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Biomedical subjects

J Schiffenbauer

Publications and source records attributed to J Schiffenbauer.

At least 37 records · Page 2Linked to original sources
PubMed1995

Accelerated induction of experimental allergic encephalomyelitis in PL/J mice by a non-V beta 8-specific superantigen.

Superantigens such as the staphylococcal enterotoxins can play an important role in exacerbation of autoimmune disorders such as experimental allergic encephalomyelitis (EAE) in mice. In fact, superantigens can reactivate EAE in PL/J mice that have been sensitized to rat myelin basic protein (MBP). The T-cell subset predominantly responsible for disease in PL/J mice bears the V beta 8+ T-cell antigen receptor (TCR). The question arises as to whether T cells bearing other V beta specificities are involved in induction or reactivation of EAE with superantigen. Thus, we have investigated the ability of a non-V beta 8-specific superantigen, staphylococcal enterotoxin A (SEA) (V beta specificities 1, 3, 10, 11, and 17), to induce EAE in PL/J mice that have been previously protected from disease by anergy and deletion of V beta 8+ T cells. PL/J mice were first pretreated with the V beta 8-specific superantigen staphylococcal enterotoxin B (SEB) and then immunized with MBP. These mice exhibited V beta 8-specific anergy and depletion and did not develop EAE, even when further treated with SEB. However, administration of SEA to these same mice induced an initial episode of EAE which was characterized by severe hindleg paralysis and accelerated onset of disease. In contrast to SEB pretreatment, PL/J mice pretreated with SEA did develop EAE when immunized with MBP, and after resolution of clinical signs of disease these mice were susceptible to relapse of EAE induced by SEB but not by SEA. Thus, superantigens can activate encephalitogenic MBP-specific non-V beta 8+ T cells to cause EAE in PL/J mice. These data suggest that superantigens can play a central role in autoimmune disorders and that they introduce a profound complexity to autoimmune diseases such as EAE, akin to the complexity seen in multiple sclerosis.

Animals↗
PubMed1995

Genetic influence in rheumatoid arthritis.

Development of rheumatoid arthritis is influenced by genetic and environmental factors. Over the years intense interest has been focused on analysis of genetic factors contributing to pathogenesis and it appears that the major histocompatibility complex class II genes make a major contribution. Utilizing epidemiological data as well as molecular techniques, an epitope located on a number of HLA-DR molecules (class II) seems to be associated with an increased susceptibility to development of the condition. Furthermore, the disease may be more severe among individuals homozygous for the disease-associated DR types. The specific immunological mechanisms accounting for these findings are not known but are likely related to the ability of class II molecules to bind autoantigens and stimulate the appropriate T cells which can lead to joint damage. A search for additional genetic factors contributing to disease development should be high on the list of objectives and would help to further elucidate the pathogenesis of this complex disorder.

Arthritis, Rheumatoid↗
PubMed1994

Polygenic control of susceptibility to murine systemic lupus erythematosus.

Susceptibility to glomerulonephritis (GN) and anti-dsDNA autoantibody production was analyzed in crosses with a newly developed systemic lupus erythematosus-susceptible inbred strain, NZM/Aeg2410. The mode of inheritance and the number and location of systemic lupus erythematosus-associated susceptibility loci were analyzed by interval mapping in a backcross with C57BL/6. Three chromosomal intervals containing strong recessive GN susceptibility alleles were identified on chromosomes 1, 4, and 7, each containing several potentially interesting candidate genes. Heterozygosity at H-2 was also found to correlate strongly with GN susceptibility, consistent with previous findings in the NZB/NZW parental strain model. Logistic regression analysis indicated that each of these susceptibility alleles independently accounted for a component of GN susceptibility, and that susceptibility was inherited as a threshold genetic liability in this model system.

Animals↗
PubMed1993

Staphylococcal enterotoxins can reactivate experimental allergic encephalomyelitis.

