A Spontaneous Model of Experimental Autoimmune Encephalomyelitis Provides Evidence of MOG-Specific B Cell Recruitment and Clonal Expansion.

The key role of B cells in the pathophysiology of multiple sclerosis (MS) is supported by the presence of oligoclonal bands in the cerebrospinal fluid, by the association of meningeal ectopic B cell follicles with demyelination, axonal loss and reduction of astrocytes, as well as by the high efficacy of B lymphocyte depletion in controlling inflammatory parameters of MS. Here, we use a spontaneous model of experimental autoimmune encephalomyelitis (EAE) to study the clonality of the B cell response targeting myelin oligodendrocyte glycoprotein (MOG). In particular, 94% of SJL/j mice expressing an I-A: MOG specific transgenic T cell receptor (TCR) spontaneously develop a chronic paralytic EAE between the age of 60-500 days.

Fc Sialylation Prolongs Serum Half-Life of Therapeutic Antibodies.

The long serum of IgGs is ensured by their interaction with the neonatal Fc receptor (FcRn), which salvages IgG from intracellular degradation. Fc glycosylation is thought not to influence FcRn binding and IgG longevity in vivo. In this article, we demonstrate that hypersialylation of asparagine 297 (N297) enhances IgG serum persistence.

Thymic-Specific Serine Protease Limits Central Tolerance and Exacerbates Experimental Autoimmune Encephalomyelitis.

The genetic predisposition to multiple sclerosis (MS) is most strongly conveyed by MHC class II haplotypes, possibly by shaping the autoimmune CD4 T cell repertoire. Whether Ag-processing enzymes contribute to MS susceptibility by editing the peptide repertoire presented by these MHC haplotypes is unclear. Thymus-specific serine protease (TSSP) is expressed by thymic epithelial cells and thymic dendritic cells (DCs) and, in these two stromal compartments, TSSP edits the peptide repertoire presented by class II molecules.

Myelin oligodendrocyte glycoprotein induces incomplete tolerance of CD4(+) T cells specific for both a myelin and a neuronal self-antigen in mice.

T-cell polyspecificity, predicting that individual T cells recognize a continuum of related ligands, implies that multiple antigens can tolerize T cells specific for a given self-antigen. We previously showed in C57BL/6 mice that part of the CD4(+) T-cell repertoire specific for myelin oligodendrocyte glycoprotein (MOG) 35-55 also recognizes the neuronal antigen neurofilament medium (NF-M) 15-35. Such bi-specific CD4(+) T cells are frequent and produce inflammatory cytokines after stimulation.

In situ expansion of T cells that recognize distinct self-antigens sustains autoimmunity in the CNS.

Polyspecific T cells recognizing multiple distinct self-antigens have been identified in multiple sclerosis and other organ-specific autoimmune diseases, but their pathophysiological relevance remains undetermined. Using a mouse model of multiple sclerosis, we show that autoimmune encephalomyelitis induction is strictly dependent on reactivation of pathogenic T cells by a peptide (35-55) derived from myelin oligodendrocyte glycoprotein (MOG). This disease-inducing response wanes after onset.

Bispecificity for myelin and neuronal self-antigens is a common feature of CD4 T cells in C57BL/6 mice.

The recognition of multiple ligands by a single TCR is an intrinsic feature of T cell biology, with important consequences for physiological and pathological processes. Polyspecific T cells targeting distinct self-antigens have been identified in healthy individuals as well as in the context of autoimmunity. We have previously shown that the 2D2 TCR recognizes the myelin oligodendrocyte glycoprotein epitope (MOG)35-55 as well as an epitope within the axonal protein neurofilament medium (NF-M15-35) in H-2(b) mice.

Invariant NKT cells regulate the CD8 T cell response during Theiler's virus infection.

Invariant NKT cells are innate lymphocytes with a broad tissue distribution. Here we demonstrate that iNKT cells reside in the central nervous system (CNS) in the absence of inflammation. Their presence in the CNS dramatically augments following inoculation of C57Bl/6 mice with the neurotropic Theiler's murine encephalomyelitis virus (TMEV).

In situ evidence of JC virus control by CD8+ T cells in PML-IRIS during HIV infection.

