RESUMEN
Dimethyl fumarate is an efficient therapy used widely in patients with relapsing-remitting multiple sclerosis (RRMS). However, lacking effect of treatment has recently been reported in patients with primary progressive MS (PPMS) (Højsgaard Chow et al., 2021). In order to further analyze the immunological treatment response we investigated the systemic and intrathecal immunological effects of dimethyl fumarate (DMF) treatment in 50 patients with PPMS who participated in a 48-week randomized controlled trial with dimethyl fumarate vs placebo. We found substantial systemic immunomodulatory effects of DMF treatment comparable with those observed in patients with RRMS. However, intrathecal effects were limited and restricted to CD4+ T cells presumably resulting in higher concentrations of intrathecal IL-7.
Asunto(s)
Dimetilfumarato/uso terapéutico , Inmunosupresores/uso terapéutico , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Adulto , Recuento de Linfocito CD4 , Líquido Cefalorraquídeo/citología , Citocinas/sangre , Dimetilfumarato/administración & dosificación , Dimetilfumarato/farmacología , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacología , Inyecciones Espinales , Interleucina-7/líquido cefalorraquídeo , Subgrupos Linfocitarios/efectos de los fármacos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/sangre , Esclerosis Múltiple Crónica Progresiva/líquido cefalorraquídeo , Esclerosis Múltiple Crónica Progresiva/inmunologíaRESUMEN
BACKGROUND: Patients with human immunodeficiency virus/AIDS-associated cryptococcal meningitis (CM) frequently experience clinical deterioration, known as cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), upon initiation of antiretroviral therapy (ART). The immunological mechanisms underlying C-IRIS are incompletely defined and no reliable predictive biomarkers exist. We investigated whether plasma or cerebrospinal fluid (CSF) levels of cytokines and chemokines predicted C-IRIS and are potential predictive biomarkers. METHODS: Patients with CM who experienced C-IRIS (N = 27) upon ART initiation were compared to CD4+ T-cell count-matched patients without C-IRIS (N = 27). Plasma and CSF collected pre-ART were assayed for cytokines and chemokines using a 17-plex Luminex kit or enzyme-linked immunosorbent assay. Cox proportional hazards regression and principal component analyses were also performed. RESULTS: Plasma interleukin (IL) 2, IL-4, IL-5, IL-7, IL-17, interferon-γ, and tumor necrosis factor-α levels were higher in C-IRIS patients compared to controls (all P < .05), with IL-5 and IL-7 significant after Bonferroni-Holm correction. In multivariate Cox proportional hazards regression, high IL-5 (hazard ratio [HR], 5.76 [95% confidence interval {CI}, .77-43.0]; P = .088) and IL-7 (HR, 9.30 [95% CI, 1.96-44.0]; P = .005) were predictive of C-IRIS. Plasma IL-5 (P = .0008) and IL-10 (P = .0089) were lower in those who achieved CSF cryptococcal culture negativity compared to those with positive cultures pre-ART. There were no significant differences in CSF cytokine or chemokine levels between cases and controls. CONCLUSIONS: High plasma IL-5 and IL-7 levels pre-ART were associated with increased risk of developing C-IRIS. High IL-5 levels may reflect a Th2 environment associated with impaired clearance of cryptococci while high IL-7 levels may reflect IL-7/IL-7R pathway dysfunction in T cells, both of which could be associated with C-IRIS immunopathogenesis.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/sangre , Criptococosis/sangre , Síndrome Inflamatorio de Reconstitución Inmune/sangre , Interleucina-5/sangre , Interleucina-7/sangre , Infecciones Oportunistas Relacionadas con el SIDA/líquido cefalorraquídeo , Infecciones Oportunistas Relacionadas con el SIDA/epidemiología , Adulto , Antirretrovirales/administración & dosificación , Antirretrovirales/uso terapéutico , Criptococosis/líquido cefalorraquídeo , Criptococosis/epidemiología , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/líquido cefalorraquídeo , Síndrome Inflamatorio de Reconstitución Inmune/epidemiología , Interleucina-5/líquido cefalorraquídeo , Interleucina-7/líquido cefalorraquídeo , Masculino , Análisis de Componente Principal , Estudios ProspectivosRESUMEN
Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12-biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels <141pg/ml (OR=6.51, p<0.001). Combination of IL-7 and CXCL10 indicated risk for a specific MS clinical form, where IL-7<141 and CXCL10<570pg/ml were associated with the highest risk for PP-MS (OR=22, p=0.01). Unexpectedly, both PP-MS and RR-MS patients shared significantly decreased prototypical biomarkers of inflammation and tissue regeneration in CSF than OND suggesting a defective intrinsic immune response playing a role at the beginning of the disease.