RESUMO
Little is known about mechanisms that drive the development of progressive multiple sclerosis (MS), although inflammatory factors, such as macrophage migration inhibitory factor (MIF), its homolog D-dopachrome tautomerase (D-DT), and their common receptor CD74 may contribute to disease worsening. Our findings demonstrate elevated MIF and D-DT levels in males with progressive disease compared with relapsing-remitting males (RRMS) and female MS subjects, with increased levels of CD74 in females vs. males with high MS disease severity. Furthermore, increased MIF and D-DT levels in males with progressive disease were significantly correlated with the presence of two high-expression promoter polymorphisms located in the MIF gene, a -794CATT5-8 microsatellite repeat and a -173 G/C SNP. Conversely, mice lacking MIF or D-DT developed less-severe signs of experimental autoimmune encephalomyelitis, a murine model of MS, thus implicating both homologs as copathogenic contributors. These findings indicate that genetically controlled high MIF expression (and D-DT) promotes MS progression in males, suggesting that these two factors are sex-specific disease modifiers and raising the possibility that aggressive anti-MIF treatment of clinically isolated syndrome or RRMS males with a high-expresser genotype might slow or prevent the onset of progressive MS. Additionally, selective targeting of MIF:CD74 signaling might provide an effective, trackable therapeutic approach for MS subjects of both sexes.
Assuntos
Antígenos de Diferenciação de Linfócitos B/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Oxirredutases Intramoleculares/metabolismo , Oxirredutases Intramoleculares/fisiologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fatores Inibidores da Migração de Macrófagos/fisiologia , Esclerose Múltipla/patologia , Índice de Gravidade de Doença , Adulto , Animais , Antígenos de Diferenciação de Linfócitos B/genética , Feminino , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Polimorfismo GenéticoRESUMO
Immature teratomas (IT) are rare and recurrences uncommon. A 12-year-old female with grade 3 (high-grade) ovarian IT underwent surgical resection but experienced early recurrences; the first was treated with surgery but the second was metastatic and managed with chemotherapy, resulting in growing-teratoma-syndrome and need for further surgery. She now remains well in uneventful clinical follow-up. We believe chemotherapy could be reserved for very carefully selected recurrent IT cases, which may alter the natural history of disease.