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Altered B cell homeostasis and toll-like receptor 9-driven response in type 1 diabetes carriers of the C1858T PTPN22 allelic variant: implications in the disease pathogenesis
Type 1 diabetes is an autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Among the genetic variants associated with type 1 diabetes, the C1858T (Lyp) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene alters the function of...
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Published in: | PloS one 2014-10, Vol.9 (10), p.e110755 |
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description | Type 1 diabetes is an autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Among the genetic variants associated with type 1 diabetes, the C1858T (Lyp) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene alters the function of T cells but also of B cells in innate and adaptive immunity. The Lyp variant was shown to diminish interferon production and responses upon Toll-like receptor stimulation in macrophages and dendritic cells, possibly leading to uncontrolled infections as triggers of the diabetogenic process. The aim of this study was to unravel the yet uncharacterized effects that the variant could exert on the immune and autoimmune responses, particularly regarding the B cell phenotype, in the peripheral blood lymphocytes of diabetic patients and healthy controls in basal conditions and after unmethylated bacterial DNA CpG stimulation. The presence of the Lyp variant resulted in a significant increase in the percentage of transitional B cells in C/T carriers patients and controls compared to C/C patients and controls, in C/T carrier patients compared to C/C controls and in C/T carrier patients compared to C/C patients. A significant reduction in the memory B cells was also observed in the presence of the risk variant. After four days of CpG stimulation, there was a significant increase in the abundance of IgM+ memory B cells in C/T carrier diabetics than in C/C subjects and in the groups of C/T carrier individuals than in C/C individuals. IgM- memory B cells tended to differentiate more precociously into plasma cells than IgM+ memory B cells in heterozygous C/T subjects compared to the C/C subjects. The increased Toll-like receptor response that led to expanded T cell-independent IgM+ memory B cells should be further investigated to determine the putative contribution of innate immune responses in the disease pathogenesis. |
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Among the genetic variants associated with type 1 diabetes, the C1858T (Lyp) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene alters the function of T cells but also of B cells in innate and adaptive immunity. The Lyp variant was shown to diminish interferon production and responses upon Toll-like receptor stimulation in macrophages and dendritic cells, possibly leading to uncontrolled infections as triggers of the diabetogenic process. The aim of this study was to unravel the yet uncharacterized effects that the variant could exert on the immune and autoimmune responses, particularly regarding the B cell phenotype, in the peripheral blood lymphocytes of diabetic patients and healthy controls in basal conditions and after unmethylated bacterial DNA CpG stimulation. The presence of the Lyp variant resulted in a significant increase in the percentage of transitional B cells in C/T carriers patients and controls compared to C/C patients and controls, in C/T carrier patients compared to C/C controls and in C/T carrier patients compared to C/C patients. A significant reduction in the memory B cells was also observed in the presence of the risk variant. After four days of CpG stimulation, there was a significant increase in the abundance of IgM+ memory B cells in C/T carrier diabetics than in C/C subjects and in the groups of C/T carrier individuals than in C/C individuals. IgM- memory B cells tended to differentiate more precociously into plasma cells than IgM+ memory B cells in heterozygous C/T subjects compared to the C/C subjects. The increased Toll-like receptor response that led to expanded T cell-independent IgM+ memory B cells should be further investigated to determine the putative contribution of innate immune responses in the disease pathogenesis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0110755</identifier><identifier>PMID: 