Gender Bias in Theiler’s Virus-Induced Demyelinating Disease Correlates with the Level of Antiviral Immune Responses

Abstract

Multiple sclerosis is an immune-mediated disease of the CNS and shows a sex-biased distribution in which 60–75% of all cases are female. A mouse model of multiple sclerosis, Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease, also displays a gender bias. However, in the C57L/J strain of mice, males are susceptible to disease whereas females are completely resistant. In this study we determined the gender differences in the TMEV-specific immune response, which may be responsible for the gender bias in clinical disease. Our data clearly demonstrate that female C57L/J mice induce significantly higher levels of TMEV-specific neutralizing Ab as well as a stronger peripheral T cell response throughout the course of viral infection. In contrast, male mice have a higher level of TMEV-specific CD4+ and CD8+ T cell infiltration into the CNS as well as viral persistence. These results suggest that a higher level of the initial antiviral immune response in female mice may be able to effectively clear virus from the periphery and CNS and therefore prevent further disease manifestations. Male mice in contrast do not mount as effective an immune response, thereby allowing for eventual viral persistence in the CNS and continuous T cell expansion leading to clinical symptoms.

Influence of Slc11a1 on the Outcome ofSalmonella entericaSerovar Enteritidis Infection in Mice Is Associated with Th Polarization

“…Estrogen is known to regulate the differentiation, survival, and function of diverse immune cells (30,37,50). In addition, female mice produce significantly more specific antibody in response to various infections (27). The difference in gender may also be explained by the immunoregulatory effect of testosterone, which is know to act directly on CD4…”

Anticapsid Immunity Level, Not Viral Persistence Level, Correlates with the Progression of Theiler's Virus-Induced Demyelinating Disease in Viral P1-Transgenic Mice

“…Mice were perfused with sterile Hanks' balanced salt solution (HBSS), and excised brains and spinal cords were homogenized. CNS-infiltrating mononuclear cells (MNCs) were then enriched in the bottom one-third fraction of a continuous 100% Percoll gradient (Pharmacia, Piscataway, NJ) after centrifugation at 27,000 ϫ g for 30 min as previously described (14).…”

“…In general, highaffinity CD8 ϩ T cells are preferentially tolerized by deletion or anergy in vivo. In fact, the relative levels of IFN-␥-producing cells upon stimulation with serial 10-fold-decreased epitope peptide concentrations indicated that functional avidity to the dominant epitope (VP3 159-166 ) is 50-and 100-fold higher than those to the subdominant epitopes (VP3 173-181 and VP1 [11][12][13][14][15][16][17][18][19][20] , respectively) (data not shown). These results are consistent with the preferential reduction of high-affinity VP3 159-166 -specific CD8 ϩ T cells over low-affinity subdominant epitope-reactive CD8 ϩ T cells.…”

“…ϩ T-cell levels specific for the predominant epitope, VP3 159-166 , were significantly reduced in SJL P1-Tg mice, although CD8 ϩ T-cell levels specific for subdominant epitopes (VP3 173-181 and VP1 [11][12][13][14][15][16][17][18][19][20] were largely unaffected throughout the course of infection (Fig. 5).…”

Predominant Clonal Accumulation of CD8+T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

“…Brains and spinal cords were removed, minced with steel mesh, and treated with collagenase IV and DNase I (Sigma) for 45 min at 37°C. Mononuclear cells were isolated after 100% Percoll continuous gradient centrifugation at 27,000 ϫ g for 30 min as previously described (16).…”