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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 2010 December 1.
Published in final edited form as:
PMCID: PMC2797319
NIHMSID: NIHMS154344

Primary immunodeficiencies: 2009 update

The International Union of Immunological Societies (IUIS) Primary Immunodeficiencies (PID) Expert Committee
IUIS Expert Committee on Primary Immunodeficiencies:, Luigi D. Notarangelo, M.D.,a Alain Fischer, M.D.,b Raif. S. Geha, M.D., (Co-chairs),a Jean-Laurent Casanova, M.D.,c Helen Chapel, M.D.,d Mary Ellen Conley, M.D.,e Charlotte Cunningham-Rundles, M.D., Ph.D.,f Amos Etzioni, M.D.,g Lennart Hammartröm, M.D.,h Shigeaki Nonoyama, M.D.,i Hans D. Ochs, M.D.,j Jennifer Puck, M.D.,k Chaim Roifman, M.D.,l Reinhard Seger, M.D.,m and Josiah Wedgwood, M.D., Ph.D.n

Abstract

More than 50 years after Ogdeon Bruton’s discovery of congenital agammaglobulinemia, human primary immunodeficiencies (PIDs) continue to unravel novel molecular and cellular mechanisms that govern development and function of the human immune system. This report provides the updated classification of PIDs, that has been compiled by the International Union of Immunological Societies (IUIS) Expert Committee of Primary Immunodeficiencies after its biannual meeting, in Dublin (Ireland) in June 2009. Since the appearance of the last classification in 2007, novel forms of PID have been discovered, and additional pathophysiology mechanisms that account for PID in humans have been unraveled. Careful analysis and prompt recognition of these disorders is essential to prompt effective forms of treatment and thus to improve survival and quality of life in patients affected with PIDs.

Keywords: primary immunodeficiencies, T cells, B cells, severe combined immune deficiency, predominantly antibody deficiencies, DNA repair defects, phagocytes, complement, immune dysregulation syndromes, innate immunity, autoinflammatory disorders

Since 1970, a Committee of experts in the field of Primary Immunodeficiencies (PID) has met every two years with the goal of classifying and defining these disorders. The most recent meeting, organized by the Experts Committee on Primary Immunodeficiencies 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 Dublin, Ireland, in June 2009. In addition to members of the Experts Committee, the meeting gathered more than 30 speakers and over 200 participants from six continents. Recent discoveries on the molecular and cellular bases of PID and advances in the diagnosis and treatment of these disorders were discussed. At the end of the meeting, the IUIS Experts Committee on Primary Immunodeficiencies met to update the classification of PIDs, presented in Table 1Table 8.

TABLE I
Combined T and B cell immunodeficiencies
Table VIII
Complement deficiencies

The general outline of the classification has remained substantially unchanged. Novel PIDs, whose molecular basis has been identified and reported in the last two years, have been added to the list. In Table I (Combined T and B cell immunodeficiencies), coronin-1A deficiency (resulting in impaired thymic egress) has been added to the genetic defects causing T B+ SCID. The first case of DNA-PKcs deficiency has also been reported, and adds to the list of defects of non-homologous end-joining resulting in T B SCID. Among calcium flux defects, defects of Stim-1, a Ca++ sensor, have been reported in children with immunodeficiency, myopathy and autoimmunity. Mutations of the gene encoding the dedicator of cytokinesis 8 (DOCK8) protein have been shown to cause an autosomal recessive combined immunodeficiency with hyper-IgE, also characterized by extensive cutaneous viral infections, severe atopy and increased risk of cancer. In the same Table, mutations of the adenylate kinase 2 (AK2) gene have been shown to cause reticular dysgenesis, and mutations in DNA ligase IV, ADA and γc have been added to the list of genetic defects that may cause Omenn syndrome.

