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Traumatic spinal cord injury (SCI) damages the nerve tissue of the spinal cord, resulting in loss of motor and/or sensory functions at and below the injury level. SCI provokes a long-lasting immune response that extends beyond the spinal cord and induces changes in the composition and function of the peripheral immune system. Seemingly contradictory findings have been observed, as both systemic immune activation, including inflammation and autoimmunity, and immune suppression have been reported. Differences in the levels and functions of various cell types and components of both the innate and adaptive immune system supporting these changes have been described at (sub)acute and chronic stages post-injury. Further research is needed for a more comprehensive understanding of the peripheral immune reactions following SCI, their possible correlations with clinical characteristics, and how these immune responses could be targeted to facilitate the therapeutic management of SCI. In this review, we provide an overview of the current literature discussing changes in the peripheral immune system and their occurrence over time following a traumatic SCI.

B cells possess a predominant role in adaptive immune responses antibody-dependent and -independent functions. The microbiome of the gastrointestinal tract is currently being intensively investigated due to its profound impact on various immune responses, including B cell maturation, activation, and IgA antibody responses. Recent findings have demonstrated the interplay between dietary components, gut microbiome, and autoantibody production. \"Western\" dietary patterns, such as high fat and high salt diets, can induce alterations in the gut microbiome that in turn affects IgA responses and the production of autoantibodies. This could contribute to multiple pathologies including autoimmune and inflammatory diseases. Here, we summarize current knowledge on the influence of various dietary components on B cell function and (auto)antibody production in relation to the gut microbiota, with a particular focus on the gut-brain axis in the pathogenesis of multiple sclerosis.

The long term effects of fingolimod, an oral treatment for relapsing-remitting (RR) multiple sclerosis (MS), on blood circulating B and T cell subtypes in MS patients are not completely understood. This study describes for the first time the longitudinal effects of fingolimod treatment on B and T cell subtypes. Furthermore, expression of surface molecules involved in antigen presentation and costimulation during fingolimod treatment are assessed in MS patients in a 12 month follow-up study. Using flow cytometry, B and T cell subtypes, and their expression of antigen presentation, costimulation and migration markers were measured during a 12 month follow-up in the peripheral blood of MS patients. Data of fingolimod-treated MS patients (n = 49) were compared to those from treatment-naive (n = 47) and interferon-treated (n = 27) MS patients. In the B cell population, we observed a decrease in the proportion of non class-switched and class-switched memory B cells (p<0.001), both implicated in MS pathogenesis, while the proportion of naive B cells was increased during fingolimod treatment in the peripheral blood (PB) of MS patients (p<0.05). The remaining T cell population, in contrast, showed elevated proportions of memory conventional and regulatory T cells (p<0.01) and declined proportions of naive conventional and regulatory cells (p<0.05). These naive T cell subtypes are main drivers of MS pathogenesis. B cell expression of CD80 and CD86 and programmed death (PD) -1 expression on circulating follicular helper T cells was increased during fingolimod follow-up (p<0.05) pointing to a potentially compensatory mechanism of the remaining circulating lymphocyte subtypes that could provide additional help during normal immune responses. MS patients treated with fingolimod showed a change in PB lymphocyte subtype proportions and expression of functional molecules on T and B cells, suggesting an association with the therapeutic efficacy of fingolimod.

The WHO defines different COVID-19 disease stages in which the pathophysiological mechanisms differ. We evaluated the characteristics of these COVID-19 disease stages. Forty-four PCR-confirmed COVID-19 patients were included in a prospective minimal invasive autopsy cohort. Patients were classified into mild-moderate (n = 4), severe-critical (n = 32) and post-acute disease (n = 8) and clinical, radiological, histological, microbiological and immunological data were compared. Classified according to Thoracic Society of America, patients with mild-moderate disease had no typical COVID-19 images on CT-Thorax versus 71.9% with typical images in severe-critical disease and 87.5% in post-acute disease ( P  < 0.001). Diffuse alveolar damage was absent in mild-moderate disease but present in 93.8% and 87.5% of patients with severe-critical and post-acute COVID-19 respectively ( P  = 0.002). Other organs with COVID-19 related histopathological changes were liver and heart. Interferon-γ levels were significantly higher in patients with severe-critical COVID-19 ( P  = 0.046). Anti-SARS CoV-2 IgG was positive in 66%, 40.6% and 87.5% of patients with mild-moderate, severe-critical and post-acute COVID-19 respectively (n.s.). Significant differences in histopathological and immunological characteristics between patients with mild-moderate disease compared to patients with severe-critical disease were found, whereas differences between patients with severe-critical disease and post-acute disease were limited. This emphasizes the need for tailored treatment of COVID-19 patients.

