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• W2017007390 abstract "Primary immunodeficiencies are typically seen as rare monogenic conditions associated with detectable immunologic abnormalities, resulting in a broad susceptibility to multiple and recurrent infections caused by weakly pathogenic and more virulent microorganisms. By opposition to these conventional primary immunodeficiencies, we describe nonconventional primary immunodeficiencies as Mendelian conditions manifesting in otherwise healthy patients as a narrow susceptibility to infections, recurrent or otherwise, caused by weakly pathogenic or more virulent microbes. Conventional primary immunodeficiencies are suspected on the basis of a rare, striking, clinical phenotype and are defined on the basis of an overt immunologic phenotype, often leading to identification of the disease-causing gene. Nonconventional primary immunodeficiencies are defined on the basis of a more common and less marked clinical phenotype, which remains isolated until molecular cloning of the causal gene reveals a hitherto undetected immunologic phenotype. Similar concepts can be applied to primary immunodeficiencies presenting other clinical features, such as allergy and autoimmunity. Nonconventional primary immunodeficiencies thus expand the clinical boundaries of this group of inherited disorders considerably, suggesting that Mendelian primary immunodeficiencies are more common in the general population than previously thought and might affect children with a single infectious, allergic, or autoimmune disease. Primary immunodeficiencies are typically seen as rare monogenic conditions associated with detectable immunologic abnormalities, resulting in a broad susceptibility to multiple and recurrent infections caused by weakly pathogenic and more virulent microorganisms. By opposition to these conventional primary immunodeficiencies, we describe nonconventional primary immunodeficiencies as Mendelian conditions manifesting in otherwise healthy patients as a narrow susceptibility to infections, recurrent or otherwise, caused by weakly pathogenic or more virulent microbes. Conventional primary immunodeficiencies are suspected on the basis of a rare, striking, clinical phenotype and are defined on the basis of an overt immunologic phenotype, often leading to identification of the disease-causing gene. Nonconventional primary immunodeficiencies are defined on the basis of a more common and less marked clinical phenotype, which remains isolated until molecular cloning of the causal gene reveals a hitherto undetected immunologic phenotype. Similar concepts can be applied to primary immunodeficiencies presenting other clinical features, such as allergy and autoimmunity. Nonconventional primary immunodeficiencies thus expand the clinical boundaries of this group of inherited disorders considerably, suggesting that Mendelian primary immunodeficiencies are more common in the general population than previously thought and might affect children with a single infectious, allergic, or autoimmune disease. An immunologic definition and classification of primary immunodeficiencies currently prevails and is expected to do so for the foreseeable future.1Notarangelo L. Casanova J.L. Fischer A. Puck J. Rosen F. Seger R. et al.Primary immunodeficiency diseases: an update.J Allergy Clin Immunol. 2004; 114: 677-687Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar Unfortunately, this has resulted in studies of otherwise healthy patients with specific infectious clinical diseases but no overt immunologic phenotype being largely neglected. The attention of most investigators and clinicians has remained focused on the tip of the iceberg: those rare patients with a noisy clinical phenotype (multiple, recurrent, and severe infections) and a visible immunologic phenotype (defining the primary immunodeficiency). The most striking example of such conventional primary immunodeficiencies is reticular dysgenesia, an exceedingly rare disorder associated with agranulocytosis and alymphocytosis, resulting in early-onset vulnerability to virtually all microorganisms and a rapidly fatal outcome in the absence of hematopoietic stem cell transplantation.2Bertrand Y. Muller S.M. Casanova J.L. Morgan G. Fischer A. Friedrich W. Reticular dysgenesis: HLA non-identical bone marrow transplants in a series of 10 patients.Bone Marrow Transplant. 