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• W2002785655 abstract "To the Editor:Chronic mucocutaneous candidiasis (CMCC) is a heterogeneous group of disorders with a common manifestation of persistent or recurrent candidial and fungal infections of the skin, nails, and mucous membranes. The best delineated entity, autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), is caused by mutations in the autoimmune regulator (AIRE) gene. However, AIRE mutations are found in only about a third of cases with CMCC in our institution. In a search for genetic predisposition to CMCC in patients without APECED, we studied the protein tyrosine phosphatase nonreceptor 22 (PTPN22), 1858T, a variant of the lymphoid protein tyrosine phosphatase (LYP) R620W.1Bottini N. Musumeci L. Alonso A. Rahmouni S. Nika K. Rostamkhani M. et al.A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.Nat Genet. 2004; 36: 337-338Crossref PubMed Scopus (1116) Google ScholarLymphoid protein tyrosine phosphatase, which was first cloned and sequenced in our laboratory, was found to have a primary role in regulation of T-cell and B-cell antigen receptor signaling.2Cohen S. Dadi H. Shaoul E. Sharfe N. Roifman C.M. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase.Lyp. Blood. 1999; 93: 2013-2024PubMed Google Scholar, 3Cloutier J.F. Veillette A. Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase.J Exp Med. 1999; 189: 111-121Crossref PubMed Scopus (351) Google Scholar, 4Gjörloff-Wingren A. Saxena M. Williams S. Hammi D. Mustelin T. Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP.Eur J Immunol. 1999; 29: 3845-3854Crossref PubMed Scopus (158) Google ScholarAn association of a single nucleotide transition in PTPN22 1858C>T with a variety of autoimmune diseases including rheumatoid arthritis, type I diabetes, and SLE as well as Graves disease and Addison disease has been established.1Bottini N. Musumeci L. Alonso A. Rahmouni S. Nika K. Rostamkhani M. et al.A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.Nat Genet. 2004; 36: 337-338Crossref PubMed Scopus (1116) Google Scholar, 5Begovich A.B. Carlton V.E. Honigberg L.A. Schrodi S.J. Chokkalingam A.P. Alexander H.C. et al.A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.Am J Hum Genet. 2004; 75: 330-337Abstract Full Text Full Text PDF PubMed Scopus (1175) Google Scholar, 6Wu H. Cantor R.M. Graham D.S. Lingren C.M. Farwell L. Jager P.L. et al.Association analysis of the R620W polymorphism of protein tyrosine phosphatase PTPN22 in systemic lupus erythematosus families: increased T allele frequency in systemic lupus erythematosus patients with autoimmune thyroid disease.Arthritis Rheum. 2005; 52: 2396-2402Crossref PubMed Scopus (77) Google Scholar The R620W variant is known to disrupt LYP's interaction with the regulatory kinase, c-src tyrosine kinase (CSK), although the functional consequences of this remain to be determined.1Bottini N. Musumeci L. Alonso A. Rahmouni S. Nika K. Rostamkhani M. et al.A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.Nat Genet. 2004; 36: 337-338Crossref PubMed Scopus (1116) Google Scholar We have studied here the clinical manifestations and immunologic laboratory findings of patients with PTPN22 1858T.Fourteen patients with CMCC and autoimmune features (without AIRE mutations) were identified. In addition, 5 other patients carrying mutations in the AIRE gene were included in this study for comparison purposes. None of the patients in our cohort were members of same kindred, and no autosomal-dominant pattern of inheritance was suggested from family history. The median age of patients with CMCC was 38 years (range, 7-55 years), and the median age at presentation was 3 years. For patients with APECED, the median age was 18 years (range, 3.5-30 years), and median age of presentation was 1.5 years (Table I).Table IDemographic data on patients with CMCCCMCC with no AIRE mutationAPECEDNo. of patients145Sex Male42 Female103Median age of presentation3 y1.5 yRange of age of presentation1 week to 40 y0.1-3 yCurrent median age38 y18 y Open table in a new tab Genomic sequencing of the PTPN22 gene revealed that 6 of 14 patients, all white, had heterozygous variant allele 1858T, whereas in our control group, matched for sex and ethnicity, 34 of 189 carried the variant allele. The allele frequencies were significantly different between the patients and control groups, with a frequency of 0.428 in the patient group and 0.179 in the control group (similar to historic controls) χ2 = 5.095; P = .024; odds ratio, 3.42; 95% CI, 1.11-10.48.None of the 5 patients with APECED with homozygous mutations in the AIRE gene carried the PTPN22 variant, 1858T.All 14 patients, regardless of their PTPN22 alleles, had chronic candidiasis; 86% of the patients had oral candidiasis; 92% had chronic fungal skin infections; and 64% had typical involvement of the nails.Analysis of the group of patients carrying PTPN22 1858T revealed a high prevalence of endocrinopathies, affecting 83% (5/6) of the patients. Hypothyroidism and gonadal failure were the most common, each found in 50% of the patients, whereas only 1 patient had adrenal insufficiency. Gonadal failure was found only in the group with the 1858T allele. This endocrine disorder is also a common feature of APECED, affecting about 60% of the patients.7Ahonen P. Myllärniemi S. Sipila I. Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients.N Engl J Med. 1990; 322: 1829-1836Crossref PubMed Scopus (848) Google ScholarBy comparison, only 3 of the 8 patients with the common PTPN22 allele, 1858C, had endocrinopathy, all with hypothyroidism. In the distinct APECED group, polyendocrinopathy affected 4 of the 5 patients, most commonly with hypoparathyroidism and Addison disease (Table II).Table IIClinical features of patients with CMCCLYP 1858T (N = 6)LYP 1858C (N = 8)APECED (N = 5)Clinical features Oral candidiasis575 Skin candidiasis and/or dystrophy685 Nails dystrophy, onychomycosis255 Enemal defectNoneNone4 Pneumonia521 Bronchiectasis31NoneEndocrinopathies Hypothyroidism331 Gonadal failure3None1 Adrenal insufficiency1None3 HypoparathyroidismNoneNone4Other autoimmune manifestations ITPNone1None AlopeciaNone21 VitiligoNoneNone3 Arthritis22None PolymyositisNone1None Gastrointestinal211ITP, Idiopathic thrombocytopenic purpura. Open table in a new tab Other autoimmune disorders were identified more frequently in the group of the common PTPN22 allele, including arthritis (25%), alopecia (25%), idiopathic thrombocytopenic purpura, polymyositis, and enteropathy. In the PTPN22 1858T group, 2 patients had arthritis, and another had chronic enteritis. In the patients with APECED, vitiligo was the most common autoimmune feature. Conversely, none of the patients with the 1858T allele had vitiligo (Table II).Remarkably, patients carrying the PTPN22 1858T had a higher frequency of infections than patients who carry the common allele or patients with APECED. Eighty-three percent of patients within the PTPN22 1858T group had severe pulmonary infections including bronchiectasis, compared with only 25% in the common 1858C allele group. This is likely explained by laboratory studies revealing that 4 of the 6 patients carrying the variant allele had antibody defects, including hypogammaglobulinemia (p1,5) or dysgammaglobulinemia (p2,3), manifested as inadequate responses to protein and/or polysaccharide vaccinations (Table III). The exact mechanism whereby PTPN22 1858T predisposes individuals to microbial infections remains unclear.8Chapman S.J. Khor C.C. Vannberg F.O. Maskell N.A. Davies C.W. Hedley E.L. et al.PTPN22 and invasive bacterial disease.Nat Genet. 2006; 38: 499-500Crossref PubMed Scopus (48) Google Scholar In part, this may be explained, as recently shown, by the finding that lymphocytes carrying the PTPN22 variant had decreased responses to stimulation by anti-CD3 and by anti-IgM as well as decreased numbers of memory B cells (CD19+CD27+ population).9Rieck M. Arechiga A. Onengut-Gumuscu S. Greenbaum C. Concannon P. Buckner J.H. Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes.J Immunol. 2007; 179: 4704-4710PubMed Google Scholar In the future, similar additional abnormalities may eventually evolve in patients with CMCC with the PTPN22 variant 1858T.Table IIILaboratory indices of patients with the LYP variant 1858TPatients with 1858T123456Normal rangePatients with 1858C¶Number of patients with abnormal results.Age at evaluation (y)102013433546ALC (cells 109/L)2.711.683.21.781.553.191.4-3.31 of 8In vitro response to Candida∗Stimulation index.1.60.6617250.7>20Low in 6 of 8Immunoglobulins IgG g/L4.78.713.212.15.211.37.2-15.8None IgA g/L1.571.20.91.73.51.50.5-3.5None IgM g/L1.450.50.60.70.42.10.2-3.1None Tetanus IU/mL†Level post vaccination.NA0.150.024.0NA1.26>0.04§Protective level./>1.00‖Level after tetanus boost.1 of 8 Pneumococcus mg/L (fold increase)‡Fold increase 4 to 6 weeks postvaccination.NA130 (<2)10.1 (<1)>270 (>4)NA>270 (>4)>270 (>4 fold increase)1 of 8ALC, Absolute lymphocyte count; NA, not available.∗ Stimulation index.† Level post vaccination.‡ Fold increase 4 to 6 weeks postvaccination.§ Protective level.‖ Level after tetanus boost.