Multiple Sclerosis Autoimmune Diseases Research Articles

The novel TH17-associated cytokine IL-26 mediates BBB breakdown and neuroinflammation

It is well established that TH17 lymphocytes are crucial in the pathogenesis of the chronic autoimmune disease multiple sclerosis (MS). However, the importance of IL-17 in MS is still under debate, and other TH17-associated cytokines are likely more crucial in the initiation and maintenance of neuroinflammation. In this study, we demonstrate that IL-26 is specifically produced by human TH17 lymphocytes and that it correlates strongly to other TH17-associated markers (IL-17, IL-22, IL-23R, RORc and MCAM).

An increase in tolerogenic dendritic cell and natural regulatory T cell numbers during experimental autoimmune encephalomyelitis in Rras-/- mice results in attenuated disease.

R-Ras is a member of the Ras superfamily of small GTPases, which are regulators of various cellular processes, including adhesion, survival, proliferation, trafficking, and cytokine production. R-Ras is expressed by immune cells and has been shown to modulate dendritic cell (DC) function in vitro and has been associated with liver autoimmunity. We used Rras-deficient mice to study the mechanism whereby R-Ras contributes to autoimmunity using experimental autoimmune encephalomyelitis (EAE), a mouse model of the CNS autoimmune disease multiple sclerosis. We found that a lack of R-Ras in peripheral immune cells resulted in attenuated EAE disease. Further investigation revealed that, during EAE, absence of R-Ras promoted the formation of MHC II(low) DC concomitant with a significant increase in proliferation of natural regulatory T cells, resulting in an increase in their cell numbers in the periphery. Our study suggests a novel role for R-Ras in promoting autoimmunity through negative regulation of natural regulatory T cell numbers by inhibiting the development of MHCII(low) DC with tolerogenic potential.

R-Ras promotes autoimmunity through negative regulation of natural T regulatory cell numbers by inhibiting tolerogenic dendritic cell development (IRC4P.488)

Abstract R-Ras is a member of the Ras family of small GTPases, which regulate various cellular processes including adhesion, survival, proliferation, trafficking, and cytokine production. R-Ras is expressed by immune cells and has been shown to modulate dendritic cell (DC) function in vitro. Although, higher expression of R-Ras is associated with liver autoimmunity in humans, its pathogenic mechanism is unknown. We used Rras-/- mice to identify the mechanism whereby R-Ras contributes to autoimmunity using experimental autoimmune encephalomyelitis (EAE), a mouse model of the CNS autoimmune disease multiple sclerosis. We found that a lack of R-Ras in peripheral immune cells resulted in attenuated EAE disease. In accordance with reduced EAE disease, numbers of inflammatory immune cells in the CNS of Rras-/- mice at the peak of EAE were significantly reduced. Further investigation revealed that during EAE, absence of R-Ras promoted the formation of MHC IIlo tolerogenic DC concomitant with a significant increase in Neuropilin-1hiCD4+Foxp3+ natural T regulatory cell (nTreg) numbers in the periphery. Mechanistically, we found that Rras-/- tolerogenic DCs induced proliferation of nTregs thereby enhancing their numbers and maintaining them in vivo. Our study suggests a novel role for R-Ras in promoting autoimmunity through negative regulation of nTreg numbers by inhibiting tolerogenic DC development.

Cladribine exerts an immunomodulatory effect on human and murine dendritic cells

Cladribine is a purine nucleoside analog developed to treat lymphoid malignancies. Reported therapeutic benefits for the autoimmune disease multiple sclerosis indicate additional immunomodulatory effects beyond the well-characterized cytotoxic activity causing lymphopenia. Here, we demonstrate that cladribine reduces the secretion of inflammatory cytokines and chemokines by murine and human dendritic cells, the most potent antigen-presenting cells. This compound also modulates the expression of the activation markers CD86 and MHC II. Furthermore, cladribine affects the T cell priming capacity of dendritic cells, resulting in reduced induction of interferon-γ- and tumor necrosis factor-α-producing T cells and increased induction of interleukin-10-producing T cells. These effects, observed at cladribine concentrations in the therapeutically relevant range of serum steady-state concentrations for leukemia and multiple sclerosis, confirm the immunomodulatory activity of cladribine.