2002; 29: 759-762Crossref PubMed Scopus (38) Google Scholar Immunodeficiency is commonly ruled out in patients with a single severe infectious disease (even if recurrent or life-threatening) and normal routine immunologic workup (searching for signs of inherited or acquired immunodeficiency). Self-contradictory titles in the medical literature, such as “Fatal infection in an immunocompetent individual,” remain common. Unusual infectious diseases are often described as idiopathic, demonstrating caution and a desire to avoid the direct incrimination of the patient's genetic background. However, some infections typically caused by weakly virulent (opportunist) microbes have been found to be associated with a high frequency of familial forms, parental consanguinity, or both, suggesting Mendelian predisposition. This group of nonconventional primary immunodeficiencies is characterized by a very narrow spectrum of opportunistic infections limited to one microbial genus or species possibly, but not necessarily, recurrent in otherwise healthy patients with no detectable immunologic abnormality on initial investigation.3Casanova J.L. Schurr E. Abel L. Skamene E. Forward genetics of infectious diseases: immunological impact.Trends Immunol. 2002; 23: 469-472Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar These diseases do not fit easily into the classical classification of primary immunodeficiencies. Nonconventional primary immunodeficiencies include the syndromes of Mendelian susceptibility to mycobacterial diseases (OMIM 209950,4McKusick V.A. Mendelian inheritance in man. Catalogs of human genes and genetic disorders. Johns Hopkins University Press, Baltimore (MD)1998Google Scholar first described in 1951) in patients with mutations in the IL-12/23–IFN-γ circuit (first identified in 1996)5Newport M.J. Huxley C.M. Huston S. Hawrylowicz C.M. Oostra B.A. Williamson R. et al.A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection.N Engl J Med. 1996; 335: 1941-1949Crossref PubMed Scopus (1069) Google Scholar, 6Jouanguy E. Altare F. Lamhamedi S. Revy P. Emile J.F. Newport M. et al.Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection.N Engl J Med. 1996; 335: 1956-1961Crossref PubMed Scopus (638) Google Scholar, 7Dorman S.E. Holland S.M. Interferon-gamma and interleukin-12 pathway defects and human disease.Cytokine Growth Factor Rev. 2000; 11: 321-333Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, 8Casanova J.L. Abel L. Genetic dissection of immunity to mycobacteria: the human model.Annu Rev Immunol. 2002; 20: 581-620Crossref PubMed Scopus (834) Google Scholar; recurrent invasive disease caused by Neisseiria species in patients with mutations affecting the terminal components of complement (C5 to C9) forming the membrane attack complex (first described in 1974)9Würzner R. Orren A. Lachmann P.J. Inherited deficiencies of the terminal components of human complement.Immunodef Rev. 1992; 3: 123-147PubMed Google Scholar, 10Würzner R. Witzel-Schlomp K. Tokunaga K. Fernie B.A. Hobart M.J. Orren A. Reference typing report for complement components C6, C7 and C9 including mutations leading to deficiencies.Exp Clin Immunogenet. 1998; 15: 268-285Crossref PubMed Scopus (23) Google Scholar; isolated chronic mucocutaneous candidiasis (OMIM 114580, first described in 1969), which remains unexplained genetically11Kirkpatrick C.H. Chronic mucocutaneous candidiasis.Pediatr Infect Dis J. 2001; 20: 197-206Crossref PubMed Scopus (156) Google Scholar, 12Lilic D. New perspectives on the immunology of chronic mucocutaneous candidiasis.Curr Opin Infect Dis. 2002; 15: 143-147Crossref PubMed Scopus (100) Google Scholar; epidermodysplasia verruciformis with disseminated warts caused by human papillomaviruses belonging to group B1 (OMIM 226400, first described clinically in 1922 and subsequently shown to be a Mendelian trait [1939] conferring susceptibility to papillomaviruses [1946-1966]) in patients with mutations in EVER1 and EVER2 (first described in 2002)13Ramoz N. Rueda L.A. Bouadjar B. Montoya L.S. Orth G. Favre M. Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis.Nat Genet. 2002; 32: 579-581Crossref PubMed Scopus (345) Google Scholar, 14Orth G. Human papillomaviruses and the skin: more to be learned.J Invest Dermatol. 