MS Genes why they may not always cause MS

Ooi JD, Petersen J, Tan YH, Huynh M, Willett ZJ, Ramarathinam SH, Eggenhuizen PJ, Loh KL, Watson KA, Gan PY, Alikhan MA, Dudek NL, Handel A, Hudson BG, Fugger L, Power DA, Holt SG, Coates PT, Gregersen JW, Purcell AW, Holdsworth SR, La Gruta NL, Reid HH, Rossjohn J, Kitching AR. Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. Nature. 2017;545(7653):243-247

Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4+ T-cell self-epitope derived from the α3 chain of type IV collagen (α3135-145). While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective with HLA-DR15. We show that autoreactive α3135-145-specific T cells expand in patients with Goodpasture disease and, in α3135-145-immunized HLA-DR15 transgenic mice, α3135-145-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the α3135-145 epitope in different binding registers.

HLA-DR15-α3135-145 tetramer+ T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-α3135-145 tetramer+ T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+ regulatory T cells (Treg cells) expressing tolerogenic cytokines. HLA-DR1-induced Treg cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+ and HLA-DR1+ healthy human donors display altered α3135-145-specific T-cell antigen receptor usage, HLA-DR15-α3135-145 tetramer+ Foxp3- Tconv and HLA-DR1-α3135-145tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes.  Moreover, patients with Goodpasture disease display a clonally expanded α3135-145-specific CD4+ T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative abundance of self-epitope specific Treg cells that leads to protection or causation of autoimmunity.

We know that MS is associated with genetic susceptibility and this susceptibility is linked to the major histocompatibility complex and the human leucocyte antigen HLA-DR and there are variants associated with susceptibility and in this case it it the HLA-DR15 from the HLA-DRB1*1501 genetic variant that is common in Northern Europeans. Look in the education section to see what these are.

Goodpastures disease is one of the side-effects to alemtuzumab, which is caused by an antibody response to the basement membranes in the kidney. Antibodies need T cells to be produced and this is probably why the secondary autoimmunities after alemtuzumab take time to appear as CD4 T cells are depleted for years after alemtuzumab. 

This study is not about MS but makes a relevant point why having an MS gene does not mean you get MS. We get one gene from our mum and another from our dad. These can be genetically identical so we are called homozygous (two of the same genes) or we can be heterozygous (two different variants of the same gene). T cells recognise peptides (9-13 amino acids)

What this shows is you have HLA-DR15, it recognises a peptide in one way and you get a pathogenic response, but if the same pepide is presented by HLA-DR1 variant it is seen in a slightly different way and causes T regulatory cells to occur. If you have HLA-DR15 and HLA-DR1 in the same person the DR1 generated regulatory cells dominate and stop the DR15-generated pathogenic cells from occuring and disease is prevented.

This is one reason why you may not pass MS onto your children as your MS risk risk gene effect may be controlled in your next generation

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  • I knew last week a case of MS between mother and adult son. The son is even studying medicine, until then only knew cases of family EM between relatives uncles and nephews, or grandparents and grandchildren.

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