25333705</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adaptive immunity ; Adolescent ; Adult ; Alleles ; Antigens ; Arthritis ; Autoimmunity ; B cells ; B-Lymphocytes - immunology ; B-Lymphocytes - pathology ; Beta cells ; Biological response modifiers ; Biology and life sciences ; Carriers ; Cell Differentiation ; Child ; CpG islands ; CpG Islands - genetics ; Dendritic cells ; Deoxyribonucleic acid ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (insulin dependent) ; Diabetes Mellitus, Type 1 - genetics ; Diabetes Mellitus, Type 1 - immunology ; Diabetes Mellitus, Type 1 - pathology ; Diabetics ; DNA ; DNA, Bacterial - administration & dosage ; Drug therapy ; Endocrinology ; Female ; Gene polymorphism ; Genetic Association Studies ; Genetic diversity ; Genetic polymorphisms ; Genetic Predisposition to Disease ; Genetic variance ; Health aspects ; Homeostasis ; Humans ; Immune response ; Immune system ; Immunity ; Immunoglobulin M ; Immunoglobulins ; Immunological memory ; Immunology ; Innate immunity ; Insulin-Secreting Cells - immunology ; Insulin-Secreting Cells - pathology ; Interferon ; Laboratories ; Lupus ; Lymphocyte receptors ; Lymphocytes ; Lymphocytes T ; Macrophages ; Male ; Medicine and Health Sciences ; Memory cells ; Pancreas ; Pancreatic beta cells ; Pathogenesis ; Patients ; Peripheral blood ; Phenotypes ; Phosphatase ; Plasma cells ; Polymorphism ; Polymorphism, Single Nucleotide ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 - immunology ; Protein-tyrosine-phosphatase ; Proteins ; Rodents ; Stimulation ; Systemic lupus erythematosus ; T cell receptors ; T cells ; T-Lymphocytes - immunology ; T-Lymphocytes - pathology ; Toll-Like Receptor 9 - genetics ; Toll-Like Receptor 9 - immunology ; Toll-like receptors ; Tyrosine</subject><ispartof>PloS one, 2014-10, Vol.9 (10), p.e110755</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Gianchecchi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Gianchecchi et al 2014 Gianchecchi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-f32842c4843b449a4ef03c31239767c84f6b787fe56564733a62af56168ae1893</citedby><cites>FETCH-LOGICAL-c692t-f32842c4843b449a4ef03c31239767c84f6b787fe56564733a62af56168ae1893</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1615769808/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1615769808?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25333705$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Pietropaolo, Massimo</contributor><creatorcontrib>Gianchecchi, Elena</creatorcontrib><creatorcontrib>Crinò, Antonino</creatorcontrib><creatorcontrib>Giorda, Ezio</creatorcontrib><creatorcontrib>Luciano, Rosa</creatorcontrib><creatorcontrib>Perri, Valentina</creatorcontrib><creatorcontrib>Russo, Anna Lo</creatorcontrib><creatorcontrib>Cappa, Marco</creatorcontrib><creatorcontrib>Rosado, M Manuela</creatorcontrib><creatorcontrib>Fierabracci, Alessandra</creatorcontrib><title>Altered B cell homeostasis and toll-like receptor 9-driven response in type 1 diabetes carriers of the C1858T PTPN22 allelic variant: implications in the disease pathogenesis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Type 1 diabetes is an autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Among the genetic variants associated with type 1 diabetes, the C1858T (Lyp) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene alters the function of T cells but also of B cells in innate and adaptive immunity. The Lyp variant was shown to diminish interferon production and responses upon Toll-like receptor stimulation in macrophages and dendritic cells, possibly leading to uncontrolled infections as triggers of the diabetogenic process. The aim of this study was to unravel the yet uncharacterized effects that the variant could exert on the immune and autoimmune responses, particularly regarding the B cell phenotype, in the peripheral blood lymphocytes of diabetic patients and healthy controls in basal conditions and after unmethylated bacterial DNA CpG stimulation. The presence of the Lyp variant resulted in a significant increase in the percentage of transitional B cells in C/T carriers patients and controls compared to C/C patients and controls, in C/T carrier patients compared to C/C controls and in C/T carrier patients compared to C/C patients. A significant reduction in the memory B cells was also observed in the presence of the risk variant. After four days of CpG stimulation, there was a significant increase in the abundance of IgM+ memory B cells in C/T carrier diabetics than in C/C subjects and in the groups of C/T carrier individuals than in C/C individuals. IgM- memory B cells tended to differentiate more precociously into plasma cells than IgM+ memory B cells in heterozygous C/T subjects compared to the C/C subjects. The increased Toll-like receptor response that led to expanded T cell-independent IgM+ memory B cells should be further investigated to determine the putative contribution of innate immune responses in the disease pathogenesis.