Staphylococcal enterotoxins (SEs) are one member of a unique group of molecules known as superantigens. They are potent T-cell activators and stimulate a large number of T cells bearing specific T-cell-receptor beta-chain variable regions. It has been proposed that superantigens may trigger autoimmune disorders by stimulation of autoreactive T cells with restricted beta-chain variable-chain usage. We investigated the effects of SEs B and A (SEB and SEA) on the reactivation of experimental allergic encephalomyelitis, an animal model for multiple sclerosis. We report that SEB can reinduce encephalitis multiple times in PL/J mice that had previously recovered from an acute episode. SEB was also able to induce encephalitis in mice previously immunized with myelin basic protein but did not show clinical signs of disease. In addition, it was observed that T cells from PL/J mice that had been previously activated by myelin basic protein in complete Freund's adjuvant or in complete Freund's adjuvant alone were resistant to the induction of anergy by SEB. To determine whether reactivation of experimental allergic encephalomyelitis was specific for SEB, another superantigen, SEA, was employed. It was found that SEA was also able to reinduce experimental allergic encephalomyelitis in mice previously recovered from an acute episode and those that had been previously immunized with myelin basic protein but did not show clinical signs of disease. These results indicate that SEs are capable of reactivating autoreactive T cells and inducing autoimmune disease.

Animals↗
PubMed1993

Treatment of PL/J mice with the superantigen, staphylococcal enterotoxin B, prevents development of experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE), an antigen induced autoimmune disease, is mediated by V beta 8+ CD4+ T cells in PL/J mice after injection with the autoantigen, myelin basic protein (MBP). Recently the superantigen, staphylococcal enterotoxin B (SEB), has been shown to peripherally anergize and delete T cells in a V beta specific manner. By treatment of PL/J mice with SEB, we have been able to protect PL/J mice from the development of EAE. Two-color FACS analysis of the spleens of SEB treated mice showed depletion of V beta 8+ CD4+ T cells. Consistent with this observation, spleen cells of SEB treated mice that did not show signs of EAE could not be stimulated in vitro with SEB but did respond to SEA. Thus, V beta specific superantigens may prove to be a preventative therapy for autoimmune diseases mediated by V beta specific T lymphocytes.

Animals↗
PubMed1993

Mixed haplotypes and autoimmunity.

Why do (NZB x NZW)F1 mice develop an autoimmune lupus-like syndrome? The second exons of the class II genes of NZB and NZW are identical to their counterparts of H-2d and H-2u haplotypes. Several lines of evidence suggest that this allows the production of a mixed haplotype molecule, I-E alpha dE beta z, and that this molecule plays a key role in the development of autoimmunity.

Amino Acid Sequence↗
PubMed1992

Background genes mediate the development of autoimmunity in (NZB x PL/J)F1 or (NZB x BIO.PL)F1 mice.

The (NZB x NZW)F1 mouse develops a lupus-like disease including anti-double-stranded DNA antibodies and renal disease. It has been demonstrated that genes linked to the H-2 locus contributed by NZW correlate with development of this disease. We investigated whether mice with identical class II molecules but different background genes could contribute to autoimmunity when crossed with NZB. We report that two strains, PL/J and BIO.PL, when crossed to NZB, do not result in F1 with autoimmunity. Therefore, background genes present in NZW but not in PL/J or BIO.PL contribute to the development of disease.

Amino Acid Sequence↗
PubMed1991

Sequence of class II major histocompatibility complex genes from MRL mice. Conserved amino acids in the I-E beta chains from autoimmune mice.

Class II major histocompatibility complex molecules are critical in both normal and abnormal immune responses. Both in mice and in humans, these molecules have been implicated in the development of various diseases, including insulin-dependent diabetes mellitus and systemic lupus erythematosus. The MRL/lpr mouse strain spontaneously develops a lupus-like illness with features that include anti-DNA antibodies, glomerulonephritis, and early death. We evaluated the structure of class II molecules from these mice, to investigate for unique sequences that might contribute to autoimmunity. Utilizing the polymerase chain reaction, we sequenced the second exons from the I-A and I-E genes of MRL/lpr and MRL-+/+ mice. We found that at the nucleotide level, there are several changes between MRL class II genes and the previously sequenced "k" haplotype, but at the protein level, they are identical. Furthermore, by comparing the sequences of class II genes from several strains of autoimmune mice, we found that there are conserved amino acids in the third hypervariable region of the I-E beta chain which may be important in the development of autoimmunity.

Amino Acid Sequence↗
PubMed1989

A unique sequence of the NZW I-E beta chain and its possible contribution to autoimmunity in the (NZB x NZW)F1 mouse.

