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H O McDevitt

Publications and source records attributed to H O McDevitt.

At least 73 records · Page 4Linked to original sources
PubMed1992

Genomic polymorphism, recombination, and linkage disequilibrium in human major histocompatibility complex-encoded antigen-processing genes.

Recently, two subunits of a large cytosolic protease and two putative peptide transporter proteins were found to be encoded by genes within the class II region of the major histocompatibility complex (MHC). These genes have been suggested to be involved in the processing of antigenic proteins for presentation by MHC class I molecules. Because of the high degree of polymorphism in MHC genes, and previous evidence for both functional and polypeptide sequence polymorphism in the proteins encoded by the antigen-processing genes, we tested DNA from 27 consanguineous human cell lines for genomic polymorphism by restriction fragment length polymorphism (RFLP) analysis. These studies demonstrate a strong linkage disequilibrium between TAP1 and LMP2 RFLPs. Moreover, RFLPs, as well as a polymorphic stop codon in the telomeric TAP2 gene, appear to be in linkage disequilibrium with HLA-DR alleles and RFLPs in the HLA-DO gene. A high rate of recombination, however, seems to occur in the center of the complex, between the TAP1 and TAP2 genes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

A polyalanine peptide with only five native myelin basic protein residues induces autoimmune encephalomyelitis.

The minimum structural requirements for peptide interactions with major histocompatibility complex (MHC) class II molecules and with T cell receptors (TCRs) were examined. In this report we show that substituting alanines at all but five amino acids in the myelin basic protein (MBP) peptide Ac1-11 does not alter its ability to bind A alpha uA beta u (MHC class II molecules), to stimulate specific T cells and, surprisingly, to induce experimental autoimmune encephalomyelitis (EAE) in (PL/J x SJL/J)F1 mice. Most other amino acid side chains in the Ac1-11 peptide are essentially irrelevant for T cell stimulation and for disease induction. Further analysis revealed that binding to A alpha uA beta u occurred with a peptide that consists mainly of alanines and only three of the original residues of Ac1-11. Moreover, when used as a coimmunogen with MBP Ac1-11, this peptide inhibited EAE. The finding that a specific in vivo response can be generated by a peptide containing only five native residues provides evidence that disease-inducing TCRs recognize only a very short sequence of the MHC-bound peptide.

Amino Acid Sequence↗
PubMed1992

Evolution of major histocompatibility complex class II allelic diversity: direct descent in mice and humans.

The high degree of polymorphism seen at major histocompatibility complex (MHC) class II loci is a feature unique to the MHC. Most of the beta-chain polymorphism is localized in "hypervariable" regions (HVRs). HVR amino acid sequence similarity between distantly related species has recently been found. We have employed a Monte-Carlo statistic to show that shared HVR polymorphism between beta-chain genes of humans and mice represents direct descent of ancestral sequences rather than convergent evolution. Furthermore, half the sequence polymorphism seen in class II beta-chain genes of mice persists in evolution and is encoded by the same DNA sequence in humans. No evidence for increased mutation rate within the HVR was found. We postulate that the HVR can be considered the genetic unit of recombination, with selection for HVR sequences and combinations of HVRs constrained by functional considerations.

Alleles↗
PubMed1992

Inhibition of experimental autoimmune encephalomyelitis by a nonimmunogenic non-self peptide that binds to I-Au.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory neurologic disease initiated by myelin basic protein-reactive CD4+ T cells, which are restricted by a particular MHC class II molecule. Recent studies have utilized inhibitor peptides that bind to restricting MHC class II molecules in order to inhibit EAE, presumably by means of competing with encephalitogenic epitopes. However, these studies leave open the possibility of alternative explanations, such as Ag-specific nonresponsiveness and immunodominance. In order to demonstrate that competition for MHC binding alone can inhibit EAE, the inhibitor peptide should ideally be structurally unrelated and nonimmunogenic yet physically associate with the MHC class II molecule. In this study, we show that the OVA-323-339 peptide, which is unrelated to the disease-inducing peptide, binds to A alpha uA beta u. However, although OVA-323-339 is extremely immunogenic in A alpha dA beta d-expressing BALB/c mice, it is nonimmunogenic in (PL/J x SJL)F1 and PL/J mice expressing A alpha uA beta u. When administered as a coimmunogen with Ac1-11, OVA-323-339 inhibited induction of EAE in (PL/J x SJL)F1 mice. Myelin basic protein-89-101, which does not bind A alpha uA beta u, had no effect on the disease process. This study provides evidence that MHC class II binding alone can modulate the induction of EAE. The use of a nonimmunogenic non-self peptide to modulate an autoimmune disease minimizes the potential complications of immunodominance or alternative regulatory mechanisms associated with immunogenic peptide therapies and further confirms the MHC-blocking model of immunosuppression.

