A novel form of complete IL-12/IL-23 receptor  1 deficiency with cell surface-expressed nonfunctional receptors

Abstract

IntroductionMendelian susceptibility to mycobacterial disease (MSMD) (Mendelian Inheritance in Man, MIM209950; Online Mendelian Inheritance in Man [OMIM]: http://www.ncbi.nlm.nih.gov/ Omim/) 1 is a rare syndrome predisposing affected individuals to infectious diseases caused by poorly virulent mycobacteria, such as bacille Calmette-Guérin (BCG) vaccines and environmental mycobacteria (EM), and poorly virulent Salmonella strains, such as nontyphoidal "minor" serovars. Patients are also susceptible to infections caused by the more virulent Mycobacterium tuberculosis and typhoidal "major" Salmonella serotypes. 1,2 Unlike patients with "classic" immunodeficiencies, these patients are otherwise quite healthy and only rarely suffer from other unusually severe bacterial, viral, fungal, or parasitic diseases. 2,3 The spectrum of infections is narrow, but the spectrum of severity is broad-from disseminated BCG disease in infancy to localized environmental mycobacterial disease in the elderly. Moreover, whereas some sporadic and most familial cases seem to involve autosomal recessive heredity, the syndrome has been found to segregate in an autosomal dominant 4,5 or X-linked recessive 6 pattern in other families, further suggesting genetic heterogeneity.Five disease-causing autosomal genes have been identified since 1996, 7,8 and allelic heterogeneity accounts for the existence of 9 defined disorders, all of which result in impaired interferon-␥ (IFN-␥)-mediated immunity. 1,2 Null recessive mutations in the IFN-␥ receptor ligand-binding chain (IFN-␥R1)-encoding gene (IFNGR1) abolish either receptor expression 7,8 or the binding of surface-expressed receptors to IFN-␥. 9,10 Partial recessive 11 and dominant 4 IFN-␥R1 deficiencies have also been described. Different recessive mutations in the gene encoding the IFN-␥ signaling chain (IFN-␥R2), IFNGR2, are responsible for complete 12 or partial 13 IFN-␥R2 deficiency. A dominant mutation in STAT1 is responsible for partial signal transducer and activator of transcription-1 (STAT-1) deficiency and defines the remaining disease in which cellular responses to IFN-␥ are impaired. 5 Complete recessive STAT-1 deficiency is a related but distinct disorder involving susceptibility to both mycobacteria and viruses, due to the impairment of IFN-␥-and IFN-␣/␤-mediated immunity. 14 From [17][18][19][20][21][22][23][24][25][26]28 have no detectable IL-12R␤1 on the cell surface, due to mutations that either interrupt the open reading frame (ORF) (nonsense and frameshift mutations) or disrupt folding of the protein (missense mutations). We report here the molecular investigation of a patient with complete IL-12R␤1 deficiency despite the presence of IL-12R␤1 at the cell surface. Patients, materials, and methods The patientThe patient (P) is a 6-year-old boy born to first-cousin parents of Bedouin origin living in Israel (Figure 1). He was not inoculated with BCG and was first seen at the age of 12 months with disseminated Salmonella enteritidis disease (septicemia and multiple adenitis). Betw...

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

“…The cell-surface expression of dysfunctional receptors is the second genetic form of AR IL-17RA deficiency to be described. The detection of surface IL-17RA should not, therefore, exclude a diagnosis of IL-17RA deficiency, as previously shown for other cytokine receptors, such as IFN-γR1 (66-69), IFN-γR2 (70,71), IL-12Rβ1 (72,73), and IL-10RA (74,75). IL-17RA deficiency has recently been reported in two siblings from Sri Lanka (60).…”

Human Complete Stat-1 Deficiency Is Associated with Defective Type I and II IFN Responses In Vitro but Immunity to Some Low Virulence Viruses In Vivo

“…Flow cytometry assays were performed as previously described (8,9). Briefly, skin-derived SV40-transformed fibroblasts were left untreated or were treated with 10 5 IU/ml IFN-␥ for 48 h and were then incubated with PE-anti-HLA-DR Ab (BD Biosciences) for 45 min on ice.…”

“…IL-12p70 fluorescence-binding experiments were performed as previously described (9). Briefly, PHA-T cell blasts were incubated with or without 50 ng of IL-12p70 (R&D Systems) for 30 min at 4°C and then with mouse anti-IL-12p40-p70 IgG1, biotinylated rat anti-mouse IgG1, and finally with streptavidin-PE (BD Pharmingen).…”

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

“…IL12RB1 deficiency is associated with Mendelian susceptibility to mycobacterial diseases. [32][33][34][35] These diseases predispose affected individuals to mycobacterial infections (tuberculosis) due to disturbance of IL12/IL23/IFNg signaling. IL12RB1 also associates with IL23R to form the IL23 receptor.…”