</description><subject>Adaptive immunity</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Alleles</subject><subject>Antigens</subject><subject>Arthritis</subject><subject>Autoimmunity</subject><subject>B cells</subject><subject>B-Lymphocytes - immunology</subject><subject>B-Lymphocytes - pathology</subject><subject>Beta cells</subject><subject>Biological response modifiers</subject><subject>Biology and life sciences</subject><subject>Carriers</subject><subject>Cell Differentiation</subject><subject>Child</subject><subject>CpG islands</subject><subject>CpG Islands - genetics</subject><subject>Dendritic cells</subject><subject>Deoxyribonucleic acid</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (insulin dependent)</subject><subject>Diabetes Mellitus, Type 1 - genetics</subject><subject>Diabetes Mellitus, Type 1 - immunology</subject><subject>Diabetes Mellitus, Type 1 - pathology</subject><subject>Diabetics</subject><subject>DNA</subject><subject>DNA, Bacterial - administration & dosage</subject><subject>Drug therapy</subject><subject>Endocrinology</subject><subject>Female</subject><subject>Gene polymorphism</subject><subject>Genetic Association Studies</subject><subject>Genetic diversity</subject><subject>Genetic polymorphisms</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic variance</subject><subject>Health aspects</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunity</subject><subject>Immunoglobulin M</subject><subject>Immunoglobulins</subject><subject>Immunological memory</subject><subject>Immunology</subject><subject>Innate immunity</subject><subject>Insulin-Secreting Cells - immunology</subject><subject>Insulin-Secreting Cells - pathology</subject><subject>Interferon</subject><subject>Laboratories</subject><subject>Lupus</subject><subject>Lymphocyte receptors</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Macrophages</subject><subject>Male</subject><subject>Medicine and Health Sciences</subject><subject>Memory cells</subject><subject>Pancreas</subject><subject>Pancreatic beta cells</subject><subject>Pathogenesis</subject><subject>Patients</subject><subject>Peripheral blood</subject><subject>Phenotypes</subject><subject>Phosphatase</subject><subject>Plasma cells</subject><subject>Polymorphism</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics</subject><subject>Protein Tyrosine Phosphatase, Non-Receptor Type 22 - immunology</subject><subject>Protein-tyrosine-phosphatase</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Stimulation</subject><subject>Systemic lupus erythematosus</subject><subject>T cell receptors</subject><subject>T cells</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes - pathology</subject><subject>Toll-Like Receptor 9 - genetics</subject><subject>Toll-Like Receptor 9 - immunology</subject><subject>Toll-like receptors</subject><subject>Tyrosine</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9tuEzEQhlcIREvhDRBYQkJwkeDTer1cIJWIQ6WKVlC4tSbe2cTFWQfbqehL8Yw4aVo1qBdoL3Y9-_3_eMaeqnrK6JiJhr05D6s4gB8vw4Bjyhht6vpetc9awUeKU3H_1vde9Silc0proZV6WO3xWgjR0Hq_-nPoM0bsyHti0XsyDwsMKUNyicDQkRy8H3n3E0lEi8scImlHXXQXOJRIKskTEjeQfLlEwkjnYIoZE7EQo8OYSOhJniOZMF3rM3J6dvqFcwLeo3eWXEB0MOS3xC2WZQ3ZFb-NXZF0LiEU9yXkeZjhgGVPj6sHPfiET7bvg-r7xw9nk8-j45NPR5PD45FVLc-jXnAtuZVaiqmULUjsqbCCcdE2qrFa9mra6KbHWtVKNkKA4tDXiikNyHQrDqrnV75LH5LZtjoZpljdqFZTXYijK6ILcG6W0S0gXpoAzmwCIc4MxOysR9Mhby3lgtYcJC-JsZkKqG2neykpxeL1bpttNV1gZ3HIEfyO6e6fwc3NLFwYyWlNS1UH1autQQy_VpiyWbi0Pk8YMKw2-1ZSU96sK3vxD3p3dVtqBqUAN_Sh5LVrU3MomWa8oYwWanwHVZ4OF86We9m7Et8RvN4RFCbj7zyDVUrm6NvX_2dPfuyyL2-xcwSf5yn41eY-7YLyCrQxpBSxv2kyo2Y9VtfdMOuxMtuxKrJntw_oRnQ9R-IvN-ocMw</recordid><startdate>20141021</startdate><enddate>20141021</enddate><creator>Gianchecchi, Elena</creator><creator>Crinò, Antonino</creator><creator>Giorda, Ezio</creator><creator>Luciano, Rosa</creator><creator>Perri, Valentina</creator><creator>Russo, Anna