Primary immunodeficiency diseases: An update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee

Article Outline

• Abstract
• Acknowledgment
• References

Primary immunodeficiency diseases (PIDs) are a genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system, such as neutrophils, macrophages, dendritic cells, complement proteins, natural killer cells, and T and B lymphocytes. The study of these diseases has provided essential insights into the functioning of the immune system. More than 120 distinct genes have been identified, whose abnormalities account for more than 150 different forms of PID. The complexity of the genetic, immunologic, and clinical features of PID has prompted the need for their classification, with the ultimate goal of facilitating diagnosis and treatment. To serve this goal, an international committee of experts has met every 2 years since 1970. In its last meeting in Jackson Hole, Wyo, after 3 days of intense scientific presentations and discussions, the committee has updated the classification of PID, as reported in this article.

Key words: Primary immunodeficiency diseases, T cells, B cells, phagocytes, complement, immune dysregulation syndromes, innate immunity

Abbreviations used: NK, Natural killer, PID, Primary immunodeficiency disease, STAT, Signal transducer and activator of transcription, TRAPS, TNF receptor–associated periodic syndrome

After the original invitation by the World Health Organization in 1970, a committee of experts in the field of primary immunodeficiency diseases (PIDs) has met every 2 years with the goal of classifying and defining this group of disorders. The most recent meeting, organized under the aegis of the International Union of Immunological Societies, with support from the Jeffrey Modell Foundation and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, took place in Jackson Hole, Wyo, in June 2007. In addition to members of the Experts Committee, the meeting gathered more than 30 speakers and more than 150 participants from 6 continents. Recent updates in the molecular and cellular pathophysiology of PID were reviewed and provided the basis for updating the classification of PID.

After an opening lecture in which Tom Waldmann, a founding member of the committee, highlighted some of his most remarkable achievements in the fields of PID and tumor immunology, Kenneth Murphy reviewed the signals that govern T_H cell development and differentiation into T_H1, T_H2, and T_H17 cells. This paved the way to presentations by Bill Paul and Anna Villa, who illustrated how 2 different mechanisms (ie, homeostatic proliferation of CD4⁺ T cells in a lymphopenic host, and impaired central and peripheral tolerance in mice with hypomorphic defects of V[D]J recombination) may lead to similar phenotypic manifestations that mimic Omenn syndrome.¹, 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 to tumor development. Later in the meeting, Qiang Pan-Hammarström expanded on chromosome instability syndromes, and in particular on the role played by ATM, the gene mutated in Ataxia-Telangiectasia, in DNA repair.⁶

John Ziegler reported on a recently identified form of PID, familial hepatic veno-occlusive disease and immunodeficiency, a combined immunodeficiency caused by mutations of the SP110 gene, a component of PML nuclear bodies.⁷ Stefan Feske presented his work on cloning of the ORAI1 gene, which encodes for an integral component of calcium channels, whose mutations lead to a severe combined immune deficiency in which T-cell development is not arrested but peripheral T cells are unresponsive to proliferative signals.⁸ Genevieve de Saint Basile discussed the basic mechanisms involved in cell-mediated cytotoxicity, and especially generation and trafficking of exocytic vesicles and cytolytic granules, as unraveled through the study of human models of impaired cytotoxicity.⁹ Dale Umetsu reviewed the biology of natural killer (NK) T cells, and Sylvain Latour described a novel form of X-linked lymphoproliferative disease caused by mutations of the X-linked inhibitor of apoptosis gene, in which impaired apoptosis is associated with a severe decrease in NK T cells in the periphery.¹⁰

Amos Etzioni reported on leukocyte adhesion deficiency type 3, a disease characterized by impaired inside-out integrin signaling in leukocytes and platelets caused by mutations of the CALDAG-GEF1 gene.¹¹ The different requirements for T-cell and B-cell immunologic memory by cytopathic versus noncytopathic viruses, and the possible need for persistence/boosting with antigen in this process, were reviewed by Rolf Zinkernagel.

In the last year, major advances have been achieved in the molecular and cellular characterization of hyper-IgE syndrome. Hajime Karasuyama gave an update on mutations of the TYK2 gene and abnormal cytokine-mediated signaling in an autosomal-recessive form of the disease.¹² Steven Holland reported that heterozygous mutations of signal transducer and activator of transcription (STAT)–3 account for the more common autosomal-dominant form of the disease, a previously unknown finding also confirmed by the group of Karasuyama.¹³ Two young investigators, Lilit Garibyan and Lalit Kumar, discussed the molecular mechanisms of transmembrane activator and CAML interactor (TACI) deficiency (providing evidence for intracellular preassembly of high-order multimers of the protein)¹⁴ and the phenotype of LRRC8 knockout mice, respectively.