The PTEN inhibitor bisperoxovanadium enhances myelination by amplifying IGF‐1 signaling in rat and human oligodendrocyte progenitors

Oligodendrocytes (OLGs) produce and maintain myelin in the central nervous system (CNS). In the demyelinating autoimmune disease multiple sclerosis, OLGs are damaged and those remaining fail to fully remyelinate CNS lesions. Therefore, current therapies directed to restrain the inflammation process with approaches that protect and reconstitute oligodendrocyte density would be essential to pave the way of myelin repair. A critical signal for oligodendrocytes is insulin-like growth factor-1 (IGF-1), which promotes their development and ultimately myelin formation. PTEN inhibits the phosphoinositide 3-kinase (PI3K)/Akt signaling, a convergence downstream pathway for growth factors such as IGF-1. In this report, we temporarily inhibited PTEN activity by treating rat and human oligodendrocyte progenitors (OLPs) cultured alone or with dorsal root ganglion neurons (DRGNs) with bisperoxovanadium (phen). Our findings show that phen potentiates IGF-1 actions by increasing proliferation of OLPs in a concentration-dependent manner, and caused a sustained and time-dependent activation of the main pathways: PI3K/Akt/mammalian target of rapamycin (mTOR) and MEK/ERK. At low concentrations, IGF-1 and phen stimulated the differentiation of rat and human OLPs. Concordantly, the PTEN inhibitor together with IGF-1 robustly augmented myelin basic protein accumulation in rat newborn and human fetal OLGs co-cultured with DRGNs in a longer timeframe by promoting the elaboration of organized myelinated fibers as evidenced by confocal microscopy. Thus, our results suggest that a transient suppression of a potential barrier for myelination in combination with other therapeutic approaches including growth factors may be promising to improve the functional recovery of CNS injuries.

The Human Environment and the Vitamin D Compromise: Scotland as a Case Study in Human Biocultural Adaptation and Disease Susceptibility

Year-round human habitation of environments with highly seasonal regimes of ultraviolet B radiation (UVB) depended on adaptive complexes of biological and cultural traits to ensure adequacy of vitamin D. Perturbations of such adaptive complexes resulting from changes in the physical environment, human behavior and culture, or both have had unexpected and untoward consequences for health. Scotland is an excellent case study of the changing nature of human biocultural adaptation to low-UVB environments. Occupation of Scotland after the last Pleistocene glaciation event about 14,000 YBP was made possible by maximally depigmented skin, which facilitated cutaneous biosynthesis of vitamin D3, and by a diet that emphasized foods rich in vitamin D. Changes in human subsistence and diet began with the introduction of agriculture and grazing about 5,000 YBP and accelerated greatly in the last 200 years through industrialization and urbanization. The resulting changes in domiciles, patterns of daily activity and behavior, and diet have led to reduced exposure to UVB and reduced consumption of vitamin D–rich foods. This has perturbed the “vitamin D compromise,” an adaptive complex established in Scotland during the Mesolithic and Neolithic. We describe the UVB environment of Scotland from remotely sensed data and combine these data with information from the archaeological record to describe the vitamin D compromise in Scotland. Changes in human exposure to UVB and vitamin D consumption, which occurred as the result of urbanization and the dietary shift away from the consumption of oily fish, are traced. Vitamin D deficiency contributes to increased disease prevalence in Scotland, including that of the autoimmune disease multiple sclerosis, a debilitating neurodegenerative disease caused by demyelination of the central nervous system. These conditions have created an “imperfect storm” of poor health that should command the attention of public health experts and policy makers.

The human environment and the vitamin D compromise: Scotland as a case study in human biocultural adaptation and disease susceptibility.

