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Mireia Sospedra

Publications and source records attributed to Mireia Sospedra.

13 recordsLinked to original sources
PubMed2006

Cerebrospinal fluid-infiltrating CD4+ T cells recognize Borrelia burgdorferi lysine-enriched protein domains and central nervous system autoantigens in early lyme encephalitis.

Neurological manifestations of Lyme disease are usually accompanied by inflammatory changes in the cerebrospinal fluid (CSF) and the recruitment of activated T cells into the CSF compartment. In order to characterize the phenotype and identify target antigens of CSF-infiltrating T cells in early neuroborreliosis with central nervous system (CNS) involvement, we combined T-cell cloning, functional testing of T-cell responses with positional scanning synthetic combinatorial peptide libraries, and biometric data analysis. We demonstrate that CD4+ gamma interferon-producing T cells specifically responding to Borrelia burgdorferi lysate were present in the CSF of a patient with acute Lyme encephalitis. Some T-cell clones recognized previously uncharacterized B. burgdorferi epitopes which show a specific enrichment for lysine, such as the heat shock-induced chaperone HSP90. Degenerate T-cell recognition that included T-cell responses to borrelia-specific and CNS-specific autoantigens derived from the myelin protein 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) could be demonstrated for one representative clone. Our results show that spirochetal antigen-specific and Th1-polarized CD4+ lymphocytes infiltrate the CSF during monophasic CNS symptoms of Lyme disease and demonstrate that cross-recognition of CNS antigens by B. burgdorferi-specific T cells is not restricted to chronic and treatment-resistant manifestations.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2006

When T cells recognize a pattern, they might cause trouble.

The mechanisms of self and non-self discrimination by T cells remain a fascinating topic for immunologists. How the immune system achieves protection of the host against an ever-changing realm of pathogens using a rather limited repertoire of T-cell receptors and at the same time avoids inflicting damage against its own tissues is equally puzzling. Although a better understanding of these questions has come from studies of the extent of cross reactivity of T-cell clones specific for foreign or self antigens, and also from examination of the different antigen avidities by which they recognize either type of antigen, many details are still lacking. Recently, there has been investigation into how T cells of the adaptive immune system can recognize functional protein domains or amino acid patterns. This type of T-cell reactivity is reminiscent of the pattern recognition that is firmly established as an important function of innate immune receptors such as Toll-like receptors. Many functional protein domains are conserved in evolution and are shared by a wide spectrum of pathogens, as well as by proteins of animals and humans. Hence, pattern recognition by adaptive immune cells might represent an efficient mechanism for host protection by the above-mentioned limited number of T-cell receptors. However, the fact that such functional domains occur so frequently in nature also implies that pattern recognition by T cells might cause autoimmunity, and recent data support this hypothesis.

Amino Acids↗
PubMed2006

Redundancy in antigen-presenting function of the HLA-DR and -DQ molecules in the multiple sclerosis-associated HLA-DR2 haplotype.

The three HLA class II alleles of the DR2 haplotype, DRB1*1501, DRB5*0101, and DQB1*0602, are in strong linkage disequilibrium and confer most of the genetic risk to multiple sclerosis. Functional redundancy in Ag presentation by these class II molecules would allow recognition by a single TCR of identical peptides with the different restriction elements, facilitating T cell activation and providing one explanation how a disease-associated HLA haplotype could be linked to a CD4+ T cell-mediated autoimmune disease. Using combinatorial peptide libraries and B cell lines expressing single HLA-DR/DQ molecules, we show that two of five in vivo-expanded and likely disease-relevant, cross-reactive cerebrospinal fluid-infiltrating T cell clones use multiple disease-associated HLA class II molecules as restriction elements. One of these T cell clones recognizes >30 identical foreign and human peptides using all DR and DQ molecules of the multiple sclerosis-associated DR2 haplotype. A T cell signaling machinery tuned for efficient responses to weak ligands together with structural features of the TCR-HLA/peptide complex result in this promiscuous HLA class II restriction.

Amino Acid Sequence↗
PubMed2006

Molecular mimicry in multiple sclerosis.

