Thymic function in MHC class II–deficient patients
Background MHC class II (MHC-II) molecules play a pivotal role in the development, activation, and homeostasis of CD4+ TH cells in the thymus. The absence of MHC-II molecules causes severe T-cell immunodeficiency. Objective We sought to study thymic function, including T-cell receptor excision circl...
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creator | Lev, Atar, MSc Simon, Amos J., BSc Broides, Arnon, MD Levi, Jacob, MD Garty, Ben Zion, MD Rosenthal, Ester, MSc Amariglio, Ninette, PhD Rechavi, Gideon, MD, PhD Somech, Raz, MD, PhD |
description | Background MHC class II (MHC-II) molecules play a pivotal role in the development, activation, and homeostasis of CD4+ TH cells in the thymus. The absence of MHC-II molecules causes severe T-cell immunodeficiency. Objective We sought to study thymic function, including T-cell receptor excision circle (TREC) quantification, in patients with MHC-II deficiency. Methods Eight MHC-II–deficient patients underwent a thorough T-cell immunologic work-up, including thymic activity, which was estimated based on TREC levels and T-cell receptor (TCR) genes, as well as analysis of several sequential human TCR gene rearrangements. Results In vitro responses to mitogens were normal or only slightly reduced, and flow cytometric evaluations of the TCR-Vβ repertoires of total CD3+ lymphocytes were normal in all patients. However, both the flow cytometric evaluation of the TCR-Vβ repertoire on CD4+ cells and spectratyping evaluation of the TCR-Vγ repertoire on total CD3+ lymphocytes showed clonal abnormalities. TRECs were present in all patients in both total lymphocytes and sorted CD4+ cells. Additionally, TRECs were detected in genomic DNA obtained from Guthrie cards with dried blood spots. Quantitative RT-PCR assessment of different TCR gene rearrangement events revealed lower levels in MHC-II–deficient patients compared with levels seen in healthy control subjects. This was irrespective of the total lymphocyte numbers, suggesting a reduced global thymic activity. Conclusions Our report highlights potential pitfalls in diagnosing MHC-II deficiency and emphasizes the probable importance of MHC-II molecules in the normal thymic maturation process of T cells. Patients with MHC-II deficiency have detectable TRECs and might therefore be missed by a TREC-based newborn screening program. |
doi_str_mv | 10.1016/j.jaci.2012.10.040 |
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The absence of MHC-II molecules causes severe T-cell immunodeficiency. Objective We sought to study thymic function, including T-cell receptor excision circle (TREC) quantification, in patients with MHC-II deficiency. Methods Eight MHC-II–deficient patients underwent a thorough T-cell immunologic work-up, including thymic activity, which was estimated based on TREC levels and T-cell receptor (TCR) genes, as well as analysis of several sequential human TCR gene rearrangements. Results In vitro responses to mitogens were normal or only slightly reduced, and flow cytometric evaluations of the TCR-Vβ repertoires of total CD3+ lymphocytes were normal in all patients. However, both the flow cytometric evaluation of the TCR-Vβ repertoire on CD4+ cells and spectratyping evaluation of the TCR-Vγ repertoire on total CD3+ lymphocytes showed clonal abnormalities. TRECs were present in all patients in both total lymphocytes and sorted CD4+ cells. Additionally, TRECs were detected in genomic DNA obtained from Guthrie cards with dried blood spots. Quantitative RT-PCR assessment of different TCR gene rearrangement events revealed lower levels in MHC-II–deficient patients compared with levels seen in healthy control subjects. This was irrespective of the total lymphocyte numbers, suggesting a reduced global thymic activity. Conclusions Our report highlights potential pitfalls in diagnosing MHC-II deficiency and emphasizes the probable importance of MHC-II molecules in the normal thymic maturation process of T cells. Patients with MHC-II deficiency have detectable TRECs and might therefore be missed by a TREC-based newborn screening program.