Exciting results have recently appeared on the molecular and cellular characterization of severe congenital neutropenia. Cristoph Klein reported on the identification of 2 such defects: mutations of p14,¹⁵ an endosomal scaffold protein, and of HCLS1-associated protein x1 (HAX1),¹⁶ involved in control of apoptosis. The inflammasome was reviewed by Nunez, who showed that both gain-of-function and loss-of-function mutations of nucleotide-binding oligomerization domain (NOD)-like receptors may cause disease in human beings. Nunez especially focused on the interplay between pathogens and molecules of the innate immunity system.¹⁷ Jean-Laurent Casanova reported on an unusual phenotype associated with mutations of the CYBB gene (which usually cause chronic granulomatous disease), further illustrating the importance of studying human patients to unravel novel molecules and functions within the immune system. The interplay between molecules of the immune system and pathogens was also discussed by Cox Terhorst, who reported on the role played by signaling lymphocyte activation molecule (SLAM) and SLAM family members in controlling bacterial infections. Michael Carroll illustrated the role played by complement in governing memory B-cell responses, whereas Peter Zipfel discussed how defects of the alternative pathway may lead to kidney disease.¹⁸

Immunodysregulatory disorders were introduced by Sasha Rudensky, who discussed the development and biology of regulatory T cells. Scott Snapper showed how mutations in Wiskott-Aldrich syndrome protein (WASP) lead to inflammatory bowel disease in mice. Alberto Bosque presented novel data on Fas ligand mutations in a subgroup of patients with autoimmune lymphoproliferative syndrome that result in impaired Bcl2-interacting protein (Bim) expression and hence in decreased apoptosis.¹⁹ Richard Siegel discussed the molecular mechanisms involved in TNF receptor–associated periodic syndrome (TRAPS) and showed that retention of TRAPS-associated mutant TNF receptor 1 molecules in the endoplasmic reticulum results in ligand-independent signaling.²⁰

In his concluding remarks, Alain Fischer summarized the heuristic value of PID. He pointed out that a substantial number of immune genes have been discovered (even in recent years) through the study of patients with PID, whereas for many others, the function has been clarified (or revealed) through the careful study of human patients. Although PIDs have been traditionally viewed as predisposing to a broad range of infectious pathogens, more and more examples are being identified in which they cause selective susceptibility to single pathogens. Furthermore, PIDs have illustrated the multiple pathways (impaired negative selection, defective development/function of regulatory T cells, perturbed apoptosis of self-reactive lymphocytes in the periphery) that may cause autoimmunity. Much more than generation of artificial models in mice, the study of human beings with PID has demonstrated the variability of phenotypes that may associate with distinct mutations in the same gene. As Fischer emphasized, it is now time to look at novel approaches to therapy for PID based on the study of disease mechanisms. This is not restricted to gene therapy but also includes bypassing biochemical and/or cellular defects (as shown by the use of IFN-γ in familial mycobacteriosis) and exploiting the use of chemical compounds to allow reading-through nonsense mutations or correction of splice-site mutations.

At the end of the meeting, the International Union of Immunological Societies Expert Committee met to update the classification of PID, as presented in Table I, Table II, Table III, Table IV, Table V, Table VI, Table VII, Table VIII.

Table I. Combined T-cell and B-cell immunodeficiencies

Disease	Circulating T cells	Circulating B cells	Serum immunoglobulin	Associated features	Inheritance	Gene 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/CD3ɛ/CD3ζ deficiency	Markedly decreased	Normal	Decreased	Normal NK cells	AR	Defect in CD3δ CD3ɛ 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 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	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 allowing 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 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 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-cell 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-cell and dendritic cell signaling
8. PNP deficiency	Progressive decrease	Normal	Normal or decreased	Autoimmune hemolytic anemia, neurological impairment	AR	Absent PNP, T-cell and neurologic defects from elevated toxic metabolites (eg, dGTP)
9. CD3γ deficiency	Normal (reduced TCR expression)	Normal	Normal		AR	Defect in CD3γ chain
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, nonprogressive 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 interstitial pneumonitis	AR	Defects of STAT5B gene, impaired development and function of γδ T cells, T-regulatory and NK cells, impaired T-cell proliferation

