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E Hermel

Publications and source records attributed to E Hermel.

At least 19 recordsLinked to original sources
PubMed2004

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder resulting in selective neuronal loss and dysfunction in the striatum and cortex. The molecular pathways leading to the selectivity of neuronal cell death in HD are poorly understood. Proteolytic processing of full-length mutant huntingtin (Htt) and subsequent events may play an important role in the selective neuronal cell death found in this disease. Despite the identification of Htt as a substrate for caspases, it is not known which caspase(s) cleaves Htt in vivo or whether regional expression of caspases contribute to selective neuronal cells loss. Here, we evaluate whether specific caspases are involved in cell death induced by mutant Htt and if this correlates with our recent finding that Htt is cleaved in vivo at the caspase consensus site 552. We find that caspase-2 cleaves Htt selectively at amino acid 552. Further, Htt recruits caspase-2 into an apoptosome-like complex. Binding of caspase-2 to Htt is polyglutamine repeat-length dependent, and therefore may serve as a critical initiation step in HD cell death. This hypothesis is supported by the requirement of caspase-2 for the death of mouse primary striatal cells derived from HD transgenic mice expressing full-length Htt (YAC72). Expression of catalytically inactive (dominant-negative) forms of caspase-2, caspase-7, and to some extent caspase-6, reduced the cell death of YAC72 primary striatal cells, while the catalytically inactive forms of caspase-3, -8, and -9 did not. Histological analysis of post-mortem human brain tissue and YAC72 mice revealed activation of caspases and enhanced caspase-2 immunoreactivity in medium spiny neurons of the striatum and the cortical projection neurons when compared to controls. Further, upregulation of caspase-2 correlates directly with decreased levels of brain-derived neurotrophic factor in the cortex and striatum of 3-month YAC72 transgenic mice and therefore suggests that these changes are early events in HD pathogenesis. These data support the involvement of caspase-2 in the selective neuronal cell death associated with HD in the striatum and cortex.

Animals↗
PubMed2001

Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation.

The endoplasmic reticulum (ER) is the site of assembly of polypeptide chains destined for secretion or routing into various subcellular compartments. It also regulates cellular responses to stress and intracellular Ca(2+) levels. A variety of toxic insults can result in ER stress that ultimately leads to apoptosis. Apoptosis is initiated by the activation of members of the caspase family and serves as a central mechanism in the cell death process. The present study was carried out to determine the role of caspases in triggering ER stress-induced cell death. Treatment of cells with ER stress inducers such as brefeldin-A or thapsigargin induces the expression of caspase-12 protein and also leads to translocation of cytosolic caspase-7 to the ER surface. Caspase-12, like most other members of the caspase family, requires cleavage of the prodomain to activate its proapoptotic form. Caspase-7 associates with caspase-12 and cleaves the prodomain to generate active caspase-12, resulting in increased cell death. We propose that any cellular insult that causes prolonged ER stress may induce apoptosis through caspase-7-mediated caspase-12 activation. The data underscore the involvement of ER and caspases associated with it in the ER stress-induced apoptotic process.

Animals↗
PubMed1999

Isolation and mapping of the rabbit DM genes.

Proper peptide presentation by major histocompatibility complex (MHC)-encoded class II antigens is dependent on the products of the MHC DM loci. We identified the rabbit orthologues (RLA-DMA and -DMB) of human HLA-DMA and -DMB and found that they have 76.9% and 78.8% identity with HLA-DMA and -DMB, respectively. Like classical class II MHC genes, RLA-DM genes are more closely related to human HLA-DM genes than to mouse H2-DM. Among the DM family, there is a high degree of variability at the amino terminus of the DMa chains, and length variability in the cytoplasmic tails of both DMalpha and DMbeta. The rabbit DM genes are coexpressed with class II genes in lymphoid tissues, as are the DM genes of other mammals. The RLA-DM locus maps to the class II region of the rabbit MHC, and is flanked by the DP and DOB loci. Despite having some similarities to class II genes of bony fishes, the DM family represents a separate branch of the MHC class II family.

Amino Acid Sequence↗
PubMed1997

Increased class Ib antigen display on TAP-2 mutant cells by a mitochondrial function inhibitor.