Two main etiological components are considered important in human autoimmune diseases including multiple sclerosis (MS), first the immunogenetic background and second environmental factors. Among the latter, infectious organisms are probably the most relevant, and epidemiological studies in MS firmly support that viral infections often precede disease exacerbations or the onset of MS. Infectious agents can contribute to disease development or phenotypic expression in different ways. Our focus will be directed on molecular mimicry, i.e. antigenic similarity between structural epitopes or peptide sequences from infectious organisms with those found in self proteins of the host. The intriguing concept of molecular mimicry has evolved substantially since its introduction over 20 years ago. We will summarize the most important developments and discuss puzzling questions, which remain open despite many claims that molecular mimicry is involved in the development of human autoimmune disease after infections or vaccinations.

Animals↗
PubMed2005

Recognition of conserved amino acid motifs of common viruses and its role in autoimmunity.

The triggers of autoimmune diseases such as multiple sclerosis (MS) remain elusive. Epidemiological studies suggest that common pathogens can exacerbate and also induce MS, but it has been difficult to pinpoint individual organisms. Here we demonstrate that in vivo clonally expanded CD4+ T cells isolated from the cerebrospinal fluid of a MS patient during disease exacerbation respond to a poly-arginine motif of the nonpathogenic and ubiquitous Torque Teno virus. These T cell clones also can be stimulated by arginine-enriched protein domains from other common viruses and recognize multiple autoantigens. Our data suggest that repeated infections with common pathogenic and even nonpathogenic viruses could expand T cells specific for conserved protein domains that are able to cross-react with tissue-derived and ubiquitous autoantigens.

Amino Acid Sequence↗
PubMed2005

Clonotypic analysis of cerebrospinal fluid T cells during disease exacerbation and remission in a patient with multiple sclerosis.

Migration of autoreactive T cells into the central nervous system (CNS) compartment is thought to be an important step in the pathogenesis of multiple sclerosis (MS). To follow the evolution of T cell repertoire in the CNS of a patient with relapsing-remitting MS, we analyzed cerebrospinal fluid (CSF) cells obtained during an acute clinical exacerbation, and subsequent disease remission after 13 months of immunomodulatory therapy. T cell receptor CDR3 region length distribution was significantly altered during the relapse, demonstrating the presence of clonally expanded T cells in the CSF. CDR3 spectratyping is a valuable approach to identify disease-associated T cells in the CNS.

Adult↗
PubMed2005

Insulin alleles and autoimmune regulator (AIRE) gene expression both influence insulin expression in the thymus.

It is well established that the polymorphisms at the 5' of the insulin gene (IDDM2) confers susceptibility to type 1 diabetes, probably by modifying the level of insulin expression in the thymus that in turn influences immunological tolerance to insulin as self-antigen. AIRE is a transcription regulator which controls the expression of many peripheral antigens within the thymus, among them insulin. Results presented here confirm that insulin gene copies from both parental chromosomes are expressed in human thymus and that IDDM2 class III protective alleles are indeed associated with a higher level of insulin message expression. However, differences in insulin mRNA expression among different thymi were far wider than those determined by the class I and class III insulin gene alleles and maintained a clear correlation with AIRE expression. These results confirm the effect of IDDM2 alleles on insulin expression in the thymus, but suggest that the levels of AIRE may exert a stronger influence than IDDM2 alleles themselves.

Adult↗
PubMed2005

Immunology of multiple sclerosis.

Multiple sclerosis (MS) develops in young adults with a complex predisposing genetic trait and probably requires an inciting environmental insult such as a viral infection to trigger the disease. The activation of CD4+ autoreactive T cells and their differentiation into a Th1 phenotype are a crucial events in the initial steps, and these cells are probably also important players in the long-term evolution of the disease. Damage of the target tissue, the central nervous system, is, however, most likely mediated by other components of the immune system, such as antibodies, complement, CD8+ T cells, and factors produced by innate immune cells. Perturbations in immunomodulatory networks that include Th2 cells, regulatory CD4+ T cells, NK cells, and others may in part be responsible for the relapsing-remitting or chronic progressive nature of the disease. However, an important paradigmatic shift in the study of MS has occurred in the past decade. It is now clear that MS is not just a disease of the immune system, but that factors contributed by the central nervous system are equally important and must be considered in the future.

Autoantibodies↗
PubMed2004

Different patterns of nicotinic acetylcholine receptor subunit transcription in human thymus.

