CMSC, May 2004

James Bowen, MDJames Bowen, MD

VA MS Center of Excellence, WestVA MS Center of Excellence, West

VA Puget Sound Health Care SystemVA Puget Sound Health Care System

Seattle, WASeattle, WA

The Male Experience in MSDifferences in Disease

Pathogenesis

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Version 1

Pretty near nothing is know about Pretty near nothing is know about thisthis

The endThe end

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How Might Males Differ

Males have older onset, more Males have older onset, more progressive disease, less favorable progressive disease, less favorable course, less response to IFNcourse, less response to IFN

Structural DifferencesStructural Differences Chromosomal differencesChromosomal differences Endocrine DifferencesEndocrine Differences Immune DifferencesImmune Differences

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Neural Structural Differences

From www.unm.edu

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Structural Differences

Little is known about thisLittle is known about this DM20, an alternatively spliced DM20, an alternatively spliced

isoform of proteolipid protein (PLP) isoform of proteolipid protein (PLP) is expressed differently in thymic is expressed differently in thymic tissues. PLP is on the X tissues. PLP is on the X chromosome.chromosome.

Peripheral myelin proteins (Po and Peripheral myelin proteins (Po and PMP22) are altered by hormonesPMP22) are altered by hormones

Greer JM. J autoimmun 2004, Melcangi RC. Horm Behav 2001

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Chromosomal differences

Little is known about thisLittle is known about this PLP is on the X chromosomePLP is on the X chromosome HLA is unevenly distributed by gender in HLA is unevenly distributed by gender in

MSMS DR2 35.7% maleDR2 35.7% male DR2 62.2% femaleDR2 62.2% female 30.9/29.7% in M/F controls30.9/29.7% in M/F controls In London OntarioIn London OntarioDuquette P. Can J neurol Sci 1992

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Endocrine Differences

Effects of hormones on the Effects of hormones on the immune systemimmune system

Protective effects of hormonesProtective effects of hormones

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Hormone Manipulation

Males have greater peak disease, Males have greater peak disease, shorter duration, more progressive dzshorter duration, more progressive dz

Orchiectomy modestly decreased time Orchiectomy modestly decreased time to onset and increased acute severityto onset and increased acute severity

Ovariectomy increased acute Ovariectomy increased acute progressiveprogressive

Gender difference persisted after Gender difference persisted after gonadectomy (prenatal hormone or gonadectomy (prenatal hormone or genetics)genetics)Fillmore PD. AJ Path 2004

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Estriol

Estriol can decrease EAE in male or female

Palaszynski KM. J Neuroimm 2004

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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

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Fillmore PD. AJ Path 2004

SJL/J mice

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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

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Adoptive Transfer

In SJL mice adoptive transfer is:In SJL mice adoptive transfer is: TH1 mediatedTH1 mediated Class II restrictedClass II restricted Females have greater max score Females have greater max score

and more rapid onset of diseaseand more rapid onset of disease Even when T-cells derived from Even when T-cells derived from

malesmalesVoskuhl RR. Ann Neurol 1996

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Adoptive Transfer

In SJL mice adoptive transfer is:In SJL mice adoptive transfer is: TH1 mediatedTH1 mediated Class II restrictedClass II restricted Females have greater max score Females have greater max score

and more rapid onset of diseaseand more rapid onset of disease Even when T-cells derived from Even when T-cells derived from

malesmalesVoskuhl RR. Ann Neurol 1996

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Immune Differences APC more efficient in femaleAPC more efficient in female Th1 response greater in femaleTh1 response greater in female Th1 cytokines greater in femaleTh1 cytokines greater in female Increased IgG in femaleIncreased IgG in female Increased CD4/8 ratio in femaleIncreased CD4/8 ratio in female Increased lymphocyte reactivity in femaleIncreased lymphocyte reactivity in female However, this immune response may be However, this immune response may be

partially protective (female rats with SCI partially protective (female rats with SCI recover better than males)recover better than males)

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Immune Differences Gender response differs by mouse Gender response differs by mouse

strain in EAEstrain in EAE SJL/J and ASW SJL/J and ASW severity in female severity in female NZW NZW incidence in female incidence in female B10.PL and PL/J B10.PL and PL/J severity in male severity in male NOD/Lt and C57BL/6 no differenceNOD/Lt and C57BL/6 no difference Lewis rats Lewis rats incidence in male incidence in male

Papenfuss TL. J Neuroimm 2004

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Immune Differences

Lymphocytes from females respond more Lymphocytes from females respond more vigorously to cell-mediated and soluble vigorously to cell-mediated and soluble antigens in mixed lymphocyte reactionantigens in mixed lymphocyte reaction

Mice without testosterone had higher Mice without testosterone had higher responsiveness, this was further responsiveness, this was further enhanced by estrogenenhanced by estrogen

APCs more active in femaleAPCs more active in female Strongest response when APC and Strongest response when APC and

effector cells were both from femaleeffector cells were both from female

Weinstein Y. J Imm 1984

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Lymphocyte Reactions in MS

MS (170) vs control (157) vs other neuro MS (170) vs control (157) vs other neuro disease (189)disease (189)

Response of lymphocytes calculated Response of lymphocytes calculated (stimulation index = SI)(stimulation index = SI)

For PLP, % with SI For PLP, % with SI > 3 was 28 (MS), 6.8 (normal), > 3 was 28 (MS), 6.8 (normal), 11.1 (other)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 In controls and other, 29.1% female vs 18.4% male reacted

to PLP, equal to MBP (not all Ags are alike)to PLP, equal to MBP (not all Ags are alike) In MS, M = FIn MS, M = F

Greer JM. J Autoimm 2004

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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)

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Conclusions

There are substantial differences There are substantial differences between male and femalebetween male and female

Structural, chromosomal, Structural, chromosomal, endocrine, and immuneendocrine, and immune

Scant data, complicated interplayScant data, complicated interplay Many areas to investigate for Many areas to investigate for

possible differences in clinical possible differences in clinical course course