Class I histocompatibility antigen display is defective in the RMA-S mutant cell line due to a mutation in the Tap-2 gene, which encodes a peptide transporter. Incubation of RMA-S cells with oligomycin, an inhibitor of mitochondrial ATPase, strongly increased lysis by cytotoxic T lymphocytes (CTL) specific for the class Ib antigen H2-M3, and lysis by Qa-1b-specific CTL was restored. Oligomycin did not affect normal class I display on RMA cells. Treatment of RMA-S cells with other inhibitors of mitochondrial function failed to increase lysis by anti-H2-M3 or Qa-1b CTL. Lysis by allogenic CTL specific for H-2b antigens was either not enhanced or only weakly increased, depending upon the H-2 haplotype of the alloreactive effector cells used.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Difference in antigen presentation pathways between cortical and medullary thymic epithelial cells.

Antigen presentation by thymic epithelial cells (TEC) to T cells that undergo maturation is one of the major events in the selection of the T cell repertoire. We have already reported that medullary TEC lines (mTEC) established from newborn C57BL/6 (H-2b) mice are able to present a soluble antigen, ovalbumin (OVA), to OVA-specific, I-Ab restricted helper T cell lines but cortical TEC (cTEC) lines are not (Mizuochi, T. et al., J. Exp. Med. 1992. 175: 1601). In this report, to clarify the cause of this difference, we analyzed the biochemical nature as well as the distribution of both major histocompatibility complex (MHC) class II molecules and invariant chains (Ii) in both TEC by immunoprecipitation and laser confocal scanning microscopic analysis, as well as the expression of mRNA encoding H-2Ma or H-2Mb. Our results demonstrate that cTEC and mTEC are both able to present peptide antigens to peptide-specific, I-Ab-restricted helper T cell hybridoma and are able to present class II MHC alloantigens to an I-Ab-specific T cell line, that mRNA for H-2Ma and H-2Mb are expressed in both TEC, that cTEC and mTEC apparently incorporate tetramethylrhodamine isothiocyanate-labeled OVA in the same manner, and that the SDS-stable MHC class II molecules, onto which peptides were loaded, are formed in both cTEC and mTEC. However, these molecules were more rapidly degraded in mTEC than in cTEC. In addition, two Ii-derived polypeptides of approximately 21 kDa and 10 kDa were precipitated by the anti-class II monoclonal antibody Y3P; 10-kDa polypeptides were detected in the both TEC, while 21-kDa polypeptides were detected only in cTEC. Finally, beta chains of MHC class II with less sialylated oligosaccharides were precipitated from the cell surface of cTEC. Taken together, these results suggest that there are substantial differences in the antigen-presenting pathways of cTEC and mTEC, and these difference might be responsible for T cell selection events in the thymus.

Animals↗
PubMed1995

Characterization of polymorphism within the H2-M MHC class II loci.

The products of the class II-like H2-M genes of the major histocompatibility complex are required for class II antigen processing. We sequenced H2-Ma and Mb from several mouse strains to determine whether these genes are polymorphic like the classical H2-A and E genes, or are oligomorphic, like H2-O. Both Mb loci appear to be transcribed and are distinct from each other. Mb1 and Mb2 differ by about 11% at the nucleotide level and are most dissimilar in their second exons (corresponding to the beta 1 domain). Relative to the published Mb1d haplotype sequence, the products of the b, g7, f, and k2 alleles of Mb1 from Mus musculus domesticus and the separate mouse species Mus spretus differ by only one to four amino acids. The majority of the changes occurred in the second exon of Mb1, in contrast to HLA-DMB, the human orthologue. Little polymorphism was seen for Mb2, and Ma was invariant in all strains tested. The similarity of the g7 allele to those from other haplotypes makes it unlikely that the M class II genes play a role in the autoimmune diabetes of NOD strain mice. The M genes are regulated in a manner similar to classical class II genes, in that they are upregulated by IFN-gamma in macrophages, and to a lesser extent by IL4 in B cells. When modeled on the crystal structure of the HLA-DR1 class II molecule, nearly all of the differences between M beta 1 and M beta 2 affect residues facing away from the putative peptide binding groove.

Amino Acid Sequence↗
PubMed1993

Sequence divergence of B2m alleles of wild Mus musculus and Mus spretus implies positive selection.

