{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T03:18:44Z","timestamp":1790565524246,"version":"4.1.0"},"reference-count":104,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T00:00:00Z","timestamp":1675900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health (NIH)","award":["P30CA21765"],"award-info":[{"award-number":["P30CA21765"]}]},{"name":"National Institutes of Health (NIH)","award":["75N93019C00052"],"award-info":[{"award-number":["75N93019C00052"]}]},{"name":"National Cancer Institute","award":["P30CA21765"],"award-info":[{"award-number":["P30CA21765"]}]},{"name":"National Cancer Institute","award":["75N93019C00052"],"award-info":[{"award-number":["75N93019C00052"]}]},{"name":"ALSAC","award":["P30CA21765"],"award-info":[{"award-number":["P30CA21765"]}]},{"name":"ALSAC","award":["75N93019C00052"],"award-info":[{"award-number":["75N93019C00052"]}]},{"name":"Collaborative Influenza Vaccine Innovation Centers (CIVIC)","award":["P30CA21765"],"award-info":[{"award-number":["P30CA21765"]}]},{"name":"Collaborative Influenza Vaccine Innovation Centers (CIVIC)","award":["75N93019C00052"],"award-info":[{"award-number":["75N93019C00052"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Females often exhibit superior immune responses compared to males toward vaccines and pathogens such as influenza viruses and SARS-CoV-2. To help explain these differences, we first studied serum immunoglobulin isotype patterns in C57BL\/6 male and female mice. We focused on IgG2b, an isotype that lends to virus control and that has been previously shown to be elevated in murine females compared to males. Improvements in IgG2b serum levels, and\/or IgG2b ratios with other non-IgM isotypes, were observed when: (i) wildtype (WT) female mice were compared to estrogen receptor knockout mice (IgG2b, IgG2b\/IgG3, IgG2b\/IgG1, and IgG2b\/IgA were all higher in WT mice), (ii) unmanipulated female mice were compared to ovariectomized mice (IgG2b\/IgA was higher in unmanipulated animals), (iii) female mice were supplemented with estrogen in the context of an inflammatory insult (IgG2b and IgG2b\/IgG3 were improved by estrogen supplementation), and (iv) male mice were supplemented with testosterone, a hormone that can convert to estrogen in vivo (IgG2b, IgG2b\/IgG3, IgG2b\/IgG1, and IgG2b\/IgA were all improved by supplementation). We next examined data from three sets of previously described male and female human blood samples. In each case, there were higher IgG2 levels, and\/or ratios of IgG2 with non-IgM isotypes, in human females compared to males. The effects of sex and sex hormones in the mouse and human studies were subtle, but frequent, suggesting that sex hormones represent only a fraction of the factors that influence isotype patterns. Examination of the gene loci suggested that upregulation of murine IgG2b or human IgG2 could be mediated by estrogen receptor binding to estrogen response elements and cytosine-adenine (CA) repeats upstream of respective C\u03b3 genes. Given that murine IgG2b and human IgG2 lend to virus control, the isotype biases in females may be sufficient to improve outcomes following vaccination or infection. Future attention to sex hormone levels, and consequent immunoglobulin isotype patterns, in clinical trials are encouraged to support the optimization of vaccine and drug products for male and female hosts.<\/jats:p>","DOI":"10.3390\/v15020482","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T03:21:55Z","timestamp":1675912915000},"page":"482","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["How Estrogen, Testosterone, and Sex Differences Influence Serum Immunoglobulin Isotype Patterns in Mice and Humans"],"prefix":"10.3390","volume":"15","author":[{"given":"Sherri L.","family":"Surman","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart G.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhiannon R.","family":"Penkert","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Sealy","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6570-7179","authenticated-orcid":false,"given":"Tony","family":"Marion","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7955-0256","authenticated-orcid":false,"given":"Paul G.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA"},{"name":"Department of Immunology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3776-0858","authenticated-orcid":false,"given":"Geoffrey","family":"Neale","sequence":"additional","affiliation":[{"name":"Hartwell Center, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beisi","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Applied Bioinformatics, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia L.","family":"Hurwitz","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"},{"name":"Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"781","DOI":"10.4049\/jimmunol.95.5.781","article-title":"The immunoglobulins of mice. VI. Response to immunization","volume":"95","author":"Barth","year":"1965","journal-title":"J. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1001\/jama.1965.03090140079020","article-title":"Antibodies and immunoglobulins. I. Structure and function","volume":"194","author":"Fahey","year":"1965","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1084\/jem.122.1.41","article-title":"The Immunoglobulins of Mice. V. The Metabolic (Catabolic) Properties of Five Immunoglobulin Classes","volume":"122","author":"Fahey","year":"1965","journal-title":"J Exp. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1126\/science.143.3606.588","article-title":"Antibody Activity in Six Classes of Human Immunoglobulins","volume":"143","author":"Fahey","year":"1964","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1084\/jem.120.2.223","article-title":"The Immunoglobulins of Mice. I. Four Major Classes of Immunoglobulins: 7s Gamma-2-, 7s Gamma-1-, Gamma-1a (Beta-2a)-, and 18s Gamma-1m-Globulins","volume":"120","author":"Fahey","year":"1964","journal-title":"J. Exp. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1084\/jem.120.2.243","article-title":"The Immunoglobulins of Mice. Ii. Two Subclasses of Mouse 7s Gamma-2-Globulins: Gamma-2a- and Gamma-2b-Globulins","volume":"120","author":"Fahey","year":"1964","journal-title":"J. Exp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1126\/science.146.3642.400","article-title":"Subclasses of Human Gamma-2-Globulin Based on Differences in the Heavy Polypeptide Chains","volume":"146","author":"Terry","year":"1964","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-2776(06)93001-6","article-title":"Class switch recombination: A comparison between mouse and human","volume":"93","author":"Zhao","year":"2007","journal-title":"Adv. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3389\/fimmu.2014.00520","article-title":"IgG subclasses and allotypes: From structure to effector functions","volume":"5","author":"Vidarsson","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.4049\/jimmunol.146.6.1972","article-title":"Passive transfer of local immunity to influenza virus infection by IgA antibody","volume":"146","author":"Renegar","year":"1991","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.4049\/jimmunol.173.3.1978","article-title":"Role of IgA versus IgG in the control of influenza viral infection in the murine respiratory tract","volume":"173","author":"Renegar","year":"2004","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1128\/jvi.55.3.517-520.1985","article-title":"Quantitative aspects of passive immunity to respiratory syncytial virus infection in infant cotton rats","volume":"55","author":"Prince","year":"1985","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5640","DOI":"10.1182\/blood-2012-01-380121","article-title":"Properties of mouse and human IgG receptors and their contribution to disease models","volume":"119","author":"Bruhns","year":"2012","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1128\/jvi.69.4.2075-2081.1995","article-title":"Virus-neutralizing antibodies of immunoglobulin G (IgG) but not of IgM or IgA isotypes can cure influenza virus pneumonia in SCID mice","volume":"69","author":"Palladino","year":"1995","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7793","DOI":"10.1128\/JVI.00979-13","article-title":"Recombinant IgA is sufficient to prevent influenza virus transmission in guinea pigs","volume":"87","author":"Seibert","year":"2013","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41586-020-2700-3","article-title":"Sex differences in immune responses that underlie COVID-19 disease outcomes","volume":"588","author":"Takahashi","year":"2020","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1093\/intimm\/dxy074","article-title":"Complex sex-biased antibody responses: Estrogen receptors bind estrogen response elements centered within immunoglobulin heavy chain gene enhancers","volume":"31","author":"Jones","year":"2019","journal-title":"Int. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e0183922","DOI":"10.1128\/mbio.01839-22","article-title":"Greater Breadth of Vaccine-Induced Immunity in Females than Males Is Mediated by Increased Antibody Diversity in Germinal Center B Cells","volume":"13","author":"Ursin","year":"2022","journal-title":"mBio"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1093\/infdis\/jiaa289","article-title":"Differential Antibody Recognition of H3N2 Vaccine and Seasonal Influenza Virus Strains Based on Age, Vaccine Status, and Sex in the 2017-2018 Season","volume":"222","author":"Ursin","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"j5560","DOI":"10.1136\/bmj.j5560","article-title":"The science behind \u201cman flu\u201d","volume":"359","author":"Sue","year":"2017","journal-title":"BMJ"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/nri2394","article-title":"The X-files in immunity: Sex-based differences predispose immune responses","volume":"8","author":"Fish","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1073\/pnas.1321060111","article-title":"Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination","volume":"111","author":"Furman","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e12695","DOI":"10.1111\/aji.12695","article-title":"Estradiol and progesterone influence on influenza infection and immune response in a mouse model","volume":"78","author":"Davis","year":"2017","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9246","DOI":"10.1016\/j.vaccine.2011.09.110","article-title":"Antibody responses and cross protection against lethal influenza A viruses differ between the sexes in C57BL\/6 mice","volume":"29","author":"Lorenzo","year":"2011","journal-title":"Vaccine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"712688","DOI":"10.3389\/fimmu.2021.712688","article-title":"Gene-Specific Sex Effects on Susceptibility to Infectious Diseases","volume":"12","author":"Lipoldova","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2405","DOI":"10.1001\/archinternmed.2008.513","article-title":"Half- vs full-dose trivalent inactivated influenza vaccine (2004\u20132005): Age, dose, and sex effects on immune responses","volume":"168","author":"Engler","year":"2008","journal-title":"Arch. Intern. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1016\/j.vaccine.2021.02.047","article-title":"Sex-specific effects of age and body mass index on antibody responses to seasonal influenza vaccines in healthcare workers","volume":"40","author":"Kuo","year":"2022","journal-title":"Vaccine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"836642","DOI":"10.3389\/fragi.2022.836642","article-title":"Roadmap for Sex-Responsive Influenza and COVID-19 Vaccine Research in Older Adults","volume":"3","author":"Shapiro","year":"2022","journal-title":"Front. Aging"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S61","DOI":"10.1093\/cid\/ciac397","article-title":"Association of Frailty, Age, and Biological Sex with Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccine-Induced Immunity in Older Adults","volume":"75","author":"Shapiro","year":"2022","journal-title":"Clin. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1002\/oby.23417","article-title":"Sex-associated differences between BMI and SARS-CoV-2 antibody titers following the BNT162b2 vaccine","volume":"30","author":"Yamamoto","year":"2022","journal-title":"Obesity"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"786586","DOI":"10.3389\/fimmu.2022.786586","article-title":"Sex, Age, and Ethnic Background Shape Adaptive Immune Responses Induced by the SARS-CoV-2 mRNA Vaccine","volume":"13","author":"Bai","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2515","DOI":"10.1016\/j.vaccine.2011.01.080","article-title":"17beta-Estradiol restores antibody responses to an influenza vaccine in a postmenopausal mouse model","volume":"29","author":"Nguyen","year":"2011","journal-title":"Vaccine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5424","DOI":"10.1073\/pnas.77.9.5424","article-title":"Successive switching of antibody isotypes expressed within the lines of a B-cell clone","volume":"77","author":"Gearhart","year":"1980","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5370","DOI":"10.4049\/jimmunol.1401849","article-title":"IgH chain class switch recombination: Mechanism and regulation","volume":"193","author":"Stavnezer","year":"2014","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1084\/jem.20141967","article-title":"Mediator facilitates transcriptional activation and dynamic long-range contacts at the IgH locus during class switch recombination","volume":"213","author":"Robert","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.cell.2010.09.017","article-title":"Activation-induced cytidine deaminase targets DNA at sites of RNA polymerase II stalling by interaction with Spt5","volume":"143","author":"Pavri","year":"2010","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"738216","DOI":"10.3389\/fimmu.2021.738216","article-title":"Long-Range Control of Class Switch Recombination by