Changes in B and T-cell subsets and NMO-IgG levels after immunoglobulins and rituximab treatment for an acute attack of neuromyelitis optica.

BACKGROUND: There is increasing evidence supporting that neuromyelitis optica (NMO) is an inflammatory humoral mediated disorder associated with NMO-IgG/AQP-4 antibodies. However, little is known about the subsets of B cells and T cells that contribute to the pathogenesis or therapy response. OBJECTIVES: To describe the clinical and immunological changes associated with intravenous immunoglobulins (IV-Igs) plus rituximab (RTX) in a patient with a severe acute attack of NMO and intrathecal synthesis of NMO-IgG/AQP-4, who previously did not respond to intravenous methylprednisolone and plasma exchange. METHODS: We sequentially analysed the levels of NMO-IgG/AQP-4 by immunohistochemistry, and B and T cells subsets by multiparametric flow-cytometry, in the CSF and peripheral blood (PB), before and alter IV-Igs plus RTX therapy. RESULTS: In the CSF before treatment, and compared with PB, there was a higher percentage of CD4(+) T cells and a lower percentage of CD8(+) T cells and CD19(+) B cells. After therapy, the percentage of CD4(+) T cells remained high, and that of CD8(+) T cells increased. The observed decrease in the percentage of CD19(+) B cells was lower than in the PB. When the CSF was compared, it was found that the percentage of effector-memory and effector CD8(+) T cells had increased after therapy, and that of IgM memory B cells and switched-memory B cells decreased. The observed changes paralleled the decrease of NMO-IgG/AQP-4 results to negative and the clinical improvement. CONCLUSIONS: Our findings confirm that, besides intrathecal humoral immune response against AQP4, B and T cell subsets are involved in the modulation of inflammation within and outside the central nervous system.

Cambios en las Subpoblaciones de Linfocitos B y T en el Título de Anticuerpos Anti-Acuaporina-4 tras el Tratamiento de un Brote Agudo con Inmunoglobulinas y Rituximab / Changes in B and T-cell subsets and NMO-IgG levels after immunoglobulins and rituximab treatment for an acute attack of neuromyelitis optica

Antecedentes: La neuromielitis óptica (NMO) es una enfermedad predominantemente humoral mediada por anticuerpos IgG-NMO/AQP-4. Sin embargo, no se conoce bien la contribución de las diferentes subpoblaciones de células B y T en su patogenia o en la respuesta a los tratamientos. Objetivos: Describir los cambios clínicos e inmunológicos asociados al tratamiento con inmunoglobulinas intravenosas (Ig-IV) y rituximab (RTX) en una paciente con un brote grave de NMO y síntesis intratecal de IgG-NMO/AQP-4 que no había respondido a metilprednisolona y recambio plasmático. Métodos: Se analizaron, de forma secuencial en el LCR y en la sangre periférica (SP), las subpoblaciones linfocitarias mediante citometría de flujo multiparamétrica y los IgG-NMO/AQP-4, antes y después del tratamiento con Ig-IV y RTX. Resultados: En el LCR antes del tratamiento, y comparado con la SP, predominaban las células T CD4+ y estaban menos representadas las T CD8+ y las B CD19+. Tras el tratamiento, el porcentaje de células T CD4+ se mantuvo alto, el de T CD8+ aumentó y el de B CD19+ disminuyó, aunque menos que en la SP. Al comparar los LCR se vio que tras la terapia el porcentaje de células T CD8+ memoria efectoras y efectoras había aumentado, y el de células B memoria IgM y el de células B con cambio de isotipos, disminuido. Los cambios observados fueron paralelos a la negativización de los IgG-NMO/AQP-4 y a la mejoría clínica. Conclusiones: Nuestros hallazgos confirman que, además de una respuesta inmunitaria humoral intratecal durante el brote de NMO, subpoblaciones específicas de células B y T participan en la modulación de la inflamación dentro y fuera del sistema nervioso central

Background: There is increasing evidence supporting that neuromyelitis optica (NMO) is an inflammatory humoral mediated disorder associated with NMO-IgG/AQP-4 antibodies. However, little is known about the subsets of B cells and T cells that contribute to the pathogenesis or therapy response. Objectives: To describe the clinical and immunological changes associated with intravenous immunoglobulins (IV-Igs) plus rituximab (RTX) in a patient with a severe acute attack of NMO and intrathecal synthesis of NMO-IgG/AQP-4, who previously did not respond to intravenous methylprednisolone and plasma exchange. Methods: We sequentially analysed the levels of NMO-IgG/AQP-4 by immunohistochemistry, and B and T cells subsets by multiparametric flow-cytometry, in the CSF and peripheral blood (PB), before and alter IV-Igs plus RTX therapy. Results: In the CSF before treatment, and compared with PB, there was a higher percentage of CD4+ T cells and a lower percentage of CD8+ T cells and CD19+ B cells. After therapy, the percentage of CD4+ T cells remained high, and that of CD8+ T cells increased. The observed decrease in the percentage of CD19+ B cells was lower than in the PB. When the CSF was compared, it was found that the percentage of effector-memory and effector CD8+ T cells had increased after therapy, and that of IgM memory B cells and switched-memory B cells decreased. The observed changes paralleled the decrease of NMO-IgG/AQP-4 results to negative and the clinical improvement. Conclusions: Our findings confirm that, besides intrathecal humoral immune response against AQP4, B and T cell subsets are involved in the modulation of inflammation within and outside the central nervous system

Hypocomplementemia in the absence of autoantibodies in women with recurrent pregnancy loss.