Lo</creator><creator>Cappa, Marco</creator><creator>Rosado, M Manuela</creator><creator>Fierabracci, Alessandra</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20141021</creationdate><title>Altered B cell homeostasis and toll-like receptor 9-driven response in type 1 diabetes carriers of the C1858T PTPN22 allelic variant: implications in the disease pathogenesis</title><author>Gianchecchi, Elena ; Crinò, Antonino ; Giorda, Ezio ; Luciano, Rosa ; Perri, Valentina ; Russo, Anna Lo ; Cappa, Marco ; Rosado, M Manuela ; Fierabracci, Alessandra</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-f32842c4843b449a4ef03c31239767c84f6b787fe56564733a62af56168ae1893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adaptive immunity</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Alleles</topic><topic>Antigens</topic><topic>Arthritis</topic><topic>Autoimmunity</topic><topic>B cells</topic><topic>B-Lymphocytes - immunology</topic><topic>B-Lymphocytes - pathology</topic><topic>Beta cells</topic><topic>Biological response modifiers</topic><topic>Biology and life sciences</topic><topic>Carriers</topic><topic>Cell Differentiation</topic><topic>Child</topic><topic>CpG islands</topic><topic>CpG Islands - genetics</topic><topic>Dendritic cells</topic><topic>Deoxyribonucleic acid</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (insulin dependent)</topic><topic>Diabetes Mellitus, Type 1 - genetics</topic><topic>Diabetes Mellitus, Type 1 - immunology</topic><topic>Diabetes Mellitus, Type 1 - pathology</topic><topic>Diabetics</topic><topic>DNA</topic><topic>DNA, Bacterial - administration & dosage</topic><topic>Drug therapy</topic><topic>Endocrinology</topic><topic>Female</topic><topic>Gene polymorphism</topic><topic>Genetic Association Studies</topic><topic>Genetic diversity</topic><topic>Genetic polymorphisms</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic variance</topic><topic>Health aspects</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Immune response</topic><topic>Immune system</topic><topic>Immunity</topic><topic>Immunoglobulin M</topic><topic>Immunoglobulins</topic><topic>Immunological memory</topic><topic>Immunology</topic><topic>Innate immunity</topic><topic>Insulin-Secreting Cells - immunology</topic><topic>Insulin-Secreting Cells - pathology</topic><topic>Interferon</topic><topic>Laboratories</topic><topic>Lupus</topic><topic>Lymphocyte receptors</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Macrophages</topic><topic>Male</topic><topic>Medicine and Health Sciences</topic><topic>Memory cells</topic><topic>Pancreas</topic><topic>Pancreatic beta cells</topic><topic>Pathogenesis</topic><topic>Patients</topic><topic>Peripheral blood</topic><topic>Phenotypes</topic><topic>Phosphatase</topic><topic>Plasma cells</topic><topic>Polymorphism</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics</topic><topic>Protein Tyrosine Phosphatase, Non-Receptor Type 22 - immunology</topic><topic>Protein-tyrosine-phosphatase</topic><topic>Proteins</topic><topic>Rodents</topic><topic>Stimulation</topic><topic>Systemic lupus erythematosus</topic><topic>T cell receptors</topic><topic>T cells</topic><topic>T-Lymphocytes - immunology</topic><topic>T-Lymphocytes - pathology</topic><topic>Toll-Like Receptor 9 - genetics</topic><topic>Toll-Like Receptor 9 - immunology</topic><topic>Toll-like receptors</topic><topic>Tyrosine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gianchecchi, Elena</creatorcontrib><creatorcontrib>Crinò, Antonino</creatorcontrib><creatorcontrib>Giorda, Ezio</creatorcontrib><creatorcontrib>Luciano, Rosa</creatorcontrib><creatorcontrib>Perri, Valentina</creatorcontrib><creatorcontrib>Russo, Anna Lo</creatorcontrib><creatorcontrib>Cappa, Marco</creatorcontrib><creatorcontrib>Rosado, M Manuela</creatorcontrib><creatorcontrib>Fierabracci, Alessandra</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>ProQuest Biological Science Journals</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest advanced technologies & aerospace journals</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gianchecchi, Elena</au><au>Crinò, Antonino</au><au>Giorda, Ezio</au><au>Luciano, Rosa</au><au>Perri, Valentina</au><au>Russo, Anna Lo</au><au>Cappa, Marco</au><au>Rosado, M Manuela</au><au>Fierabracci, Alessandra</au><au>Pietropaolo, Massimo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Altered B cell