Cytotoxic T-Lymphocyte-Associated Protein 4 Haploinsufficiency-Associated Inflammation Can Occur Independently of T-Cell Hyperproliferation
Located contiguously on the long arm of the second chromosome are gene paralogs encoding the immunoglobulin-family co-activation receptors CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). CD28 and CTLA4 share the same B7 ligands yet each provides opposing proliferative signals to T cell...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-07-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.01715/full |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Carole Le Coz Brian E. Nolan Melissa Trofa Alicia M. Kamsheh Mustafa K. Khokha Mustafa K. Khokha Mustafa K. Khokha Saquib A. Lakhani Saquib A. Lakhani Antonio Novelli Elaine H. Zackai Elaine H. Zackai Kathleen E. Sullivan Kathleen E. Sullivan Silvana Briuglia Tricia R. Bhatti Tricia R. Bhatti Neil Romberg Neil Romberg |
| spellingShingle |
Carole Le Coz Brian E. Nolan Melissa Trofa Alicia M. Kamsheh Mustafa K. Khokha Mustafa K. Khokha Mustafa K. Khokha Saquib A. Lakhani Saquib A. Lakhani Antonio Novelli Elaine H. Zackai Elaine H. Zackai Kathleen E. Sullivan Kathleen E. Sullivan Silvana Briuglia Tricia R. Bhatti Tricia R. Bhatti Neil Romberg Neil Romberg Cytotoxic T-Lymphocyte-Associated Protein 4 Haploinsufficiency-Associated Inflammation Can Occur Independently of T-Cell Hyperproliferation Frontiers in Immunology cytotoxic T-lymphocyte-associated protein 4 CD28 type 3 innate lymphoid cell inflammation regulatory T cell |
| author_facet |
Carole Le Coz Brian E. Nolan Melissa Trofa Alicia M. Kamsheh Mustafa K. Khokha Mustafa K. Khokha Mustafa K. Khokha Saquib A. Lakhani Saquib A. Lakhani Antonio Novelli Elaine H. Zackai Elaine H. Zackai Kathleen E. Sullivan Kathleen E. Sullivan Silvana Briuglia Tricia R. Bhatti Tricia R. Bhatti Neil Romberg Neil Romberg |
| author_sort |
Carole Le Coz |
| title |
Cytotoxic T-Lymphocyte-Associated Protein 4 Haploinsufficiency-Associated Inflammation Can Occur Independently of T-Cell Hyperproliferation |
| title_short |
Cytotoxic T-Lymphocyte-Associated Protein 4 Haploinsufficiency-Associated Inflammation Can Occur Independently of T-Cell Hyperproliferation |
| title_full |
Cytotoxic T-Lymphocyte-Associated Protein 4 Haploinsufficiency-Associated Inflammation Can Occur Independently of T-Cell Hyperproliferation |
| title_fullStr |
Cytotoxic T-Lymphocyte-Associated Protein 4 Haploinsufficiency-Associated Inflammation Can Occur Independently of T-Cell Hyperproliferation |
| title_full_unstemmed |
Cytotoxic T-Lymphocyte-Associated Protein 4 Haploinsufficiency-Associated Inflammation Can Occur Independently of T-Cell Hyperproliferation |
| title_sort |
cytotoxic t-lymphocyte-associated protein 4 haploinsufficiency-associated inflammation can occur independently of t-cell hyperproliferation |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Immunology |
| issn |
1664-3224 |
| publishDate |
2018-07-01 |
| description |
Located contiguously on the long arm of the second chromosome are gene paralogs encoding the immunoglobulin-family co-activation receptors CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). CD28 and CTLA4 share the same B7 ligands yet each provides opposing proliferative signals to T cells. Herein, we describe for the first time two unrelated subjects with coexisting CD28 and CTLA4 haploinsufficiency due to heterozygous microdeletions of chromosome 2q. Although their clinical phenotype, multi-organ inflammatory disease, is superficially similar to that of CTLA4 haploinsufficient autoimmune lymphoproliferative syndrome type V (ALPS5) patients, we demonstrate our subjects’ underlying immunopathology to be distinct. Unlike ALPS5 T cells which hyperproliferate to T-cell receptor-mediated activation and infiltrate organs, T cells from our subjects are hypoproliferative and do not. Instead of T cell infiltrates, biopsies of affected subject tissues demonstrated infiltrates of lineage negative lymphoid cells. This histologic feature correlated with significant increases in circulating type 3 innate lymphoid cells (ILC3s) and ILC3 cytokines, interleukin 22, and interleukin-17A. CTLA4-Ig monotherapy, which we trialed in one subject, was remarkably effective in controlling inflammatory diseases, normalizing ILC3 frequencies, and reducing ILC3 cytokine concentrations. |