</description><identifier>ISSN: 0091-6749</identifier><identifier>EISSN: 1097-6825</identifier><identifier>DOI: 10.1016/j.jaci.2012.10.040</identifier><identifier>PMID: 23228244</identifier><identifier>CODEN: JACIBY</identifier><language>eng</language><publisher>New York, NY: Mosby, Inc</publisher><subject>Adult ; Allergy and Immunology ; Biological and medical sciences ; CD4-Positive T-Lymphocytes - immunology ; CD8-Positive T-Lymphocytes - immunology ; Cytomegalovirus ; Deoxyribonucleic acid ; Disease ; DNA ; Flow cytometry ; Fundamental and applied biological sciences. Psychology ; Fundamental immunology ; Histocompatibility Antigens Class II - immunology ; Humans ; Immune system ; immunodeficiency ; Immunopathology ; Infant ; Leukocytes, Mononuclear - cytology ; Lymphocytes ; Medical sciences ; MHC class II ; neonatal screening ; Patients ; Receptors, Antigen, T-Cell - genetics ; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis ; severe combined immunodeficiency ; Severe Combined Immunodeficiency - genetics ; Severe Combined Immunodeficiency - immunology ; T cell receptors ; T-cell receptor excision circle (TREC) ; T-cell receptor repertoire ; Thymus Gland - immunology ; Young Adult</subject><ispartof>Journal of allergy and clinical immunology, 2013-03, Vol.131 (3), p.831-839</ispartof><rights>American Academy of Allergy, Asthma & Immunology</rights><rights>2012 American Academy of Allergy, Asthma & Immunology</rights><rights>2014 INIST-CNRS</rights><rights>Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.</rights><rights>Copyright Elsevier Limited Mar 2013</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c469t-aeac1dcb928f7a5550af5c8c62fe23a2311188650f1d443a589ddca3ee3d71623</citedby><cites>FETCH-LOGICAL-c469t-aeac1dcb928f7a5550af5c8c62fe23a2311188650f1d443a589ddca3ee3d71623</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jaci.2012.10.040$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27157165$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23228244$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lev, Atar, MSc</creatorcontrib><creatorcontrib>Simon, Amos J., BSc</creatorcontrib><creatorcontrib>Broides, Arnon, MD</creatorcontrib><creatorcontrib>Levi, Jacob, MD</creatorcontrib><creatorcontrib>Garty, Ben Zion, MD</creatorcontrib><creatorcontrib>Rosenthal, Ester, MSc</creatorcontrib><creatorcontrib>Amariglio, Ninette, PhD</creatorcontrib><creatorcontrib>Rechavi, Gideon, MD, PhD</creatorcontrib><creatorcontrib>Somech, Raz, MD, PhD</creatorcontrib><title>Thymic function in MHC class II–deficient patients</title><title>Journal of allergy and clinical immunology</title><addtitle>J Allergy Clin Immunol</addtitle><description>Background MHC class II (MHC-II) molecules play a pivotal role in the development, activation, and homeostasis of CD4+ TH cells in the thymus. The absence of MHC-II molecules causes severe T-cell immunodeficiency. Objective We sought to study thymic function, including T-cell receptor excision circle (TREC) quantification, in patients with MHC-II deficiency. Methods Eight MHC-II–deficient patients underwent a thorough T-cell immunologic work-up, including thymic activity, which was estimated based on TREC levels and T-cell receptor (TCR) genes, as well as analysis of several sequential human TCR gene rearrangements. Results In vitro responses to mitogens were normal or only slightly reduced, and flow cytometric evaluations of the TCR-Vβ repertoires of total CD3+ lymphocytes were normal in all patients. However, both the flow cytometric evaluation of the TCR-Vβ repertoire on CD4+ cells and spectratyping evaluation of the TCR-Vγ repertoire on total CD3+ lymphocytes showed clonal abnormalities. TRECs were present in all patients in both total lymphocytes and sorted CD4+ cells. Additionally, TRECs were detected in genomic DNA obtained from Guthrie cards with dried blood spots. Quantitative RT-PCR assessment of different TCR gene rearrangement events revealed lower levels in MHC-II–deficient patients compared with levels seen in healthy control subjects. This was irrespective of the total lymphocyte numbers, suggesting a reduced global thymic activity. Conclusions Our report highlights potential pitfalls in diagnosing MHC-II deficiency and emphasizes the probable importance of MHC-II molecules in the normal thymic maturation process of T cells. Patients with MHC-II deficiency have detectable TRECs and might therefore be missed by a TREC-based newborn screening program.