2004; 123: XI-XIIICrossref PubMed Scopus (15) Google Scholar; and X-linked lymphoproliferative syndrome caused by Epstein-Barr virus (OMIM 308240, first described in 1975) in patients with mutations in SAP (first described in 1998).15Morra M. Howie D. Grande M.S. Sayos J. Wang N. Wu C. et al.X-linked lymphoproliferative disease: a progressive immunodeficiency.Annu Rev Immunol. 2001; 19: 657-682Crossref PubMed Scopus (176) Google Scholar, 16Nichols K.E. Ma C.S. Cannons J.L. Schwartzberg P.L. Tangye S.G. Molecular and cellular pathogenesis of X-linked lymphoproliferative disease.Immunol Rev. 2005; 203: 180-199Crossref PubMed Scopus (184) Google Scholar Needless to say, the dichotomy between conventional and nonconventional conditions is somewhat artificial because there is really a continuum between these 2 extremes.17Casanova J.L. Abel L. The human model: a genetic dissection of immunity to infection in natural conditions.Nat Rev Immunol. 2004; 4: 55-66Crossref PubMed Scopus (232) Google Scholar Patients with a recently described conventional primary immunodeficiency, IL-1 receptor-associated kinase 4 deficiency, are particularly susceptible to Streptococcus pneumoniae,18Picard C. Puel A. Bonnet M. Ku C.L. Bustamante J. Yang K. et al.Pyogenic bacterial infections in humans with IRAK-4 deficiency.Science. 2003; 299: 2076-2079Crossref PubMed Scopus (786) Google Scholar, 19Ku C.L. Yang K. Bustamante J. Puel A. von Bernuth H. Dos Santos O. et al.Inherited disorders of human Toll-like receptor signalling: immunological implications.Immunol Rev. 2005; 203: 10-20Crossref PubMed Scopus (111) Google Scholar and conversely, patients with mutations in the IL-12–IFN-γ axis are also susceptible to Salmonella species.20Fieschi C. Casanova J.L. The role of interleukin-12 in human infectious diseases: only a faint signature.Eur J Immunol. 2003; 33: 1461-1464Crossref PubMed Scopus (146) Google Scholar In any event, neither the identification of a cellular phenotype nor that of the causal gene suggested the existence of an underlying primary immunodeficiency in patients with nonconventional primary immunodeficiencies. Instead, primary immunodeficiency diagnosis was based on the relatively low virulence of the microbe and the seemingly Mendelian inheritance of predisposition to severe disease. It would not be wise to limit the group of nonconventional primary immunodeficiencies to these 5 Mendelian syndromes, to patients presenting unexplained infections caused by weakly virulent opportunistic microorganisms, or even to patients with recurrent infections caused by more virulent pathogens. There is good reason to believe that other human conditions reflect currently unknown Mendelian primary immunodeficiencies. First, genetic epidemiologic studies searching for familial forms and parental consanguinity have not been carried out for most infectious, autoimmune, and allergic clinical syndromes. Second, neither the absence of familial cases nor the lack of consanguinity are sufficient to exclude Mendelian defects, and sporadic cases might reflect a genetic lesion, as illustrated by the first genetic lesion discovered in human subjects, trisomy 21, in patients with Down syndrome.21Lejeune J. Gautier M. Turpin R. [Study of somatic chromosomes from 9 mongoloid children].C R Hebd Seances Acad Sci. 1959; 248: 1721-1722PubMed Google Scholar Third, the virulence of microorganisms is also a continuum, and many pathogenic microbes, such as Mycobacterium tuberculosis, are actually innocuous in most human beings. A number of common infectious diseases are likely to reflect nonconventional primary immunodeficiencies in at least a fraction of patients. Consistent with this view, mycobacterial diseases caused by weakly virulent BCG species were described as idiopathic infections before the identification of defects in the IL-12–IFN-γ circuit.22Casanova J.L. Jouanguy E. Lamhamedi S. Blanche S. Fischer A. Immunological conditions of children with BCG disseminated infection.Lancet. 1995; 346: 581PubMed Scopus (212) Google Scholar, 23Casanova J.L. Blanche S. Emile J.F. Jouanguy E. Lamhamedi S. Altare F. et al.Idiopathic disseminated bacillus Calmette-Guerin infection: a French national retrospective study.Pediatrics. 