Evaluation of humoral immunity profiles to identify heart recipients at risk for development of severe infections: a multicenter prospective study

[Abstract] BACKGROUND: New biomarkers are necessary to improve detection of the risk of infection in heart transplantation. We performed a multicenter study to evaluate humoral immunity profiles that could better enable us to identify heart recipients at risk of severe infections. METHODS: We prospectively analyzed 170 adult heart recipients at 8 centers in Spain. Study points were before transplantation and 7 and 30 days after transplantation. Immune parameters included IgG, IgM, IgA and complement factors C3 and C4, and titers of specific antibody to pneumococcal polysaccharide antigens (anti-PPS) and to cytomegalovirus (CMV). To evaluate potential immunologic mechanisms leading to IgG hypogammaglobulinemia, before heart transplantation we assessed serum B-cell activating factor (BAFF) levels using enzyme-linked immunoassay. The clinical follow-up period lasted 6 months. Clinical outcome was need for intravenous anti-microbials for therapy of infection. RESULTS: During follow-up, 53 patients (31.2%) developed at least 1 severe infection. We confirmed that IgG hypogammaglobulinemia at Day 7 (defined as IgG <600 mg/dl) is a risk factor for infection in general, bacterial infections in particular, and CMV disease. At Day 7 after transplantation, the combination of IgG <600 mg/dl + C3 <80 mg/dl was more strongly associated with the outcome (adjusted odds ratio 7.40; 95% confidence interval 1.48 to 37.03; p = 0.014). We found that quantification of anti-CMV antibody titers and lower anti-PPS antibody concentrations were independent predictors of CMV disease and bacterial infections, respectively. Higher pre-transplant BAFF levels were a risk factor of acute cellular rejection. CONCLUSION: Early immunologic monitoring of humoral immunity profiles proved useful for the identification of heart recipients who are at risk of severe infection.Instituto de Salud Carlos III; FIS081430Instituto de Salud Carlos III; FIS1101323Instituto de Salud Carlos III; FIS150147

Estudio del estado de maduración del linfocito B y factores solubles asociados a rechazo e infección en pacientes sometidos a trasplante de órgano sólido

El trasplante de órganos es la opción terapéutica de elección cuando se han agotado el resto de alternativas. Tras la intervención, el sistema inmunitario del receptor puede reaccionar frente a antígenos del donante causando rechazo. Para evitarlo, se recurre al uso de inmunosupresores que acaban provocando un mayor riesgo de desarrollo de infecciones y neoplasias de novo. En concreto, las complicaciones infecciosas son la principal causa de muerte durante el primer año post trasplante. Hasta ahora el principal foco de estudio en medicina del trasplante se ha centrado en la rama efectora CD3+, hay pocos estudios sobre linfocitos B y se centran en su papel como célula productora de anticuerpos. La célula B, en trasplante de órganos, no se limita a célula plasmática sino que posee funciones reguladoras mediante producción de diversas citoquinas, como IL-10, IL-35 o TGF-β. La depleción de estas poblaciones podría tener un efecto negativo en los pacientes, ya que se producen alteraciones en la homeostasis celular. El restablecimiento del compartimento B podría favorecer un perfil inmunorregulador que facilitaría el control del eje regulador/ inflamatorio en trasplante de órganos. La monitorización inmunológica postrasplante es de vital importancia para reducir la morbimortalidad, evaluando el estado del paciente durante el periodo de seguimiento para la detección temprana de eventos de rechazo o infección. El objetivo es conseguir una terapia individualizada, pero la falta de biomarcadores predictivos nos hace seguir investigando para su identificación y validación. Una de las moléculas que ha emergido con fuerza es el factor activador de linfocito B, BAFF, encargado de mantener la homeostasis de los linfocitos B. BAFF es requerido para la proliferación y supervivencia de los linfocitos B y su ausencia, o la de su receptor, se traduce en una profunda linfopenia. Por el contrario, niveles excesivos de BAFF se han asociado a la generación de linfocitos B autorreactivos, autoanticuerpos y aparición de desórdenes autoinmunes. Dada la complejidad de la respuesta del sistema inmunitario, varios marcadores deben evaluarse en conjunto..

Regulatory Cells in Multiple Sclerosis: From Blood to Brain

Multiple sclerosis (MS) is a chronic, autoimmune, and neurodegenerative disease of the central nervous system (CNS) that affects myelin. The etiology of MS is unclear, although a variety of environmental and genetic factors are thought to increase the risk of developing the disease. Historically, T cells were considered to be the orchestrators of MS pathogenesis, but evidence has since accumulated implicating B lymphocytes and innate immune cells in the inflammation, demyelination, and axonal damage associated with MS disease progression. However, more recently the importance of the protective role of immunoregulatory cells in MS has become increasingly evident, such as that of myeloid-derived suppressor cells (MDSCs), regulatory T (Treg) and B (Breg) cells, or CD56bright natural killer cells. In this review, we will focus on how peripheral regulatory cells implicated in innate and adaptive immune responses are involved in the physiopathology of MS. Moreover, we will discuss how these cells are thought to act and contribute to MS histopathology, also addressing their promising role as promoters of successful remyelination within the CNS. Finally, we will analyze how understanding these protective mechanisms may be crucial in the search for potential therapies for MS

Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis

The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients. Treatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients' peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed. Fingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment. Our data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod. The online version contains supplementary material available at 10.1186/s12974-022-02635-3

Central and peripheral myeloid-derived suppressor cell-like cells are closely related to the clinical severity of multiple sclerosis

Multiple sclerosis (MS) is a highly heterogeneous demyelinating disease of the central nervous system (CNS) that needs for reliable biomarkers to foresee disease severity. Recently, myeloid-derived suppressor cells (MDSCs) have emerged as an immune cell population with an important role in MS. The monocytic-MDSCs (M-MDSCs) share the phenotype with Ly-6C -cells in the MS animal model, experimental autoimmune encephalomyelitis (EAE), and have been retrospectively related to the severity of the clinical course in the EAE. However, no data are available about the presence of M-MDSCs in the CNS of MS patients or its relation with the future disease aggressiveness. In this work, we show for the first time cells exhibiting all the bona-fide phenotypical markers of M-MDSCs associated with MS lesions, whose abundance in these areas appears to be directly correlated with longer disease duration in primary progressive MS patients. Moreover, we show that blood immunosuppressive Ly-6C -cells are strongly related to the future severity of EAE disease course. We found that a higher abundance of Ly-6C -cells at the onset of the EAE clinical course is associated with a milder disease course and less tissue damage. In parallel, we determined that the abundance of M-MDSCs in blood samples from untreated MS patients at their first relapse is inversely correlated with the Expanded Disability Status Scale (EDSS) at baseline and after a 1-year follow-up. In summary, our data point to M-MDSC load as a factor to be considered for future studies focused on the prediction of disease severity in EAE and MS