ADA, Adenosine deaminase; DCLRE, DNA cross-link repair protein 1C; dATP, deoxyadenosine triphosphate; dGTP, deoxyguanosin triphosphate; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; AR, autosomal recessive inheritance; JAK3, Janus kinase 3; NHEJ, nonhomologous end joining; PNP, purine nucleoside phosphorylase; RAG, recombinase activating gene; RMRP, RNA of mitochondrial RNA-processing endoribonuclease; SCID, severe combined immune deficiency; TAP, transporter associated with antigen processing; TAPBP, TAP binding protein; TCR, T-cell receptor; XL, X-linked inheritance; XLF, XRCC4-like factor.

Table II. Predominantly antibody deficiencies

Disease	Serum immunoglobulin	Associated features	Inheritance	Gene 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 Burton tyrosine kinase
(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 autosomal-dominant)	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) X-linked lymphoproliferative syndrome 1‡	All isotypes may be low	Some patients have antibody deficiency, although most present with fulminant EBV 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) Activation-induced cytidine deaminase 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 centers	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) κ chain deficiency	All immunoglobulins have λ light chain	Asymptomatic	AR	Mutations in κ constant gene
(c) Isolated IgG subclass deficiency	Reduction in 1 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 1 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; a few cases progress to CVID; others coexist with CVID in the same family	Variable	Unknown
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

AR, Autosomal-recessive inheritance; BAFFR, B-cell–activating factor receptor; BLNK, B-cell linker protein; CVID, common variable immune deficiency; ICOS, inducible costimulator; Msh5, homolog of E. coli MutS; UNG, uracil-DNA glycosylase; XL, X-linked inheritance.

Table III. Other well defined immunodeficiency syndromes

Disease	Circulating T cells	Circulating B cells	Serum immunoglobulin	Associated features	Inheritance	Gene defects/presumed pathogenesis
1. 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 hematopoietic stem cell derivatives
2. DNA repair defects (other than those in Table I)
(a) Ataxia-telangiectasia	Progressive decrease	Normal	Often decreased IgA, IgE and IgG subclasses; increased IgM monomers; antibodies variably decreased	Ataxia; telangiectasia; increased α 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	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; birdlike 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; birdlike 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 factor TBX1
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; spondyloepiphyseal dysplasia; intrauterine growth retardation; nephropathy	AR	Mutation in SMARCAL1
5. Hyper-IgE syndromes (HIES)
(a) Job syndrome (AD HIES)	Normal	Normal	Elevated IgE	Recurrent skin boils and pneumonia often caused by Staphylococcus aureus; pneumatoceles; eczema, nail candidiasis; distinctive facial features (thickened skin, broad nasal tip); failure/delay of shedding primary teeth; hyperextensible joints	AD, many de novo mutations	Mutation in STAT3
(b) AR HIES with mycobacterial and viral infections	Normal	Normal	Elevated IgE	Susceptibility to intracellular bacteria (mycobacteria, Salmonella), fungi, and viruses; eczema	AR	Mutation in TYK2,
				No skeletal or connective tissue abnormalities
				i) CNS hemorrhage, fungal and viral infections		Unknown
(c) AR 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 veno-occlusive disease with immunodeficiency	Normal (decreased memory T cells)	Normal (decreased memory B cells)	Decreased IgG, IgA, IgM	Hepatic veno-occlusive disease; Pneumocystis jiroveci pneumonia; thrombocytopenia, hepatosplenomegaly	AR	Mutation in SP110
8. Hoyerall-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

AD, Autosomal-dominant inheritance; AR, autosomal-recessive inheritance; BLM, Bloom syndrome gene; CNS, central nervous system; HIES, hyper-IgE syndrome; RMRP, RNA of mitochondrial RNA-processing endoribonuclease; WAS, Wiskott-Aldrich syndrome; XL, X-linked inheritance.

