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

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

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

Neural Structural Differences A drawing showing the brain with labels to some scientific parts and some to others ie motor vehicles and football From www.unm.edu CMSC, May 2004

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

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

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

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

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

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

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

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

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

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

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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

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

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

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

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

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