RESUMO
In MS, B cells survive peripheral tolerance checkpoints to mediate local inflammation, but the underlying molecular mechanisms are relatively underexplored. In mice, the MIF pathway controls B-cell development and the induction of EAE. Here, we found that MIF and MIF receptor CD74 are downregulated, while MIF receptor CXCR4 is upregulated in B cells from early onset MS patients. B cells were identified as the main immune subset in blood expressing MIF. Blocking of MIF and CD74 signaling in B cells triggered CXCR4 expression, and vice versa, with separate effects on their proinflammatory activity, proliferation, and sensitivity to Fas-mediated apoptosis. This study reveals a new reciprocal negative regulation loop between CD74 and CXCR4 in human B cells. The disturbance of this loop during MS onset provides further insights into how pathogenic B cells survive peripheral tolerance checkpoints to mediate disease activity in MS.
Assuntos
Linfócitos B/metabolismo , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Esclerose Múltipla/metabolismo , Adulto , Idoso , Antígenos de Diferenciação de Linfócitos B/metabolismo , Apoptose/fisiologia , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Regulação para Baixo/fisiologia , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores CXCR4/metabolismo , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologia , Adulto JovemAssuntos
Antineoplásicos/efeitos adversos , Brentuximab Vedotin/efeitos adversos , Síndrome de Guillain-Barré/induzido quimicamente , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/induzido quimicamente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Brentuximab Vedotin/uso terapêutico , Feminino , Doença de Hodgkin/tratamento farmacológico , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: HTLV1-associated myelitis (HAM) is a slowly progressive myelopathy in which spinal cord MRI demonstrates no lesion or atrophy. OBJECTIVE: We examined the overlap between NMOSD features and HTLV1 infection. METHODS: We included all HTLV1-infected patients recruited in French West Indies (FWI) or referred from different centers, and suffering from at least one NMOSD feature. Literature connecting HTLV1-infection and NMOSD was reviewed. RESULTS: We included six NMOSD-like HAM with acute onset, seronegative against AQP4 and MOG-Abs. All displayed extensive longitudinal myelitis, and the optic nerve was involved in three. We gathered 39 cases of NMOSD-like HAM patients from the literature. Atypical signs of HAM were relapses (15.4%), sensory level (50%), upper limb symptoms (35.9%), optic neuritis (10.2%). Typical lesions involved lateral funiculi and featured a double rope sign (56.3%). CONCLUSION: We propose that acute onset of NMOSD-like HAM could be more frequent than expected and should be evoked in high-risk patients. Extensive but often transient cord lesions could be the hallmark of an excessive inflammation of the funiculi targeted by HTLV1 infection. Although usually minor, a few HAM cases demonstrate specific MRI lesions, and the most severe cases may mimic NMOSD attacks.