Males have it worse in autoimmunity


Nacka-Aleksić M, Djikić J, Pilipović I, Stojić-Vukanić Z, Kosec D, Bufan B, Arsenović-Ranin N, Dimitrijević M, Leposavić G. Male rats develop more severe experimental autoimmune encephalomyelitis than female rats: Sexual dimorphism and diergism at the spinal cord level. Brain Behav Immun. 2015 May 2. pii: S0889-1591(15)00124-5. doi: 10.1016/j.bbi.2015.04.017. [Epub ahead of print]

Compared with females, male Dark Agouti (DA) rats immunized for experimental autoimmune encephalomyelitis (EAE) with rat spinal cord homogenate in complete Freund’s adjuvant (CFA) exhibited lower incidence of the disease, but the maximal neurological deficit was greater in the animals that developed the disease. Consistently, at the peak of the disease greater number of reactivated CD4+CD134+CD45RC- T lymphocytes was retrieved from male rat spinal cord. Their microglia/macrophages were more activated and produced greater amount of prototypic proinflammatory cytokines in vitro. Additionally, oppositely to the expression of mRNAs for IL-12/p35, IL-10 and IL-27/p28, the expression of mRNA for IL-23/p19 was upregulated in male rat spinal cord mononuclear cells. Consequently, the IL-17+:IFN-γ+ cell ratio within T lymphocytes from their spinal cord was skewed towards IL-17+ cells. Within this subpopulation, the IL-17+IFN-γ+:IL-17+IL-10+ cell ratio was shifted towards IL-17+IFN-γ+ cells, which have prominent tissue damaging capacity. This was associated with an upregulated expression of mRNAs for IL-1β and IL-6, but downregulated TGF-β mRNA expression in male rat spinal cord mononuclear cells. The enhanced GM-CSF mRNA expression in these cells supported the greater pathogenicity of IL-17+ T lymphocytes infiltrating male spinal cord. In the inductive phase of the disease, contrary to the draining lymph node, in the spinal cord the frequency of CD134+ cells among CD4+ T lymphocytes and the frequency of IL-17+ cells among T lymphocytes were greater in male than in female rats. This most likely reflected an enhanced transmigration of mononuclear cells into the spinal cord (judging by the lesser spinal cord CXCL12 mRNA expression), the greater frequency of activated microglia/macrophages and the increased expression of mRNAs for Th17 polarizing cytokines in male rat spinal cord mononuclear cells. Collectively, the results showed cellular and molecular mechanisms underlying the target organ specific sexual dimorphism in the T lymphocyte-dependent immune/inflammatory response, and suggested a substantial role for the target organ in shaping the sexually dimorphic clinical outcome of EAE.
There has been some interest in the use sex hormones to treat autoimmunity or progressive MS and indeed there is a lot of evidence that oestrogens can inhibit immune-mediated disease, there is data that testosterones can inhibit disease. However, likewise there is data indicating that it can go the other way and it may not be a simple relationship. 

This study suggests that maleness can be associated with worse autoimmunity and imply that the CNS is involved in this. Although as it is EAE I think many of you won’t be interested but this simply serves a warning that results with sex hormones may not be a straight answer. It may also be different for progression mechanisms as compared to immune mechanisms. The studies in humans have not yet finished and so be warned about off-label use and use them, if you use them, with your “eyes wide-open”.

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  • Conversely the use of contraceptives with lower dosages of estrogen and progesterone could be involved in the mechanism of MS, but as triggering of the disease?

  • Is this stating testosterone is bad for Ms now? What about Dr Voskuhl and her studies showing testosterone as a neurprotrctive and the studies showing highe disability in those males with lower testosterone?

    • Kris
      This is animal data not human so as always caution is needed so you don't overextrapolate. Yes, there is some limited evidence in small scale trials that testosterone may have a neuroprotective element but (and we see this in our mice) there is little doubt that disease is more aggressive in males than females so there is a risk that testosterone supplementation could (and again I stress this is just a suggestion) produce a more severe relapse, which would negate any potential neuroprotective benefit of testosterone supplementation.
      We need bigger trials to tease out any potential benefit for example is the lower testosterone in more disabled male MSers a result of more aggressive MS, a result of andropause, or a cause of it? Much more needs to be done.
      At the moment I'm sitting on the fence (my arse is full of splinters).

    • That fence gets some use thkugh fair play
      Even Dr Voskuhl said it has no effect on relapses etc, I also know what your saying regarding cause or effect but would it not help feed the age related degeneration theory too and older onset Ms etc
      I think regardless of what it is, if there's a deficiency you address it surely?

  • Also where has it been shown that testosterone worsens the disease? Would you not correct a testosterone level if it was in the low range as you would with most other blood issues

    • You're putting an awful lot of faith in what the authors acknowledge is a small scale (10 subjects only) open label (ie not blinded) short-term study. There needs to be a much larger, double-blinded, placebo-controlled, longer term (3 years minimum) stdy done before any firm conclusions can be drawn.
      It might be something simple as testosterone increasing muscle mass, encouraging/enabling you to do more exercise, which seems to be beneficial on brain volume in itself.
      We'll see.

    • What is beneficial on brain volume? Exercise? Has this been proven? I'll be a testosterone exercise freak now

    • Yes there is some evidence for neuroprotection and then there is evidence that maleness is damaging. It was mentioned that testosterone can be used to over-come a medical deficiency but does that then mean it will do this or that then the data becomes wooly.We can take statins to reduce cholestero, but does thismean we shouldall eat a load of fried eggs before getting our choleserol checked just because we wanttobe on a statin becauseofits neuroprotective potential. However the dose used to lower cholesterol is 4 timeslower than the use in MS. Does this low dose work or not. The answer is I don't know just as I don't definitively know what is the the influence of sex hormones.

      So we are professional fence sitters because we wont advise one way or the other, so no wonder our bums are full of splinters:-)

    • The cholesterol comment I get
      But if you have relatively low testosterone for your age and there is a possibility of neuropototection as is believed then surely the levels should be addressed, get off that fence mouse!
      If you went to the doc like you say with high cholesterol regardless of your illness you would get statins, same goes for testo I guess

    • Same logic for cholesterol

      Take Testosterone for the medical deficiency…. but not because you think it is neuroprotecitve but because there may be a deficiency that is being rectified by the treatment.

      Testosterone or the dose of testosterone you use will be designed to treat the deficiency and may or may not be the dose required for neuroprotection,if testosterone has this function which we have to say is not sufficiently proven.

      We don't need to say any more

    • Actually, I have been taking the statins for some time in the hope of neuroprotection at high levels = 80 mg for 6 months and later had mri compared to old mri and it still showed atrophy in the white matter – the grey matter seemed to be okay, though.

      as for testosterone – for a woman i have higher levels than usual – my ms is moderate, sometimes worse than that depends when was the first attack (i have no clue when).

    • I know they did an estriol study in women at ucla again that showed some promise
      Again though it's only early days on that

  • This has been observed for a while but I'd love to see some sociology data over pure science. With a 70%/30% skew, and noted sexist bias in other areas of medicine, my feeling is that this perception – MS is always worse in men – often works against women with MS in the real world.

    • I doubt it because what you and I think of progression is not what is being talked about in the report as really concerns relapsing MS I think and one may expose a risk to PML so lets see what the authors do next. We have commented on this paper already.



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