Mouse beta 2-microglobulin (beta 2m) is polymorphic. Sequences of five allelic wild mouse B2m genes have been determined from the large exons of genomic DNA using the polymerase chain reaction. Relative to the standard B2m(a) allele, the products of four alleles of Mus musculus origin (w2, w3, w4, and w5), differ by only one or two amino acids. w5 has a single nucleotide change, Asp85-->Val, and is identical to the c allele. w3 has two changes, Val(-13)-->Ile and Lys44-->Glu. w2 differs at Arg81-->Thr and w4 at His34-->Gln, and they share the Asp85-->Val change with B2mc and B2mw5. w5 and c cells are lysed by S19.8, a monoclonal antibody specific for beta 2mb (Ala85), in a complement-mediated cytotoxicity assay, whereas w4 cells are not. Thus, distant changes appear to introduce subtle conformational effects on beta 2m structure. Five independent isolates of Mus spretus (w1) differ the most from B2m(a), with 12 amino acid changes and only one silent substitution. Replacements predicted from the nucleotide sequence occur in loops of the molecule facing away from the class I heavy chain and not in regions where beta 2m associates with class I alpha 3 domains. Concordantly, the w1-5 allelic forms of beta 2m associate well with H-2 heavy chains. The many amino acid changes in the spretus sequence and the paucity of silent substitutions suggest that B2m has been subject to positive selection.

Amino Acid Sequence↗
PubMed1992

T cell recognition of QA-1b antigens on cells lacking a functional Tap-2 transporter.

MHC class Ia H chains and beta 2-microglobulin assemble with appropriate peptides to form stable cell surface molecules that serve as targets for Ag-specific CTL. The structural similarities of class Ia and the less polymorphic Q/T/M (class Ib) molecules suggest that class Ib molecules also play a role in antigen presentation, although the origin of the peptides they present remains mostly unclear. The cell line RMA-S has a defect in class I Ag presentation, presumably due to a mutation in a peptide transporter gene. This defect can be overcome by transfection of RMA-S cells with the Tap-2 gene (formerly Ham-2) that encodes an ATP-binding transporter protein. We now show that a substantial portion of alloreactive CTL specific for Qa-1 class Ib molecules recognize Qa-1b on RMA-S cells and thus differ from most class Ia specific CTL. Those anti-Qa-1b CTL that do not recognize untransfected RMA-S do lyse RMA-S transfected with Tap-2. We also examine the effects of Qdm, a gene that maps to the D region and alters recognition of Qa-1. Qdm(k) strains lack an epitope(s) recognized by some (Qdm dependent) anti-Qa-1 CTL whereas Qdm+ strains express this epitope. Thus, Qdm-dependent CTL do not recognize Qa-1 on Qdm(k) targets whereas Qdm-independent CTL recognize Qa-1 epitopes in all strains. Although Qdm-independent CTL varied as to whether they recognized RMA-S vs RMA, all nine Qdm-dependent clones only recognized Qa-1b on RMA and not RMA-S. This result is consistent with Qdm encoding a peptide dependent upon the TAP transporter for cell membrane expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Ham-2 corrects the class I antigen-processing defect in RMA-S cells.

The murine major histocompatibility complex (MHC) contains two genes (Ham-1 and Ham-2) that encode members of a super-family of ATP-dependent transport proteins. These genes are believed to mediate the transport of peptide antigen from the cytoplasm into the lumen of the endoplasmic reticulum for binding by MHC class I molecules. Evidence for such a function has come from the rescue of class I surface expression by a cloned copy of the human homologue of Ham-1, PSF-1, in a human cell line that is defective in antigen processing. A mutant murine cell line, RMA-S, has an identical antigen-processing-defective phenotype. Here we show that expression of a cloned copy of the Ham-2 gene in RMA-S cells results in recovery of the ability to process and present class I-restricted antigens to cytotoxic T lymphocytes, and in partial recovery of class I surface expression. Processing defects for classical (H-2 K and D) and non-classical (Qa1 and HMT) class I molecules are corrected by Ham-2. These data indicate that both MHC-linked transporter genes are probably required for class I antigen processing, and that the functional transporter in this pathway may consist of a Ham-1/Ham-2 heterodimer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Generation of T cells with lytic specificity for atypical antigens. I. A mitochondrial antigen in the rat.

