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The Male Experience in MS Differences in Disease Pathogenesis

The Male Experience in MS Differences in Disease Pathogenesis. James Bowen, MD VA MS Center of Excellence, West VA Puget Sound Health Care System Seattle, WA. Version 1. Pretty near nothing is know about this The end. How Might Males Differ.

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The Male Experience in MS Differences in Disease Pathogenesis

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  1. The Male Experience in MSDifferences in Disease Pathogenesis James Bowen, MD VA MS Center of Excellence, West VA Puget Sound Health Care System Seattle, WA CMSC, May 2004

  2. Version 1 • Pretty near nothing is know about this • The end CMSC, May 2004

  3. How Might Males Differ • Males have older onset, more progressive disease, less favorable course, less response to IFN • Structural Differences • Chromosomal differences • Endocrine Differences • Immune Differences CMSC, May 2004

  4. Neural Structural Differences From www.unm.edu CMSC, May 2004

  5. Structural Differences • Little is known about this • DM20, an alternatively spliced isoform of proteolipid protein (PLP) is expressed differently in thymic tissues. PLP is on the X chromosome. • Peripheral myelin proteins (Po and PMP22) are altered by hormones Greer JM. J autoimmun 2004, Melcangi RC. Horm Behav 2001 CMSC, May 2004

  6. Chromosomal differences • Little is known about this • PLP is on the X chromosome • HLA is unevenly distributed by gender in MS • DR2 35.7% male • DR2 62.2% female • 30.9/29.7% in M/F controls • In London Ontario Duquette P. Can J neurol Sci 1992 CMSC, May 2004

  7. Endocrine Differences • Effects of hormones on the immune system • Protective effects of hormones CMSC, May 2004

  8. Hormone Manipulation • Males have greater peak disease, shorter duration, more progressive dz • Orchiectomy modestly decreased time to onset and increased acute severity • Ovariectomy increased acute progressive • Gender difference persisted after gonadectomy (prenatal hormone or genetics) Fillmore PD. AJ Path 2004 CMSC, May 2004

  9. Estriol Estriol can decrease EAE in male or female Palaszynski KM. J Neuroimm 2004 CMSC, May 2004

  10. Hormone Manipulation • Orchiectomy led to more severe EAE • Ovariectomy did not change outcome • Suggests that ovarian hormones do not increase susceptibility Palaszynski KM. J Neuroimm 2004 CMSC, May 2004

  11. SJL/J mice Fillmore PD. AJ Path 2004 CMSC, May 2004

  12. Hormone Manipulation Both testosterone and DHT improve EAE suggesting that testosterone does not need to be converted to estadiol to be effective Palaszynski KM. J Neuroimm 2004 CMSC, May 2004

  13. Adoptive Transfer • In SJL mice adoptive transfer is: • TH1 mediated • Class II restricted • Females have greater max score and more rapid onset of disease • Even when T-cells derived from males Voskuhl RR. Ann Neurol 1996 CMSC, May 2004

  14. Adoptive Transfer • In SJL mice adoptive transfer is: • TH1 mediated • Class II restricted • Females have greater max score and more rapid onset of disease • Even when T-cells derived from males Voskuhl RR. Ann Neurol 1996 CMSC, May 2004

  15. CMSC, May 2004

  16. Immune Differences • APC more efficient in female • Th1 response greater in female • Th1 cytokines greater in female • Increased IgG in female • Increased CD4/8 ratio in female • Increased lymphocyte reactivity in female • However, this immune response may be partially protective (female rats with SCI recover better than males) CMSC, May 2004

  17. Immune Differences • Gender response differs by mouse strain in EAE • SJL/J and ASW  severity in female • NZW  incidence in female • B10.PL and PL/J  severity in male • NOD/Lt and C57BL/6 no difference • Lewis rats  incidence in male Papenfuss TL. J Neuroimm 2004 CMSC, May 2004

  18. Immune Differences • Lymphocytes from females respond more vigorously to cell-mediated and soluble antigens in mixed lymphocyte reaction • Mice without testosterone had higher responsiveness, this was further enhanced by estrogen • APCs more active in female • Strongest response when APC and effector cells were both from female Weinstein Y. J Imm 1984 CMSC, May 2004

  19. Lymphocyte Reactions in MS • MS (170) vs control (157) vs other neuro disease (189) • Response of lymphocytes calculated (stimulation index = SI) • For PLP, % with SI > 3 was 28 (MS), 6.8 (normal), 11.1 (other) • Proportion lower in early disease and > 20 yrs duration. • In controls and other, 29.1% female vs 18.4% male reacted to PLP, equal to MBP (not all Ags are alike) • In MS, M = F Greer JM. J Autoimm 2004 CMSC, May 2004

  20. Cytokines • Estriol decreased: TNF, IFN, IL-2, IL-6 • Increases IL-5 • Only sig M/F difference was for IL-5 (glatiramer also increased IL-5) Palaszynski KM. J Neuroimm 2004 CMSC, May 2004

  21. Conclusions • There are substantial differences between male and female • Structural, chromosomal, endocrine, and immune • Scant data, complicated interplay • Many areas to investigate for possible differences in clinical course CMSC, May 2004

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