Animals↗
PubMed1992

Monoclonal anti-tumor necrosis factor antibody renders non-obese diabetic mice hypersensitive to irradiation and enhances insulitis development.

In attempt to evaluate biological roles of tumor necrosis factor (TNF), we studied the effects of anti-TNF mAb in non-obese diabetic (NOD) mice. Anti-murine TNF mAb rendered NOD mice hypersensitive to the lethal effects of radiation and prevented the reconstitution of lethally irradiated mice with adoptively transferred lymphocytes. While TNF-alpha reduced the incidence of diabetes development in the adoptive transfer system even when given 6 days post-transfer, mAb to TNF could not reduce or increase the incidence of diabetes compared to control mice. Administration of TNF-alpha for 4 or 8 weeks significantly reduced the incidence of spontaneous insulitis in NOD mice, while anti-TNF mAb given for 8 weeks increased the incidence of insulitis significantly.

Animals↗
PubMed1992

EAE: a model for immune intervention with synthetic peptides.

The cellular and molecular requirements for the autoimmune disease EAE are being defined in increasing detail through intense scrutiny of critical autoantigenic peptides, class II MHC molecules, and alpha beta TCRs involved in the disease process. This study has led to novel immunotherapeutic approaches, many of which are based on the administration of synthetic peptides. Since short peptides are understood to be the minimal antigenic units bound by MHC molecules for recognition by T cells, they are attractive experimental tools for finely modulating specific immune responses. It is clear that a large number of defined peptides can dramatically influence the course of EAE. Table IV lists a number of potential mechanisms which may mediate disease prevention. Increasing evidence supports the idea that prevention of autoimmune disease can result from MHC-blockade by peptides which competitively bind to class II molecules. However, for some peptides such as the perplexing partial agonist Ac1-11[4A], the mechanism by which these precisely defined units act is not yet fully understood. Numerous hurdles hinder immediate clinical application of peptide-based immunotherapy. Nevertheless, the knowledge gained by probing experimental autoimmunity with defined peptides promises to inspire original and practical approaches to treating human autoimmune disease.

Amino Acid Sequence↗
PubMed1991

An immune response defect due to low levels of class II cell surface expression. Analysis of antigen presentation and positive selection.

The effects of quantitative differences in class II cell surface expression have been difficult to address in intact animals. This study uses several lines of H-2s/s mice carrying an A beta k transgene that differ significantly in terms of class II cell surface expression. Due to inefficient chain pairing, mice carrying 60 to 65 copies of this transgene express only low levels of A alpha s/A beta k on the cell surface, and cell surface expression of the endogenous A alpha s/A beta s complex (and total Ia) is severely reduced (to 7-15% control levels). The significant decrease in class II cell surface expression in the thymic cortex of these mice did not affect the frequency of peripheral T cells expressing at least 10 distinct TCR V beta chains. However, T cell proliferative responses to the A alpha s/A beta s-restricted peptide MBP 89-101 were abrogated in high copy number A beta k mice. Experiments using bone marrow chimeras demonstrated that both inefficient Ag presentation and failure to positively select appropriate T cells contributed to this lack of response. Inefficient Ag presentation was clearly the dominant defect, and the density of class II cell surface expression required for positive selection appeared to be quite low.

Animals↗
PubMed1991

A single amino acid change in a myelin basic protein peptide confers the capacity to prevent rather than induce experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an experimental demyelinating disease of rodents. In (PL/J x SJL) F1 mice, it is induced by immunization with the myelin basic protein peptide Ac1-11. Ac1-11 [4A], a myelin basic protein peptide analog with a single amino acid substitution, (i) binds to class II major histocompatibility complex molecules and stimulates encephalitogenic T cells in vitro better than Ac1-11, (ii) is nonimmunogenic and nonencephalitogenic in vivo in (PL/J x SJL)F1 mice, (iii) prevents EAE when administered before or at the time of immunization with Ac1-11, and (iv) prevents EAE when administered later, near the time of disease onset. Initial studies suggest that Ac1-11 [4A] does not prevent EAE by competitive inhibition or by activation of regulatory cells. Thus, substitution of a single amino acid in a myelin basic protein peptide confers the capacity to prevent rather than induce EAE, even after peptide-specific encephalitogenic T cells have been activated.

Amino Acid Sequence↗
PubMed1991

A rare HLA DQB allele sequenced from patients with systemic lupus erythematosus.

Most autoimmune disorders are associated with particular alleles of the major histocompatibility complex (MHC) class II genes. However, only a minority of individuals with these alleles develop autoimmunity. The identification of alleles more closely associated with an autoimmune disorder such as lupus would facilitate screening and diagnosis and perhaps the understanding of mechanisms of disease. Analysis of sequence variation in the polymorphic first domain of the MHC genes HLA DQ beta and DQ alpha has revealed a novel DQ beta allele in two Caucasian lupus patients and no Caucasian controls. The novel DQ beta allele shares polymorphic amino acids at positions 26 to 30 and 57 with other lupus-associated DQ beta alleles. These hypervariable regions may play a role in lupus susceptibility and may provide insights into the molecular mechanism for this susceptibility.

