIP: Endosomal adaptor protein 14 |
| Mel | Hypogammaglobulinemia | |||||
| ↓CD8 cytotoxicity | ||||||
| Partial albinism | ||||||
| Growth failure | ||||||
| 8. | Leukocyte adhesion deficiency | N + M | Adherence | Delayed cord separation Skin ulcers | AR | INTGB2: Adhesion protein |
| type 1 | L + NK | Chemotaxis | Periodontitis | |||
| Endocytosis | Leukocytosis | |||||
| T/NK cytotoxicity | ||||||
| 9. | Leukocyte adhesion deficiency | N + M | Rolling | LAD type 1 features | AR | FUCT1 GDP-Fucose transporter |
| type 2 | Chemotaxis | plus hh-blood group and mental retardation | ||||
| 10. | Leukocyte adhesion deficiency | N + M | Adherence | LAD type 1 plus bleeding tendency | AR | Cal DAG-GEFI: |
| type 3 | L + NK | defective Rap1-activation of β1–3 integrins | ||||
| 11. | Rac 2 deficiency | N | Adherence | Poor wound healing | AD | RAC2: Regulation of actin cytoskeleton |
| Chemotaxis | Leukocytosis | |||||
| O2− production | ||||||
| 12. | β-actin deficiency | N + M | Motility | Mental retardation | AD | ACTB: Cytoplasmic Actin |
| Short stature | ||||||
| 13. | Localized juvenile Periodontitis | N | Formylpeptide induced chemotaxis | Periodontitis only | AR | FPR1: Chemokine receptor |
| 14. | Papillon-Lefèvre Syndrome | N + M | Chemotaxis | Periodontitis, Palmoplantar hyperkeratosis | AR | CTSC: Cathepsin C activation of serine proteases |
| 15. | Specific granule deficiency | N | Chemotaxis | N with bilobed nuclei | AR | C/EBPE: myeloid transcription factor |
| 16. | Shwachman-Diamond Syndrome | N | Chemotaxis | Pancytopenia, exocrine pancreatic insufficiency Chondrodysplasia | AR | SBDS |
| 17. | X-linked chronic granulomatous disease (CGD) | N + M | Killing (faulty O2− production) | Subgroup: McLeod phenotype | XL | CYBB: Electron transport protein (gp91phox) |
| 18.–20. | Autosomal CGD’s | N + M | Killing (faulty O2− production) | AR | CYBA: Electron transport protein (p22phox) | |
| NCF1: Adapter protein (p47phox) | ||||||
| NCF2: Activating protein (p67phox) | ||||||
| 21. | Neutrophil G-6PD deficiency | N + M | Killing (faulty O2 − production) | Hemolytic anemia | XL | G-6PD: NADPH generation |
| 22. | IL-12 and IL-23 receptor β1 chain deficiency | L + NK | IFN-γ secretion | Susceptibility to Mycobacteria and Salmonella | AR | IL-12Rβ1: IL-12 and IL-23 receptor β1 chain |
| 23. | IL-12p40 deficiency | M | IFN-γ secretion | Susceptibility to Mycobacteria and Salmonella | AR | IL-12p40 subunit of IL12/IL23: IL12/IL23 production |
| 24. | IFN-γ receptor 1 deficiency | M + L | IFN-γ binding and signaling | Susceptibility to Mycobacteria and Salmonella | AR, AD | IFN-γR1: IFN-γR binding chain |
| 25. | IFN-γ receptor 2 deficiency | M + L | IFN-γ signaling | Susceptibility to Mycobacteria and Salmonella | AR | IFN-γR2: IFN-γR signaling chain |
| 26. | STAT1 deficiency (2 forms) | M + L | IFN α/β/γ signaling | Susceptibility to Mycobacteria, Salmonella and viruses | AR | STAT1 |
| IFN-γ signaling | Susceptibility to Mycobacteria and Salmonella | AD | STAT1 |
AD, Inherited form of IFN-Rγ1 deficiency or of STAT1 deficiency is due to dominant negative mutations; XL, X-linked inheritance; AR, autosomal recessive inheritance; N, neutrophils; M, monocytes-macrophages; L, lymphocytes; NK, natural killer cells; Mel, melanocytes; STAT1, signal transducer and activator of transcription 1.
Table VI.