Oncostatin M (OSM) is an IL-6 family member which exerts neuroprotective and remyelination-promoting effects after damage to the central nervous system (CNS). However, the role of OSM in neuro-inflammation is poorly understood. Here, we investigated OSM’s role in pathological events important for the neuro-inflammatory disorder multiple sclerosis (MS). We show that OSM receptor (OSMRβ) expression is increased on circulating lymphocytes of MS patients, indicating their elevated responsiveness to OSM signalling. In addition, OSM production by activated myeloid cells and astrocytes is increased in MS brain lesions. In experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, OSMRβ-deficient mice exhibit milder clinical symptoms, accompanied by diminished T helper 17 (Th17) cell infiltration into the CNS and reduced BBB leakage. In vitro, OSM reduces BBB integrity by downregulating the junctional molecules claudin-5 and VE-cadherin, while promoting secretion of the Th17-attracting chemokine CCL20 by inflamed BBB-endothelial cells and reactive astrocytes. Using flow cytometric fluorescence resonance energy transfer (FRET) quantification, we found that OSM-induced endothelial CCL20 promotes activation of lymphocyte function-associated antigen 1 (LFA-1) on Th17 cells. Moreover, CCL20 enhances Th17 cell adhesion to OSM-treated inflamed endothelial cells, which is at least in part ICAM-1 mediated. Together, these data identify an OSM-CCL20 axis, in which OSM contributes significantly to BBB impairment during neuro-inflammation by inducing permeability while recruiting Th17 cells via enhanced endothelial CCL20 secretion and integrin activation. Therefore, care should be taken when considering OSM as a therapeutic agent for treatment of neuro-inflammatory diseases such as MS.

ObjectiveA panel of antibodies against three antigens, University Hasselt (UH)-rheumatoid arthritis (RA).305, 318 and 329, has been associated with lack of response to first-line therapy in the Care in early RA trial. This study aimed to determine the association of this antibody panel with first-line therapy response in an independent cohort.MethodsAnti-UH-RA.305/318/329 antibody reactivity was determined using ELISA in 165 baseline samples of the CAP48 cohort, an observational cohort of patients with early and naïve RA treated mainly with methotrexate monotherapy. Multivariable analyses assessed associations between baseline antibody reactivity and failure to reach remission or low disease activity (LDA) at 3, 6, 9 and 24 months according to the Disease Activity Score 28-joint C-reactive protein (DAS28CRP) and clinical/simplified disease activity index (SDAI).ResultsIn the total RA cohort, baseline anti-UH-RA.305/318/329 antibody reactivity was significantly higher in patients not achieving LDA versus those achieving LDA at 9 months (31.6% vs 11.3% for DAS28CRP/SDAI; OR 3.64, 95% CI 1.34 to 9.91, p=0.045). In patients with seronegative RA, a significant association between antibody reactivity and not achieving LDA based on DAS28CRP (42.1% vs 12.5%; OR 5.09, 95% CI 1.2 to 27.0, p=0.05) was already observed at 6 months. After 24 months, baseline antibody positivity remained significantly associated with not achieving LDA based on SDAI (OR 29.9, 95% CI 2.5 to 109.2, p=0.01) in patients with seronegative status.DiscussionIn the CAP48 cohort, the anti-UH-RA antibody panel was associated with a lack of response to first-line therapy for certain clinical measures, observed at 9 months in the total RA cohort and at 6 and 24 months in patients with seronegative status. The antibody panel should be further validated for its use in early personalised RA treatment.

The immune response in patients with Coronavirus Disease 2019 (COVID-19) is highly variable and is linked to disease severity and mortality. However, antibody and cytokine responses in the early disease stage and their association with disease course and outcome are still not completely understood. In this large, multi-centre cohort study, blood samples of 434 Belgian COVID-19 hospitalized patients with different disease severities (ranging from asymptomatic/mild to critically ill) from the first wave of the COVID-19 pandemic were obtained. Baseline antibody and cytokine responses were characterized and associations with several clinical outcome parameters were determined. Anti-spike immunoglobulin (Ig)G and IgM levels were elevated in patients with a more severe disease course. This increased baseline antibody response however was associated with decreased odds for hospital mortality. Levels of the pro-inflammatory cytokines IL-6, IP-10 and IL-8, the anti-inflammatory cytokine IL-10 and the antiviral cytokines IFN-α, IFN-β and IFN-λ1 were increased with disease severity. Remarkably, we found significantly lower levels of IFN-λ2,3 in critically ill patients compared to patients of the moderate and severe disease category. Finally, levels of IL-8, IL-6, IP-10, IL-10, IFN-α, IFN-β, IFN-γ and IFN-λ1 at baseline were positively associated with mortality, whereas higher IFN-λ2,3 levels were negatively associated with mortality.

