Gender differences have been known to occur in a variety of autoimmune diseases for decades, with females being more susceptible in most cases. Gender differences in disease susceptibility have been shown to be due at least in part to the effects of sex hormones. However, an influence of sex hormones on autoimmune disease susceptibility does not preclude an additional role for sex chromosomes in the gender differences that have been observed. The goal of this proposal will be to determine whether sex chromosomes play this additional role. To determine this, we will utilize a prototypic autoimmune disease model, experimental autoimmune encephalomyelitis (EAE) in SJL mice. The gender difference in EAE in SJL mice has been previously characterized, with females being more susceptible and more severely affected as compared to males. We will use this model to distinguish between the following two possibilities: (1) gender differences in the susceptibility and severity of EAE in SJL mice are due to effects of sex hormones only (with no influence of sex chromosomes) versus (2) gender differences in the susceptibility and severity of EAE in SJL mice are due to both sex hormones and sex chromosomes. We will distinguish between these two possibilities by creating uniquely informative mice. Mice which have a separation of sex hormone phenotype (male versus female) and sex chromosome genotype (XX versus XY) will be bred onto the SJL background, the background in which the gender differences in immune measures relevant to the development of EAE have been well characterized (pro/anti-inflammatory cytokine ratio, encephalitogenicity, disease severity). Experiments using these uniquely informative mice will then determine whether differences in these same immune measures exist in mice, which share a common sex hormone phenotype but have a different sex chromosome genotype. If immune measures are no different between genotypes (XX vs. XY) within a given phenotype, then we will conclude that gender differences in immune measures are due to sex hormones only and not sex chromosomes. On the other hand, if immune measures differ between genotypes (XX vs. XY) within a given phenotype, we will conclude that gender differences in immune measures are due to both sex hormones and sex chromosomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050839-03
Application #
6697471
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Esch, Thomas R
Project Start
2002-02-01
Project End
2005-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
3
Fiscal Year
2004
Total Cost
$228,751
Indirect Cost
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
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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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