CD40 in Clinical Inflammation: From Multiple Sclerosis to Atherosclerosis

The interactions of CD40 and CD40L have been known for some time to critically regulate B-cell responses with respect to proliferation, isotype switching, antibody production, and memory formation. More recent findings demonstrated that CD40 can be expressed on several other antigen-presenting cell (APC) types such as macrophages, dendritic cells, and fibroblasts. This expression of CD40 regulates T-cell-APC interaction and is centrally involved in a wide array of inflammatory events. Here, currently available data are reviewed demonstrating that CD40- CD40L interactions are operational in two chronic inflammatory clinical conditions, namely, multiple sclerosis and atherosclerosis. The functional correlates of these interactions are discussed in the light of recent other findings, shedding light on the multiple effects of CD40- CD40L interactions

An unexpected symbiosis of animal welfare and clinical relevance in a refined nonhuman primate model of human autoimmune disease

Aging Western populations are confronted with an increasing prevalence of chronic inflammatory and degenerative diseases for which adequate treatments are lacking. One of the major hurdles in therapy development is the poor translation of disease concepts, often developed in rodent disease models, into effective treatments for the patient. Reasons for the high failure rate of promising drug candidates are unforeseen toxicity and lack of efficacy. Essential elements of human disease are apparently lacking in the current preclinically used animal models. Results obtained in a generic nonhuman primate model of human autoimmunity, the marmoset experimental autoimmune encephalomyelitis (EAE) model, are discussed to emphasize the claim that primates are essential complementary models that can help to bridge the wide translational gap between mouse and man.</p

Bacterial Peptidoglycan as a Driver of Chronic Brain Inflammation

Peptidoglycan (PGN) is a cell wall component of both Gram-positive and Gram-negative bacteria. Signature fragments of PGN are proinflammatory through engagement of pattern recognition receptors (PRR) on resident tissue cells and circulating leukocytes. Despite its abundance in the gut microbiota, there is limited recognition that PGN could contribute to chronic neuroinflammation. This review highlights current insights into the roles of PGN as a determinant of brain inflammation, notably in multiple sclerosis (MS) and its experimental autoimmune encephalomyelitis (EAE) models. Recent studies demonstrate PGN in blood of healthy adult humans. PGN amplifies autoimmune pathology via activation of innate immune cells. Novel uptake routes through (altered) gut mucosa by myeloid leukocyte subsets promote PGN transport to the brain

Collagen-induced arthritis in common marmosets: a new nonhuman primate model for chronic arthritis

Introduction: There is an ever-increasing need for animal models to evaluate efficacy and safety of new therapeutics in the field of rheumatoid arthritis (RA). Particularly for the early preclinical evaluation of human-specific biologicals targeting the progressive phase of the disease, there is a need for relevant animal models. In response to this requirement we set out to develop a model of collagen-induced arthritis (CIA) in a small-sized nonhuman primate species (300 to 400 g at adult age); that is, the common marmoset (Callithrix jacchus).Methods: Twenty-two animals divided into three experiments were immunized with collagen type II (CII) of either bovine or chicken origin with different immunization strategies. The animals were analyzed for clinical manifestation of arthritis, hematology and clinical chemistry, immunological responses against CII and histopathological features of the arthritis.Results: Clinically manifest arthritis was observed in almost 100% (21 out of 22) of the animals. Fifty percent of the animals developed semi-acute CIA while the other 50% displayed a more chronic disease. Both cellular (CD3/CD4 and CD3/CD8) and humoral responses (IgM and IgG) against CII were involved in the development of the disease. Besides mild histopathological changes in bone and cartilage, severe inflammation in extraarticular tissues like periosteum and subcutaneous tissues was observed.Conclusions: This new model in marmosets more closely resembles chronic RA with respect to the chronic disease course and pathomorphological presentation than the more acute monophasic and destructive CIA model in macaques. This model can therefore fill a niche in preclinical testing of new human specific therapeutics

