Thread by @Sarah_L_Mackie

My summary of Prof Cornelia Weyand’s lecture on #GCA pathogenesis at @Vasculitis2022 (follow their account to see the slides themselves, but here’s what I took away)

#vasculitis22

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2/7
Four phases of #GCA pathogenesis with “checkpoints” between each
•Genetic risk, environmental exposure
•Loss of self tolerance
•Loss of tissue tolerance
•Arteritis

#vasculitis22

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Genetic risk for #GCA: HLA; other
Environmental exposures

The subsequent three stages have all been studied in the “avatar” model of immunodeficiency mouse + temporal artery + human immune cells

#Vasculitis22

4/7
Loss of self tolerance in #GCA:
•in secondary lymphoid tissue (LN, marrow)
•Age-related increase in Treg Notch4 expression impairs ability to inhibit CD4+ via NOX2-containing exosomes
•The proportion of Notch1 +ve CD4 T cells increases

jci.org/articles/view/…

5/7
Loss of tissue tolerance in #GCA:
•Aberrant Jagged1 expression on luminal aspect of endothelial cells of vasa vasorum
•So these vasa vasorum let in Notch+ T-cells

ncbi.nlm.nih.gov/pmc/articles/P…

6/
Arteritis: the unleashing of T-cells in #GCA
•Persistence of vasculitis over 1 year (Maleszewski study)
•Reduced expression of PD-L1 - unleashes PD-1+ve T-cells
•CD28 signalling switches on aerobic glycolysis, driving T-cell proliferation Ki67
pubmed.ncbi.nlm.nih.gov/30975299/

7/ Clinical implications for treating #GCA

•persistence of vasculitis in the tissue
•the need for steroid sparing agents that treat the vasculitis part of GCA better
•“how do we not make the cure worse than the disease”

Still much work to do.

#vasculitis22