Multiple sclerosis (MS) is a severe disease of the central nervous system (CNS) characterized by autoimmune inflammation and neurodegeneration. Historically, damage to the CNS was thought to be mediated predominantly by activated pro-inflammatory T cells. B cell involvement in the pathogenesis of MS was solely attributed to autoantibody production. The first clues for the involvement of antibody-independent B cell functions in MS pathology came from positive results in clinical trials of the B cell-depleting treatment rituximab in patients with relapsing-remitting (RR) MS. The survival of antibody-secreting plasma cells and decrease in T cell numbers indicated the importance of other B cell functions in MS such as antigen presentation, costimulation, and cytokine production. Rituximab provided us with an example of how clinical trials can lead to new research opportunities concerning B cell biology. Moreover, analysis of the antibody-independent B cell functions in MS has gained interest since these trials. Limited information is present on the effects of current immunomodulatory therapies on B cell functions, although effects of both first-line (interferon, glatiramer acetate, dimethyl fumarate, and teriflunomide), second-line (fingolimod, natalizumab), and even third-line (monoclonal antibody therapies) treatments on B cell subtype distribution, expression of functional surface markers, and secretion of different cytokines by B cells have been studied to some extent. In this review, we summarize the effects of different MS-related treatments on B cell functions that have been described up to now in order to find new research opportunities and contribute to the understanding of the pathogenesis of MS.

A traumatic spinal cord injury (SCI) severely damages the nerve tissue of the spinal cord, often leading to long-term impairment of motor, sensory and autonomic functions. During a secondary injury phase, an inflammatory immune response is initiated. Current evidence points toward involvement of B cells and the macrophage migration inhibitory factor (MIF)/CD74 axis in SCI pathology. This study aimed to map the complete MIF/CD74 axis across the immune system and analyze its impact on B cell function after traumatic SCI. Peripheral blood samples were obtained from a total cohort of 90 healthy controls (HC) and 70 SCI patients. SCI samples were collected longitudinally in the acute (0 weeks post-SCI), subacute (2 weeks post-SCI), intermediate (3–18 weeks post-SCI) and chronic (26–52 weeks post-SCI) phases post-injury. MIF levels in plasma of SCI patients and HC were measured using ELISA. Relative and absolute levels of immune and B cell subsets, as well as expression of members of the MIF/CD74 axis, were studied using high-dimensional flow cytometry. The functional relevance of MIF/CD74 axis signaling on B cell functions was investigated using in vitro blocking assays. SCI triggered an early immune cell reduction, characterized by decreased absolute numbers of total and MIF/CD74 axis-expressing B cells and immune cells. In contrast, the MIF/CD74 axis was upregulated as MIF receptor surface expression on B cell subsets, as well as frequencies of CD74 + , CD44 + and CXCR4 + B cells, were increased during the subacute/intermediate phase post-SCI. MIF plasma levels were increased in SCI patients, yet MIF expression levels were reduced within circulating immune cells, suggesting that the injured spinal cord is the main source of MIF. Importantly, decreased B cell proliferation, activation and cytokine production were observed after blocking of CD74, CD44 or MIF in primary B cells of SCI patients and HC. The observed effects were more pronounced in SCI B cells, highlighting their stronger dependence on MIF/CD74 axis signaling. In conclusion, the complete MIF/CD74 axis plays an important role in post-SCI B cell responses. Our findings warrant further investigation of the MIF/CD74 axis as a potential target for immunomodulatory strategies in SCI treatment.

Following a spinal cord injury (SCI), an inflammatory immune reaction is triggered which results in advanced secondary tissue damage. The systemic post-SCI immune response is poorly understood. This study aimed to extensively analyse the circulating immune cell composition in traumatic SCI patients in relation to clinical parameters. High-dimensional flow cytometry was performed on peripheral blood mononuclear cells of 18 traumatic SCI patients and 18 healthy controls to determine immune cell subsets. SCI blood samples were collected at multiple time points in the (sub)acute (0 days to 3 weeks post-SCI, (s)aSCI) and chronic (6 to >18 weeks post-SCI, cSCI) disease phase. Total and CD4 + T cell frequencies were increased in cSCI patients. Both CD4 + T cells and B cells were shifted towards memory phenotypes in (s)aSCI patients and cSCI patients, respectively. Most profound changes were observed in the B cell compartment. Decreased immunoglobulin (Ig)G + and increased IgM + B cell frequencies reflected disease severity, as these correlated with American Spinal Injury Association (ASIA) impairment scale (AIS) scores. Post-SCI B cell responses consisted of an increased frequency of CD74 + cells and CD74 expression level within total B cells and B cell subsets. Findings from this study suggest that post-SCI inflammation is driven by memory immune cell subsets. The increased CD74 expression on post-SCI B cells could suggest the involvement of CD74-related pathways in neuroinflammation following SCI. In addition, the clinical and prognostic value of monitoring circulating IgM + and IgG + B cell levels in SCI patients should be further evaluated.