Hypothesis for the pathophysiology of CM-HUS (aHUS), based on the study of Cole et al. (A) A triggering event (infection, pregnancy, inflammation, etc) may result in the appearance of polyreactive IgM antibodies. (B) If directed to glomerular endothelium, they will activate the classical pathway. If this activation is sufficiently strong, it alone may be sufficient to cause endothelial damage and thrombotic microangiopathy. This may occur in patients without genetic risk or anti-FH autoantibodies. (C) In the presence of an at-risk genetic variant (dysfunctional mut FH or CD46 presented in the figure, or factor I or gain-of-function C3 or FB, not illustrated for simplicity) or anti-FH autoantibodies, this classical pathway activation may be amplified to a level, overcoming the tolerable endothelial cell stress, causing (D) endothelial damage, leading eventually to (E) thrombotic microangiopathy. (F) Cole et al propose a new biosensor cell line, sensitive to the presence of classical pathway activators (such as polyreactive IgM), which could be used to detect complement triggers and potentially, after validation, to distinguish CMHUS from other forms of thrombotic microangiopathy. mut, mutated. Figure generated with BioRender.com.