BACKGROUND: Accumulating data suggest an immunopathogenic role for the complement system as a causative element in pregnancy loss (PL). Formation of pathogenic antibodies with activation of the classical pathway may have a role, but this mechanism fails to characterize the majority of cases with recurrent PL. We established the prevalence of hypocomplementemia without circulating autoantibodies in women with recurrent PL. METHODS: In a retrospective case control study, 201 women with recurrent PL (two or more PL) and 30 healthy women who had normal pregnancies but no PL were studied. Serum levels of C3, C4, and factor B were determined by nephelometry. Total hemolytic activity of the complement system (CH100) was investigated by radial immunodiffusion test. RESULTS: The prevalence of hypocomplementemia [low levels of C3, C4, FB or CH100 (with normal concentrations of C3, C4 and FB)] was significantly higher in women with recurrent PL (22.4%) in comparison with controls (6.6%; p = 0.019). C3, C4, FB hypocomplementemia or low CH100 were observed in 13 (6.5%), 19 (9.4%), 13 (6.5%) and 7 (3.5%) women with recurrent PL, respectively. Among patients with C3, C4, FB or CH100 hypocomplementemia, 10, 18, 12 and 5 patients had no circulating autoantibodies [antinuclear antibodies, anticardiolipin antibodies or antithyroid antibodies], respectively. In all, hypocomplementemia, in the absence of autoantibodies, was observed in 38 (18.9%) women with recurrent PL in a significantly higher frequency than controls (n = 2, p = 0.049). CONCLUSIONS: Hypocomplementemia, in the absence of autoantibodies was observed in a group of women with recurrent PL which might suggest a role of the complement system in the pathogenesis of PL in these patients.

Switching to long-acting injectable risperidone is beneficial with regard to clinical outcomes, regardless of previous conventional medication in patients with schizophrenia.

INTRODUCTION: Using an atypical long-acting antipsychotic may improve patient outcome by offering the good efficacy and tolerability of an atypical antipsychotic with improved compliance through depot administration. METHODS: This subanalysis of an international, 6-month, open-label trial of risperidone long-acting injectable (RLAI) focused on non-acute schizophrenic adult patients switching from oral or depot conventional antipsychotic. Efficacy assessments included Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), quality of life, treatment satisfaction, hospitalization rates, and treatment-emergent adverse events (TEAEs). RESULTS: Over 70% of patients switching from oral (n=100) or depot (n=565) conventional medication completed treatment. Improvements were observed for PANSS total and subscale scores, GAF, quality of life, treatment satisfaction and hospitalization. Overall RLAI was well tolerated. TEAEs occurring in >5% were: anxiety (11.0%), insomnia (9.0%), weight increase (6.0%) for patients switching from oral, and weight increase (6.0%) and disease exacerbation (5.3%) for patients switching from depot medication. CONCLUSION: Patients with schizophrenia, unsatisfactorily treated with oral or depot conventional antipsychotics, showed improvement in symptom control, tolerability, and patient satisfaction after switching to RLAI.

Potential role of hypothalamic ghrelin in the pathogenesis of human obesity.

Ghrelin is a potent appetite stimulator, mainly synthesized in the stomach but also made in the brain. Paradoxically, obese subjects have lower plasma ghrelin than lean subjects and increase their weight in spite of low ghrelin levels. We hypothesize that central, and not peripheral ghrelin, is primarily responsible for overeating in humans. The aim of this study was to determine hypothalamic ghrelin levels in lean vs obese subjects. We collected anterior hypothalamus from lean and obese patients at the time of autopsy, and Western blots and semiquantitative RT-PCR for ghrelin and neuropeptide Y (NPY) were carried out. Our results showed that ghrelin expression was significantly higher in the hypothalamus of obese subjects compared to lean ones. This finding correlates with similar increases in NPY in the obese group. Ghrelin and NPY mRNA levels followed the same trend and were significantly higher in the hypothalamus in obese compared to lean subjects, suggesting a central origin for the increased protein content in the obese subjects. In conclusion, obesity in humans is associated with elevated central ghrelin. This data questions the significance of the role of peripheral ghrelin in the regulation of appetite in humans and suggests an important role for central ghrelin in the pathogenesis of obesity in humans.

Calcium efflux from platelet vesicles of the dense tubular system. Analysis of the possible contribution of the Ca2+ pump.