Year-round human habitation of environments with highly seasonal regimes of ultraviolet B radiation (UVB) depended on adaptive complexes of biological and cultural traits to ensure adequacy of vitamin D. Perturbations of such adaptive complexes resulting from changes in the physical environment, human behavior and culture, or both have had unexpected and untoward consequences for health. Scotland is an excellent case study of the changing nature of human biocultural adaptation to low-UVB environments. Occupation of Scotland after the last Pleistocene glaciation event about 14,000 YBP was made possible by maximally depigmented skin, which facilitated cutaneous biosynthesis of vitamin D3, and by a diet that emphasized foods rich in vitamin D. Changes in human subsistence and diet began with the introduction of agriculture and grazing about 5,000 YBP and accelerated greatly in the last 200 years through industrialization and urbanization. The resulting changes in domiciles, patterns of daily activity and behavior, and diet have led to reduced exposure to UVB and reduced consumption of vitamin D-rich foods. This has perturbed the "vitamin D compromise," an adaptive complex established in Scotland during the Mesolithic and Neolithic. We describe the UVB environment of Scotland from remotely sensed data and combine these data with information from the archaeological record to describe the vitamin D compromise in Scotland. Changes in human exposure to UVB and vitamin D consumption, which occurred as the result of urbanization and the dietary shift away from the consumption of oily fish, are traced. Vitamin D deficiency contributes to increased disease prevalence in Scotland, including that of the autoimmune disease multiple sclerosis, a debilitating neurodegenerative disease caused by demyelination of the central nervous system. These conditions have created an "imperfect storm" of poor health that should command the attention of public health experts and policy makers.

Imatinib Mesylate: An Innovation in Treatment of Autoimmune Diseases

Imatinib mesylate is a selective protein tyrosine kinase inhibitor, which can inhibit BCR/Abl, PDGF-R, c-KIT, c-fms, TCR/Abl, Lck, FLT-3 and MAPKs activities on various cell types. On immune system, imatinib has antiproliferative activity and immunomodulatory effects in lymphocytes, macrophages, mast cells and dendritic cells with abrogating multiple signal transduction pathways involved in pathogenesis of autoimmune diseases e.g. inhibiting IFN-γ, TNF-α, IL-1β and IL-17 pro-inflammatory cytokines and MMPs secretion. To date, the efficacy of imatinib in numerous animal model of autoimmune diseases (rheumatoid arthritis, multiple sclerosis, autoimmune diabetes and glomerulonephritis) has been demonstrated, but application of this drug in human autoimmune diseases should be tested in future clinical trials. This review provides an update on the use of tyrosine kinase inhibitor imatinib mesylate in treatment of autoimmune diseases and its related recent patents that could be developed as a novel and available therapy for the management of the autoimmunity improvement.

The development of tertiary lymphoid organs in the central nervous system facilitates determinant spreading of the MP4-specific T cell response (P4164)

Abstract Accumulating evidence indicates that B cells aggregate into tertiary lymphoid organs (TLOs) in the central nervous system (CNS) in the human autoimmune disease multiple sclerosis (MS). In patients with secondary-progressive MS the presence of ectopic B cell aggregates has been linked to more severe clinical disease and cortical pathology. Here we demonstrate the formation of TLOs in myelin basic protein (MBP)-proteolipid protein (PLP) fusion protein MP4-induced experimental autoimmune encephalomyelitis (EAE) of C57BL/6 mice. TLOs were a characteristic feature of the chronic disease stage and most prevalent in the cerebellum, while also being present in the spinal cord and cerebrum, but absent in the brain stem. TLOs were characterized by B and T cell compartmentalization, the presence of high endothelial venules and germinal center formation. An association with TH17, but not TH1 cells was evident. In addition, results obtained from ELISPOT analysis of the antigen-specific T cell response suggest that TLOs facilitate determinant spreading of the MP4-specific T cell response to myelin oligodendrocyte glycoprotein (MOG). Our data add novel insights into the contribution of TLOs to disease progression in the context of CNS autoimmunity. We suggest that the blockade of TLO development is a therapeutic strategy that needs to be carefully considered in future studies.

