Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11

• Published in: Blood 2013-01, Vol.121 (4), p.595-603
• Main Authors: Sepulveda, Fernando E., Debeurme, Franck, Ménasché, Gaël, Kurowska, Mathieu, Côte, Marjorie, Pachlopnik Schmid, Jana, Fischer, Alain, de Saint Basile, Geneviève
• Format: Article
• Language: English
• Subjects: Adaptive immunology; Animals; Cell Degranulation; Cytotoxicity, Immunologic - genetics; Disease Models, Animal; Human health and pathology; Humans; Immunology; Life Sciences; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocytic choriomeningitis virus; Lymphohistiocytosis, Hemophagocytic - genetics; Lymphohistiocytosis, Hemophagocytic - immunology; Lymphohistiocytosis, Hemophagocytic - virology; Male; Mice; Mice, Knockout; Mutation; Pore Forming Cytotoxic Proteins - genetics; Pore Forming Cytotoxic Proteins - immunology; Qa-SNARE Proteins - genetics; Qa-SNARE Proteins - immunology; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - immunology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-07-440339

Inherited defects of granule-dependent cytotoxicity led to the life-threatening immune disorder hemophagocytic lymphohistiocytosis (HLH), characterized by uncontrolled CD8 T-cell and macrophage activation. In a cohort of HLH patients with genetic abnormalities expected to result in the complete absence of perforin, Rab27a, or syntaxin-11, we found that disease severity as determined by age at HLH onset differed significantly, with a severity gradient from perforin (early onset) > Rab27a > syntaxin-11 (late onset). In parallel, we have generated a syntaxin-11–deficient (Stx11−/−) murine model that faithfully reproduced the manifestations of HLH after lymphocytic choriomeningitis virus (LCMV) infection. Stx11−/− murine lymphocytes exhibited a degranulation defect that could be rescued by expression of human syntaxin-11 but not expression of a C-terminal–truncated mutant. Comparison of the characteristics of LCMV infection-induced HLH in the murine counterparts of the 3 human conditions revealed a similar gradient in the phenotypic severity of HLH manifestations. Strikingly, the severity of HLH was not correlated with the LCMV load and not fully with differences in the intensity of cytotoxic activity. The capacity of antigen presentation differed in vivo between Rab27a- and Syntaxin-11–deficient mutants. Our data indicate that cytotoxic effectors may have other immune-regulatory roles in addition to their role in controlling viral replication. •Syntaxin-11–deficient (Stx11−/−) murine model faithfully reproduced the manifestations of HLH after LCMV infection.•HLH severity differed significantly with a severity gradient from perforin (early onset) Rab27a syntaxin-11 (late onset).