Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Allergy Clin Immunol. Author manuscript; available in PMC 2008 December 12.
Published in final edited form as:
J Allergy Clin Immunol. 2007 October; 120(4): 776–794.
doi:  10.1016/j.jaci.2007.08.053
PMCID: PMC2601718

The International Union of Immunological Societies (IUIS) Primary Immunodeficiency Diseases (PID) Classification Committee


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 18.

Table I
Combined T and B cell immunodeficiencies
Table VIII
Complement deficiencies
Table II
Predominantly antibody deficiencies
Table III
Other well-defined immunodeficiency syndromes.
Table IV
Diseases of immune Dysregulaton
Table V
Congenital defects of phagocyte number, function, or both
Table VI
Defects in Innate Immunity


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

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.


Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.


1. Marrella V, Poliani PL, Casati A, Rucci F, Frascoli L, Gougeon ML, et al. A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome. J Clin Invest. 2007;117:1260–1269. [PMC free article] [PubMed]
2. Milner JD, Ward JM, Keane-Myers A, Paul WE. Lymphopenic mice reconstituted with limited repertoire T cells develop severe, multiorgan, Th2-associated inflammatory disease. Proc Natl Acad Sci USA. 2007;104:576–581. [PubMed]
3. Buck D, Malivert L, de Chasseval R, Barraud A, Fondaneche MC, Sanal O, et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell. 2006;124:287–299. [PubMed]
4. Van der Burg M, van Veelen LR, Verkaik NS, Wiegant WW, Hartwig NG, Barendregt BH, et al. A new type of radiosensitive TBNK+ severe combined immunodeficiency caused by a LIG4 mutation. J Clin Invest. 2006;116:137–145. [PMC free article] [PubMed]
5. Zha S, Alt FW, Cheng HL, Brush JW, Li G. Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficienct murine ES cells. Proc Natl Acad Sci USA. 2007;104:4518–4523. [PubMed]
6. Pan-Hammarstrom Q, Lahdesmaki A, Zhao Y, Du L, Zhao Z, Wen S, et al. Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation. J Exp Med. 2006;203:99–110. [PMC free article] [PubMed]
7. Roscioli T, Cliffe ST, Bloch DB, Bell CG, Mullan G, Taylor PJ, et al. Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and veno-occlusive disease. Nat Genet. 2006;38:620–622. [PubMed]
8. Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature. 2006;441:179–185. [PubMed]
9. Menager MM, Menasche G, Romao M, Knapnougel P, Ho CH, Garfa M, et al. Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4. Nat Immunol. 2007;8:257–267. [PubMed]
10. Riagud S, Fontaneche MC, Lambert N, Pasquier B, Mateo V, Soulas P, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006;444:110–114. [PubMed]
11. Pasvolsky R, Feigelson SW, Kilic SS, Simon AJ, Tal-Lapidot G, Grabovsky V, et al. A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J Exp Med. 2007;204:1571–1582. [PMC free article] [PubMed]
12. Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. 2006;25:745–755. [PubMed]
13. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007 Aug 5; [Epub ahead of print] [PubMed]
14. Garibyan L, Lobito AA, Siegel RM, Call ME, Wucherpfennig KW, Geha RS. Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID) J Clin Invest. 2007;117:1550–1557. [PMC free article] [PubMed]
15. Bohn G, Allroth A, Brandes G, Thiel J, Glocker E, Schaffer AA, et al. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nat Med. 2007;13:38–45. [PubMed]
16. Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schaffer AA, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease) Nat Genet. 2007;39:86–92. [PubMed]
17. Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L, et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature. 2006;440:233–236. [PubMed]
18. Zipfel PF, Edey M, Heinen S, Jozsi M, Richter H, Misselwitz J, et al. Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome. PloS Genet. 2007;3:e41. [PubMed]
19. Bosque A, Aguilo JI, Alava MA, Paz-Artal E, Naval J, Allende LM, et al. The induction of Bim expression in human T-cell blasts is dependent on nonapoptotic Fas/CD95 signaling. Blood. 2007;109:1627–1635. [PubMed]
20. Lobito AA, Kimberley FC, Muppidi JR, Komarow H, Jackson AJ, Hull KM, et al. Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS) Blood. 2006;108:1320–1327. [PubMed]