¶ Number of patients with abnormal results. Open table in a new tab None of the patients had lymphopenia, and lymphocyte markers showed normal numbers of CD3, CD4, CD8, CD19, and CD56-positive cells in 4 patients. One patient had a low CD4 count (P2), and another had a relatively low number of B cells (P6).In vitro mitogenic responses to phytohemagglutinin or anti-CD3 antibody were comparable to controls, but proliferative responses to Candida were low or absent in 4 of 6 patients.In contrast, only 1 of 8 patients with the common allele showed low responses to tetanus vaccine, and another patient had mild lymphopenia with a count of 1040 cells/μL. As expected, the APECED group of patients exhibited only an isolated defect in cellular response to Candida antigen (Table III).In summary, we have identified a group of patients who carry the PTPN22 variant allele 1858T, who in addition to chronic candidiasis frequently have recurrent microbial infections caused by antibody deficiency as well as gonadal failure and hypothyroidism. To the Editor: Chronic mucocutaneous candidiasis (CMCC) is a heterogeneous group of disorders with a common manifestation of persistent or recurrent candidial and fungal infections of the skin, nails, and mucous membranes. The best delineated entity, autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), is caused by mutations in the autoimmune regulator (AIRE) gene. However, AIRE mutations are found in only about a third of cases with CMCC in our institution. In a search for genetic predisposition to CMCC in patients without APECED, we studied the protein tyrosine phosphatase nonreceptor 22 (PTPN22), 1858T, a variant of the lymphoid protein tyrosine phosphatase (LYP) R620W.1Bottini N. Musumeci L. Alonso A. Rahmouni S. Nika K. Rostamkhani M. et al.A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.Nat Genet. 2004; 36: 337-338Crossref PubMed Scopus (1116) Google Scholar Lymphoid protein tyrosine phosphatase, which was first cloned and sequenced in our laboratory, was found to have a primary role in regulation of T-cell and B-cell antigen receptor signaling.2Cohen S. Dadi H. Shaoul E. Sharfe N. Roifman C.M. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase.Lyp. Blood. 1999; 93: 2013-2024PubMed Google Scholar, 3Cloutier J.F. Veillette A. Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase.J Exp Med. 1999; 189: 111-121Crossref PubMed Scopus (351) Google Scholar, 4Gjörloff-Wingren A. Saxena M. Williams S. Hammi D. Mustelin T. Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP.Eur J Immunol. 1999; 29: 3845-3854Crossref PubMed Scopus (158) Google Scholar An association of a single nucleotide transition in PTPN22 1858C>T with a variety of autoimmune diseases including rheumatoid arthritis, type I diabetes, and SLE as well as Graves disease and Addison disease has been established.1Bottini N. Musumeci L. Alonso A. Rahmouni S. Nika K. Rostamkhani M. et al.A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.Nat Genet. 2004; 36: 337-338Crossref PubMed Scopus (1116) Google Scholar, 5Begovich A.B. Carlton V.E. Honigberg L.A. Schrodi S.J. Chokkalingam A.P. Alexander H.C. et al.A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.Am J Hum Genet. 2004; 75: 330-337Abstract Full Text Full Text PDF PubMed Scopus (1175) Google Scholar, 6Wu H. Cantor R.M. Graham D.S. Lingren C.M. Farwell L. Jager P.L. et al.Association analysis of the R620W polymorphism of protein tyrosine phosphatase PTPN22 in systemic lupus erythematosus families: increased T allele frequency in systemic lupus erythematosus patients with autoimmune thyroid disease.Arthritis Rheum. 2005; 52: 2396-2402Crossref PubMed Scopus (77) Google Scholar The R620W variant is known to disrupt LYP's interaction with the regulatory kinase, c-src tyrosine kinase (CSK), although the functional consequences of this remain to be determined.1Bottini N. Musumeci L. Alonso A. Rahmouni S. Nika K. Rostamkhani M. et al.A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.Nat Genet. 2004; 36: 337-338Crossref PubMed Scopus (1116) Google Scholar We have studied here the clinical manifestations and immunologic laboratory findings of patients with PTPN22 1858T. Fourteen patients with CMCC and autoimmune features (without AIRE mutations) were identified. In addition, 5 other patients carrying mutations in the AIRE gene were included in this study for comparison purposes. None of the patients in our cohort were members of same kindred, and no autosomal-dominant pattern of inheritance was suggested from family history. The median age of patients with CMCC was 38 years (range, 7-55 years), and the median age at presentation was 3 years. For patients with APECED, the median age was 18 years (range, 3.5-30 years), and median age of presentation was 1.5 years (Table I). Genomic sequencing of the PTPN22 gene revealed that 6 of 14 patients, all white, had heterozygous variant allele 1858T, whereas in our control group, matched for sex and ethnicity, 34 of 189 carried the variant