The (NZB x NZW)F1 mouse strain develops a syndrome of accelerated autoimmunity including severe renal disease and early death. Evidence suggests that class II molecules play a central role in this process. Previous studies have suggested that the NZW strain contributes at least one gene to the development of accelerated autoimmunity that is linked to the H-2 complex, and antibodies to murine class II molecules have been used to ameliorate disease in (NZB x NZW)F1 mice. We therefore wished to sequence the class II molecules from NZW mice to identify any unique sequences that may contribute to disease development. We constructed oligonucleotide primers corresponding to the 5' and 3' regions of the second exon of class II genes from a variety of haplotypes, and used these primers in a polymerase chain reaction to sequence the second exon of the NZW I-A alpha, I-A beta, and I-E beta genes. We report that the second exons of NZW I-A alpha, I-A beta, and I-E alpha are identical to their counterparts of the previously sequenced u haplotype, and that the second exon of NZW I-E beta is identical to its counterpart from u except for a single base change that results in a substitution of arginine for threonine at amino acid 72. This base and amino acid are identical to those found at the same positions in the s haplotype.

Amino Acid Sequence↗
PubMed1989

Evidence for heterogeneity of the DPA and DPB alleles derived from a DRw11,DQw7,DPw4 cell line.

We have previously reported the complete sequence of the cDNAs corresponding to the alleles at the polymorphic loci (DRB1, DRB3, DQA1, DQB1) of the DRw11(5) cell line Swei. We now report the nucleotide and derived amino acid sequence of the alleles at the remaining two polymorphic loci, DPA1 and DPB1, from Swei, which types as DPw4b. Comparison of the DPw4b alpha sequence with previous DP alpha sequences indicates that it is identical to the DP alpha chains of DPw4 and DPw2. However, the DPw4b alpha cDNA encodes a unique 3' untranslated region that corresponds to sequences contained within the last intron of the DP alpha genomic gene. These results indicate that alternative splicing occurs within the Swei DP alpha RNA. Comparison of the DPw4b beta sequence with previously reported DP beta sequences indicates that the first domain is identical to the sequence of the DP beta chain derived from the Burkhardt (Burk) cell line, but that the second domain differs by two amino acids. In addition, a single amino acid difference from DPw2 at position 69 in the first domain of the DPw4b beta chain suggests that this residue is important in determining DP specificity. Furthermore, comparison with other DP beta DNA sequences suggests that variable regions occur at positions 8-11, 55-57, and 84-87.

Amino Acid Sequence↗
PubMed1988

Characterization of the cDNA encoding a protein binding to the major histocompatibility complex class II Y box.

The expression of HLA class II genes is regulated by a series of cis-acting elements and trans-acting factors. Several cis-acting elements have been identified and have been termed the Z box, X box, Y box, octamer, and "TATA" box. The Y box contains an inverted CCAAT box. By probing a phage lambda gt11 library with double-stranded oligonucleotides, we have directly isolated a cDNA encoding a Y box-binding protein designated YB-1. YB-1 binding has an absolute requirement for the CCAAT box and relative specificity for the Y box. It has a Mr of 35,414, contains 18% basic residues, and contains putative nuclear localization signals. An inverse correlation of YB-1 and HLA-DR beta chain mRNA levels suggests that YB-1 is a negative regulatory factor.

Amino Acid Sequence↗
PubMed1988

Serial pulmonary function testing in patients with systemic lupus erythematosus.

Previous studies have documented the pulmonary function abnormalities associated with systemic lupus erythematosus (SLE). There are very few data, however, regarding the progression of such changes. To study this question, we evaluated the pulmonary function of a group of 25 patients with SLE from two to seven years after a set of pulmonary function tests had been performed as part of their overall initial assessment. Reductions in diffusing capacity, FVC, and total lung capacity did not change significantly for the group over the period of our study. The mean FEF25-75%, which was initially low, and the mean FEV1/FVC ratio, which was initially normal, both decreased significantly. The observed abnormalities in airway function were not related to smoking history. Other aspects of lupus activity, as measured by serum creatinine levels and clinical activity, did not appear related to progression of lung disease.

Adult↗
PubMed1987

Complete sequence of the HLA DQ alpha and DQ beta cDNA from a DR5/DQw3 cell line.