Expansion of CD27high plasmablasts in transverse myelitis patients that utilize VH4 and JH6 genes and undergo extensive somatic hypermutation

Patients with the autoimmune disease multiple sclerosis (MS) typically present with the clinically isolated syndromes (CIS) transverse myelitis (TM) or optic neuritis (ON). B-cell disturbances have been well documented in patients with MS and CIS patients with ON, but not in CIS patients with TM, despite the fact that these patients have the worst clinical outcome of all CIS types. The goal of this study was to characterize the B-cell populations and immunoglobulin genetics in TM patients. We found a unique expansion of CD27(high) plasmablasts in both the cerebrospinal fluid and periphery of TM patients that is not present in ON patients. Additionally, plasmablasts from TM patients show evidence for positive selection with increased somatic hypermutation accumulation in VH4(+) B cells and receptor editing that is not observed in ON patients. These characteristics unique to TM patients may impact disease severity and progression.

Estimating the ratio of CD4 + to CD8 + T cells using high-throughput sequence data

Mature T cells express either CD8 or CD4, defining two physiologically distinct populations of T cells. CD8+ T cells, or killer T-cells, and CD4+ T cells, or helper T cells, effect different aspects of T cell mediated adaptive immunity. Currently, determining the ratio of CD4+ to CD8+ T cells requires flow cytometry or immunohistochemistry. The genomic T cell receptor locus is rearranged during T cell maturation, generating a highly variable T cell receptor locus in each mature T cell. As part of thymic maturation, T cells that will become CD4+ versus CD8+ are subjected to different selective pressures. In this study, we apply high-throughput next-generation sequencing to T cells from both a healthy cohort and a cohort with an autoimmune disease (multiple sclerosis) to identify sequence features in the variable CDR3 region of the rearranged T cell receptor gene that distinguish CD4+ from CD8+ T cells. We identify sequence features that differ between CD4+ and CD8+ T cells, including Variable gene usage and CDR3 region length. We implement a likelihood model to estimate relative proportions of CD4+ and CD8+ T cells using these features. Our model accurately estimates the proportion of CD4+ and CD8+ T cell sequences in samples from healthy and diseased immune systems, and simulations indicate that it can be applied to as few as 1000 T cell receptor sequences; we validate this model using in vitro mixtures of T cell sequences, and by comparing the results of our method to flow cytometry using peripheral blood samples. We believe our computational method for determining the CD4:CD8 ratio in T cell samples from sequence data will provide additional useful information for any samples on which high-throughput TCR sequencing is performed, potentially including some solid tumors.

Analysis of reasons for the impossibility of creating Copaxone generics

The characteristics of Copaxone (glatiramer acetate, GA), an immunomodulating drug for the treatment of the serious autoimmune CNS disease multiple sclerosis, were presented. GA is the acetate of a mixture of synthetic polypeptides of various lengths composed of the natural amino acids L-glutamine, L-alanine, L-tyrosine, and L-lysine in stable molecular ratios that are prepared in definite and strictly controlled laboratory and manufacturing conditions. The polymerization reaction is carried out by addition of separate monomers and not whole peptide chains. The average length of the heterogeneous peptides in GA varies from 20 to 200 amino acids. The amino-acid sequence of the GA polypeptides is controlled to a large extent by the polymerization reaction conditions. The average molecular weight of the GA polypeptides varies in the range 5000 – 9000 Da. The majority of GA polypeptides have a molecular-weight distribution of approximately 2,500 – 20,000 Da. An analysis of the materials regarding features of the chemical structure, pharmacological and toxicological properties of GA and its analogs (glatiramoids) indicated that creating GA generics is at present practically impossible.

Symptoms Related to Tumor Necrosis Factor Receptor 1-associated Periodic Syndrome, Multiple Sclerosis, and Severe Rheumatoid Arthritis in Patients Carrying the TNF Receptor Superfamily 1A D12E/p.Asp41Glu Mutation

Tumor necrosis factor (TNF) receptor 1-associated periodic syndrome (TRAPS) is an autoinflammatory disorder caused by autosomal dominantly inherited mutations in the TNF receptor superfamily 1A (TNFRSF1A) gene. The D12E substitution has been described only once to date, in a 4-year-old boy with fever. For DNA sequence analysis of the TNFRSF1A gene, genomic DNA was isolated, amplified by PCR, purified, and sequenced. We describe 3 families (8 subjects) with the TNFRSF1A D12E substitution and TRAPS-related symptoms, in 4 cases associated with the autoimmune diseases multiple sclerosis and rheumatoid arthritis. The clinical phenotype might be associated with the TNFRSF1A D12E mutation. There is a close pathophysiological relationship between TNF signaling and autoimmune disorders.

