HLA‐DR‐restricted presentation of purified myelin basic protein is independent of intracellular processing

Vergelli, Marco; Pinet, Valérie; Vogt, Anne B.; Kalbus, Matthias; Malnati, Mauro S.; Riccio, P.; Long, Eric O.; Martin, Roland

doi:10.1002/eji.1830270421

Cited by 47 publications

(45 citation statements)

References 42 publications

(21 reference statements)

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“…We did not find any significant skewing in the cytokine profiles between these two types of TCL that would account for the observed differential effect. This effect is not mediated by the need for antigenic processing of MBP compared with Flu-HA and tetanus peptides, because it was shown that MBP presentation by HLA-DR molecules does not require processing (33) and because we have noted a similar effect of PDE inhibition on seven MBP-specific TCL stimulated with the peptide epitope (data not shown). The two likely explanations are that either the signal delivered by the autoantigen may be qualitatively different (partial agonist vs full agonist signal) or the dysregulation in the cAMP system is more pronounced in autoreactive T cells.…”

Section: Discussionmentioning

confidence: 52%

Therapeutic Potential of Phosphodiesterase-4 and -3 Inhibitors in Th1-Mediated Autoimmune Diseases

Bielekova

Lincoln

McFarland

et al. 2000

The Journal of Immunology

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Phosphodiesterase-4 (PDE4) inhibitors have the potential to modulate immune responses from the Th1 toward the Th2 phenotype and are considered candidate therapies for Th1-mediated autoimmune disorders. However, depending on the model and cell types employed, studies of atopic individuals have come to the opposite conclusion, i.e., that PDE inhibitors may be beneficial in asthma. Using in vitro immunopharmacologic techniques we analyzed the effects of PDE4 and PDE3 inhibitors on human immune cells to address these discrepancies and broaden our understanding of their mechanism of action. Our results indicate that PDE inhibitors have complex inhibitory effects within in vivo achievable concentration ranges on Th1-mediated immunity, whereas Th2-mediated responses are mostly unaffected or enhanced. The Th2 skewing of the developing immune response is explained by the effects of PDE inhibitors on several factors contributing to T cell priming: the cytokine milieu; the type of costimulatory signal, i.e., up-regulation of CD86 and down-regulation of CD80; and the Ag avidity. The combination of PDE4 and PDE3 inhibitors expresses synergistic effects and may broaden the therapeutic window. Finally, we observed a differential sensitivity to PDE inhibition in autoreactive vs foreign Ag-specific T cells and cells derived from multiple sclerosis patients vs those derived from healthy donors. This suggests that PDE inhibition weakens the strength of the T cell stimulus and corrects the underlying disease-associated cytokine skew in T cell-mediated autoimmune disorders. These new findings broaden the understanding of the immunomodulatory actions of PDE inhibitors and underscore their promising drug profile for the treatment of autoimmune disorders.

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Section: Discussionmentioning

confidence: 52%

Therapeutic Potential of Phosphodiesterase-4 and -3 Inhibitors in Th1-Mediated Autoimmune Diseases

Bielekova

Lincoln

McFarland

et al. 2000

The Journal of Immunology

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“…These data suggest that resting microglia most closely resemble an immature myeloid precursor and may have important implications as to potential pathways for antigen presentation. Notably, antigenic determinants derived from myelin basic protein have been reported to be presented in the CNS through a pathway that does not involve internalization and endosomal processing (22). Presentation of exogenous proteins has previously been shown to occur with bone marrowderived immature DC (23).…”

Section: Resultsmentioning

confidence: 99%

Developmental plasticity of CNS microglia

Santambrogio

Belyanskaya

Fischer

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

286

234

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Microglia arise from CD45 ؉ bone marrow precursors that colonize the fetal brain and play a key role in central nervous system inflammatory conditions. We report that parenchymal microglia are uncommitted myeloid progenitors of immature dendritic cells and macrophages by several criteria, including surface expression of ''empty'' class II MHC protein and their cysteine protease (cathepsin) profile. Microglia express receptors for stem cell factor and can be skewed toward more dendritic cell or macrophage-like profiles in response to the lineage growth factors granulocyte͞ macrophage colony-stimulating factor or macrophage colonystimulating factor. Thus, in contrast to other organs, where terminally differentiated populations of resident dendritic cells and͞ or macrophages outnumber colonizing precursors, the majority of microglia within the brain remain in an undifferentiated state. P arenchymal microglia are ubiquitously distributed in the central nervous system (CNS) where they comprise up to 20% of the total non-neuronal cell population (1). These cells are thought to play a prominent role in infectious, traumatic, inflammatory, ischemic, and degenerative CNS disease processes. The role of microglia as mediators of CNS inflammation is, in part, promulgated through their ability to process and present class II-restricted antigens to CD4 ϩ T cells (2, 3).Microglial cells are derived from CD45 ϩ bone marrow precursors of the myeloid lineage, which also can give rise to macrophages, dendritic cells (DC), and granulocytes. Studies by using irradiation chimeras show that the adult brain has two subsets of microglia (3): the resting microglia, which are ramified throughout the brain parenchyma and are mostly a permanent population, and the perivascular microglia, which are periodically replaced by bone marrow-derived elements and are strategically located in the basal lamina of brain capillaries and the choroid plexus. The only known difference between these microglial populations is CD45 expression, which is high on perivascular and low on parenchymal microglia (4). In general, CD45 high cells also express more class II MHC and costimulatory molecules. However, it is still unclear whether the parenchymal and perivascular microglia represent the same cellular population at a different activation state, owing to microenvironmental influences, or whether these populations are more distinct.Traditionally, parenchymal microglia have been considered to be resident macrophages of the brain. However, several pieces of evidence suggest a more complex picture. For example, op͞op mice, which are deficient in macrophage colony-stimulating factor (M-CSF) and consequently are depleted of tissue-resident macrophages in several areas, do not exhibit a large reduction in the overall brain microglial population (5-7). Also, previous studies show generation of ''DC-like'' antigen-presenting cells (APC) from mixed glial cultures (8). Cells clearly displaying macrophage-and DC-like characteristics have been identified from the CNS of m...