The HLA-D region is composed of three subregions termed DR, DQ, and DP. We previously reported the sequence of a DR5 beta I and two DR5 beta III cDNA from the DR5 cell line Swei. We now report on the nucleotide and deduced amino acid sequence of the DQ alpha and DQ beta cDNA from the same DR5 cell line, which also types as DQw3. Comparison with other available DQ sequences indicates that DQ alpha has one region of major variability, whereas DQ beta appears to have four regions of variability. In addition, these comparisons indicate that DQw3 alpha from DR5 is different from DQw3 alpha from DR4, but identical to DQw2 alpha from DR3. In contrast, DQw3 beta from DR5 is very similar to DQw3 beta from DR4. These data indicate that at least for DQw2 and DQw3 it is the DQ beta chain that is responsible for DQ typing. Most sequence differences in DQ alleles can be attributed to point mutations; however, codon additions/deletions in the DQ alpha chain may contribute to variability. In addition, regions of possible gene conversion in the DQ alpha and DQ beta chains is suggested by the presence of a chi-like sequence in each chain. Finally, comparison of available haplotypes suggest recombination events may take place between DQ beta and DQ alpha, between DQ alpha and DR beta I, and between DR beta I and DR beta III.

Amino Acid Sequence↗
PubMed1987

The HLA complex and its relationship to rheumatic diseases.

The HLA complex has been shown to be involved in the regulation of several aspects of the immune response, and has been shown to be associated with several rheumatologic diseases. The mechanisms by which HLA molecules predispose to disease has been an area of intense interest. Recent work has provided some possible explanations for the lack of absolute associations between a particular disease and a particular HLA antigen. There is now some evidence to suggest that specific epitopes rather than entire class I or II molecules may be responsible for disease predisposition. Furthermore, it appears that these epitopes may be transferred between different class I and II molecules by a mechanism known as gene conversion. Work evaluating the influence of other genes, such as those for the T cell receptor, on disease susceptibility has just begun. Many of the rheumatic diseases are quite diverse in their presentation. If only one of a heterogeneous group of diseases is associated with an HLA antigen, study of the entire group of diseases will of necessity dilute the association. Better definitions of clinical subsets should lead to improved correlations of HLA and disease. Little is known of etiologic agents or pathogenesis. As our knowledge of the interaction of HLA antigens, T cell receptors, and etiologic agents increases, we will come closer to an understanding of the mechanisms by which these molecules predispose to disease.

Amino Acid Sequence↗
PubMed1986

Characterization of two distinct DR beta chain alleles at the beta III locus of the DR5 haplotype: beta III alleles are highly conserved.

The HLA-DR beta region of at least two members of the DRw52 (MT2) supertypic group (DR3, DR5, DRw6, and DRw8) has recently been shown to contain three beta-chain genes--beta I, beta II, and beta III, ordered in the direction of transcription. beta III is apparently a duplication of beta I. Both beta I and beta III are expressed, whereas beta II is a pseudogene. We previously reported the sequence of the DR5 beta I cDNA from the homozygous DR5 cell line Swei. We report here the sequence of two different DR5 beta III cDNA from the same cell line. The assignment of the genes of this and other members of the DRw52 supertypic group to specific loci allow comparisons between products of known alleles and between products of distinct loci. beta I allelic products showed approximately 11% divergence in the first domain, whereas beta I and beta III products showed 17% difference. These differences were clustered and found predominantly in the previously described variable regions (amino acid residues 9 through 13, 26 through 38, and 67 through 74). These data, coupled with the finding of shared variable regions among different DR beta chains, suggest gene conversion as a means of generating polymorphism in the beta I alleles. In contrast, the beta III allelic products showed less than 1% amino acid and nucleotide divergence in the first domain. These differences were outside the variable regions, and attributable to single nucleotide changes. The polymorphism at the beta I locus and the conservation at the beta III locus suggest selective pressure conserving the beta III locus and/or generating polymorphism at the beta I locus, and further suggest that gene conversion may be acting unidirectionally from beta III to beta I.

Alleles↗
PubMed1985

The molecules recognized by anti-MT2 alloantisera and anti-MT2-like (DRw52) monoclonal antibodies are different.

The human class II alloantigens include the HLA-DR, DQ, and MT determinants. Previous reports in the literature suggest that while the DQ determinants appear to be on a molecule separate from DR, the MT determinants are variably present on DR or DQ molecules. We have previously reported, using the homozygous DR5 cell line Swei, that the MT4 determinant defined by the allosera, MGH88B, was only on the DQw3 molecule, while MT2, defined by the functionally monospecific anti-MT2 alloantiserum MGH87B, was present on both the DR5 and DQw3 molecules. We now report using the monoclonal antibody ILR2 directed against an MT2-like determinant DRw52, that DRw52 is present on the DR molecules only. The MT2 determinant(s) recognized by the functionally monospecific alloantisera MGH87B appear to include the DRw52 determinant(s) recognized by the monoclonal antibody ILR2.

Animals↗