| topic |
cytotoxic T-lymphocyte-associated protein 4 CD28 type 3 innate lymphoid cell inflammation regulatory T cell |
| url |
https://www.frontiersin.org/article/10.3389/fimmu.2018.01715/full |
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doaj-95a98da4b24f4d1281b27b42988a5c532020-11-25T00:04:01ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-07-01910.3389/fimmu.2018.01715385251Cytotoxic T-Lymphocyte-Associated Protein 4 Haploinsufficiency-Associated Inflammation Can Occur Independently of T-Cell HyperproliferationCarole Le Coz0Brian E. Nolan1Melissa Trofa2Alicia M. Kamsheh3Mustafa K. Khokha4Mustafa K. Khokha5Mustafa K. Khokha6Saquib A. Lakhani7Saquib A. Lakhani8Antonio Novelli9Elaine H. Zackai10Elaine H. Zackai11Kathleen E. Sullivan12Kathleen E. Sullivan13Silvana Briuglia14Tricia R. Bhatti15Tricia R. Bhatti16Neil Romberg17Neil Romberg18Division of Immunology and Allergy, The Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesDivision of Rheumatology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesDivision of Immunology and Allergy, The Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesDivision of Immunology and Allergy, The Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesDepartment of Genetics, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Pediatrics, Yale University School of Medicine, New Haven, CT, United StatesThe Pediatric Genomics Discovery Program, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Pediatrics, Yale University School of Medicine, New Haven, CT, United StatesThe Pediatric Genomics Discovery Program, Yale University School of Medicine, New Haven, CT, United StatesLaboratory of Molecular Genetics, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyDivision of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesDepartment of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United StatesDivision of Immunology and Allergy, The Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesDepartment of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Biomedical Science, University of Messina, Messina, ItalyDepartment of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States0Division of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesDivision of Immunology and Allergy, The Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesDepartment of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United StatesLocated contiguously on the long arm of the second chromosome are gene paralogs encoding the immunoglobulin-family co-activation receptors CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). CD28 and CTLA4 share the same B7 ligands yet each provides opposing proliferative signals to T cells. Herein, we describe for the first time two unrelated subjects with coexisting CD28 and CTLA4 haploinsufficiency due to heterozygous microdeletions of chromosome 2q. Although their clinical phenotype, multi-organ inflammatory disease, is superficially similar to that of CTLA4 haploinsufficient autoimmune lymphoproliferative syndrome type V (ALPS5) patients, we demonstrate our subjects’ underlying immunopathology to be distinct. Unlike ALPS5 T cells which hyperproliferate to T-cell receptor-mediated activation and infiltrate organs, T cells from our subjects are hypoproliferative and do not. Instead of T cell infiltrates, biopsies of affected subject tissues demonstrated infiltrates of lineage negative lymphoid cells. This histologic feature correlated with significant increases in circulating type 3 innate lymphoid cells (ILC3s) and ILC3 cytokines, interleukin 22, and interleukin-17A. CTLA4-Ig monotherapy, which we trialed in one subject, was remarkably effective in controlling inflammatory diseases, normalizing ILC3 frequencies, and reducing ILC3 cytokine concentrations.https://www.frontiersin.org/article/10.3389/fimmu.2018.01715/fullcytotoxic T-lymphocyte-associated protein 4CD28type 3 innate lymphoid cellinflammationregulatory T cell |