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Biomedical subjects

R Winchester

Publications and source records attributed to R Winchester.

At least 73 records · Page 4Linked to original sources
PubMed1987

The co-occurrence of Reiter's syndrome and acquired immunodeficiency.

Thirteen patients who had the co-occurrence of severe Reiter's syndrome and the acquired immunodeficiency syndrome (AIDS) or its syndromes were studied. The arthritis was reactive in three patients and without defined cause in the others. Nine patients had HLA-B27. The two syndromes appeared simultaneously in four patients, suggesting a common biologic process, and in the others the immunodeficiency either preceded or followed the arthritis. Reiter's syndrome occurring in the setting of this profound immunodeficiency suggests that helper T cells were not involved in the pathogenesis of the rheumatic disease. Difficulties were encountered in the diagnosis of either syndrome in the presence of the other. Two patients with Reiter's syndrome developed Kaposi's sarcoma and fulminant AIDS after receiving methotrexate, which emphasizes the need for caution in the use of immunosuppressive therapy in Reiter's syndrome. An additional patient with undifferentiated spondylarthropathy subsequently developed psoriasis in conjunction with the onset of AIDS.

AIDS-Related Complex↗
PubMed1987

Complement activation and vascular injury in systemic lupus erythematosus.

The deposition of immune complexes within blood vessel walls results in the potential for complement activation and the release of chemotactic factors, such as fragments of C5 (C5fr). The generation of C5fr results in the intravascular aggregation of neutrophils with subsequent leukostatic occlusion of the pulmonary arterioles. The generation of C5fr may contribute to the pathogenesis of adult respiratory distress syndrome and other diseases. Studies were undertaken to determine the role of circulating complement derived peptides and intravascular neutrophil activation in systemic lupus erythematosus.

Antigen-Antibody Complex↗
PubMed1987

Human leukemic B cell activation: functional consequence of membrane IgM interaction with anti-IgM ligand is an alterable cell characteristic.

A functional study of several human malignant B cell populations has indicated that occasional leukemic clones are extraordinarily sensitive to signal transduction through membrane IgM. One isolated hairy cell leukemia (HCL) with low background DNA synthesis was stimulated to significant levels of DNA synthesis when cultured with high (100 micrograms/mL) concentrations of soluble anti-IgM ligands. In contrast to the activation of normal peripheral blood polyclonal B cells, this DNA synthesis was completely independent of accessory T cell factors. Although the HCL clone could also be induced to enter S phase by incubation in media supplemented with only activated T cell supernatant, culture of the clone with activated T cell supernatant plus anti-IgM Ab resulted in DNA synthesis that was significantly less than that induced by either activator alone. Factor(s) in T cell supernatant appear to modulate the leukemic clone so that the binding of ligand to membrane IgM is perceived as an inhibitory rather than a stimulatory signal for DNA synthesis. In terms of Ig Fc independence and low ligand dose requirements, anti-IgM-mediated inhibitory signal transduction in the T cell supernatant-activated HCL clone was found to mimic anti-IgM mediated suppression of the spontaneous DNA synthesis of an alternative HCL clone. The functional results suggest that the type of signal transduced anti-Ig ligands may reflect differences in the activation state of receptive leukemic B cells.

Antibodies, Anti-Idiotypic↗
PubMed1986

Complexity of the supertypic HLA-DRw53 specificity: two distinct epitopes differentially expressed on one or all of the DR beta-chains depending on the HLA-DR allotype.