F1 rats primed with normal parental strain lymphocyte populations and restimulated in culture with parental lymphoblasts generate potent cytotoxic T cell responses to unusual antigen systems. Here we describe in the Lewis (L)/DA anti-DA combination an antigen system most likely of mitochondrial origin with the following properties: it is transmitted maternally from DA strain females, inherited in an extra-chromosomal manner, restricted by class I RT1Aa major histocompatibility complex gene products, extinguished on target cells treated with chloramphenicol, and its pattern of expression in different rat strains correlates with restriction fragment-length polymorphisms of mitochondrial DNA. Sequence analysis of the rat ND1 gene indicates that the maternally transferred factor in the rat is not a homologue of the maternally transmitted factor responsible for the mitochondrial antigen in mice. In keeping with its inheritance from DA females, this antigen is present on target cells from (DA female x L male)F1 donors and all other F1 combinations derived from DA female parents, but absent from target cells from some F1 combinations (L/DA and Wistar-Furth [WF]/DA) derived from DA strain males. The presence of this antigen in other F1 combinations (Brown Norway [BN]/DA, August 2880 [AUG]/DA, and PVG/DA) indicates that this mitochondrial antigen system is shared by the DA, BN, and PVG strains, but not by the L and WF strains.

Amino Acid Sequence↗
PubMed1991

Expression of medial class I histocompatibility antigens on RMA-S mutant cells.

The RMA-S mutant T cell line is defective in H-2b restricted antigen presentation and has markedly reduced surface expression of Kb and Db. We examined RMA-S for the expression of the medial class I histocompatibility antigens Qa1b and Mta. While RMA-S targets varied in their susceptibility to lysis by cytotoxic T lymphocytes (CTL) specific for Qa1b, Mta levels were detectable but consistently low compared to the parent RMA cell line. Addition of synthetic ND1 alpha 1-26 or ND1 alpha 1-17 peptides that mimic MTF alpha (the ligand of Mta) increased killing of RMA-S by anti-Mta alpha CTL to levels comparable to or better than RMA, with 300 nM peptide being fully effective. None of the MTF peptides increased the killing of RMA-S by anti-H-2b or anti-Qa1b CTL, even at the highest (1 microM) peptide concentrations. RMA-S cells treated with 100 microM of either the ND1 alpha 4-26 or ND1 alpha 1-26 peptides showed a small increase in the fluorescent staining for beta 2-microglobulin but not for H-2Kb or H-2Db. These results show that Mta and Qa1b, although affected, are not obliterated by the defect in RMA-S cells; that the association of MTF peptides with HMT is exclusive; and that MTF enters the endoplasmic reticulum in the same fashion as other endogenous peptides.

Animals↗
PubMed1991

Maternally transmitted antigen of mice: a model transplantation antigen.

Molecular identification proved Mta, the maternally transmitted antigen of mice, to be a model minor histocompatibility (H) antigen. It consists of a peptide, MTF, that is presented on the cell surface by an H-2 class-I molecule, HMT. MTF is derived from ND1, a mitochondrially encoded protein, and the amino-terminal N-formyl-methionine is essential for binding to HMT; conservative substitutions at the sixth residue causes MTF to be a minor H antigen. HMT is encoded by the M3 gene at the telomeric end of the H-2 complex. The peptide-binding site of HMT is hydrophobic, and allelic forms of the mature protein differ by only three amino acids. Homologues and analogues of the mouse Mta system have recently been identified in rats.

Amino Acid Sequence↗
PubMed1990

Maternally transmitted histocompatibility antigen of mice: a hydrophobic peptide of a mitochondrially encoded protein.

MTF, a murine minor histocompatibility antigen, is maternally inherited and thought to be encoded by a mitochondrial gene. We sequenced the entire mitochondrial genomes from three strains that differ in MTF Mtf beta, Mtf gamma, and Mtf delta) and compared the sequences with the known, Mtf alpha, mitochondrial DNA sequence. We found only one site where all four genomes differed, affecting amino acid residue 6 of ND1, a subunit of NADH dehydrogenase. Incubation of non-Mtf alpha target cells with synthetic peptide ND1 alpha 1-17 (the first 17 amino acid of the ND1 protein of Mtf alpha mice) rendered them susceptible to lysis by MTF alpha-specific cytotoxic T cells (CTLs). Similarly, non-Mtf beta target cells were lysed by MTF beta-specific CTLs after incubation with the allelic form ND1 beta 1-17. Thus, Mtf is attributable to allelic variation at a single residue of the ND1 protein. Cells can therefore display peptides derived from mitochondrially encoded proteins, and such peptides can be histocompatibility antigens.

Amino Acid Sequence↗