RESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystemic hyperinflammatory disease commonly associated with hepatic dysfunction. Liver injury is mediated by unchecked antigen presentation, hypercytokinemia, dysregulated cytotoxicity by natural killer and CD8 T cells, and disruption of intrinsic hepatic metabolic pathways. Over the past decade, there have been significant advances in diagnostics and expansion in therapeutic armamentarium for this disorder allowing for improved morbidity and mortality. This review discusses the clinical manifestations and pathogenesis of HLH hepatitis in both familial and secondary forms. It will review growing evidence that the intrinsic hepatic response to hypercytokinemia in HLH perpetuates disease progression and the novel therapeutic approaches for patients with HLH-hepatitis/liver failure.
Assuntos
Linfo-Histiocitose Hemofagocítica , Humanos , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , Síndrome da Liberação de Citocina/complicações , Fígado/metabolismo , Linfócitos T CD8-Positivos/metabolismoRESUMO
RAG1/RAG2 (RAG) endonuclease-mediated assembly of diverse lymphocyte Ag receptor genes by V(D)J recombination is critical for the development and immune function of T and B cells. The RAG1 protein contains a ubiquitin ligase domain that stabilizes RAG1 and stimulates RAG endonuclease activity in vitro. We report in this study that mice with a mutation that inactivates the Rag1 ubiquitin ligase in vitro exhibit decreased rearrangements and altered repertoires of TCRß and TCRα genes in thymocytes and impaired thymocyte developmental transitions that require the assembly and selection of functional TCRß and/or TCRα genes. These Rag1 mutant mice present diminished positive selection and superantigen-mediated negative selection of conventional αß T cells, decreased genesis of invariant NK T lineage αß T cells, and mature CD4+ αß T cells with elevated autoimmune potential. Our findings reveal that the Rag1 ubiquitin ligase domain functions in vivo to stimulate TCRß and TCRα gene recombination and influence differentiation of αß T lineage cells, thereby establishing replete diversity of αß TCRs and populations of αß T cells while restraining generation of potentially autoreactive conventional αß T cells.
Assuntos
Proteínas de Homeodomínio , Receptores de Antígenos de Linfócitos T alfa-beta , Ubiquitina , Animais , Linhagem da Célula , Endonucleases/genética , Proteínas de Homeodomínio/genética , Ligases/genética , Camundongos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Superantígenos , Recombinação V(D)J/genéticaRESUMO
We report a 6-year-old man with chronic severe recalcitrant bilateral anterior uveitis and a remote history of hemophagocytic lymphocytic histiocytosis secondary to Epstein-Barr virus infection. The patient was treated for idiopathic uveitis after an initial extensive evaluation failed to reveal a specific diagnosis. The patient failed to achieve sustained inactive disease with multiple monotherapies including topical glucocorticoid, methotrexate, infliximab, mycophenolate mofeti, and cyclosporine. Disease control was finally attained with a combination of cyclosporine and adalimumab. After more recent testing, he was found to have a novel deletion on the BIRC4 (baclovirus inhibitor of apoptosis repeat containing protein 4) gene, the causative gene for X-linked lymphoproliferative syndrome type 2. We conclude that male patients with chronic idiopathic uveitis should be questioned about a history of hemophagocytic lymphocytic histiocytosis during their workup and screened for BIRC4 mutation if appropriate.