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Biomedical subjects

B D Schwartz

Publications and source records attributed to B D Schwartz.

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

Collagen-induced arthritis in the BB rat. Prevention of disease by treatment with CTLA-4-Ig.

Antigen-specific T cell activation requires two independent signalling events, one mediated through T cell receptor engagement by the antigen-presenting cell-expressed peptide/class II major histocompatibility complex, and the second through the cognate interactions of costimulatory molecules expressed on the T cell and antigen-presenting cell. There is evidence from in vitro and in vivo experimental systems suggesting that the CD28/B7 costimulatory pathway is crucial for induction of maximal T cell proliferation and T helper-B cell collaboration for IgG production. This pathway can be blocked by CTLA-4-Ig, a soluble form of CTLA-4 which binds with high avidity to the CD28 ligands, B7-1 and B7-2. Here, we show that CTLA-4-Ig treatment prevents clinical and histological manifestations of disease in a collagen-induced arthritis model of rheumatoid arthritis in the diabetes resistant BB/Wor rat, when therapy is initiated before immunization with bovine type II collagen (BIIC). Anti-BIIC antibody titers are reduced in CTLA-4-Ig-treated rats compared to diseased control animals. Histologically, joints from CTLA-4-Ig-treated animals show no histological abnormalities, in contrast to control antibody-treated animals, which show complete erosion of the articular cartilage and bone. Despite the efficacy of CTLA-4-Ig in preventing clinical and histological signs of arthritis and reducing antibody responses to BIIC, delayed type hypersensitivity responses to collagen 18 d or more after CTLA-4-Ig treatment ends are similar in CTLA-4-Ig-treated and untreated rats, suggesting that the prolonged disease suppression observed does not result from induction of T cell anergy.

Abatacept↗
PubMed1995

HLA typing in women with breast implants.

Since the 1970s, anecdotal reports have described a relatively small number of women who received silicone gel breast implants and later developed either a recognized rheumatologic disease or unexplained symptoms suggestive of an autoimmune disorder. The study reported here examined whether there is any association between the symptoms seen in implant patients and HLA molecules. One-hundred and ninety-nine subjects were evaluated by HLA typing: symptomatic patients with implants (group I, n = 77), asymptomatic women with implants (group II, n = 37), healthy female volunteers without implants (group III, n = 54), and fibromyalgia patients without implants (group IV, n = 31). A statistically significant 68 percent of group I were positive for HLA-DR53, compared with 35 percent of group II and 52 percent of group III. The fibromyalgia patients were strikingly similar to group I women in terms of HLA-DR molecules, with 65 percent of group IV being positive for DR53. Group I also had a statistically significant increased frequency of HLA-DQ2. Asymptomatic women with implants (group II) had an increased frequency of DR1 and DQ1. In addition, 42 percent of symptomatic patients with implants formed autoantibodies to their own B cells; of these, 81 percent were DR53-positive. Although frequencies of capsular contracture and implant rupture were not significantly different in the two groups with implants, there were statistically significant associations in group I between contractures and ruptures and the presence of DR53 and B-cell autoantibodies. These data suggest that symptomatic patients with implants share important genetic characteristics (primarily HLA-DR53 positivity) that differentiate them from their asymptomatic counterparts. DR53 may be a marker of women who are predisposed by their HLA genotype to develop symptoms following exposure to silicone gel breast implants.

Adolescent↗
PubMed1994

Visible persistence decay rates for schizophrenics and substance abusers.

Information-processing deficits are consistently reported for schizophrenics. The findings from the majority of psychophysical tasks indicate that the deficit is specific to schizophrenics and thus may represent a marker for schizophrenia. The present study evaluated for specificity of impairment by including controls using methadone. A two-pulsed forced choice information-processing task that required the detection of a line or a blank-field during an interstimulus interval (ISI) indexed efficiency of processing (i.e., visible persistence). There were 19 schizophrenic, 9 schizoaffective, 8 depressed, 12 on methadone, and 12 normal subjects. The visual stimuli were low and high spatial frequency gratings. Either a line of equivalent width to those of the gratings or a blank field was presented during the ISI. The gratings were presented for 150 msec prior to and following an ISI of 30, 60, 90, 120, 150, and 350 msec. The results support previous findings for impaired processing during a 90-150 msec interval for schizophrenics. Also, the methadone-using controls were not significantly different from schizophrenics. Normal and depressed controls' profiles did not differ from each other, however, they were significantly different from the other groups. The results support an early information-processing deficit in schizophrenic individuals and may implicate dysregulation of dopaminergic neuromodulation.

Adult↗
PubMed1994

YB-1 DNA-binding protein represses interferon gamma activation of class II major histocompatibility complex genes.

