1. 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
CMSC, May 2004

2. Version 1 Pretty near nothing is know about this The end
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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
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4. Neural Structural Differences
A drawing showing the brain with labels to some scientific parts and some to others ie motor vehicles and football
From
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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
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7. Endocrine Differences
Effects of hormones on the immune system
Protective effects of hormones
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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
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10. Hormone Manipulation Orchiectomy led to more severe EAE
Ovariectomy did not change outcome
Suggests that ovarian hormones do not increase susceptibility
A chart on the left shows hormone manipulation
Palaszynski KM. J Neuroimm 2004
CMSC, May 2004

11. SJL/J mice Fillmore PD. AJ Path 2004 CMSC, May 2004
A chart shows a mice study of acute and chronic disease
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
The slide shows the improvement of EAE with the use of testosterone and DHT in the form of 2 charts
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
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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
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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)
A chart on the left shows the effects of varying doses of Estriol on both males and females
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