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

Fernando E. Sepulveda, Franck Debeurme, Gaël Ménasché, Mathieu Kurowska, Marjorie Côte, Jana Pachlopnik Schmid, Alain Fischer and Geneviève de Saint Basile


Inherited defects of granule-dependent cytotoxicity lead 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 following 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 three 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. 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.

  • Submitted July 3, 2012.
  • Accepted November 4, 2012.