1996; 98: 774-778PubMed Google Scholar The identification of these defects has led to the recent description of 3 unrelated families with a purely Mendelian form of predisposition to bona fide tuberculosis,24Altare F. Ensser A. Breiman A. Reichenbach J. Baghdadi J.E. Fischer A. et al.Interleukin-12 receptor beta1 deficiency in a patient with abdominal tuberculosis.J Infect Dis. 2001; 184: 231-236Crossref PubMed Scopus (154) Google Scholar, 25Caragol I. Raspall M. Fieschi C. Feinberg J. Larrosa M.N. Hernandez M. et al.Clinical tuberculosis in 2 of 3 siblings with interleukin-12 receptor beta1 deficiency.Clin Infect Dis. 2003; 37: 302-306Crossref PubMed Scopus (103) Google Scholar, 26Özbek N. Fieschi C. Yilmaz B.T. De Beaucoudrey L. Bikmaz Y.E. Feinberg J. et al.Interleukin-12 receptor beta 1 chain deficiency in a child with disseminated tuberculosis.Clin Infect Dis. 2005; 40: e55-e58Crossref PubMed Scopus (77) Google Scholar following on from the observation that IL-12Rβ1 deficiency had low penetrance for the case-definition phenotype of clinical disease caused by weakly virulent mycobacteria.20Fieschi C. Casanova J.L. The role of interleukin-12 in human infectious diseases: only a faint signature.Eur J Immunol. 2003; 33: 1461-1464Crossref PubMed Scopus (146) Google Scholar, 27Fieschi C. Dupuis S. Catherinot E. Feinberg J. Bustamante J. Breiman A. et al.Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications.J Exp Med. 2003; 197: 527-535Crossref PubMed Scopus (260) Google Scholar Currently unexplained candidate infectious diseases include invasive pneumococcal disease18Picard C. Puel A. Bonnet M. Ku C.L. Bustamante J. Yang K. et al.Pyogenic bacterial infections in humans with IRAK-4 deficiency.Science. 2003; 299: 2076-2079Crossref PubMed Scopus (786) Google Scholar, 19Ku C.L. Yang K. Bustamante J. Puel A. von Bernuth H. Dos Santos O. et al.Inherited disorders of human Toll-like receptor signalling: immunological implications.Immunol Rev. 2005; 203: 10-20Crossref PubMed Scopus (111) Google Scholar and herpes simplex encephalitis,28Dupuis S. Jouanguy E. Al-Hajjar S. Fieschi C. Al-Mohsen I.Z. Al-Jumaah S. et al.Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency.Nat Genet. 2003; 33: 388-391Crossref PubMed Scopus (641) Google Scholar, 29Niehues T. Reichenbach J. Neubert J. Gudowius S. Puel A. Horneff G. et al.A NEMO-deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia.J Allergy Clin Immunol. 2004; 114: 1456-1462Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar which have been diagnosed in at least a few patients with conventional immunodeficiencies. Many life-threatening infectious diseases might well turn out to result from the Mendelian inheritance of a specific predisposition, reflecting a nonconventional primary immunodeficiency. Nonconventional primary immunodeficiencies are defined on clinical grounds, raising the issue of the classification of primary immunodeficiencies. In fact, there has never been a fully satisfactory classification of primary immunodeficiencies.1Notarangelo L. Casanova J.L. Fischer A. Puck J. Rosen F. Seger R. et al.Primary immunodeficiency diseases: an update.J Allergy Clin Immunol. 2004; 114: 677-687Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 30Stiehm E.R. Ochs H.D. Winkelstein J.A. Immunologic disorders in infants and children. Elsevier Saunders, Philadelphia2004Google Scholar, 31Ochs H. Smith C.I.E. Puck J. Primary Immunodeficiencies: a molecular and genetic approach. Oxford University Press, New York2005Google Scholar This problem has become increasingly acute because of the explosion of knowledge in the field in the last 20 years, with at least 200 conditions described clinically and more than 100 disease-causing genes identified. Moreover, many more conventional and nonconventional primary immunodeficiencies are likely to be identified in the near future. A genetic classification was impossible in the early days before identification of the disease-causing genes. Even today, genetic classification would be hindered by the lack of a well-defined temporal and spatial expression pattern for the disease-causing genes, limiting our understanding of pathogenesis. Furthermore, different clinical syndromes might be caused by different mutations in the same gene, and the same syndrome might be caused by different genetic causes. Even if it were possible, a genetic classification would not actually be sufficient because phenotypes are obviously more important than genotypes; the chief value of a genotype