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Hemophagocytic lymphohistiocytosis (HLH) is a disease process that is not the result of a single condition or stimulus but is instead caused by a constellation of genetic predispositions, changes in immune status, and triggers all of which result in sustained CD8+ T-cell activation. The cells most classically involved in this activation are macrophages and antigen-presenting cells each contributing to an inflammatory milieu. Some of the values most classically used to detect these changes are (1) ferritin, (2) sCD163, and (3) sIL-2R (all demarked by * in the figure). The cellular activation can be caused by direct alterations to the immune system through genetic deficiencies, primary immune deficiency, or impaired host response to Epstein-Barr virus (EBV) infection all of which contribute to the uncontrolled activation of CD8+ T-cell and the runaway amplification of cytokine signaling seen in HLH. As a whole, HLH could be worsened by either an overactive immune system or underactive immune system; however, triggering events are often emphasized in the literature. Such triggers include intracellular pathogens, innate immune activation caused by toll-like receptor stimulation, drugs, immunotherapy, or hematologic malignancy. 1