The ATP dependent Ca2+ uptake of platelet vesicles was inhibited by the two hydrophobic drugs trifluoperazine (TFP) and propranolol (PROP). Inhibition was significantly lowered when Pi was used instead of oxalate as a precipitant agent. When the ATPase ligands substrate (Mg2+ and Pi) were absent of the efflux medium, a slow release of Ca2+ which did not couple with ATP synthesis (passive Ca2+ efflux) was observed. Both, TFP and PROP enhanced the passive Ca2+ efflux. This enhanced efflux was partially inhibited only when Mg2+ and Pi were added together to the efflux reaction media, but it was not affected by spermidine, ruthenium red or thapsigargin (TG). The Ca2+ ionophores A23187 and ionomycin, also enhanced passive Ca2+ efflux. However, in this case, Ca2+ efflux was inhibited just by inclusion of Mg2+ to the medium. Ca2+ efflux promoted by Triton X-100 was not affected by either Mg2+ or Pi, included together or separately into the efflux medium. The ATP <==> Pi measured in the presence of Triton X-100 and millimolar Ca2+ concentrations was inhibited by both TFP and PROP, but not by Ca2+ ionophores up to 4 microM. The data suggest that the observed enhancement of passive Ca2+ efflux promoted by TFP and PROP could be attributed to a direct effect of these drugs over the platelet Ca2+ pump isoforms (Sarco Endoplasmic Reticulum Calcium ATPase, SERCA2b and SERCA3) themselves, as it was reported for the sarcoplasmic reticulum Ca2+ ATPase (SERCA1).

Hypocomplementemia in the absence of autoantibodies in women with recurrent pregnancy loss / Hipocomplementemia en ausencia de autoanticuerpos en mujeres con abortos repetidos

Background. Accumulating data suggest an immunopathogenic role for the complement system as a causative element in pregnancy loss (PL). Formation of pathogenic antibodies with activation of the classical pathway may have a role, but this mechanism fails to characterize the majority of cases with recurrent PL. We established the prevalence of hypocomplementemia without circulating autoantibodies in women with recurrent PL. Methods: In a retrospective case control study, 201 women with recurrent PL (two or more PL) and 30 healthy women who had normal pregnancies but no PL were studied. Serum levels of C3, C4, and factor B were determined by nephelometry. Total hemolytic activity of the complement system (CH100) was investigated by radial immunodiffusion test. Results: The prevalence of hypocomplementemia [low levels of C3, C4, FB or CH100 (with normal concentrations of C3, C4 and FB)] was significantly higher in women with recurrent PL (22,4 %) in comparison with controls (6.6 %; p = 0.019). C3, C4, FB hypocomplementemia or low CH100 were observed in 13 (6,5 %), 19 (9,4 %), 13 (6.5 %) and 7 (3,5 %) women with recurrent PL, respectively. Among patients with C3, C4, FB or CH100 hypocomplementemia, 10, 18, 12 and 5 patients had no circulating autoantibodies [antinuclear antibodies, anticardiolipin antibodies or antithyroid antibodies], respectively. In all, hypocomplementemia, in the absence of autoantibodies, was observed in 38 (18,9 %) women with recurrent PL in a significantly higher frequency than controls (n = 2, p = 0.049). Conclusions: Hypocomplementemia, in the absence of autoantibodies was observed in a group of women with recurrent PL which might suggest a role of the complement system in the pathogenesis of PL in these patients

Antecedentes. Un cúmulo de datos sugiere que el sistema complemento juega un papel destacado como elemento inmunopatogénico en la interrupción espontánea del embarazo. La formación de anticuerpos patógenos que activen la vía clásica del complemento puede jugar un papel, pero este mecanismo falla al caracterizar la mayoría de los casos de aborto recurrente. Nosotros establecemos la prevalencia de la hipocomplementemia sin anticuerpos circulantes en mujeres con abortos recurrentes. Métodos. En un estudio retrospectivo se estudiaron 201 mujeres con aborto recurrente (2 o más abortos) y 30 mujeres sanas que habían tenido embarazos normales, pero no abortos. Por nefelometría se valoraron los niveles de C3, C4 y factor B. La actividad del sistema complemento (CH100) se estudio por inmunodifusión radial. Resultados. La prevalencia de hypocomplementemia (niveles bajos de C3, C4, FB o CH100 –con concentraciones normales de C3, C4 y FB) fue significativamente más elevada en mujeres con aborto recurrente (22,4%) en comparación con los controles (6,6%; p=0.019). C3, C4, hypocomplementemia FB o CH100 bajo, se observaron respectivamente en 13 (6,6%), 19 (9,4%), 13 (6,5%) y 7 (3,5%) de mujeres con abortos repetidos. Entre las pacientes con C3, C4, FB o CH100 hipocomplementemia, 10, 18, 12 y 5, respectivamente no tenían autoanticuerpos circulantes (anticuerpos antinucleares, anticardiolipina o antitiroides). En todas, hipocomplementemia en ausencia de autoanticuerpos, se observó en 38 (18,9%) mujeres con aborto recurrente y con una significativa mayor frecuencia que en los controles (n=2, p=0.049). Conclusiones. Hipocomplementemia en ausencia de autoanticuerpos se observó en un grupo de mujeres con aborto recurrente, lo que podría sugerir el papel del sistema complemento en la patogénesis de los abortos de estas pacientes