</description><subject>Adult</subject><subject>Allergy and Immunology</subject><subject>Biological and medical sciences</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>Cytomegalovirus</subject><subject>Deoxyribonucleic acid</subject><subject>Disease</subject><subject>DNA</subject><subject>Flow cytometry</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Fundamental immunology</subject><subject>Histocompatibility Antigens Class II - immunology</subject><subject>Humans</subject><subject>Immune system</subject><subject>immunodeficiency</subject><subject>Immunopathology</subject><subject>Infant</subject><subject>Leukocytes, Mononuclear - cytology</subject><subject>Lymphocytes</subject><subject>Medical sciences</subject><subject>MHC class II</subject><subject>neonatal screening</subject><subject>Patients</subject><subject>Receptors, Antigen, T-Cell - genetics</subject><subject>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</subject><subject>severe combined immunodeficiency</subject><subject>Severe Combined Immunodeficiency - genetics</subject><subject>Severe Combined Immunodeficiency - immunology</subject><subject>T cell receptors</subject><subject>T-cell receptor excision circle (TREC)</subject><subject>T-cell receptor repertoire</subject><subject>Thymus Gland - immunology</subject><subject>Young Adult</subject><issn>0091-6749</issn><issn>1097-6825</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcuKFDEUQIMoTs_oD7iQAhFmU21u3gERpFGnYcSF4zpk8sCU1VVtUiX0zn_wD_0SU3TrwCxcXRLOfZ2L0DPAa8AgXnXrzrq0JhhI_Vhjhh-gFWAtW6EIf4hWGGtohWT6DJ2X0uH6pko_RmeEEqIIYyvEbr4edsk1cR7clMahSUPz8WrTuN6W0my3v3_-8iEml8IwNXs7LbE8QY-i7Ut4eooX6Mv7dzebq_b604ft5u1165jQU2uDdeDdrSYqSss5xzZyp5wgMRBqCQUApQTHETxj1HKlvXeWhkC9BEHoBbo81t3n8fscymR2qbjQ93YI41wMUGASC61xRV_cQ7txzkOdzkBtrKjkCipFjpTLYyk5RLPPaWfzwQA2i1PTmcWpWZwuf9VpTXp-Kj3f7oL_l_JXYgVengBbnO1jtoNL5Y6TwOs6vHKvj1yozn6kkE1ZvLrgUw5uMn5M_5_jzb1016ch1Y7fwiGUu31NIQabz8v1l-NDLSIFSPoH0Hanrg</recordid><startdate>20130301</startdate><enddate>20130301</enddate><creator>Lev, Atar, MSc</creator><creator>Simon, Amos J., BSc</creator><creator>Broides, Arnon, MD</creator><creator>Levi, Jacob, MD</creator><creator>Garty, Ben Zion, MD</creator><creator>Rosenthal, Ester, MSc</creator><creator>Amariglio, Ninette, PhD</creator><creator>Rechavi, Gideon, MD, PhD</creator><creator>Somech, Raz, MD, PhD</creator><general>Mosby, Inc</general><general>Elsevier</general><general>Elsevier Limited</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SS</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20130301</creationdate><title>Thymic function in MHC class II–deficient patients</title><author>Lev, Atar, MSc ; Simon, Amos J., BSc ; Broides, Arnon, MD ; Levi, Jacob, MD ; Garty, Ben Zion, MD ; Rosenthal, Ester, MSc ; Amariglio, Ninette, PhD ; Rechavi, Gideon, MD, PhD ; Somech, Raz, MD, PhD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c469t-aeac1dcb928f7a5550af5c8c62fe23a2311188650f1d443a589ddca3ee3d71623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adult</topic><topic>Allergy and Immunology</topic><topic>Biological and medical sciences</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>Cytomegalovirus</topic><topic>Deoxyribonucleic acid</topic><topic>Disease</topic><topic>DNA</topic><topic>Flow cytometry</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Fundamental immunology</topic><topic>Histocompatibility Antigens Class II - immunology</topic><topic>Humans</topic><topic>Immune system</topic><topic>immunodeficiency</topic><topic>Immunopathology</topic><topic>Infant</topic><topic>Leukocytes, Mononuclear - cytology</topic><topic>Lymphocytes</topic><topic>Medical sciences</topic><topic>MHC class II</topic><topic>neonatal screening</topic><topic>Patients</topic><topic>Receptors, Antigen, T-Cell - genetics</topic><topic>Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis</topic><topic>severe combined immunodeficiency</topic><topic>Severe Combined Immunodeficiency - genetics</topic><topic>Severe Combined Immunodeficiency - immunology</topic><topic>T cell receptors</topic><topic>T-cell receptor excision circle (TREC)</topic><topic>T-cell receptor repertoire</topic><topic>Thymus