Antibody cross-reactivity between casein and myelin-associated glycoprotein results in central nervous system demyelination.

Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease of the central nervous system (CNS) with a high socioeconomic relevance. The pathophysiology of MS, which is both complex and incompletely understood, is believed to be influenced by various environmental determinants, including diet. Since the 1990s, a correlation between the consumption of bovine milk products and MS prevalence has been debated. Here, we show that C57BL/6 mice immunized with bovine casein developed severe spinal cord pathology, in particular, demyelination, which was associated with the deposition of immunoglobulin G. Furthermore, we observed binding of serum from casein-immunized mice to mouse oligodendrocytes in CNS tissue sections and in culture where casein-specific antibodies induced complement-dependent pathology. We subsequently identified myelin-associated glycoprotein (MAG) as a cross-reactive antigenic target. The results obtained from the mouse model were complemented by clinical data showing that serum samples from patients with MS contained significantly higher B cell and antibody reactivity to bovine casein than those from patients with other neurologic diseases. This reactivity correlated with the B cell response to a mixture of CNS antigens and could again be attributed to MAG reactivity. While we acknowledge disease heterogeneity among individuals with MS, we believe that consumption of cow's milk in a subset of patients with MS who have experienced a previous loss of tolerance to bovine casein may aggravate the disease. Our data suggest that patients with antibodies to bovine casein might benefit from restricting dairy products from their diet.

Strategies for Neuroprotection in Multiple Sclerosis and the Role of Calcium.

Calcium ions are vital for maintaining the physiological and biochemical processes inside cells. The central nervous system (CNS) is particularly dependent on calcium homeostasis and its dysregulation has been associated with several neurodegenerative disorders including Parkinson's disease (PD), Alzheimer's disease (AD) and Huntington's disease (HD), as well as with multiple sclerosis (MS). Hence, the modulation of calcium influx into the cells and the targeting of calcium-mediated signaling pathways may present a promising therapeutic approach for these diseases. This review provides an overview on calcium channels in neurons and glial cells. Special emphasis is put on MS, a chronic autoimmune disease of the CNS. While the initial relapsing-remitting stage of MS can be treated effectively with immune modulatory and immunosuppressive drugs, the subsequent progressive stage has remained largely untreatable. Here we summarize several approaches that have been and are currently being tested for their neuroprotective capacities in MS and we discuss which role calcium could play in this regard.

Strong Associations Between Inflammation, Pruritus and Mental Health in Dialysis Patients.

Pruritus, impaired mental health and inflammation contribute to morbidity in end-stage renal disease. There are no studies on all 3 conditions. We therefore obtained inflammatory parameter data (C-reactive protein and interleukin-6), pruritus data and psychological test data (36-Item Short-Form Health Survey, "Allgemeine Depressionsskala" and Toronto Alexithymia Scale-20) for 19 dialysis patients with pruritus, 20 dialysis patients without pruritus and 15 healthy controls. Non-parametric hierarchical clustering revealed 3 clusters of parameters: one mainly driven by pruritus scores (chronic kidney disease-associated pruritus cluster), one by mental health scores (mental health cluster) and one by inflammatory parameters (inflammatory cluster). Factor analysis showed strong associations (mental health cluster/chronic kidney disease-associated pruritus cluster, r=-0.49; mental health cluster/inflammatory cluster, r=-0.52; inflammatory cluster/chronic kidney disease-associated pruritus cluster, r=0.48). For the first time, complete correlations between inflammation, mental health and pruritus in dialysis patients have been established. As all 3 conditions are associated with mortality, knowledge about their interdependence helps to understand end-stage renal disease pathophysiology.

The prevalence of IgG antibodies against milk and milk antigens in patients with multiple sclerosis.

Introduction: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). The pathophysiology of MS is complex and is said to be influenced by multiple environmental determinants, including diet. We and others have previously demonstrated how consumption of bovine milk can aggravate disease severity in MS patients, which can be explained by molecular mimicry between milk antigens and those expressed within the CNS. In this study we set out to identify alternatives to drinking cow milk which might be less detrimental to MS patients who have a genetic predisposition towards developing antibody titers against bovine milk antigens that cross-react with CNS antigens. Methods: To this end, we screened 35 patients with MS and 20 healthy controls for their IgG reactivity against an array of animal-sourced milk, plant-based alternatives as well as individual antigens from bovine milk. Results: We demonstrate that MS patients have a significantly higher IgG response to animal-sourced milk, especially cow milk, in comparison to healthy donors. We also show that the reactivity to cow milk in MS patients can be attributed to reactivity against different bovine milk antigens. Finally, our correlation data indicate the co-existence of antibodies to individual bovine milk antigens and their corresponding cross-reactive CNS antigens. Discussion: Taken together, we suggest screening of blood from MS patients for antibodies against different types of milk and milk antigens in order to establish a personalized diet regimen.

Immune monitoring of SARS-CoV-2-specific T cell and B cell responses in patients with multiple sclerosis treated with ocrelizumab.

Introduction: Since the development of the coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there has been significant interest in determining the effectiveness of SARS-CoV-2 vaccines in patients under immunomodulatory or immunosuppressive therapies. The aim of this study was to evaluate the impact of ocrelizumab, a monoclonal anti-CD20 antibody, on SARS-CoV-2-specific T cell and B cell responses in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: To this end, peripheral blood mononuclear cells (PBMCs) were isolated from n = 23 patients with RRMS. Of these patients, n = 17 were tested before (time point t0) and one month after (time point t1) their first dose of ocrelizumab. In addition, we studied n = 9 RRMS patients that got infected with SARS-CoV-2 over the course of ocrelizumab therapy (time point t2). PBMCs were also isolated from n = 19 age- and gender-matched healthy controls (HCs) after vaccination or infection with SARS-CoV-2, respectively. Interferon-γ (IFN-γ)/interleukin-2 (IL-2) and granzyme B (GzB)/perforin (PFN) double-color enzyme-linked immunospot (ELISPOT) assays or single-color ELISPOT assays were performed to measure SARS-CoV-2 antigen-specific T cell and B cell responses. Anti-viral antibody titers were quantified in the serum by chemiluminescence immunoassay. Results: Our data indicate a significant difference in the SARS-CoV-2 specific IFN-γ (P = 0.0119) and PFN (P = 0.0005) secreting T cell compartment in the MS cohort at t0 compared to HCs. Following the first dose of ocrelizumab treatment, a significant decrease in the number of SARS-CoV-2 spike protein-specific B cells was observed (P = 0.0012). Infection with SARS-CoV-2 in MS patients under ocrelizumab therapy did not significantly alter their existing immune response against the virus. Kaplan-Meier survival analysis suggested that the spike S1 protein-specific immunoglobulin (Ig)G response might be a key parameter for predicting the probability of (re)infection with SARS-CoV-2. Discussion: Our results call for a critical discussion regarding appropriate vaccination intervals and potential biomarkers for the prediction of (re)infection with SARS-CoV-2 in patients with MS receiving ocrelizumab. Unique identifier: DRKS00029110; URL: http://apps.who.int/trialsearch/.