Alleles↗
PubMed1990

Autoimmune diseases: the failure of self tolerance.

The ability to discriminate between self and nonself antigens is vital to the functioning of the immune system as a specific defense against invading microorganisms. Failure of the immune system to "tolerate" self tissues can result in pathological autoimmune states leading to debilitating illness and sometimes death. The induction of autoimmunity involves genetic and environmental factors that have focused the attention of researchers on the trimolecular complex formed by major histocompatibility complex molecules, antigen, and T cell receptors. Detailed molecular characterization of these components points to potential strategies for disease intervention.

Animals↗
PubMed1990

Idiotypic characteristics of immunoglobulins associated with human systemic lupus erythematosus. Association of high serum levels of IdGN2 with nephritis but not with HLA class II genes predisposing to nephritis.

Serum levels of IdGN2 (an idiotype enriched in nephritogenic antibodies), IdX (an idiotype not enriched in nephritogenic antibodies), IgG, and anti-DNA were measured in 23 Caucasian patients with lupus nephritis, in age- and sex-matched lupus patients without nephritis, and in similarly matched healthy individuals. Serum levels of IdGN2 were significantly higher in the patients with lupus nephritis than in those without, and they were higher in all lupus patients compared with the healthy control subjects. However, the same observations were true for serum levels of IdX. There were significant positive correlations between the serum levels of IgG, IdGN2, IdX, and anti-DNA. HLA typing at the DR and DQ loci was performed in 105 lupus patients of different races (Caucasian, black, and Asian/Polynesian/Filipino). Serum levels of IdGN2 in 83 of these individuals did not correlate with any of the HLA class II haplotypes currently known to predispose to lupus nephritis. We conclude that the high serum levels of IdGN2, which are characteristic of some patients with lupus nephritis, may often result from polyclonal B cell activation rather than from idiotype-specific upregulation associated with one or more of the class II genes that predispose to nephritis in this disease.

Genes, MHC Class II↗
PubMed1990

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus.

Susceptibility to systemic lupus erythematosus is associated with major histocompatibility complex (MHC)--encoded genes. We have used nucleotide sequence analysis to better define the disease-associated MHC alleles. HLA-DR2, DQw1, and especially the rare allele DQ beta 1. AZH confer high relative risk (RR = 14) for lupus nephritis in a Caucasian population of patients. Pilot studies using historical controls suggest that these genes also confer a high risk in non-Caucasian ethnic groups (RR = 24-78). We have found that DR4 is significantly decreased in patients with lupus nephritis. Fifty percent of the patients with lupus nephritis had either the DQ beta 1.1, the DQ beta 1.AZH, or the DQ beta 1.9 alleles. These alleles share amino acid residues that have been predicted to be the contact points for antigen and the T cell receptor. These HLA alleles appear to have a direct role in the predisposition to lupus nephritis, whereas DR4 may have a "protective" effect.

Alleles↗
PubMed1990

The effect of excess beta-chain synthesis on cell-surface expression of allele-mismatched class II heterodimers in vivo.

We have recently described 12 lines of H-2s/s mice carrying from 1 to 65 copies of an A beta k transgene. The transgene was coexpressed with the endogenous allele, and A beta K mRNA expression correlated well with transgene copy number. Overexpression of the transgene was associated with a variety of defects, including a significant reduction in I-A cell-surface expression. In this paper, we assess the effect of increased levels of A beta k mRNA synthesis on I-A cell-surface expression in these mice. Crossing representatives from several lines of A beta k mice to A alpha k transgenic mice demonstrated that the A beta k mRNA was translated and expressed at high levels on the cell surface in association with A alpha k. In H-2s/s (A alpha s /A beta s) mice carrying greater than 10 copies of the A beta k transgene, excess A beta k mRNA and protein synthesis did drive cell-surface expression of the less favored A alpha s/A beta k heterodimers. However, the highest levels of A beta k detected on the cell surface were only 50-70% of those observed in [B10.A(4R) x nontransgenic]F1 controls. Maximum levels of A alpha s/A beta k cell-surface expression were accompanied by a significant reduction in A alpha s/A beta s expression. Unpaired and improperly paired complexes were not detected intracellularly and appeared to be degraded quite rapidly. Thus, only a fraction of the chains competing for pairing reached the cell surface under conditions of asymmetric chain synthesis in these mice. This markedly reduced total Ia cell-surface levels in mice carrying greater than 10 copies of the A beta k transgene.

Alleles↗