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TLR7 gain-of-function genetic variation causes human lupus, 2022, Brown et al

Discussion in 'Other health news and research' started by Andy, Apr 29, 2022.

  1. Andy

    Andy Committee Member

    Messages:
    21,811
    Location:
    Hampshire, UK
    Abstract

    Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1,2,3,4,5,6,7, evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA8,9 and binds to guanosine10,11,–12.

    We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10,11,12, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.

    Open access, https://www.nature.com/articles/s41586-022-04642-z
     
    cassava7, leokitten, Samuel and 3 others like this.
  2. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    13,274
    Location:
    London, UK
    It is a very neat story. This is how real science works. Most lupus is probably not primarily due to a TLR7 abnormality but if TLR7 can be blocked it might break the cycle of lupus whatever the initial trip. It might also break the cycle for things like RA although it might turn out to not work in that particular cycle.

    There is a real chance that something like a TLR7 or MyD88 inhibitor might be a way to produce long term cure for autoimmune diseases after initial remission induction with B cell depletion. I think it less likely that it would work alone but it is possible. At least people are finally focusing on B cell survival mechanisms rather than T cells.
     
    cassava7, Marky, leokitten and 6 others like this.

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