lies in its ability to account for a given phenotype. Accordingly, the McKusick catalog of human genetic disorders is merely a catalog and not a classification.4McKusick V.A. Mendelian inheritance in man. Catalogs of human genes and genetic disorders. Johns Hopkins University Press, Baltimore (MD)1998Google Scholar Any classification system for academic and clinical purposes must therefore be primarily phenotypic, although improvements in our understanding of the genetic basis of primary immunodeficiencies might lead to changes in phenotypic classification. The phenotypic definition of primary immunodeficiencies is clearly the necessary starting point for phenotypic classification. Historically, the identification of agammaglobulinemia in 1952 by Ogden Bruton32Bruton O.C. Agammaglobulinemia.Pediatrics. 1952; 9: 722-728PubMed Google Scholar and the subsequent discovery that its inheritance was X-linked and recessive33Bruton O.C. A decade with agammaglobulinemia.J Pediatr. 1962; 60: 672-676Abstract Full Text PDF PubMed Scopus (23) Google Scholar was the origin of current classifications of primary immunodeficiencies on the basis of a combination of immunologic phenotypes and modes of inheritance.1Notarangelo L. Casanova J.L. Fischer A. Puck J. Rosen F. Seger R. et al.Primary immunodeficiency diseases: an update.J Allergy Clin Immunol. 2004; 114: 677-687Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 30Stiehm E.R. Ochs H.D. Winkelstein J.A. Immunologic disorders in infants and children. Elsevier Saunders, Philadelphia2004Google Scholar, 31Ochs H. Smith C.I.E. Puck J. Primary Immunodeficiencies: a molecular and genetic approach. Oxford University Press, New York2005Google Scholar, 34Good R.A. Historical aspects of immunologic deficiency diseases.in: Kagen B.M. Stiehm E.R. Immunologic incompetence. Year Book Medical Publishing, Chicago1971: 149-177Google Scholar, 35Hitzig W.H. The discovery of agammaglobulinaemia in 1952.Eur J Pediatr. 2003; 162: 289-304PubMed Google Scholar, 36Stiehm ER, Johnston RB Jr. A history of pediatric immunology. Pediatr Res. In Press 2005.Google Scholar, 37Stiehm E.R. New and old immunodeficiencies.Pediatr Res. 1993; 33: S2-S8PubMed Google Scholar, 38Fischer A. Primary immunodeficiency diseases: an experimental model for molecular medicine.Lancet. 2001; 357: 1863-1869Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 39Conley M.E. Molecular basis of immunodeficiency.Immunol Rev. 2005; 203: 5-9Crossref Scopus (6) Google Scholar Primary immunodeficiencies are commonly classified into disorders of T cells, B cells, phagocytes, and complement. They are then further classified according to the mode of inheritance and, when known, genetic cause. This method of classification poses a serious problem of definition because it tightly links the concept of primary immunodeficiency with the observation of an immunologic phenotype. According to this view, even asymptomatic IgA-deficient individuals are immunodeficient, unlike, paradoxically, patients dying of infectious disease without immunologic abnormality. Moreover, because many disease-causing genes are expressed in different cell types in which mutant alleles might have different effects, clinical phenotypes, whether infectious, allergic, or autoimmune, are far from being consistent within each of the 4 cell type–based groups. What is the clinical similarity between defects of C1 inhibitor and C9? Conversely, X-linked agammaglobulinemia (primarily, but not exclusively, a B-cell defect) clinically resembles HLA class I deficiency (often improperly classified as a T-cell defect). This situation also results in paradoxical classifications, with an immunologic phenotype attributed to one cell type but a genetic defect actually affecting another cell type. For example, CD40L deficiency is generally described as a B-cell defect because of the hyper-IgM syndrome,40Etzioni A. Ochs H.D. The hyper IgM syndrome—an evolving story.Pediatr Res. 2004; 56: 519-525Crossref PubMed Scopus (123) Google Scholar but CD40L is expressed on T cells and is involved in the interaction of T cells with both B cells and macrophages–dendritic cells. The focus on certain immunologic phenotypes, such as hyper-IgM syndrome, is misleading in itself: there are more differences than common points between patients with mutations in CD40L (expressed on T cells), AID (expressed in B cells), and NEMO (expressed ubiquitously), all of which can result in hyper-IgM syndrome. The current immunologic classification of primary immunodeficiencies is thus imperfect both immunologically and clinically. An ideal definition and classification of primary immunodeficiencies and inborn deficiencies should evidently rely on clinical phenotype because this best reflects the physiologic effect of any deleterious genotype. Indeed, immunodeficiencies in general, whether inherited or acquired, should be defined clinically, as opposed to immunologically. Would anyone seriously suggest that it would be better to define respiratory failure in terms of epithelial abnormalities rather than the physiologic consequences of insufficient oxygen inhalation? It is certainly useful to assess various parameters in the course of any organ failure, but the definition and monitoring of organ failure must be physiologic. Immunodeficiency is a failure to achieve immune function to provide efficient, self-limited host defense against the biotic and abiotic environment while preserving tolerance to self. Immunodeficiencies are thus best defined in terms of the diverse forms of life-threatening infections, allergies, or autoimmune reactions. The detection of an identifiable immunologic abnormality is less important and depends on the tools available to the investigator. Immunodeficiencies might also be considered in terms of whether they are inherited or acquired. Most immunodeficiencies are actually idiosyncratic, reflecting both nature (genetic background) and nurture (the effect of the environment on the host). An ideal classification of primary immunodeficiencies should take this into account, considering infectious syndromes one by one (and possibly autoimmune and allergic syndromes as well). For example, primary immunodeficiencies associated with mycobacterial41Reichenbach J. Rosenzweig S. Doffinger R. Dupuis S. Holland S.M. Casanova J.L. Mycobacterial diseases in primary immunodeficiencies.Curr Opin Allergy Clin Immunol. 2001; 1: 503-511Crossref PubMed Scopus (86) Google Scholar or pneumococcal42Picard C. Puel A. Ku C.L. Casanova J.L. Primary immunodeficiencies associated with pneumococcal disease.Curr Opin Allergy Clin Immunol. 2003; 3: 451-459Crossref PubMed Scopus (141) Google Scholar diseases are specifically associated with defects of interaction between T-cells and phagocytes (involving in particular the IL-12/23–IFN-γ circuit and the respiratory burst) and bacterial sensing and opsonization (involving mucosal inflammation, complement, carbohydrate-specific antibodies, and splenic macrophages), respectively. This classification is not operational yet because it awaits investigators in the field to review all pathogens one by one, perhaps in a collaborative effort (eg, primary immunodeficiencies associated with, for example, Pneumocystis species infection or Toxoplasma species infection). This classification will address the most relevant clinical question at the bedside (Which immunodeficiency should the physician consider in a given infected patient?) and the most relevant immunologic question at the bench (What role does a particular molecule play in immunity to infection in vivo?). Of course, the genotype and immunologic phenotype are invaluable both clinically to tailor treatment options to individual patients and immunologically to decipher the molecular basis of immune responses. A corollary of this purely clinical definition and classification of primary immunodeficiencies is that inborn Mendelian deficiencies of immunity are more common than initially thought. Accordingly, newly described primary immunodeficiencies, such as partial IFN-γR1 and signal transducer and activator of transcription 1 deficiencies, have been shown to be transmitted as autosomal dominant traits in multiplex families, at odds with the classical view that primary immunodeficiencies are necessarily recessive traits because of their severity.43Lawrence T. Puel A. Reichenbach J. Ku C.L. Chapgier A. Renner E. et al.Autosomal-dominant primary immunodeficiencies.Curr Opin Hematol. 2005; 12: 22-30Crossref PubMed Scopus (25) Google Scholar Not all severe infectious diseases will be found to reflect a Mendelian primary immunodeficiency or to be due to the inheritance of a major susceptibility gene, as seen in leprosy with mutations in Parkin,44Mira M.T. Alcais A. Nguyen V.T. Moraes M.O. Di Flumeri C. Vu H.T. et al.Susceptibility to leprosy is associated with PARK2 and PACRG.Nature. 