Gland - immunology</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lev, Atar, MSc</creatorcontrib><creatorcontrib>Simon, Amos J., BSc</creatorcontrib><creatorcontrib>Broides, Arnon, MD</creatorcontrib><creatorcontrib>Levi, Jacob, MD</creatorcontrib><creatorcontrib>Garty, Ben Zion, MD</creatorcontrib><creatorcontrib>Rosenthal, Ester, MSc</creatorcontrib><creatorcontrib>Amariglio, Ninette, PhD</creatorcontrib><creatorcontrib>Rechavi, Gideon, MD, PhD</creatorcontrib><creatorcontrib>Somech, Raz, MD, PhD</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of allergy and clinical immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lev, Atar, MSc</au><au>Simon, Amos J., BSc</au><au>Broides, Arnon, MD</au><au>Levi, Jacob, MD</au><au>Garty, Ben Zion, MD</au><au>Rosenthal, Ester, MSc</au><au>Amariglio, Ninette, PhD</au><au>Rechavi, Gideon, MD, PhD</au><au>Somech, Raz, MD, PhD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Thymic function in MHC class II–deficient patients</atitle><jtitle>Journal of allergy and clinical immunology</jtitle><addtitle>J Allergy Clin Immunol</addtitle><date>2013-03-01</date><risdate>2013</risdate><volume>131</volume><issue>3</issue><spage>831</spage><epage>839</epage><pages>831-839</pages><issn>0091-6749</issn><eissn>1097-6825</eissn><coden>JACIBY</coden><abstract>Background MHC class II (MHC-II) molecules play a pivotal role in the development, activation, and homeostasis of CD4+ TH cells in the thymus. The absence of MHC-II molecules causes severe T-cell immunodeficiency. Objective We sought to study thymic function, including T-cell receptor excision circle (TREC) quantification, in patients with MHC-II deficiency. Methods Eight MHC-II–deficient patients underwent a thorough T-cell immunologic work-up, including thymic activity, which was estimated based on TREC levels and T-cell receptor (TCR) genes, as well as analysis of several sequential human TCR gene rearrangements. Results In vitro responses to mitogens were normal or only slightly reduced, and flow cytometric evaluations of the TCR-Vβ repertoires of total CD3+ lymphocytes were normal in all patients. However, both the flow cytometric evaluation of the TCR-Vβ repertoire on CD4+ cells and spectratyping evaluation of the TCR-Vγ repertoire on total CD3+ lymphocytes showed clonal abnormalities. TRECs were present in all patients in both total lymphocytes and sorted CD4+ cells. Additionally, TRECs were detected in genomic DNA obtained from Guthrie cards with dried blood spots. Quantitative RT-PCR assessment of different TCR gene rearrangement events revealed lower levels in MHC-II–deficient patients compared with levels seen in healthy control subjects. This was irrespective of the total lymphocyte numbers, suggesting a reduced global thymic activity. Conclusions Our report highlights potential pitfalls in diagnosing MHC-II deficiency and emphasizes the probable importance of MHC-II molecules in the normal thymic maturation process of T cells. Patients with MHC-II deficiency have detectable TRECs and might therefore be missed by a TREC-based newborn screening program.</abstract><cop>New York, NY</cop><pub>Mosby, Inc</pub><pmid>23228244</pmid><doi>10.1016/j.jaci.2012.10.040</doi><tpages>9</tpages></addata></record> |
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subjects | Adult Allergy and Immunology Biological and medical sciences CD4-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - immunology Cytomegalovirus Deoxyribonucleic acid Disease DNA Flow cytometry Fundamental and applied biological sciences. Psychology Fundamental immunology Histocompatibility Antigens Class II - immunology Humans Immune system immunodeficiency Immunopathology Infant Leukocytes, Mononuclear - cytology Lymphocytes Medical sciences MHC class II neonatal screening Patients Receptors, Antigen, T-Cell - genetics Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis severe combined immunodeficiency Severe Combined Immunodeficiency - genetics Severe Combined Immunodeficiency - immunology T cell receptors T-cell receptor excision circle (TREC) T-cell receptor repertoire Thymus Gland - immunology Young Adult |
title | Thymic function in MHC class II–deficient patients |
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