Sex-Biased Aging Effects on Ig Somatic Hypermutation Targeting
Aged individuals, particularly males, display an impaired level of Ab response compared with their younger counterparts, yet the molecular mechanisms responsible for the discrepancy are not well understood. We hypothesize that some of this difference may be linked to B cell somatic hypermutation (SH...
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Veröffentlicht in: | The Journal of immunology (1950) 2021-01, Vol.206 (1), p.101-108 |
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description | Aged individuals, particularly males, display an impaired level of Ab response compared with their younger counterparts, yet the molecular mechanisms responsible for the discrepancy are not well understood. We hypothesize that some of this difference may be linked to B cell somatic hypermutation (SHM) targeting, including error-prone DNA repair activities that are crucial to Ab diversification. To examine the effects of aging on SHM targeting, we analyzed B cell Ig repertoire sequences from 27 healthy male and female human subjects aged 20-89. By studying mutation patterns based on 985,069 mutations obtained from 123,415 sequences, we found that the SHM mutability hierarchies on microsequence motifs (i.e., SHM hot/cold spots) are mostly consistent between different age and sex groups. However, we observed a lower frequency in mutations involving Phase II SHM DNA repair activities in older males, but not in females. We also observed, from a separate study, a decreased expression level of DNA mismatch repair genes involved in SHM in older individuals compared with younger individuals, with larger fold changes in males than in females. Finally, we showed that the balance between Phase I versus Phase II SHM activities impacts the resulting Ig phenotypes. Our results showed that the SHM process is altered in some older individuals, providing insights into observed clinical differences in immunologic responses between different age and sex groups. |
doi_str_mv | 10.4049/jimmunol.2000576 |
format | Article |
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We hypothesize that some of this difference may be linked to B cell somatic hypermutation (SHM) targeting, including error-prone DNA repair activities that are crucial to Ab diversification. To examine the effects of aging on SHM targeting, we analyzed B cell Ig repertoire sequences from 27 healthy male and female human subjects aged 20-89. By studying mutation patterns based on 985,069 mutations obtained from 123,415 sequences, we found that the SHM mutability hierarchies on microsequence motifs (i.e., SHM hot/cold spots) are mostly consistent between different age and sex groups. However, we observed a lower frequency in mutations involving Phase II SHM DNA repair activities in older males, but not in females. We also observed, from a separate study, a decreased expression level of DNA mismatch repair genes involved in SHM in older individuals compared with younger individuals, with larger fold changes in males than in females. Finally, we showed that the balance between Phase I versus Phase II SHM activities impacts the resulting Ig phenotypes. Our results showed that the SHM process is altered in some older individuals, providing insights into observed clinical differences in immunologic responses between different age and sex groups.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.2000576</identifier><identifier>PMID: 33288546</identifier><language>eng</language><publisher>United States</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Aging - immunology ; B-Lymphocytes - immunology ; DNA Repair - genetics ; Female ; Humans ; Immunity, Humoral - physiology ; Immunoglobulins - genetics ; Male ; Middle Aged ; Mutation - genetics ; Sex Characteristics ; Sex Factors ; Somatic Hypermutation, Immunoglobulin ; Young Adult</subject><ispartof>The Journal of immunology (1950), 2021-01, Vol.206 (1), p.101-108</ispartof><rights>Copyright © 2020 by The American Association of Immunologists, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c341t-3b0fa50f40ec98a52a384af09f6b2e2f2c122d8789a0251fb5b76d2419001ac93</citedby><cites>FETCH-LOGICAL-c341t-3b0fa50f40ec98a52a384af09f6b2e2f2c122d8789a0251fb5b76d2419001ac93</cites><orcidid>0000-0001-7667-9337 ; 0000-0003-4957-1544 ; 0000-0002-1087-8568</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33288546$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cui, Ang</creatorcontrib><creatorcontrib>Chawla, Daniel G</creatorcontrib><creatorcontrib>Kleinstein, Steven H</creatorcontrib><title>Sex-Biased Aging Effects on Ig Somatic Hypermutation Targeting</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>Aged individuals, particularly males, display an impaired level of Ab response compared with their younger counterparts, yet the molecular mechanisms responsible for the discrepancy are not well understood. We hypothesize that some of this difference may be linked to B cell somatic hypermutation (SHM) targeting, including error-prone DNA repair activities that are crucial to Ab diversification. To examine the effects of aging on SHM targeting, we analyzed B cell Ig repertoire sequences from 27 healthy male and female human subjects aged 20-89. By studying mutation patterns based on 985,069 mutations obtained from 123,415 sequences, we found that the SHM mutability hierarchies on microsequence motifs (i.e., SHM hot/cold spots) are mostly consistent between different age and sex groups. However, we observed a lower frequency in mutations involving Phase II SHM DNA repair activities in older males, but not in females. We also observed, from a separate study, a decreased expression level of DNA mismatch repair genes involved in SHM in older individuals compared with younger individuals, with larger fold changes in males than in females. Finally, we showed that the balance between Phase I versus Phase II SHM activities impacts the resulting Ig phenotypes. Our results showed that the SHM process is altered in some older individuals, providing insights into observed clinical differences in immunologic responses between different age and sex groups.