In Table II (Predominantly antibody deficiencies), mutations in TACI and in BAFF-receptor (BAFF-R) have been added to the list of gene defects that may cause hypogammaglobulinemia. However, it should be noted that only few TACI mutations appear to be disease-causing. Furthermore, variability of clinical expression has been associated with the rare BAFF-R deficiency. Table III lists other well-defined immunodeficiency syndromes. PMS2 deficiency and ICF syndrome (immunodeficiency with centromeric instability and facial anomalies) have been added to the list of DNA repair defects, whereas Comel-Netherton syndrome is now included among the immune-osseous dysplasias, and hyper-IgE syndrome due to DOCK8 mutation has also been added. ITK deficiency has been included among the molecular causes of lymphoproliferative syndrome in Table IV (Diseases of immune dysregulation). In the same Table, CD25 deficiency has been listed, to reflect the occurrence of autoimmuninty in this rare disorder. Progress in the molecular characterization of congenital neutropenia and other innate immunity defects has resulted in the inclusion of G6PT1 and G6PC3 defects in Table V (Congenital defects of phagocyte number, function, or both), and of MyD88 deficiency (causing recurrent pyogenic bacterial infections) in Table VI (Defects of innate immunity), respectively. These two Tables also include two novel genetic defects that result in clinical phenotypes distinct from the classical definition of PIDs. In particular, mutations of the CSFR2A gene, encoding for granulocyte macrophage-colony stimulating factor receptor α (GM-CSF Rα), have been shown to cause primary alveolar proteinosis due to defective surfactant catabolism by alveolar macrophages (see: Table V). Mutations in APOL-I are associated with trypanosomiasis, as reported in Table VI. It can be anticipated that a growing number of defects in immune-related genes will be shown to be responsible for non-classical forms of PIDs in the future. Along the same line, the spectrum of genetically defined autoinflammatory disorders (Table VIII) has expanded to include NLRP12 mutations (responsible for familial cold autoinflammatory syndrome) and IL1RN defects (causing deficiency of the Interleukin-1 receptor antagonist). Again, it is expected that a growing number of genetic defects will be identified in other inflammatory conditions. Finally, defects of Ficolin 3 (that plays an important role in complement activation) have been shown to cause recurrent pyogenic infections in the lung (Table VIII).

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

While the revised classification of PIDs is meant to assist with the identification, diagnosis and management of patients with these conditions, it should not be used dogmatically. In particular, although the typical clinical and immunological phenotype is reported for each PID, it has been increasingly recognized that the phenotypic spectrum of these disorders is wider than originally thought. This variability reflects both the effect of different mutations within PID-causing genes, and the role of other genetic, epigenetic and environmental factors in modifying the phenotype. For example, germline hypomorphic mutations or somatic mutations in SCID-related genes may result in atypical/leaky SCID or Omenn syndrome, the latter associated with significant immunopathology. Furthermore, infections may also significantly modify the clinical and immunological phenotype, even in patients who initially present with typical SCID. Thus, the phenotype associated with single-gene defects listed in the revised classification should by no means be considered absolute.

Finally, a new column has been added to the revised classification, to illustrate the relative frequency of the various PID disorders. It should be noted that these frequency estimates are based on what has been reported in the literature, since, with few exceptions, no solid epidemiologic data exist that can be reliably used to define the incidence of PID disorders. Furthermore, the frequency of PIDs may vary in different countries. Certain populations (and especially, some restricted ethnic groups of geographical isolates) have a higher frequency of specific PID mutations, due to a founder effect and genetic drift. For example, DCLER1C (Artemis) and ZAP70 defects are significantly more common in Athabascan-speaking Native Americans and in members of the Mennonite Church, respectively, than in other populations. Similarly, MHC class II deficiency is more frequent in Northern Africa. Furthermore, the frequency of autosomal recessive immunodeficiencies is higher among populations with a high consanguinity rate.

Table VII
Autoinflammatory Disorders

ACKNOWLEDGMENT

The Dublin meeting was supported by the Jeffrey Modell Foundation and by the NIAID grant R13-AI-066891. Preparation of this report was supported by NIH grant AI-35714 to R.S.G. and L.N.

Footnotes

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