Defects in Innate Immunity
| Disease | Affected Cell | Functional Defect | Associated Features | Inheritance | Gene Defect/Presumed pathogenesis |
|---|---|---|---|---|---|
| Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) | Lymphocytes + Monocytes | NFκB signalling pathway | anhidrotic ectodermal dysplasia + specific antibody deficiency (lack of Ab response to polysaccharides) various infections (mycobacteria and pyogens) | XR | Mutations of NEMO (IKBKG), a modulator of NF-κB activation |
| Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) | Lymphocytes + Monocytes | NFκB signalling pathway | anhidrotic ectodermal dysplasia + T cell defect + various infections | AD | Gain-of-function mutation of IKBA, resulting in impaired activation of NF-κB |
| Interleukin-1 Receptor Associated kinase 4 (IRAK4) deficiency | Lymphocytes + Monocytes | TIR-IRAK signalling patwhay | Bacterial infections (pyogens) | AR | Mutation of IRAK4, a component of TLR-signaling pathway |
| WHIM (Warts, Hypogammaglobulinemia infections,Myelokathexis) syndrome | Granulocytes + Lymphocytes | Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1) | Hypogammaglobulinemia, reduced B cell number, severe reduction of neutrophil count, warts/HPV infection | AD | Gain-of-function mutations of CXCR4, the receptor for CXCL12 |
| Epidermodysplasia verruciformis | Keratinocytes and leukocytes | ? | Human Papilloma virus (group B1) infections and cancer of the skin | AR | Mutations of EVER1, EVER2 |
| Herpes simplex encephalitis (HSE) | Central nervous system resident cells, epithelial cells and leukocytes | UNC-93B-dependent IFN-α, -β, and –γ induction | Herpes simplex virus 1 encephalitis and meningitis | AR | Mutations of UNC93B1 |
| Herpes simplex encephalitis (HSE) | Central nervous system resident cells, epithelial cells, dendritic cells, cytotoxic lymphocytes | TLR3-dependent IFN-α, -β, and –γ induction | Herpes simplex virus 1 encephalitis and meningitis | AD | Mutations of TLR3 |
NF-κB: nuclear factor Kappa B; TIR: Toll and Interleukin 1 Receptor; HPV: human papilloma virus; TLR: Toll-like receptor
ACKNOWLEDGMENT
We thank Dr. Richard Siegel (NIAIM, NIH, Bethesda, MD, USA) for his contribution of Table 7 and Ms. Sayde El-Hachem for invaluable assistance in constructing the Tables.
Table VII.
Autoinflammatory Disorders
| Disease | Affected cells | Functional defects | Associated Features | Inheritance | Gene defects |
|---|---|---|---|---|---|
| Familial Mediterranean Fever | Mature granulocytes, cytokine-activated monocytes. | Decreased production of pyrin permits ASC-induced IL-1 processing and inflammation following subclinical serosal injury; macrophage apoptosis decreased. | Recurrent fever, serositis and inflammation responsive to colchicine. Predisoposes to vasculitis and inflammatory bowel disease. | AR | Mutations of MEFV |
| TNF receptor-associated periodic syndrome (TRAPS) | PMNs, monocytes | Mutations of 55-kD TNF receptor leading to intracellular receptor retention or diminished soluble cytokine receptor available to bind TNF | Recurrent fever, serositis, rash, and ocular or joint inflammation | AD | Mutations of TNFRSF1A |
| Hyper IgD syndrome | Mevalonate kinase deficiency affecting cholesterol synthesis; pathogenesis of disease unclear | Periodic fever and leukocytosis with high IgD levels | AR | Mutations of MVK | |
| Muckle-Wells syndrome* | PMNs, monocytes | Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signalling and IL-1 processing | Urticaria, SNHL, amyloidosis. Responsive to IL-1R/antagonist (Anakinra) | AD | Mutations of CIAS1 (also called PYPAF1 or NALP3) |
| Familial Cold autoinflammatory syndrome* | PMNs, chondrocytes | same as above | Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure. Responsive to IL-1R/antagonist (Anakinra) | AD | Mutations of CIAS1 |
| Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA)* | PMNs, chondrocytes | same as above | Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation responsive to IL-1R antagonist (Anakinra) | AD | Mutations of CIAS1 |
| Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome | hematopoietic tissues, upregulated in activated T-cells | Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response | Destructive arthritis, inflammatory skin rash, myositis | AD | Mutations of PSTPIP1 (also called C2BP1) |
| Blau syndrome | Monocytes | Mutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NF-κB signaling | Uveitis, granulomatous synovitis, camptodactyly, rash and cranial neuropathies, 30% develop Crohn's disease | AD | Mutations of NOD2 (also called CARD15) |
| Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome) | Neutrophils, bone marrow cells | Undefined | Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders | AR | Mutations of LPIN2 |
All three syndromes associated with similar CIAS1 mutations; disease phenotype in any individual appears to depend on modifying effects of other genes and environmental factors.
Abbreviations: As for Table 1; N, neutrophils; M, monocytes/macrophages; L, lymphocytes; NK, natural killer cells; AD, autosomal dominant inheritance. ASC, apoptosis-asocated speck-like protein with a caspase recruitment domain; CARD, caspase recruitment domain; CD2BP1, CD2 binding protein-1; PSTPIP1, Proline/serine/threonine phosphatase-interacting protein 1; SNHL - sensorineural hearing loss;CIAS1- cold-induced autoinflammatory syndrome 1
The Jackson Hole meeting was partially supported by the Jeffrey Modell Foundation and by the NIAID grant R13-AI-066891. Preparation of this report was supported in part by a European Union Euro-Policy-PID grant to L.D. N. and by NIH grant AI-35714 to R.S.G.
Footnotes
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