Guidelines of the Brazilian Society of Bone Marrow Transplantation on hematopoietic stem cell transplantation as a treatment for the autoimmune diseases systemic sclerosis and multiple sclerosis

. The procedure has improved and the incidence of complications and mortality decreased over time. There are still many points of discussion, some of which should be clarified by ongoing randomized studies. This consensus paper aims to gather data available in the international literature and to compare it to the Brazilian experience in order to establish evidence-based recommendations for the application of hematopoietic stem cell transplantation (HSCT) in the treatments of systemic and multiple sclerosis in Brazil. Systemic sclerosis Systemic sclerosis is an autoimmune disease in which the skin and, in most cases, internal organs are involved. The clinical evolution usually begins from vascular hyperreactivity and endothelial changes associated with inflammatory phenomena that result in progressive tissue damage, leading to fibrosis. The etiology is still unknown, but it certainly comes from the interaction between genetic predisposition and environmental stimuli that cause an immune imbalance and tissue lesions. Cardiopulmonary involvement is common and affects up to 80% of patients (1) . The

The complement system contributes to the pathology of experimental autoimmune encephalomyelitis by triggering demyelination and modifying the antigen-specific T and B cell response

So far, studies of the human autoimmune disease multiple sclerosis (MS) have largely been hampered by the absence of a pathogenic B cell component in its animal model, experimental autoimmune encephalomyelitis (EAE). To overcome this shortcoming, we have previously introduced the myelin basic protein (MBP)-proteolipid protein (PLP) MP4-induced EAE, which is B cell and autoantibody-dependent. Here we show that MP4-immunized wild-type C57BL/6 mice displayed a significantly lower disease incidence when their complement system was transiently depleted by a single injection of cobra venom factor (CVF) prior to immunization. Considering the underlying pathomechanism, our data suggest that the complement system is crucial for MP4-specific antibodies to trigger CNS pathology. Demyelinated lesions in the CNS were colocalized with complement depositions. In addition, B cell deficient JHT mice reconstituted with MP4-reactive serum showed significantly attenuated clinical and histological EAE after depletion of complement by CVF. The complement system was also critically involved in the generation of the MP4-specific T and B cell response: in MP4-immunized wild-type mice treated with CVF the MP4-specific cytokine and antibody response was significantly attenuated compared to untreated wild-type mice. Taken together, we propose two independent mechanisms by which the complement system can contribute to the pathology of autoimmune encephalomyelitis. Our data corroborate the role of complement in triggering antibody-dependent demyelination and antigen-specific T cell immunity and also provide first evidence that the complement system can modify the antigen-specific B cell response in EAE and possibly MS.

T cells become licensed in the lung to enter the central nervous system

The blood–brain barrier (BBB) and the environment of the central nervous system (CNS) guard the nervous tissue from peripheral immune cells. In the autoimmune disease multiple sclerosis, myelin-reactive T-cell blasts are thought to transgress the BBB and create a pro-inflammatory environment in the CNS, thereby making possible a second autoimmune attack that starts from the leptomeningeal vessels and progresses into the parenchyma. Using a Lewis rat model of experimental autoimmune encephalomyelitis, we show here that contrary to the expectations of this concept, T-cell blasts do not efficiently enter the CNS and are not required to prepare the BBB for immune-cell recruitment. Instead, intravenously transferred T-cell blasts gain the capacity to enter the CNS after residing transiently within the lung tissues. Inside the lung tissues, they move along and within the airways to bronchus-associated lymphoid tissues and lung-draining mediastinal lymph nodes before they enter the blood circulation from where they reach the CNS. Effector T cells transferred directly into the airways showed a similar migratory pattern and retained their full pathogenicity. On their way the T cells fundamentally reprogrammed their gene-expression profile, characterized by downregulation of their activation program and upregulation of cellular locomotion molecules together with chemokine and adhesion receptors. The adhesion receptors include ninjurin 1, which participates in T-cell intravascular crawling on cerebral blood vessels. We detected that the lung constitutes a niche not only for activated T cells but also for resting myelin-reactive memory T cells. After local stimulation in the lung, these cells strongly proliferate and, after assuming migratory properties, enter the CNS and induce paralytic disease. The lung could therefore contribute to the activation of potentially autoaggressive T cells and their transition to a migratory mode as a prerequisite to entering their target tissues and inducing autoimmune disease.

