Monday, 12 May 2014

Why do women get autoimmunity. Its all in the blood vessels

Cruz-Orengo L, Daniels BP, Dorsey D, Basak SA, Grajales-Reyes JG, McCandless EE, Piccio L, Schmidt RE, Cross AH, Crosby SD, Klein RS. Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. J Clin Invest. 2014 May 8. pii: 73408
Multiple sclerosis (MS) is an inflammatory disease of the CNS that is characterized by BBB dysfunction and has a much higher incidence in females. Compared with other strains of mice, EAE in the SJL mouse strain models multiple features of MS, including an enhanced sensitivity of female mice to disease; however, the molecular mechanisms that underlie the sex- and strain-dependent differences in disease susceptibility have not been described. 
We identified sphingosine-1-phosphate receptor 2 (S1PR2) as a sex- and strain-specific, disease-modifying molecule that regulates BBB permeability by destabilizing adherens junctions. S1PR2 expression was increased in disease-susceptible regions of the CNS of both female SJL EAE mice and female patients with MS compared with their male counterparts. Pharmacological blockade or lack of S1PR2 signaling decreased EAE disease severity as the result of enhanced endothelial barrier function. Enhanced S1PR2 signaling in an in vitro BBB model altered adherens junction formation via activation of Rho/ROCK, CDC42, and caveolin endocytosis-dependent pathways, resulting in loss of apicobasal polarity and relocation of abluminal CXCL12 to vessel lumina. Furthermore, S1PR2-dependent BBB disruption and CXCL12 relocation were observed in vivo. These results identify a link between S1PR2 signaling and BBB polarity and implicate S1PR2 in sex-specific patterns of disease during CNS autoimmunity.
Sphingosine-1-phosphate receptor binds to the sphingosine-1-phosphate receptors. Gilenya works because it modulates sphingosine-1-phosphate one (and others but not really S1P2 receptor). In this study it is suggested that a reason why females may get more autoimmunity is because they have more S1P2 receptor in their blood brain barrier (but it would have to be every where as the enhanced autoimmunity in females is common to all adult onset autoimmunities). This affects the  processes that control the (actin) cytoskeleton of the cell, which influence the cell shape and the ability of the blood vessel to allow a cell can migrate through it to get into the brain and also influences the position of a cell attractant called a chemokine called CXCL12. This may be seen as a flag telling white blood cells to enter into the tissue as shown in other studies. Blockade of  S1P2 was used to control EAE. 

The manufacturers of the many Gilenya me-toos, in the pipeline will be checking to see if their compounds block S1P2, to give it a sales boost.

4 comments:

  1. Mouse Doc - I couldn't fathom from your comment if you see this discovery as very interesting indeed or another red herring??

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    Replies
    1. Very interesting but it will need repeating, anyone got some S1P2-specific antibodies?

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    2. Mouse Doc - I've got another important question that no doc here can advise me on: it's about a herbal asthma drug that I'd need to take in addition to teriflunomid.

      The herbal drug is anti-inflammatory but I don't know if it increases or decreases the immune system (I suspect the former). It contains:

      Columbine 15 mg, valerian root 10 mg,D-camphor 4 mg, aconite 1 mg, lettuce leaf 6 mg, clove 12 mg, golden cinquefoil 15 mg, kaempferia galanga rhizome10 mg, costus root 40mg, Iceland moss 40 mg,cardamom fruit 30 mg, Bengal quince 20 mg, myrobalan fruit 30 mg, calcium sulphate 20 mg, allspice 25 mg, neem fruit 35 mg, calendula flower 5 mg, redsandalwood 30 mg, heart-leaved sida 10 mg, ribwort plantain 15 mg, liquorice root 15 mg, knotgrass 15mg.

      I know you can't recommend but perhaps some thoughts?

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    3. Any thoughts

      Not surprised no doc can advise I suspect there is no evidence either way. There can't be any empirical data with such a concoction,

      Pro or anti-immune system, no idea but most nutriceuticals are likely to have limited potent impact otherwise they would come with big health warning...they should perhaps come with a purse warning as they do get you to part company with your cash.

      Take with your neuro

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