Myelin oligodendrocyte glycoprotein has a dual role in T cell autoimmunity against central nervous system myelin

Background Myelin oligodendrocyte glycoprotein (MOG) is a candidate primary target of the autoimmune attack on the central nervous system (CNS) in multiple sclerosis (MS). However, the physiological function of MOG has been unclear for a long time. Objective We propose that MOG has a central role in the regulation of tolerance and autoimmunity. Conclusion The interaction of MOG with DC-SIGN, an innate antigen receptor of myeloid antigen-presenting cells (m-APCs), present inside the CNS (microglia) or in draining lymph nodes (dendritic cells; DCs), keeps these cells in an immature/tolerogenic state. We postulate that this tolerogenic mechanism may be disturbed in MS by unknown factors

Modulation of Multiple Sclerosis and its Animal Model experimental Autoimmune encephalomyelitis by Food and Gut Microbiota

Multiple sclerosis (MS) is an autoimmune neurological disease characterized by chronic inflammation of the central nervous system (CNS), leading to demyelination, axonal damage, and symptoms such as fatigue and disability. Although the cause of MS is not known, the infiltration of peripherally activated immune cells into the CNS has a key pathogenic role. Accumulating evidence supports an important role of diet and gut microbiota in immune-mediated diseases. Preclinical as well as clinical studies suggest a role for gut microbiota and dietary components in MS. Here, we review these recent studies on gut microbiota and dietary interventions in MS and its animal model experimental autoimmune encephalomyelitis. We also propose directions for future research

Multiple sclerosis is linked to MAPK(ERK) overactivity in microglia

Reassessment of published observations in patients with multiple sclerosis (MS) suggests a microglial malfunction due to inappropriate (over)activity of the mitogen-activated protein kinase pathway ERK (MAPKERK). These observations regard biochemistry as well as epigenetics, and all indicate involvement of this pathway. Recent preclinical research on neurodegeneration already pointed towards a role of MAPK pathways, in particular MAPKERK. This is important as microglia with overactive MAPK have been identified to disturb local oligodendrocytes which can lead to locoregional demyelination, hallmark of MS. This constitutes a new concept on pathophysiology of MS, besides the prevailing view, i.e., autoimmunity. Acknowledged risk factors for MS, such as EBV infection, hypovitaminosis D, and smoking, all downregulate MAPKERK negative feedback phosphatases that normally regulate MAPKERK activity. Consequently, these factors may contribute to inappropriate MAPKERK overactivity, and thereby to neurodegeneration. Also, MAPKERK overactivity in microglia, as a factor in the pathophysiology of MS, could explain ongoing neurodegeneration in MS patients despite optimized immunosuppressive or immunomodulatory treatment. Currently, for these patients with progressive disease, no effective treatment exists. In such refractory MS, targeting the cause of overactive MAPKERK in microglia merits further investigation as this phenomenon may imply a novel treatment approach

Multiple sclerosis and drug discovery:A work of translation

Multiple sclerosis (MS) is after trauma the most important neurological disease in young adults, affecting 1 per 1000 individuals. With currently available medications, most of these targeting the immune system, satisfactory results have been obtained in patients with relapsing MS, but these can have serious adverse effects. Moreover, despite some promising developments, such as with B cell targeting therapies or sphingosine-1-phosphate modulating drugs, there still is a high unmet need of safe drugs with broad efficacy in patients with progressive MS. Despite substantial investments and intensive preclinical research, the proportion of promising lead compounds that reaches the approved drug status remains disappointingly low. One cause lies in the poor predictive validity of MS animal models used in the translation of pathogenic mechanisms into safe and effective treatments for the patient. This disturbing situation has raised criticism against the relevance of animal models used in preclinical research and calls for improvement of these models. This publication presents a potentially useful strategy to enhance the predictive validity of MS animal models, namely, to analyze the causes of failure in forward translation (lab to clinic) via reverse translation (clinic to lab). Through this strategy new insights can be gained that can help generate more valid MS models