Table IV. Diseases of immune dysregulaton

Disease	Circulating T cells	Circulating B cells	Serum Ig	Associated features	Inheritance	Gene defects/presumed pathogenesis
1. Immunodeficiency 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 vesicles
(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 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 vesicles for fusion
(c) Syntaxin 11 deficiency	Normal	Normal	Normal	Severe inflammation, fever, decreased NK and CTL activities	AR	Defects in STX11, involved in vesicle trafficking and fusion
3. X-linked lymphoproliferative syndrome
(a) XLP1	Normal	Normal or reduced	Normal or low immuno-globulins	Clinical and immunologic abnormalities triggered by EBV infection, including hepatitis, aplastic anemia, lymphoma	XL	Defects in SH2D1A encoding an adaptor protein regulating intracellular signals
(b) XLP2	Normal	Normal or reduced	Normal or low immuno-globulins	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) 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	Defects in TNFSF6, ligand for CD95 apoptosis receptor
					AR
(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 after 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

AD, Autosomal-dominant inheritance; AIRE, autoimmune regulator; ALPS, autoimmune lymphoproliferative syndrome; AP-3, adaptor-related protein complex 3; AR, autosomal-recessive inheritance; CTL, cytotoxic T lymphocytes; GTPase, guanosine triphosphatase; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked; NRAS, neuroblastoma ras viral oncogene homolog; XL, X-linked inheritance; XLP, X-linked lymphoproliferative syndrome.

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 (LAD) type 1	N + M	Adherence	Delayed cord separation	AR	ITGB2: adhesion protein
		L + NK	Chemotaxis	Skin ulcers
			Endocytosis	Periodontitis
			T/NK cytotoxicity	Leukocytosis
9.	Leukocyte adhesion deficiency type 2	N + M	Rolling	LAD type 1 features plus hh-blood group and mental retardation	AR	FUCT1 GDP-fucose transporter
		N + M	Chemotaxis
10.	Leukocyte adhesion deficiency type 3	L + NK	Adherence	LAD type 1 plus bleeding tendency	AR	Cal DAG-GEF1: defective Rap1-mediated 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	AR	SBDS
				Chondrodysplasia
17.	X-linked chronic granulomatous disease	N + M	Killing (faulty O2– production)	Subgroup: McLeod phenotype	XL	CYBB: electron transport protein (gp91phox)
18.-20.	Autosomal chronic granulomatous diseases	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

ACTB, Actin beta; AD, inherited form of IFN-Rγ1 deficiency or of STAT1 deficiency caused by dominant-negative mutations; AR, autosomal recessive inheritance; Cal DAG-GEF1, calcium and diacylglycerol-regulated guanine nucleotide exchange factor 1; ELA, neutrophil elastase; FPR, formyl peptide; FUCT, fucosidase regulator; G-CSF, granulocyte colony-stimulating factor; G-CSFR, G-CSF receptor; GDP, guanosine diphosphate; GFI, growth factor independent 1; HAX, HSLS1-associated protein X1; ITGB2, integrin beta-2; L, lymphocytes; M, monocytes-macrophages; MAPBPIP, MAPBP-interacting protein; Mel, melanocytes; N, neutrophils; WASP, Wiskott-Aldrich syndrome protein; XL, X-linked inheritance.

Table VI. Defects in innate immunity

AD, Autosomal-dominant inheritance; AR, autosomal-recessive inheritance; EDA-ID, anhidrotic ectodermal dysplasia with immunodeficiency; IKBA, inhibitor of kappa light chain gene enhancer in B cells, alpha; IRAK, IL-1 receptor associated kinase; NEMO, NF-κB essential modulator; NF-κB, nuclear factor-κB; TLR, Toll-like receptor.

Table VII. Autoinflammatory disorders

AD, Autosomal-dominant inheritance; AR, autosomal-recessive inheritance; CARD, caspase recruitment domain; CARD15, caspase recruitment domain-containing protein 15; CIAS, cold-induced autoinflammatory syndrome; MEFV, familial Mediterranean fever; MVK, mevalonate kinase; NOD2, nucleotide-binding oligomerization domain protein 2; PMN, polymorphonuclear cells; TNFRSF1A, tumor necrosis factor receptor superfamily member 1A; TRAPS, tumor necrosis factor receptor–associated periodic syndrome.

Table VIII. Complement deficiencies

AD, Autosomal-dominant inheritance; AR, autosomal-recessive inheritance; ITGB2, integrin beta-2; MAC, membrane attack complex; MASP, mannose-binding protein–associated serine protease; MBP, mannose-binding protein; MCP, membrane cofactor complex; PIGA, phosphatidylinositol glycan class A; SLE, systemic lupus erythematosus.

The manuscript that reports on STAT3 mutations in patients with hyper-IgE syndrome, presented by Dr Holland at the meeting, is now in press.²¹

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We thank Dr Richard Siegel (National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md) for his contribution of Table VII and Ms Sayde El-Hachem for invaluable assistance in constructing the tables.

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