Transcriptional Regulatory Elements","volume":"12","author":"Dauba","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7084","DOI":"10.1038\/ncomms8084","article-title":"Elucidation of IgH 3\u2019 region regulatory role during class switch recombination via germline deletion","volume":"6","author":"Saintamand","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1101\/gr.10.8.1108","article-title":"GT repeats are associated with recombination on human chromosome 22","volume":"10","author":"Majewski","year":"2000","journal-title":"Genome Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1038\/sj.emboj.7600677","article-title":"Intronic CA-repeat and CA-rich elements: A new class of regulators of mammalian alternative splicing","volume":"24","author":"Hui","year":"2005","journal-title":"EMBO J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1126\/science.8153633","article-title":"Association of poly(CA).poly(TG) DNA fragments into four-stranded complexes bound by HMG1 and 2","volume":"264","author":"Gaillard","year":"1994","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e45056","DOI":"10.7554\/eLife.45056","article-title":"Global donor and acceptor splicing site kinetics in human cells","volume":"8","author":"Wachutka","year":"2019","journal-title":"Elife"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Jones, B.G., Penkert, R.R., Surman, S.L., Sealy, R.E., and Hurwitz, J.L. (2020). Nuclear Receptors, Ligands and the Mammalian B Cell. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21144997"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"103996","DOI":"10.1016\/j.cellimm.2019.103996","article-title":"Matters of life and death: How estrogen and estrogen receptor binding to the immunoglobulin heavy chain locus may influence outcomes of infection, allergy, and autoimmune disease","volume":"346","author":"Jones","year":"2019","journal-title":"Cell Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.molimm.2016.07.015","article-title":"Binding of estrogen receptors to switch sites and regulatory elements in the immunoglobulin heavy chain locus of activated B cells suggests a direct influence of estrogen on antibody expression","volume":"77","author":"Jones","year":"2016","journal-title":"Mol. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1089\/vim.2019.0144","article-title":"From Influenza Virus Infections to Lupus: Synchronous Estrogen Receptor alpha and RNA Polymerase II Binding Within the Immunoglobulin Heavy Chain Locus","volume":"33","author":"Jones","year":"2020","journal-title":"Viral Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Sealy, R.E., Jones, B.G., Surman, S.L., Penkert, R.R., Pelletier, S., Neale, G., and Hurwitz, J.L. (2019). Will Attention by Vaccine Developers to the Host\u2019s Nuclear Hormone Levels and Immunocompetence Improve Vaccine Success?. Vaccines, 7.","DOI":"10.3390\/vaccines7010026"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1084\/jem.20082311","article-title":"Ikaros controls isotype selection during immunoglobulin class switch recombination","volume":"206","author":"Sellars","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/ng1901","article-title":"Genome-wide analysis of estrogen receptor binding sites","volume":"38","author":"Carroll","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.molonc.2007.04.001","article-title":"Identifying estrogen receptor target genes","volume":"1","author":"Welboren","year":"2007","journal-title":"Mol. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0039-128X(99)00107-5","article-title":"Estrogen receptor interaction with co-activators and co-repressors","volume":"65","author":"Klinge","year":"2000","journal-title":"Steroids"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1021\/bi00327a001","article-title":"Correlation in isolated nuclei of template-engaged RNA polymerase II, ovalbumin mRNA synthesis, and estrogen receptor concentrations","volume":"24","author":"Taylor","year":"1985","journal-title":"Biochemistry"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"127","DOI":"10.4161\/trns.24556","article-title":"Transcriptional stalling in B-lymphocytes: A mechanism for antibody diversification and maintenance of genomic integrity","volume":"4","author":"Sun","year":"2013","journal-title":"Transcription"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1038\/emboj.2009.88","article-title":"ChIP-Seq of ERalpha and RNA polymerase II defines genes differentially responding to ligands","volume":"28","author":"Welboren","year":"2009","journal-title":"EMBO J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/s41593-021-00806-8","article-title":"Considering sex as a biological variable will require a global shift in science culture","volume":"24","author":"Shansky","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Surman, S.L., Penkert, R.R., Sealy, R.E., Jones, B.G., Marion, T.N., Vogel, P., and Hurwitz, J.L. (2020). Consequences of Vitamin A Deficiency: Immunoglobulin Dysregulation, Squamous Cell Metaplasia, Infectious Disease, and Death. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155570"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1093\/intimm\/12.11.1569","article-title":"Induction of anti-DNA antibody with DNA-peptide complexes","volume":"12","author":"Desai","year":"2000","journal-title":"Int. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/cei.12718","article-title":"Retinol binding protein and vitamin D associations with serum antibody isotypes, serum influenza virus-specific neutralizing activities and airway cytokine profiles","volume":"183","author":"Jones","year":"2016","journal-title":"Clin. Exp. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Patel, N., Penkert, R.R., Jones, B.G., Sealy, R.E., Surman, S.L., Sun, Y., Tang, L., DeBeauchamp, J., Webb, A., and Richardson, J. (2019). Baseline Serum Vitamin A and D Levels Determine Benefit of Oral Vitamin A&D Supplements to Humoral Immune Responses Following Pediatric Influenza Vaccination. Viruses, 11.","DOI":"10.3390\/v11100907"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Patel, N., Penkert, R.R., Sealy, R.E., Surman, S.L., Jones, B.G., Ringwald-Smith, K., Ross, A.C., and Hurwitz, J.L. (2022). Retinol Binding Protein, Sunlight Hours, and the Influenza Virus-Specific Immune Response. Biomedicines, 10.","DOI":"10.3390\/biomedicines10092322"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1164\/rccm.201309-1616OC","article-title":"Mucosal immune responses predict clinical outcomes during influenza infection independently of age and viral load","volume":"189","author":"Oshansky","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3955","DOI":"10.1210\/jc.2010-0102","article-title":"The effects of injected testosterone dose and age on the conversion of testosterone to estradiol and dihydrotestosterone in young and older men","volume":"95","author":"Lakshman","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1113\/jphysiol.2006.114850","article-title":"Conversion from testosterone to oestradiol is required to modulate respiratory long-term facilitation in male rats","volume":"576","author":"Zabka","year":"2006","journal-title":"J. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1515\/JPEM.2006.19.7.901","article-title":"Estradiol levels and secretory dynamics in normal girls and boys as determined by an ultrasensitive bioassay: A 10 year experience","volume":"19","author":"Janfaza","year":"2006","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1172\/JCI117616","article-title":"Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay","volume":"94","author":"Klein","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1203\/00006450-197311000-00006","article-title":"Plasma estrogens in childhood and puberty under physiologic and pathologic conditions","volume":"7","author":"Bidlingmaier","year":"1973","journal-title":"Pediatr. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1038\/s41423-019-0267-4","article-title":"A novel regulatory region controls IgH locus transcription and switch recombination to a subset of isotypes","volume":"16","author":"Rogier","year":"2019","journal-title":"Cell. Mol. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.gene.2004.10.009","article-title":"Evolution of human IgH3\u2019EC duplicated structures: Both enhancers HS1,2 are polymorphic with variation of transcription factor\u2019s consensus sites","volume":"346","author":"Giambra","year":"2005","journal-title":"Gene"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.cell.2014.03.012","article-title":"Nuclear Receptors, RXR, and the Big Bang","volume":"157","author":"Evans","year":"2014","journal-title":"Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1016\/j.vaccine.2014.03.025","article-title":"Oral retinyl palmitate or retinoic acid corrects mucosal IgA responses toward an intranasal influenza virus vaccine in vitamin A deficient mice","volume":"32","author":"Surman","year":"2014","journal-title":"Vaccine"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1128\/CVI.00757-13","article-title":"Intranasal administration of retinyl palmitate with a respiratory virus vaccine corrects impaired mucosal IgA response in the vitamin A-deficient host","volume":"21","author":"Surman","year":"2014","journal-title":"Clin. Vaccine Immunol. CVI"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Rudraraju, R., Jones, B.G., Surman, S.L., Sealy, R.E., Thomas, P.G., and Hurwitz, J.L. (2014). Respiratory tract epithelial cells express retinaldehyde dehydrogenase ALDH1A and enhance IgA production by stimulated B cells in the presence of vitamin A. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086554"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/nri2378","article-title":"Vitamin effects on the immune system: Vitamins A and D take centre stage","volume":"8","author":"Mora","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1038\/mi.2017.62","article-title":"The regulation of gut mucosal IgA B-cell responses: Recent developments","volume":"10","author":"Lycke","year":"2017","journal-title":"Mucosal Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.smim.2008.08.002","article-title":"Role of retinoic acid in the imprinting of gut-homing IgA-secreting cells","volume":"21","author":"Mora","year":"2009","journal-title":"Semin. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1006\/cimm.1996.1069","article-title":"Retinoic acid induces the expression of germ-line C alpha transcript mainly by a TGF-beta-independent mechanism","volume":"176","author":"Tokuyama","year":"1997","journal-title":"Cell Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.humimm.2014.06.021","article-title":"Retinoic acid acts as a selective human IgA switch factor","volume":"75","author":"Seo","year":"2014","journal-title":"Hum. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1089\/vim.2015.0104","article-title":"Hotspots for Vitamin-Steroid-Thyroid Hormone Response Elements within Switch Regions of Immunoglobulin Heavy Chain Loci Predict a Direct Influence of Vitamins and Hormones on B Cell Class Switch Recombination","volume":"29","author":"Hurwitz","year":"2016","journal-title":"Viral Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"143","DOI":"10.2147\/ITT.S274746","article-title":"Immunoglobulin G2 Antibody as a Potential Target for COVID-19 Vaccine","volume":"9","author":"Andualem","year":"2020","journal-title":"Immunotargets Ther."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"41","DOI":"10.7196\/AJTCCM.2021.v27i2.134","article-title":"Lymphopenia and IgG2 subclass deficiency in patients with severe COVID-19 pneumonia","volume":"27","author":"Taban","year":"2021","journal-title":"Afr. J. Thorac. Crit. Care Med."},{"key":"ref_81","first-page":"672","article-title":"Association between severe pandemic 2009 influenza A (H1N1) virus infection and immunoglobulin G(2) subclass deficiency","volume":"50","author":"Gordon","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1006\/viro.1993.1015","article-title":"The Fc portion of antibody to yellow fever virus NS1 is a determinant of protection against YF encephalitis in mice","volume":"192","author":"Schlesinger","year":"1993","journal-title":"Virology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1086\/430320","article-title":"Combination of HIV-1-specific CD4 Th1 cell responses and IgG2 antibodies is the best predictor for persistence of long-term nonprogression","volume":"191","author":"Martinez","year":"2005","journal-title":"J. Infect. Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1099\/0022-1317-70-9-2439","article-title":"The immunoglobulin G subclass responses of mice to influenza A virus: The effect of mouse strain, and the neutralizing abilities of individual protein A-purified subclass antibodies","volume":"70","author":"Hocart","year":"1989","journal-title":"J. Gen. Virol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"814598","DOI":"10.1155\/2014\/814598","article-title":"Gender differences of B cell signature in healthy subjects underlie disparities in incidence and course of SLE related to estrogen","volume":"2014","author":"Fan","year":"2014","journal-title":"J. Immunol. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1006\/jaut.1996.0121","article-title":"Characterization of estrogen-induced autoantibodies to cardiolipin in non-autoimmune mice","volume":"10","author":"Verthelyi","year":"1997","journal-title":"J. Autoimmun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1093\/rheumatology\/41.1.62","article-title":"IgG subclass distribution of autoantibodies differs between renal and extra-renal relapses in patients with systemic lupus erythematosus","volume":"41","author":"Bijl","year":"2002","journal-title":"Rheumatology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"6092","DOI":"10.1073\/pnas.1701631114","article-title":"Inducible CTCF insulator delays the IgH 3\u2019 regulatory region-mediated activation of germline promoters and alters class switching","volume":"114","author":"Braikia","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1084\/jem.20130166","article-title":"The cohesin complex regulates immunoglobulin class switch recombination","volume":"210","author":"Schiavo","year":"2013","journal-title":"J. Exp. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.4049\/jimmunol.167.6.3257","article-title":"HS1,2 enhancer regulation of germline epsilon and gamma2b promoters in murine B lymphocytes: Evidence for specific promoter-enhancer interactions","volume":"167","author":"Laurencikiene","year":"2001","journal-title":"J. Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"10730","DOI":"10.1038\/ncomms10730","article-title":"Deciphering the importance of the palindromic architecture of the immunoglobulin heavy-chain 3\u2019 regulatory region","volume":"7","author":"Saintamand","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1073\/pnas.1514090113","article-title":"Sequential activation and distinct functions for distal and proximal modules within the IgH 3\u2019 regulatory region","volume":"113","author":"Garot","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Serone, E., Daleno, C., Principi, N., Porretti, L., Iacoacci, V., Gargioli, C., Magrini, A., Massoud, R., D\u2019Addabbo, P., and Cattalini, M. (2014). The change in Ig regulation from children to adults disconnects the correlation with the 3\u2019RR hs1.2 polymorphism. BMC Immunol., 15.","DOI":"10.1186\/s12865-014-0045-0"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Penkert, R.R., Patel, N., Webby, R.J., Ross, T.M., and Hurwitz, J.L. (2021). Month of Influenza Virus Vaccination Influences Antibody Responses in Children and Adults. Vaccines, 9.","DOI":"10.3390\/vaccines9020068"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"10045","DOI":"10.1074\/jbc.RA119.011614","article-title":"Agonist binding directs dynamic competition among nuclear receptors for heterodimerization with retinoid X receptor","volume":"295","author":"Fadel","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1126\/science.aan6414","article-title":"Synthetic transcription elongation factors license transcription across repressive chromatin","volume":"358","author":"Erwin","year":"2017","journal-title":"Science"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1172\/JCI0214873","article-title":"Estrogen alters thresholds for B cell apoptosis and activation","volume":"109","author":"Grimaldi","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/S0091-6749(99)70503-8","article-title":"Estrogen enhances immunoglobulin production by human PBMCs","volume":"103","author":"Kanda","year":"1999","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.1073\/pnas.040577497","article-title":"Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells","volume":"97","author":"Bynoe","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Vom Steeg, L.G., Dhakal, S., Woldetsadik, Y.A., Park, H.S., Mulka, K.R., Reilly, E.C., Topham, D.J., and Klein, S.L. (2020). Androgen receptor signaling in the lungs mitigates inflammation and improves the outcome of influenza in mice. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008506"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1038\/s41467-018-04408-0","article-title":"Testosterone is an endogenous regulator of BAFF and splenic B cell number","volume":"9","author":"Wilhelmson","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.imlet.2016.12.002","article-title":"Gender differences of B cell signature related to estrogen-induced IFI44L\/BAFF in systemic lupus erythematosus","volume":"181","author":"Fan","year":"2017","journal-title":"Immunol. Lett."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cellimm.2015.02.004","article-title":"Suppressive effects of androgens on the immune system","volume":"294","author":"Trigunaite","year":"2015","journal-title":"Cell Immunol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1210\/jcem-64-1-32","article-title":"Influence of testosterone therapy on clinical and immunological features of autoimmune diseases associated with Klinefelter\u2019s syndrome","volume":"64","author":"Bizzarro","year":"1987","journal-title":"J. Clin. Endocrinol. Metab."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/2\/482\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:28:10Z","timestamp":1760120890000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/2\/482"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,9]]},"references-count":104,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["v15020482"],"URL":"https:\/\/doi.org\/10.3390\/v15020482","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,9]]}}}