Interferon gamma (IFN-gamma) is the most potent inducer of class II major histocompatibility complex (MHC) genes. This induction is uniquely mediated by three DNA elements in the promoter region of class II MHC genes. One of these DNA elements, Y, contains an inverted CCAAT box. Previously, we have screened a lambda gt11 library for Y-binding proteins and identified the YB-1 gene. Here we provide evidence that YB-1 can repress the IFN-gamma induction of class II MHC promoter as well as the Invariant chain (Ii) gene which also contains a Y element in its promoter. This was demonstrated by cotransfecting a YB-1 expression vector with promoter-reporter gene constructs. As an alternate approach, an efficient transient transfection system was developed which resulted in a > 70% transfection efficiency. Transfection of YB-1 by this procedure resulted in the near abrogation of IFN-gamma induced HLA-DR antigen and mRNA expression. These findings show the functional suppression of class II MHC gene induction by the YB-1 protein.

Animals↗
PubMed1994

Peptide binding to surface class II molecules is the major pathway of formation of immunogenic class II-peptide complexes for viable antigen presenting cells.

Although studies on fixed APCs have demonstrated that peptide can bind to cell surface class II molecules, the mechanisms by which peptide-class II complexes are formed in viable cells is largely unexplored. To explore the possibility that peptide loading of class II molecules was occurring after endocytosis of peptides as well as by surface binding, we utilized an immunogenic hemagglutinin peptide (HAP 128-145) from the influenza strain A/Japan/57, and studied the appearance of surface complexes of HAP 128-145 bound to HLA-DRw11 molecules on human B-lymphoblastoid cells (BLCLs). Detection of the bound peptide was made possible by a rabbit anti-serum (alpha HAP) raised against HAP 128-145, which recognizes both the free peptide as well as peptide bound to DRw11 on living APCs. Pretreatment of the BLCLs with a variety of inhibitors of protein synthesis and intracellular trafficking failed to decrease the levels of HAP 128-145/DRw11 surface complexes. However, significant inhibition in the appearance of these complexes was caused by a decrease in the temperature at which the cells were incubated with peptide. Temperature-specific inhibition was also observed for fixed DRw11-positive APCs and purified DRw11 molecules indicating that the effect of temperature was directly on the class II molecules. We conclude that surface binding of peptide by class II molecules on human B cells is a major pathway of formation of immunogenic class II-peptide complexes for at least some soluble antigenic peptides, and that endocytosis of soluble peptides with subsequent binding of peptide by intracellular class II molecules plays little if any role in the formation of such complexes. Moreover, class II molecules have evolved to stably bind peptide optimally at physiologic temperatures, independent of cell metabolism.

Amino Acid Sequence↗
PubMed1993

Induction of peri-insulitis but not diabetes in islet transplants expressing a single foreign antigen. A multi-stage model of disease.

We have created a new transgenic model in which the human Epstein-Barr virus receptor, CR2 (CD21), has been expressed in pancreatic beta-cells. Mice derived from three transgenic founders bred into H-2b (C57BL/6) or H-2k (CBA) genetic backgrounds did not become spontaneously diabetic. After transplantation of CR2-expressing islets under the kidney capsule of genetically matched recipients, a histologic picture of peri-insulitis was found. However, animals did not manifest cellular invasion of the islets, destruction of the islets, or diabetes for at least 230 days. Significant numbers of both T and B lymphocytes were found in the cell population surrounding the islets. A pronounced serologic response to CR2 was also present and appeared to precede the onset of peri-insulitis. Thus, in this model, we have separated the process of diabetes induction into at least two phases. One is associated with peri-islet infiltration and an antibody response. However, at least one second signal is likely necessary for the process of islet destruction to follow.

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↗
PubMed1993

Polymorphism in the promoter region of HLA-DRB genes.

Polymorphism is a hallmark of the molecules encoded within the MHC of humans and other mammals. Recently, evidence of polymorphism has also been shown to exist in the transcriptional regulatory regions of HLA-DQB genes. In this article, we report that polymorphism exists also in the promoter region of HLA-DRB genes. The sequence of the regulatory region of DRB genes from five homozygous DR B-cell lines, each of a distinct DR haplotype, revealed a number of differences, some of which are in the critical class II boxes that are generally conserved in class II promoters. The major differences occurred in a comparison of DR4 to the other DR haplotypes. These data suggest the existence of another important source of HLA class II polymorphism that may play a role in susceptibility to HLA-associated autoimmune disease.

Base Sequence↗
PubMed1993

Peripheral nerve functions improve in chronic alcoholic patients on abstinence.