Objective: To determine the pathophysiologic features of progressive multifocal leukoencephalopathy (PML) associated with immune reconstitution inflammatory syndrome (PML-IRIS) in HIV-infected patients.

Methods: In a cross-sectional study, we retrospectively analyzed 11 HIV-infected patients with a firm diagnosis of PML-IRIS. Brain biopsies were collected from 5 patients and their histopathologic features were compared to those of 4 HIV-infected patients with classic PML.

Tc17 CD8+ T cells potentiate Th1-mediated autoimmune diabetes in a mouse model.

An increase in IL-17-producing CD8+ T (Tc17) cells has been reported in the peripheral blood of children with recent onset type 1 diabetes (T1D), but their contribution to disease pathogenesis is still unknown. To directly study the pathogenic potential of β cell-specific Tc17 cells, we used an experimental model of T1D based on the expression of the neo-self Ag hemagglutinin (HA) in the β cells of the pancreas. When transferred alone, the IL-17-producing HA-specific CD8+ T cells homed to the pancreatic lymph nodes without causing any pancreatic infiltration or tissue destruction.

T cell apoptosis and induction of Foxp3+ regulatory T cells underlie the therapeutic efficacy of CD4 blockade in experimental autoimmune encephalomyelitis.

The pathogenesis of multiple sclerosis requires the participation of effector neuroantigen-specific T cells. Thus, T cell targeting has been proposed as a promising therapeutic strategy. However, the mechanism underlying effective disease prevention following T cell targeting remains incompletely known.

Pathogenesis of the immune reconstitution inflammatory syndrome in HIV-infected patients.

Purpose Of Review: The immune reconstitution inflammatory syndrome (IRIS) is an important clinical complication in HIV-infected patients initiating antiretroviral therapy. This review focuses on the latest literature pertaining to the pathogenesis of IRIS.

Recent Findings: The clinical manifestations of IRIS are heterogeneous due to the variety of opportunistic infections that are associated with this inflammatory syndrome.

Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility.

The tyrosine kinase 2 variant rs34536443 has been established as a genetic risk factor for multiple sclerosis in a variety of populations. However, the functional effect of this variant on disease pathogenesis remains unclear. This study replicated the genetic association of tyrosine kinase 2 with multiple sclerosis in a cohort of 1366 French patients and 1802 controls.

Pathogenesis of the immune reconstitution inflammatory syndrome affecting the central nervous system in patients infected with HIV.

Anti-retroviral therapy partially restores the immune function of patients infected with human immunodeficiency virus, thereby drastically reducing morbidity and mortality. However, the clinical condition of a subset of patients on anti-retroviral therapy secondarily deteriorates due to an inflammatory process termed immune reconstitution inflammatory syndrome. This condition results from the restoration of the immune system that upon activation can be detrimental to the host.

Transgenic mouse models of multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system (CNS) and a frequent cause of neurological disability in young adults. Multifocal inflammatory lesions in the CNS white matter, demyelination, oligodendrocyte loss, axonal damage, as well as astrogliosis represent the histological hallmarks of the disease. These pathological features of MS can be mimicked, at least in part, using animal models.

Contribution of CD8 T lymphocytes to the immuno-pathogenesis of multiple sclerosis and its animal models.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by multi-focal demyelination, axonal loss, and immune cell infiltration. Numerous immune mediators are detected within MS lesions, including CD4(+) and CD8(+) T lymphocytes suggesting that they participate in the related pathogenesis. Although CD4(+) T lymphocytes are traditionally considered the main actors in MS immunopathology, multiple lines of evidence suggest that CD8(+) T lymphocytes are also implicated in the pathogenesis.

Cell-cell cooperation at the T helper cell/mast cell immunological synapse.

It has been suggested that mast cells might serve, under certain circumstances, as antigen-presenting cells (APCs) for T cells. However, whether cognate interactions between mast cells and class II-restricted CD4(+) T cells actually occur is still an open question. We addressed this question by using peritoneal cell-derived mast cells (PCMCs) and freshly isolated peritoneal mast cells as APC models.

Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis.