allele. The allele frequencies were significantly different between the patients and control groups, with a frequency of 0.428 in the patient group and 0.179 in the control group (similar to historic controls) χ2 = 5.095; P = .024; odds ratio, 3.42; 95% CI, 1.11-10.48. None of the 5 patients with APECED with homozygous mutations in the AIRE gene carried the PTPN22 variant, 1858T. All 14 patients, regardless of their PTPN22 alleles, had chronic candidiasis; 86% of the patients had oral candidiasis; 92% had chronic fungal skin infections; and 64% had typical involvement of the nails. Analysis of the group of patients carrying PTPN22 1858T revealed a high prevalence of endocrinopathies, affecting 83% (5/6) of the patients. Hypothyroidism and gonadal failure were the most common, each found in 50% of the patients, whereas only 1 patient had adrenal insufficiency. Gonadal failure was found only in the group with the 1858T allele. This endocrine disorder is also a common feature of APECED, affecting about 60% of the patients.7Ahonen P. Myllärniemi S. Sipila I. Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients.N Engl J Med. 1990; 322: 1829-1836Crossref PubMed Scopus (848) Google Scholar By comparison, only 3 of the 8 patients with the common PTPN22 allele, 1858C, had endocrinopathy, all with hypothyroidism. In the distinct APECED group, polyendocrinopathy affected 4 of the 5 patients, most commonly with hypoparathyroidism and Addison disease (Table II). ITP, Idiopathic thrombocytopenic purpura. Other autoimmune disorders were identified more frequently in the group of the common PTPN22 allele, including arthritis (25%), alopecia (25%), idiopathic thrombocytopenic purpura, polymyositis, and enteropathy. In the PTPN22 1858T group, 2 patients had arthritis, and another had chronic enteritis. In the patients with APECED, vitiligo was the most common autoimmune feature. Conversely, none of the patients with the 1858T allele had vitiligo (Table II). Remarkably, patients carrying the PTPN22 1858T had a higher frequency of infections than patients who carry the common allele or patients with APECED. Eighty-three percent of patients within the PTPN22 1858T group had severe pulmonary infections including bronchiectasis, compared with only 25% in the common 1858C allele group. This is likely explained by laboratory studies revealing that 4 of the 6 patients carrying the variant allele had antibody defects, including hypogammaglobulinemia (p1,5) or dysgammaglobulinemia (p2,3), manifested as inadequate responses to protein and/or polysaccharide vaccinations (Table III). The exact mechanism whereby PTPN22 1858T predisposes individuals to microbial infections remains unclear.8Chapman S.J. Khor C.C. Vannberg F.O. Maskell N.A. Davies C.W. Hedley E.L. et al.PTPN22 and invasive bacterial disease.Nat Genet. 2006; 38: 499-500Crossref PubMed Scopus (48) Google Scholar In part, this may be explained, as recently shown, by the finding that lymphocytes carrying the PTPN22 variant had decreased responses to stimulation by anti-CD3 and by anti-IgM as well as decreased numbers of memory B cells (CD19+CD27+ population).9Rieck M. Arechiga A. Onengut-Gumuscu S. Greenbaum C. Concannon P. Buckner J.H. Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes.J Immunol. 2007; 179: 4704-4710PubMed Google Scholar In the future, similar additional abnormalities may eventually evolve in patients with CMCC with the PTPN22 variant 1858T. ALC, Absolute lymphocyte count; NA, not available. None of the patients had lymphopenia, and lymphocyte markers showed normal numbers of CD3, CD4, CD8, CD19, and CD56-positive cells in 4 patients. One patient had a low CD4 count (P2), and another had a relatively low number of B cells (P6). In vitro mitogenic responses to phytohemagglutinin or anti-CD3 antibody were comparable to controls, but proliferative responses to Candida were low or absent in 4 of 6 patients. In contrast, only 1 of 8 patients with the common allele showed low responses to tetanus vaccine, and another patient had mild lymphopenia with a count of 1040 cells/μL. As expected, the APECED group of patients exhibited only an isolated defect in cellular response to Candida antigen (Table III). In summary, we have identified a group of patients who carry the PTPN22 variant allele 1858T, who in addition to chronic candidiasis frequently have recurrent microbial infections caused by antibody deficiency as well as gonadal failure and hypothyroidism." @default.
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• W2002785655 title "Association of the lymphoid protein tyrosine phosphatase, R620W variant, with chronic mucocutaneous candidiasis" @default.
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