| First Author | Humblet-Baron S | Year | 2019 |
| Journal | J Allergy Clin Immunol | Volume | 143 |
| Issue | 6 | Pages | 2215-2226.e7 |
| PubMed ID | 30578871 | Mgi Jnum | J:287372 |
| Mgi Id | MGI:6415757 | Doi | 10.1016/j.jaci.2018.10.068 |
| Citation | Humblet-Baron S, et al. (2019) IFN-gamma and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis. J Allergy Clin Immunol 143(6):2215-2226.e7 |
| abstractText | BACKGROUND: Inflammatory activation of CD8(+) T cells can, when left unchecked, drive severe immunopathology. Hyperstimulation of CD8(+) T cells through a broad set of triggering signals can precipitate hemophagocytic lymphohistiocytosis (HLH), a life-threatening systemic inflammatory disorder. OBJECTIVE: The mechanism linking CD8(+) T-cell hyperactivation to pathology is controversial, with excessive production of IFN-gamma and, more recently, excessive consumption of IL-2, which are proposed as competing hypotheses. We formally tested the proximal mechanistic events of each pathway in a mouse model of HLH. METHODS: In addition to reporting a complete autosomal recessive IFN-gamma receptor 1-deficient patient with multiple aspects of HLH pathology, we used the mouse model of perforin (Prf1)(KO) mice infected with lymphocytic choriomeningitis virus to genetically eliminate either IFN-gamma production or CD25 expression and assess the immunologic, hematologic, and physiologic disease measurement. RESULTS: We found a striking dichotomy between the mechanistic basis of the hematologic and inflammatory components of CD8(+) T cell-mediated pathology. The hematologic features of HLH were completely dependent on IFN-gamma production, with complete correction after loss of IFN-gamma production without any role for CD8(+) T cell-mediated IL-2 consumption. By contrast, the mechanistic contribution of the immunologic features was reversed, with no role for IFN-gamma production but substantial correction after reduction of IL-2 consumption by hyperactivated CD8(+) T cells. These results were complemented by the characterization of an IFN-gamma receptor 1-deficient patients with HLH-like disease, in whom multiple aspects of HLH pathology were observed in the absence of IFN-gamma signaling. CONCLUSION: These results synthesize the competing mechanistic models of HLH pathology into a dichotomous pathogenesis driven through discrete pathways. A holistic model provides a new paradigm for understanding HLH and, more broadly, the consequences of CD8(+) T-cell hyperactivation, thereby paving the way for clinical intervention based on the features of HLH in individual patients. |