homeostasis and toll-like receptor 9-driven response in type 1 diabetes carriers of the C1858T PTPN22 allelic variant: implications in the disease pathogenesis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-10-21</date><risdate>2014</risdate><volume>9</volume><issue>10</issue><spage>e110755</spage><pages>e110755-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Type 1 diabetes is an autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Among the genetic variants associated with type 1 diabetes, the C1858T (Lyp) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene alters the function of T cells but also of B cells in innate and adaptive immunity. The Lyp variant was shown to diminish interferon production and responses upon Toll-like receptor stimulation in macrophages and dendritic cells, possibly leading to uncontrolled infections as triggers of the diabetogenic process. The aim of this study was to unravel the yet uncharacterized effects that the variant could exert on the immune and autoimmune responses, particularly regarding the B cell phenotype, in the peripheral blood lymphocytes of diabetic patients and healthy controls in basal conditions and after unmethylated bacterial DNA CpG stimulation. The presence of the Lyp variant resulted in a significant increase in the percentage of transitional B cells in C/T carriers patients and controls compared to C/C patients and controls, in C/T carrier patients compared to C/C controls and in C/T carrier patients compared to C/C patients. A significant reduction in the memory B cells was also observed in the presence of the risk variant. After four days of CpG stimulation, there was a significant increase in the abundance of IgM+ memory B cells in C/T carrier diabetics than in C/C subjects and in the groups of C/T carrier individuals than in C/C individuals. IgM- memory B cells tended to differentiate more precociously into plasma cells than IgM+ memory B cells in heterozygous C/T subjects compared to the C/C subjects. The increased Toll-like receptor response that led to expanded T cell-independent IgM+ memory B cells should be further investigated to determine the putative contribution of innate immune responses in the disease pathogenesis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25333705</pmid><doi>10.1371/journal.pone.0110755</doi><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2014-10, Vol.9 (10), p.e110755 |
issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_1615769808 |
source | Publicly Available Content Database (Proquest) (PQ_SDU_P3); PubMed Central |
subjects | Adaptive immunity Adolescent Adult Alleles Antigens Arthritis Autoimmunity B cells B-Lymphocytes - immunology B-Lymphocytes - pathology Beta cells Biological response modifiers Biology and life sciences Carriers Cell Differentiation Child CpG islands CpG Islands - genetics Dendritic cells Deoxyribonucleic acid Diabetes Diabetes mellitus Diabetes mellitus (insulin dependent) Diabetes Mellitus, Type 1 - genetics Diabetes Mellitus, Type 1 - immunology Diabetes Mellitus, Type 1 - pathology Diabetics DNA DNA, Bacterial - administration & dosage Drug therapy Endocrinology Female Gene polymorphism Genetic Association Studies Genetic diversity Genetic polymorphisms Genetic Predisposition to Disease Genetic variance Health aspects Homeostasis Humans Immune response Immune system Immunity Immunoglobulin M Immunoglobulins Immunological memory Immunology Innate immunity Insulin-Secreting Cells - immunology Insulin-Secreting Cells - pathology Interferon Laboratories Lupus Lymphocyte receptors Lymphocytes Lymphocytes T Macrophages Male Medicine and Health Sciences Memory cells Pancreas Pancreatic beta cells Pathogenesis Patients Peripheral blood Phenotypes Phosphatase Plasma cells Polymorphism Polymorphism, Single Nucleotide Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics Protein Tyrosine Phosphatase, Non-Receptor Type 22 - immunology Protein-tyrosine-phosphatase Proteins Rodents Stimulation Systemic lupus erythematosus T cell receptors T cells T-Lymphocytes - immunology T-Lymphocytes - pathology Toll-Like Receptor 9 - genetics Toll-Like Receptor 9 - immunology Toll-like receptors Tyrosine |
title | Altered B cell homeostasis and toll-like receptor 9-driven response in type 1 diabetes carriers of the C1858T PTPN22 allelic variant: implications in the disease pathogenesis |
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