The Hyper IgE Syndrome and Mutations in TYK2

Abstract

The hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency, characterized by the clinical triad of recurrent staphylococcal skin abscesses, recurrent respiratory-tract infections, and serum IgE concentrations of >2000 IU/mL. Autosomal dominant (AD) and autosomal recessive (AR) forms have been described (Grimbacher et al., 1999Grimbacher B. Holland S.M. Gallin J.I. Greenberg F. Hill S.C. Malech H.L. Miller J.A. O'Connell A.C. Puck J.M. N. Engl. J. Med. 1999; 4: 692-702Crossref Scopus (607) Google Scholar, Renner et al., 2004Renner E.D. Puck J.M. Holland S.M. Schmitt M. Weiss M. Frosch M. Bergmann M. Davis J. Belohradsky B.H. Grimbacher B. J. Pediatr. 2004; 144: 93-99Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar). The AR-HIES variant includes, in addition to this HIES triad, recurrent viral infections, extreme eosinophilia, and neurological complications but no skeletal symptoms. In the November 2006 issue of Immunity, Minegishi et al., 2006Minegishi Y. Saito M. Morio T. Watanabe K. Agematsu K. Tsuchiya S. Takada H. Hara T. Kawamura N. Ariga T. et al.Immunity. 2006; 25: 745-755Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar reported the first monogenetic defect in a single patient, from consanguineous parents, who was presented with some clinical features of autosomal-recessive HIES. The patient had a homozygous defect in the receptor-associated cytoplasmatic tyrosine kinase TYK2. However, the authors did not report whether they investigated TYK2 in additional patients with AR-HIES. Thus, it remains an open question whether Tyk2 deficiency might be a common cause of AR-HIES. This prompted us to analyze TYK2 in a collection of patients with the characteristic appearance of the autosomal-recessive HIES. All patients participating in this study were consented according to protocols approved by a local ethics-review board. We screened a total of 15 autosomal-recessive families with HIES (seven of them from consanguineous marriages including three unrelated patients out of the initially six published families; see Renner et al., 2004Renner E.D. Puck J.M. Holland S.M. Schmitt M. Weiss M. Frosch M. Bergmann M. Davis J. Belohradsky B.H. Grimbacher B. J. Pediatr. 2004; 144: 93-99Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar) by genotyping and linkage analysis. The affected individuals in five families were homozygous at marker D19S586 within 1 Mb of the TYK2 gene. Four of the five families had at least one unaffected child, and in three of these four, the genotype data were consistent with genetic linkage to the TYK2 locus on chromosome 19. We subsequently performed sequence analysis on the genomic DNA of one patient from each of these five families, by using the primers for human TYK2 kindly provided by Minegishi et al., 2006Minegishi Y. Saito M. Morio T. Watanabe K. Agematsu K. Tsuchiya S. Takada H. Hara T. Kawamura N. Ariga T. et al.Immunity. 2006; 25: 745-755Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar. We did not find any mutation in the coding regions of exons and the adjacent intronic sequences of TYK2. However, we did not analyze the full intronic regions and the promoter of the gene. We conclude that Tyk2 deficiency is most likely not a common cause of the AR-HIES and suggest that human Tyk2 deficiency is a distinct disease entity that is genetically and clinically different from the previously published patients with AR-HIES. This hypothesis is supported by atypical features in the clinical history of the patient described by Minegishi et al., 2006Minegishi Y. Saito M. Morio T. Watanabe K. Agematsu K. Tsuchiya S. Takada H. Hara T. Kawamura N. Ariga T. et al.Immunity. 2006; 25: 745-755Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar, such as a BCG lymphadenitis and a non-Typhi Salmonella infection. The susceptibility to these certain viral and intracellular bacterial infections may imply that human TYK2 deficiency is clinically and pathophysiologically closely related to patients with particular defects in the interleukin-12-interferon axis as described by Casanova and Abel, 2004Casanova J.L. Abel L. Nat. Rev. Immunol. 2004; 4: 55-66Crossref PubMed Scopus (223) Google Scholar. Therefore, it might be rewarding to analyze TYK2 further in these cohorts in addition to patients with AR-HIES. We thank the patients and their families. The work was supported by the Deutsche Forschungsgemeinschaft (DFG) grant GR 1617/3-3 and in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine, and National Institute of Allergy and Infectious Diseases. Response: The Hyper IgE Syndrome and Mutations in TYK2Minegishi et al.ImmunityMay 25, 2007In BriefWe would like to thank Woellner et al. for their thoughtful comments and additional data to our recent article (Minegishi et al., 2006). Full-Text PDF Open Archive