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

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

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

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

5. CMSC, May 2004 Structural Differences Little is known about this 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. 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 Peripheral myelin proteins (Po and PMP22) are altered by hormones Greer JM. J autoimmun 2004, Melcangi RC. Horm Behav 2001

6. CMSC, May 2004 Chromosomal differences Little is known about this Little is known about this PLP is on the X chromosome PLP is on the X chromosome HLA is unevenly distributed by gender in MS 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

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

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

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

10. CMSC, May 2004 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

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

12. CMSC, May 2004 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

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

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

15. CMSC, May 2004

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

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

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

19. CMSC, May 2004 Lymphocyte Reactions in MS MS (170) vs control (157) vs other neuro disease (189) MS (170) vs control (157) vs other neuro disease (189) Response of lymphocytes calculated (stimulation index = SI) Response of lymphocytes calculated (stimulation index = SI) For PLP, % with SI > 3 was 28 (MS), 6.8 (normal), 11.1 (other) For PLP, % with SI > 3 was 28 (MS), 6.8 (normal), 11.1 (other) Proportion lower in early disease and > 20 yrs duration. 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 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 In MS, M = F Greer JM. J Autoimm 2004

20. CMSC, May 2004 Cytokines Palaszynski KM. J Neuroimm 2004 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)

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