Finding the culprits

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Going fishing for MS genes in T cells and hoping that you find the pathogenic key is what we had in the “Cure of the Week” yesterday. You are looking for a “Needle in a haystack”

The first question you have is can the technology work? Because if it can’t then it tells you nothing. This is a gripe I have with some imaging in that they use imaging of MS to define the pathology that they are imaging, such that they say that MTRXY technique detects this pathological feature like remyelination, by imaging some thing that they cannot say is remyelination without killing the subject they are imaging. So if you want to find the T cells that cause MS, first should show that you can find the disease causing T cells that you know are the causative T cells to validate the technique. The technology to identify the T cell receptor of every cell is there. The question is how best to you identify the antigen. It is easier to do with antibodies. This problem is not insurmountable. But once you have found the target(s) next you need a solution. Is this part of the pathway to a cure?

Gabaglia CR, Booker AT, Braciak TA. The Potential for Immunospecific Therapy in Multiple Sclerosis Based on Identification of Driver Clones of the Disease. Crit Rev Immunol. 2020;40(3):237-246.

The autoimmune disease multiple sclerosis (MS) is driven by T cells that are reactive to self-antigens of the brain and spinal cord. Many drugs have been developed to treat MS, but we believe that immune-specific targeting of pathogenic T cells may be a better approach for treatment. This type of therapy identifies specific components of the self-reactive T-cell repertoire that would undergo similar natural selection criteria as those found in driver genes in cancer genesis. In the context of autoimmunity, we propose that a focused subpopulation of T cells “drive” disease and could be found in higher frequency and become over-represented during disease induction and subsequent MS relapses. In addition, identification of other key signatures of driver T cells is important. One such marker could be interleukin (IL)-17- producing T cells. Here, we discuss the use of experimental autoimmune encephalomyelitis (EAE) animal models (that mimic many pathologic mechanisms involved in MS) to identify possible driver clones of this autoimmunity within the set of T cells expressing the IL-17 cytokine. EAE can be induced by myelin injection-associated proteins in adjuvants. The disease model in the Swiss/Jackson laboratory mouse strain represents the most common form of MS in humans (Delusion sets in and SJL mouse is not a human) : relapsing remitting MS. Finally, we discuss the concept of using IL-17 as a marker for pathogenic T cells, combined with identifying their T-cell receptor V repertoire, which could provide targeted approaches designed to neutralize driver T cells for MS immunotherapy.

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