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Aging - immunology</subject><subject>B-Lymphocytes - immunology</subject><subject>DNA Repair - genetics</subject><subject>Female</subject><subject>Humans</subject><subject>Immunity, Humoral - physiology</subject><subject>Immunoglobulins - genetics</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mutation - genetics</subject><subject>Sex Characteristics</subject><subject>Sex Factors</subject><subject>Somatic Hypermutation, Immunoglobulin</subject><subject>Young Adult</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kE1Lw0AQhhdRbK3ePcn-gdTZ2Y8kF6GWagsFD63nsNnshpTmg90E7L830tbT8DLvMzAPIc8M5gJE-nqo6npo2uMcAUDG6oZMmZQQKQXqlkwBECMWq3hCHkI4jB0FKO7JhHNMEinUlLzt7E_0XulgC7ooq6akK-es6QNtG7op6a6tdV8Zuj511tdDP4Zxsde-tP3YfiR3Th-DfbrMGfn-WO2X62j79blZLraR4YL1Ec_BaQlOgDVpoiVqngjtIHUqR4sODUMskjhJNaBkLpd5rAoULAVg2qR8RuB81_g2BG9d1vmq1v6UMcj-VGRXFdlFxYi8nJFuyGtb_APX3_kvdoRbOA</recordid><startdate>20210101</startdate><enddate>20210101</enddate><creator>Cui, Ang</creator><creator>Chawla, Daniel G</creator><creator>Kleinstein, Steven H</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0001-7667-9337</orcidid><orcidid>https://orcid.org/0000-0003-4957-1544</orcidid><orcidid>https://orcid.org/0000-0002-1087-8568</orcidid></search><sort><creationdate>20210101</creationdate><title>Sex-Biased Aging Effects on Ig Somatic Hypermutation Targeting</title><author>Cui, Ang ; Chawla, Daniel G ; Kleinstein, Steven H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c341t-3b0fa50f40ec98a52a384af09f6b2e2f2c122d8789a0251fb5b76d2419001ac93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Aging - immunology</topic><topic>B-Lymphocytes - immunology</topic><topic>DNA Repair - genetics</topic><topic>Female</topic><topic>Humans</topic><topic>Immunity, Humoral - physiology</topic><topic>Immunoglobulins - genetics</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mutation - genetics</topic><topic>Sex Characteristics</topic><topic>Sex Factors</topic><topic>Somatic Hypermutation, Immunoglobulin</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cui, Ang</creatorcontrib><creatorcontrib>Chawla, Daniel G</creatorcontrib><creatorcontrib>Kleinstein, Steven H</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cui, Ang</au><au>Chawla, Daniel G</au><au>Kleinstein, Steven H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sex-Biased Aging Effects on Ig Somatic Hypermutation Targeting</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2021-01-01</date><risdate>2021</risdate><volume>206</volume><issue>1</issue><spage>101</spage><epage>108</epage><pages>101-108</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>Aged individuals, particularly males, display an impaired level of Ab response compared with their younger counterparts, yet the molecular mechanisms responsible for the discrepancy are not well understood. We hypothesize that some of this difference may be linked to B cell somatic hypermutation (SHM) targeting, including error-prone DNA repair activities that are crucial to Ab diversification. To examine the effects of aging on SHM targeting, we analyzed B cell Ig repertoire sequences from 27 healthy male and female human subjects aged 20-89. By studying mutation patterns based on 985,069 mutations obtained from 123,415 sequences, we found that the SHM mutability hierarchies on microsequence motifs (i.e., SHM hot/cold spots) are mostly consistent between different age and sex groups. However, we observed a lower frequency in mutations involving Phase II SHM DNA repair activities in older males, but not in females. We also observed, from a separate study, a decreased expression level of DNA mismatch repair genes involved in SHM in older individuals compared with younger individuals, with larger fold changes in males than in females. Finally, we showed that the balance between Phase I versus Phase II SHM activities impacts the resulting Ig phenotypes. Our results showed that the SHM process is altered in some older individuals, providing insights into observed clinical differences in immunologic responses between different age and sex groups.</abstract><cop>United States</cop><pmid>33288546</pmid><doi>10.4049/jimmunol.2000576</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-7667-9337</orcidid><orcidid>https://orcid.org/0000-0003-4957-1544</orcidid><orcidid>https://orcid.org/0000-0002-1087-8568</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Adult Aged Aged, 80 and over Aging - immunology B-Lymphocytes - immunology DNA Repair - genetics Female Humans Immunity, Humoral - physiology Immunoglobulins - genetics Male Middle Aged Mutation - genetics Sex Characteristics Sex Factors Somatic Hypermutation, Immunoglobulin Young Adult |
title | Sex-Biased Aging Effects on Ig Somatic Hypermutation Targeting |
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