We describe here the paradoxical development of spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a myelin oligodendrocyte glycoprotein (MOG)-specific T cell antigen receptor (TCR) in the absence of MOG. We report that in Mog-deficient mice (Mog-/-), the autoimmune response by transgenic T cells is redirected to a neuronal cytoskeletal self antigen, neurofilament-M (NF-M). Although components of radically different protein classes, the cross-reacting major histocompatibility complex I-Ab-restricted epitope sequences of MOG35-55 and NF-M18-30 share essential TCR contact positions.

Invariant NKT cells inhibit development of the Th17 lineage.

T cells differentiate into functionally distinct effector subsets in response to pathogen encounter. Cells of the innate immune system direct this process; CD1d-restricted invariant natural killer T (iNKT) cells, for example, can either promote or inhibit Th(1) and Th(2) responses. Recently, a new subset of CD4(+) T helper cells, called Th(17), was identified that is implicated in mucosal immunity and autoimmune disorders.

Invariant NKT cells regulate experimental autoimmune encephalomyelitis and infiltrate the central nervous system in a CD1d-independent manner.

Invariant NKT cells are CD1d-restricted T cells specific for glycolipid Ags. Their activation or transgenic enrichment abrogates the development of experimental autoimmune encephalomyelitis (EAE). Herein, we demonstrate that in NKT-enriched mice the protection from EAE is associated with the infiltration of NKT cells in the CNS and the local expression of CD1d.

Cutting edge: Multiple sclerosis-like lesions induced by effector CD8 T cells recognizing a sequestered antigen on oligodendrocytes.

CD8 T cells are emerging as important players in multiple sclerosis (MS) pathogenesis, although their direct contribution to tissue damage is still debated. To assess whether autoreactive CD8 T cells can contribute to the pronounced loss of oligodendrocytes observed in MS plaques, we generated mice in which the model Ag influenza hemagglutinin is selectively expressed in oligodendrocytes. Transfer of preactivated hemagglutinin-specific CD8 T cells led to inflammatory lesions in the optic nerve, spinal cord, and brain.

CD8 T cell responses to myelin oligodendrocyte glycoprotein-derived peptides in humanized HLA-A*0201-transgenic mice.

Multiple sclerosis (MS) is a demyelinating inflammatory disease of the CNS. Though originally believed to be CD4-mediated, additional immune effector mechanisms, including myelin-specific CD8(+) T cells, are now proposed to participate in the pathophysiology of MS. To study the immunologic and encephalitogenic behavior of HLA-A*0201-binding myelin-derived epitopes in vivo, we used a humanized HLA-A*0201-transgenic mouse model.

Multimerized T cell epitopes protect from experimental autoimmune diabetes by inducing dominant tolerance.

Immunotherapy by using multimerized self-peptides has demonstrated a clear protective effect on experimental models of autoimmune diseases. However, the mechanisms involved remain ill-defined. Here we have evaluated the therapeutic efficacy of multimerized self-peptides at the effector phase of autoimmune diabetes and examined their mechanisms of action.

Pertussis toxin reduces the number of splenic Foxp3+ regulatory T cells.

Pertussis toxin (PTx) is a bacterial toxin used to enhance the severity of experimental autoimmune diseases such as experimental autoimmune encephalomyelitis. It is known to promote permeabilization of the blood-brain barrier, maturation of APC, activation of autoreactive lymphocytes and alteration of lymphocyte migration. In this study, we show that i.

LF 15-0195 treatment protects against central nervous system autoimmunity by favoring the development of Foxp3-expressing regulatory CD4 T cells.

Experimental autoimmune encephalomyelitis (EAE) is an instructive model for the human demyelinating disease multiple sclerosis. Lewis (LEW) rats immunized with myelin-basic protein (MBP) develop EAE characterized by a single episode of paralysis, from which they recover spontaneously and become refractory to a second induction of disease. LF 15-0195 is a novel molecule that has potent immunosuppressive effects in several immune-mediated pathological manifestations, including EAE.

Invariant NKT cells exacerbate type 1 diabetes induced by CD8 T cells.

Invariant NKT (iNKT) cells have been implicated in the regulation of autoimmune diseases. In several models of type 1 diabetes, increasing the number of iNKT cells prevents the development of disease. Because CD8 T cells play a crucial role in the pathogenesis of diabetes, we have investigated the influence of iNKT cells on diabetogenic CD8 T cells.