Abstract

The SJL strain of mice has a known dimorphism in the immune response, with females having more robust cytokine production than males. Mice which differ in the complement of sex chromosomes, while having the same gonadal type, have been created and backcrossed onto the SJL strain to determine the effect of sex chromosomes on immune responses in the absence of confounding effects of exposure to different types of adult or developmental sex hormones. Surprisingly, we found that the male XY genotype is relatively stimulatory, while the male sex hormone (testosterone) is inhibitory, for cytokine production of lymph node cells (LNCs) from SJL mice immunized with the autoantigen myelin basic protein (MBP). This is the first experimental evidence of a compensatory effect of sex chromosomes and sex hormones on a biologic process.
In aim #1 of this proposal, we will determine whether other key immune parameters, in addition to cytokine production, are also influenced by sex chromosome genotype.
In aim #2, we will ascertain whether sex chromosome genotype does or does not influence immune responses in a strain not characterized by greater immune responses in females as compared to males, the C57BL/6. Finally, in aim #3, we will determine if the sex chromosome effect on immune responses is attributed to the dose of X or Y genes. Together these proposed studies will greatly advance the understanding of the role of sex chromosomes on immune responses.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050839-08
Application #
7558317
Study Section
Special Emphasis Panel (ZRG1-IMM-E (02))
Program Officer
Gondre-Lewis, Timothy A
Project Start
2002-02-01
Project End
2010-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
8
Fiscal Year
2009
Total Cost
$359,276
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Sasidhar, Manda V; Itoh, Noriko; Gold, Stefan M et al. (2012) The XX sex chromosome complement in mice is associated with increased spontaneous lupus compared with XY. Ann Rheum Dis 71:1418-22
Voskuhl, Rhonda R; Gold, Stefan M (2012) Sex-related factors in multiple sclerosis susceptibility and progression. Nat Rev Neurol 8:255-63
Arnold, Arthur P (2009) Mouse models for evaluating sex chromosome effects that cause sex differences in non-gonadal tissues. J Neuroendocrinol 21:377-86
Gold, Stefan M; Voskuhl, Rhonda R (2009) Estrogen treatment in multiple sclerosis. J Neurol Sci 286:99-103
Arnold, Arthur P; Chen, Xuqi (2009) What does the ""four core genotypes"" mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol 30:1-9
Gold, Stefan M; Sasidhar, Manda V; Morales, Laurie B et al. (2009) Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ERalpha). Lab Invest 89:1076-83
Smith-Bouvier, Deborah L; Divekar, Anagha A; Sasidhar, Manda et al. (2008) A role for sex chromosome complement in the female bias in autoimmune disease. J Exp Med 205:1099-108
Smith, Deborah L; Dong, Xin; Du, Sienmi et al. (2007) A female preponderance for chemically induced lupus in SJL/J mice. Clin Immunol 122:101-7
Palaszynski, Karen M; Smith, Deborah L; Kamrava, Shana et al. (2005) A yin-yang effect between sex chromosome complement and sex hormones on the immune response. Endocrinology 146:3280-5
Palaszynski, Karen M; Loo, Kyi Kyi; Ashouri, Judith F et al. (2004) Androgens are protective in experimental autoimmune encephalomyelitis: implications for multiple sclerosis. J Neuroimmunol 146:144-52

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