IgGs containing λ‐ and κ‐type light chains and of all subclasses (IgG1–IgG4) from the sera of patients with autoimmune diseases and viral and bacterial infections hydrolyze DNA

We present the first evidence demonstrating that small fractions of IgGs of all four subclasses (IgG1-IgG4) from patients with viral (tick-borne encephalitis), bacterial infections (streptococcal infection or erysipelas), and suppurative surgical infections caused by epidermal staphylococci as well as from patients with autoimmune diseases (systemic lupus erythematosus and multiple sclerosis) are catalytically active in the hydrolysis of supercoiled DNA. The hydrolysis of DNA was analyzed by agarose gel electrophoresis. The catalytic activities of nonfractionated IgGs increased in the following order: tick-borne encephalitis < suppurative surgical infection < streptococcal infection < multiple sclerosis < systemic lupus erythematosus, whereas IgGs of healthy donors were inactive. However, the pools of antibodies corresponding to any particular disease were characterized by a specific ratio of IgGs of all four subclasses (IgG1-IgG4) and IgGs containing λ- and κ-type light chains, and each of these subfractions of immunoglobulins demonstrated characteristic relative DNase activity. The relative activities of IgGs containing λ-type light chains may on average be higher, lower, or comparable with those for IgGs with κ-type light chains. The relative contributions of IgGs of different subclasses to the total activity of IgGs also varied widely in the case of various diseases: IgG1 (7%-45%), IgG2 (0.4%-73%), IgG3 (0%-12%), and IgG4 (9%-66%). Thus, immune systems of patients with different diseases can generate a variety of anti-DNA abzymes of different types and with different catalytic properties, which can play an important role in the pathogenesis or protection from the development of these diseases.

A Patient with Leiden V Mutation, Multiple Sclerosis, Psoriasis, and Sicca Syndrome: Could Celecoxib and Fingolimod Adversely Affect the Heart?

The paper describes the case of a patient affected by a combination of genetic and autoimmune diseases (multiple sclerosis, psoriatic arthritis, Leiden V mutation, and sicca syndrome) and hypertension. The psoriatic arthritis was treated with celecoxib and multiple sclerosis with fingolimod. The patient developed high fever and endocarditis, resulting in severe mitral regurgitation, atrial fibrillation, and congestive heart failure. Evidence is suggestive of adverse effects of potent immunosuppressive and anti-inflammatory therapies with biologic agents and the cardiovascular system. Fingolimod increases susceptibility to infections and induced endocarditis resulting in severe mitral regurgitation, atrial fibrillation, and congestive heart failure. Managed care systems limit the contact among basic care physicians and specialists. However, the process by which the optimal decision may be reached for a patient with a complex pathology is shared decision making, where the risk of severe complications and medical expenses may be reduced.

Pathogenic and regulatory roles for B cells in experimental autoimmune encephalomyelitis

A dual role of B cells in experimental autoimmune encephalomyelitis (EAE), the animal model of the human autoimmune disease multiple sclerosis (MS), has been established. In the first role, B cells contribute to the pathogenesis of EAE through the production of anti-myelin antibodies that contribute to demyelination. On the contrary, B cells have also been shown to have protective functions in that they play an essential role in the spontaneous recovery from EAE. In this review, we summarize studies conducted in a number of species demonstrating the conditions under which B cells are pathogenic in EAE. We also discuss the phenotype and anti-inflammatory mechanisms of regulatory B cells.

A Phase II Study of Ofatumumab in Combination with ICE or DHAP Chemotherapy in Relapsed or Refractory Aggressive B-Cell Lymphoma Prior to Autologous Stem Cell Transplantation (ASCT)

A Phase II Study of Ofatumumab in Combination with ICE or DHAP Chemotherapy in Relapsed or Refractory Aggressive B-Cell Lymphoma Prior to Autologous Stem Cell Transplantation (ASCT)