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“…This applies not only for fully processed peptide antigens but also for proteins or protein fragments. For several proteins, such as the encephalitogenic myelin basic protein (MBP) or hen egg lysozyme, it has been shown that they can bind directly to surface MHC class II molecules (43) and even extracellular processing mechanisms seem to exist (25). Hydroxyl groups or other functional groups capable of acting as H-bond donors are present in numerous natural and synthetic small molecules and macromolecules.…”

Section: Discussionmentioning

confidence: 99%

Ligand Exchange of Major Histocompatibility Complex Class II Proteins Is Triggered by H-bond Donor Groups of Small Molecules

Falk¹,

Lau²,

Santambrogio³

et al. 2002

Journal of Biological Chemistry

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Hydrogen bonds (H-bonds) are crucial for the stability of the peptide-major histocompatibility complex (MHC) complex. In particular, the H-bonds formed between the peptide ligand and the MHC class II binding site appear to have a great influence on the half-life of the complex. Here we show that functional groups with the capacity to disrupt hydrogen bonds (e.g. -OH) can efficiently catalyze ligand exchange reactions on HLA-DR molecules. In conjunction with simple carrier molecules (such as propyl or benzyl residues), they trigger the release of low affinity ligands, which permits the rapid binding of peptides with higher affinity. Similar to HLA-DM, these compounds are able to influence the MHC class II ligand repertoire. In contrast to HLA-DM, however, these simple small molecules are still active at neutral pH. Under physiological conditions, they increase the number of "peptide-receptive" MHC class II molecules and facilitate exogenous peptide loading of dendritic cells. The drastic acceleration of the ligand exchange on these antigen presenting cells suggests that, in general, availability of H-bond donors in the extracellular milieu controls the rate of MHC class II ligand exchange reactions on the cell surface. These molecules may therefore be extremely useful for the loading of antigens onto dendritic cells for therapeutic purposes.Peptide ligands bind to the peptide-binding groove of MHC 1 class II molecules by an array of intermolecular hydrogen bonds (H-bonds). These hydrogen bonds are mostly formed between the backbone of the peptide and conserved residues of the MHC class II molecule. Some of these H-bonds are particularly crucial for the stability of the ligand complex (1). It has been shown for a murine MHC class II molecule that the elimination of H-bonds between the ligand and residues His-81 or Asp-82 of the I-A d ␤-chain results in a rapid loss of the bound peptide (2). Detailed kinetic studies with these mutated MHC molecules revealed peptide dissociation rates that were increased up to 200-fold (3). This increase was in the same range observed after addition of HLA-DM to the peptide complex of the nonmutated I-A d molecule. It was therefore proposed that HLA-DM-mediated ligand release (4, 5) is also accomplished by the disruption of H-bonds (6), a hypothesis also introduced when the crystal structure of HLA-DM was published (7).Because H-bonds appear to be fundamental in maintaining the stability of the MHC class II peptide complexes, we started to investigate small molecules capable of disrupting H-bonds with the goal of achieving an HLA-DM-like catalytic effect on the kinetics of peptide binding. H-bonds require a hydrogen donor and an acceptor group, which provides a free electron pair. Some of the functional groups that can fulfill this function are hydroxyl or amino groups. They are present in a variety of natural and synthetic molecules, such as lipids, metabolites, amino acids, and pharmaceutical drugs. One example is ethanol, where the well known physiological effects appear to resul...

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HLA‐DR‐restricted presentation of purified myelin basic protein is independent of intracellular processing

Cited by 47 publications

References 42 publications

Therapeutic Potential of Phosphodiesterase-4 and -3 Inhibitors in Th1-Mediated Autoimmune Diseases

Therapeutic Potential of Phosphodiesterase-4 and -3 Inhibitors in Th1-Mediated Autoimmune Diseases

Developmental plasticity of CNS microglia

Ligand Exchange of Major Histocompatibility Complex Class II Proteins Is Triggered by H-bond Donor Groups of Small Molecules

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