We studied the peripheral nerve functions of 24 chronic alcoholic patients admitted to the alcohol rehabilitation ward. The study included clinical examination, detailed evaluation of nutritional status, quantitative vibration sense estimation and electrodiagnostic study of the peripheral nerves in the upper and lower limbs. During the subsequent 6 months all of the above measures were repeated at invervals of 1, 3 and 6 months, while the patients abstained from alcohol. Several of the parameters studied showed mild but definite improvement during 6 months.

Adult↗
PubMed1992

HLA-DR associates with specific stress proteins and is retained in the endoplasmic reticulum in invariant chain negative cells.

The major histocompatibility complex class II molecules are composed of two polymorphic chains which, in cells normally expressing them, transiently associate with a third, nonpolymorphic molecule, the invariant chain (Ii). To determine differences in the biology of class II molecules synthesized in the presence or absence of Ii, a comparative study was performed of BALB/c 3T3 cells that had been transfected with human class II HLA-DR molecules with or without cotransfection with human Ii. It was observed that in the absence of Ii, at least three high molecular weight proteins coimmunoprecipitate with HLA-DR molecules. These proteins did not coimmunoprecipitate with HLA-DR from cells cotransfected with Ii, nor did they coimmunoprecipitate with class I molecules from any of the transfectants. NH2-terminal sequence and/or Western blot analysis revealed the identity of two of the proteins as the endoplasmic reticulum (ER) resident stress proteins GRP94 and ERp72. Neither of these proteins was found to have an increased level of synthesis in the Ii- versus the Ii+ transfectants, indicating that their synthesis was not induced over constitutive levels. Fluorescence microscopy revealed that in the Ii- transfectants, the majority of the HLA-DR molecules were present in the ER, whereas in the Ii+ transfectants, the HLA-DR molecules were found in vesicular structures. We hypothesize that in the absence of Ii, ER resident stress proteins bind to class II molecules and retain them in the ER. This process, in turn, could prevent class II molecules from exiting the ER with endogenous peptides bound in their peptide binding cleft, and therefore could minimize autoimmune responses to endogenously processed self-peptides.

3T3 Cells↗
PubMed1992

Deficits in initial feature registration of schizophrenics and substance abusers.

Information processing deficits are consistently reported for schizophrenics. The present study evaluated if the longer duration required by schizophrenics to visually recognize a target may qualify, as proposed by previous studies, as a vulnerability and/or trait biological marker. Critical stimulus duration (CSD) was used as the index of initial target registration and recognition. The CSD is the minimal duration, in ms, to meet task criterion, which in the present study was seven consecutive identifications of the target letter 'T' or 'A'. There were 13 normal controls, 11 methadone maintenance experimental controls, 21 chronic schizophrenics and 12 subacute schizophrenics. Analysis of variance revealed that the CSDs of normal controls and subacute schizophrenics were not statistically different (p > 0.05); the CSDs of chronic schizophrenics were not statistically different from methadone controls (p > 0.05), while the chronic schizophrenics and the methadone controls' CSDs were statistically different from the normal controls and the subacute schizophrenics. The results support earlier reports of long target duration required by chronic schizophrenics for feature recognition. Since retarded CSDs were obtained for methadone control but not for acute schizophrenics, the CSD does not qualify as a specificity or a vulnerability index for schizophrenia. A neurophysiological explanation is proposed for the findings.

Adult↗
PubMed1992

Schizophrenic feature recognition deficits are independent of task criterion.

The present study determined the minimal exposure time (i.e., critical stimulus duration (CSD) necessary for feature registration and recognition by normals and chronic schizophrenics. Our interest was whether the longer exposure times required by schizophrenics than by normals could be attributed to an inability of schizophrenics to maintain attention when the task criteria were stringent as opposed to 'loose'. The present findings support previous findings of impaired feature recognition by chronic schizophrenics. Chronic schizophrenics' and normals' CSDs were not affected by task criterion. The consistent performance by these groups on the 'loose' and 'rigid' task criteria suggest that if attentional lapses occur then they are as likely to occur for chronic schizophrenics as for normals and they are independent of the task's criterion. It is concluded that impaired feature registration for chronic schizophrenics is a consequence of a deficit at the earliest stage of encoding.

Adult↗
PubMed1991

Recognition of the influenza hemagglutinin by class II MHC-restricted T lymphocytes and antibodies. I. Site definition and implications for antigen presentation and T lymphocyte recognition.