Clinical observations suggest that the thymus is strongly implicated in the pathogenesis of myasthenia gravis (MG), but questions such as the level and location of nicotinic acetylcholine receptor (AChR) subunit expression that are fundamental to postulate any pathogenic mechanism, remain controversial. We have re-examined this question by combining calibrated RT-PCR and real-time PCR to study nicotinic AChR subunit mRNA expression in a panel of normal and myasthenic thymi. The results suggest that the expression of the different AChR subunits follows three distinct patterns: constitutive for, neonatal for gamma and individually variable for alpha1, beta1 and delta. Experiments using confocal laser microdissection suggest that AChR is mainly expressed in the medullary compartment of the thymus but there is not a clear compartmentalization of subunit expression. The different patterns of subunit expression may influence decisively the level of central tolerance to the subunits and explain the focusing of the T cell response to the alpha and gamma subunits.

Adolescent↗
PubMed2003

Use of combinatorial peptide libraries for T-cell epitope mapping.

T lymphocytes play important roles not only in infectious diseases and autoimmunity, but also in immune responses against tumors. For many of these disorders, the relevant target antigens are not known. Designing effective methods that allow the search for T-cell epitopes is therefore an important goal in the areas of infectious diseases, oncology, vaccine development, and numerous other biomedical specialties. So far, the strategies used to examine T-cell recognition have been based largely on mapping T-cell epitopes with overlapping peptides from known proteins or with entire proteins, e.g., from a specific virus, bacterium, or human tissue. These approaches are tedious and have a number of limitations. It is, for example, almost impossible to isolate T cells that infiltrate an organ or infectious site and identify their specificity unless one already has a concept as to which antigens may be relevant. During recent years, a number of laboratories have developed less biased approaches that employ either the selection of putative T-cell epitopes based on the prediction of binding to certain major histocompatibilty complex (MHC) molecules and peptide or protein libraries that have been generated in expression systems, e.g. phage, or rely on combinatorial peptide chemistry. The latter technique has been refined by a number of laboratories including ours. Bead-bound or, preferably, positional scanning synthetic and soluble combinatorial peptide libraries allow the identification of T-cell epitopes within complex mixtures of proteins even for T cells that have been expanded from an organ infiltrate with a polyclonal stimulus. The practical steps that are involved in the latter method are described in this article.

Amino Acid Sequence↗
PubMed2002

Multiple sclerosis candidate autoantigens except myelin oligodendrocyte glycoprotein are transcribed in human thymus.

An important feature of central nervous system (CNS) immune privilege is that antigens expressed in CNS are sequestered and not available for central tolerance induction. Tissue distribution and, more specifically, thymic expression of many of the CNS putative autoantigens have not yet been clearly established in humans. We have addressed this question for the putative multiple sclerosis(MS) autoantigens alphaB-crystallin, S100beta, proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG)-alpha and MOG-beta isoforms, using quantitative RT-PCR on human thymus (total, cell fractions and microdissected specimen) and on a panel of peripheral tissues. alphaB-crystallin, S100beta and the DM20 isoform of PLP were clearly expressed in the thymus and also in selected peripheral tissues. In contrast, the expression of MOG out of the CNS was not observed. Within the human thymus, the level of CNS antigen expression was found higher in the stromal epithelial enriched cell fraction, and in microdissected samples of the medullary compartment. These results indicate that most of the antigens involved in MS are expressed in the thymus, suggesting a possible role in central tolerance. However, MOG and, to a lesser extent PLP, conform the classical concept of sequestered antigens, thus supporting the involvement of MOG in autoimmune demyelinating diseases.

Adolescent↗
PubMedDate not supplied

Antigen-specific therapies in multiple sclerosis.

During recent years, many new therapies for human autoimmune diseases such as multiple sclerosis (MS) have been considered based on promising in vitro data or animal experiments. A number of them have proceeded to early clinical testing. However, very few finally advanced to approval by the regulatory agencies and are currently available to patients. The main reasons for failure were either lack of efficacy in humans and/or unexpected and untolerable adverse events. Although previous attempts toward antigen-specific immunomodulation have often been disappointing, these difficulties have led to renewed interest in therapies that aim at reestablishing tolerance to autoantigens at the level of either T cell-mediated or antibody-mediated immune responses or both. Such antigen-specific immunotherapies offer the prospect of correcting pathological immune reactivity against autoantigens in a highly specific and effective manner and also achievement of this goal with relatively little side effects. Here we will review the various approaches that are currently being considered for antigen-specific immunotherapies in MS.

Animals↗