Immune dysregulation, lymphoproliferation and autoinflammatory disease — viva

Opening (must-hit)

"I hold this group of diseases on a three-mechanism framework. Immune dysregulation is failed tolerance (FOXP3, AIRE, CTLA4, LRBA); lymphoproliferation is failed apoptosis (the FAS pathway, in ALPS); autoinflammation is innate cytokine over-activation (NLRP3, MEFV, TNFRSF1A, MVK). The intersection is the cytokine storm, HLH or MAS. My first move in every case is to clear the HLH/MAS threat gate — fever plus splenomegaly plus cytopenias plus a very high ferritin — before anything else. Then I phenotype by the dominant mechanism, match therapy to the pathway, and reserve haematopoietic stem cell transplant for the severe immune-dysregulation and primary-HLH diseases." ^{[1] [8]}