We have identified the site encompassing residues 126-145 on the A/Japan/57 influenza hemagglutinin molecule that is recognized in association with HLA-DRw11 by a clonal population of human, influenza specific, CD4+ cytolytic T lymphocytes. The critical core sequence of the T cell determinant spans hemagglutinin residues 129-140 and overlaps a putative antibody binding site. Hemagglutinins of influenza field strains that are not recognized by the T cell clones contain sequence alterations within the 129-140 target site of the CD4+ T cells. Functional analyses, with synthetic peptides, of the contribution of each of the residues within the sequence toward the capacity of the antigenic fragment to associate with both the restriction element and the TCR revealed a continuous linear array of residues necessary for MHC binding and/or Ag receptor engagement. At least one residue, the lysine at position 134, was shown to be critical for both DRw11 association and TCR recognition. The significance of these findings for recognition of glycoproteins by human CD4+ T cells is discussed.

Amino Acid Sequence↗
PubMed1991

Invariant chain influences post-translational processing of HLA-DR molecules.

HLA class II MHC molecule alpha- and beta-chains are normally synthesized in the presence of a third molecule, the invariant chain (Ii). Although Ii is not required for surface expression of HLA class II molecules, the influence of Ii on post-translational processing and maturation HLA class II molecules has not been thoroughly studied. In the present study, BALB/c 3T3 cells were transfected with HLA-DR alpha- and beta-chains with or without co-transfection with human Ii. Although Ii had no effect on the surface expression of DR, Ii did have a profound effect on the post-translational processing of both the alpha- and beta-chains. In the absence of Ii, the major species of alpha- and beta-chains were of lower m.w. than when expressed in the presence of Ii. The differences in m.w. were shown to be caused by differences in glycosylation with the majority of alpha- and beta-chains remaining unprocessed and endo H sensitive in the absence of Ii. The small proportion of alpha-chains that were processed in the absence of Ii showed an altered m.w. and altered sensitivity to treatment with endo H relative to alpha-chains processed in the presence of Ii. Pulse/chase studies demonstrated that although the majority of the alpha- and beta-chains remained unprocessed in the absence of Ii, the small amount that was processed was done so at a rate similar to that observed for alpha- and beta-chains processed in the presence of Ii. These studies demonstrate that Ii influences the post-translational processing of human class II molecules by affecting the proportion of alpha- and beta-chains that are processed and by determining the degree of processing of oligosaccharides on mature alpha-chains.

Animals↗
PubMed1990

The sites in the I-Ak histocompatibility molecule photoaffinity labeled by an immunogenic lysozyme peptide.

The class II histocompatibilty molecule I-Ak was photoaffinity labeled by NH2- and COOH-terminal photoreactive conjugates of an immunogenic hen egg white lysozyme (HEL) peptide. The labeled alpha and beta chains were digested with protease from Staphylococcus aureus strain V-8 (protease V-8) and/or trypsin, and the proteolytic fragments were separated by high performance liquid chromatography (HPLC) (peptide mapping). Reproducible peptide maps containing a major labeled component were obtained from the three conjugates reported here whose photoreactive group was attached via short spacers of limited flexibility. The COOH-terminal conjugate N-acetyl HEL-(49-61)-iodo-4-azidosalicyloyl thioester (compound 1) labeled hydrophilic tryptic digest fragments on both chains of I-Ak. The labeled digest fragments were homogeneous in reverse-phase and anion-exchange HPLC, indicating that the photoaffinity labeling was site-specific. Conversely, the NH2-terminal conjugate iodo-4-azidosalicyloyl HEL-(46-61) (compound 2: IASA-(46-61)) labeled exceptionally hydrophobic sequences on both chains of I-Ak. The labeling was also site-specific because reverse-phase HPLC of primary digests with protease V-8 and secondary digests with trypsin showed single major labeled components. The labeling of I-Ak by IASA-(46-61) was fully inhibitible by HEL-(46-61). In contrast, IASA attached to the smallest immunogenic peptide 52-61 (compound 3) labeled a distinctly different hydrophilic tryptic fragment. The site of the I-Ak molecule that was photoaffinity labeled by IASA-(46-61) (compound 2) was determined. IASA-(46-61) labeled selectively at Pro-118 of a primary alpha chain fragment most likely encompassing residues 115-134. It labeled Thr-121 of a primary beta chain fragment most likely encompassing residues 109-138. We also obtained evidence that IASA-(46-61) occupied the antigen-specific site; the conjugate stimulated a T-cell hybridoma that recognizes the sequence 52-61 and also competed for the binding of this smaller peptide to I-Ak. Thus, peptides that bind to the allele-specific binding site and are long enough to extend beyond it can interact with a hydrophobic area of class II molecules. This area is formed by sequences of the first halves of the second domain of both alpha and beta chains.

Affinity Labels↗