2004; 427: 636-640Crossref PubMed Scopus (394) Google Scholar, 45Mira M.T. Alcais A. Van Thuc N. Thai V.H. Huong N.T. Ba N.N. et al.Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population.Nat Genet. 2003; 33: 412-415Crossref PubMed Scopus (155) Google Scholar, 46Alcais A. Mira M. Casanova J.L. Schurr E. Abel L. Genetic dissection of immunity in leprosy.Curr Opin Immunol. 2005; 17: 44-48Crossref PubMed Scopus (79) Google Scholar because predisposition to infection might display truly polygenic determinism. Nevertheless, it will be important in the future to decipher the Mendelian genetic basis of infectious diseases. Studies of autoimmune and allergic syndromes are also likely to reveal novel Mendelian disorders. Once a clinical definition of immunodeficiency is accepted, patients with infectious diseases, allergy, or autoimmunity (in the broad sense of these terms, including angioedema, hemophagocytosis, and autoinflammation) should be considered as potential bearers of Mendelian primary immunodeficiencies. Accordingly, several primary immunodeficiencies were recently shown to present purely as autoimmune,47Arkwright P.D. Abinun M. Cant A.J. Autoimmunity in human primary immunodeficiency diseases.Blood. 2002; 99: 2694-2702Crossref PubMed Scopus (161) Google Scholar autoinflammatory,48Hull K.M. Shoham N. Chae J.J. Aksentijevich I. Kastner D.L. The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations.Curr Opin Rheumatol. 2003; 15: 61-69Crossref PubMed Scopus (206) Google Scholar and hemophagocytosis49de Saint Basile G. Fischer A. Defective cytotoxic granule-mediated cell death pathway impairs T lymphocyte homeostasis.Curr Opin Rheumatol. 2003; 15: 436-445Crossref PubMed Scopus (33) Google Scholar syndromes. Intriguingly, only one Mendelian disorder, C1 inhibitor deficiency, has thus far been found to be purely associated with autosomal-dominant angioedema, a syndrome related to (but possibly different from) allergy.50Davis 3rd, A.E. The pathophysiology of hereditary angioedema.Clin Immunol. 2005; 114: 3-9Crossref PubMed Scopus (212) Google Scholar Noninfectious immunologic diseases have only recently emerged as a public health problem and do not threaten mankind as acutely as infections. Records show that life expectancy in Western Europe in the 18th century was about 25 years, whereas life expectancy is currently about 40 years in Sub-Saharan Africa, largely because of the burden of infection.17Casanova J.L. Abel L. The human model: a genetic dissection of immunity to infection in natural conditions.Nat Rev Immunol. 2004; 4: 55-66Crossref PubMed Scopus (232) Google Scholar, 51Cairns J. Matters of life and death. Princeton University Press, Princeton1997Crossref Google Scholar The current longer life expectancy in developed countries primarily reflects recent developments in hygiene (preventing infection), vaccines (preventing disease), and antibiotics (preventing a fatal outcome), rather than the intrinsic efficiency of our immune system.51Cairns J. Matters of life and death. Princeton University Press, Princeton1997Crossref Google Scholar Although the immune system serves well at the population level, ensuring the reproduction of species, it is the least efficient physiologic system at the individual level. As indicated by medical and demographic data, most human subjects are immunodeficient and exposed to life-threatening infectious diseases.51Cairns J. Matters of life and death. Princeton University Press, Princeton1997Crossref Google Scholar Many might carry a Mendelian primary immunodeficiency, being thus perhaps the rule rather than the exception and paradoxically raising hope for scientists, physicians, and patients. We thank Laurent Abel for critical reading of the manuscript and other members of the laboratory of Human Genetics of Infectious Diseases for helpful discussions. We also thank Gérard Orth for helpful discussions, and we thank 2 anonymous reviewers for their constructive criticisms." @default.
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• W2017007390 title "From idiopathic infectious diseases to novel primary immunodeficiencies" @default.
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