The supertypic HLA-DRw53 specificity is associated with three allelic class II specificities defined by alloantisera: HLA-DR4, -DR7, and DRw9. The present study demonstrates the complexity of this supertypic DR specificity by comparing two DRw53-related determinants defined by the monoclonal antibodies PL3 and 109d6. For every HLA-DR4 cell line tested, both monoclonal antibodies were found to bind to the same subpopulation of DR molecules. This PL3+, 109d6+ DR subpopulation is also found on most, but not all, DR7+ cell lines with a beta-chain pattern that is identical to the beta-chain pattern of the PL3+, 109d6+ subpopulation on DR4 cell lines. However, some DR7+ cells which carry the HLA haplotype Bw57, DR7, DRw53, DQw3 were also found which completely lack the expression of the 109d6 determinant, but continue to express the PL3 determinant and some of the DRw53 determinants recognized by alloantisera. This results from the fact that the PL3 determinant is expressed on all of the DR molecules found on DR7 cells, including the distinct subpopulation of molecules that carry the HLA-DR7 determinant recognized by the monoclonal antibody SFR16-DR7. This PL3+, SFR16-DR7+ subpopulation does not carry the 109d6 determinant, demonstrating that the PL3 and 109d6 DRw53-related determinants are distinct and can be expressed on a different number of DR molecules, depending on the allotype of the cells. Blocking studies were also performed by using these monoclonal antibodies with alloreactive HLA-DR7-specific cytotoxic T cell clones. In these studies, the T cell-defined HLA-DR7 determinants were found to be carried by the same subpopulation of DR molecules recognized by the HLA-DR7-specific monoclonal antibody and not carried by the DR molecules recognized by 109d6. The DR7+ cell lines which do not express the 109d6 determinant also fail to express another supertypic determinant recognized by the monoclonal antibody IIIE3 carried on this molecule. Furthermore, no additional allelic forms of this unique DR beta-chain were found associated with the nonpolymorphic DR alpha-chain on these cells, suggesting that this DR beta-chain gene is not expressed. These cells also behave as homozygous typing cells for the Dw11 subtype of DR7 in HLA-D typing in the mixed lymphocyte culture assay. This suggests that the lack of expression of a specific class II gene may contribute additional genetic polymorphism within the known HLA-DR allotypes.

Alleles↗
PubMed1986

Structural relationships between the DR beta 1 and DR beta 2 subunits in DR4, 7, and w9 haplotypes and the DRw53 (MT3) specificity.

The class II molecules of DR4, DR7, and DRw9 haplotypes were analyzed by immunoprecipitation, followed by two-dimensional gel electrophoresis and N-terminal amino acid sequencing. By using HLA-DR chain-specific monoclonal antibodies, two distinct DR beta-chains were identified. One beta-chain, designated DR beta 2, had a characteristic acidic mobility. In all three DR types the DR beta 2-chains were indistinguishable by two-dimensional gel electrophoresis and partial N-terminal sequencing. A second DR beta-chain designated beta 1 had a more basic mobility on two-dimensional gel electrophoresis, and differed from the DR beta 2-chains by the consistent presence of phenylalanine at position 18. In contrast to the DR beta 2-chains, the DR beta 1-chains were clearly polymorphic, with specific amino acid sequence differences characteristic of each DR type. The monoclonal antibodies 109d6 and 17-3-3S, recognizing distinct polymorphic epitopes similarly correlated with the DRw53 allospecificity, were found to react with different DR beta-chains. The epitope recognized by monoclonal antibody 109d6 was identified on the DR beta 2-chain in the prototypic DR4, DR7, and DRw9 cell lines. However, the DR7, Dw11, DQw3 cell line BEI was unreactive with antibody 109d6 by either immunofluorescence or immunoprecipitation despite the presence of the DRw53 allodeterminant on this cell line. The other DRw53-like monoclonal antibody, 17-3-3S, reacted with the DR beta 1-rather than the DR beta 2-chain in all DR4 and DR7 cell lines tested, including the cell line BEI. However, antibody 17-3-3S did not react with the DRw53-positive DRw9 cell line ISK. These studies suggest that the DRw53 allospecificity is more complex than previously thought and may comprise a number of distinct epitopes encoded by two different DR beta loci.

Amino Acid Sequence↗
PubMed1985

Human B cell activation. Evidence for diverse signals provided by various monoclonal anti-IgM antibodies.

Seven murine monoclonal antibodies (mAb) with different binding characteristics for human IgM varied markedly in their ability to induce proliferation of T cell-depleted human splenocytes. Two mAb (HB57 and 5D7) that bound to distinct epitopes on IgM were highly effective initiators of B cell proliferation at very low concentrations, in the presence of a T cell factor source. In the absence of T cell supernatant, both HB57 and 5D7 mAbs produced a markedly reduced degree of stimulation at all concentrations. Two additional anti-IgM mAb (VIIIE11 and Mu53) were distinctive in that, even at high concentrations, only limited proliferation was observed compared with the first group of mAb. This proliferation depended on the presence of T cell supernatant. Competitive-binding studies revealed that the epitope recognized by mAb Mu53 may be identical or very proximate to that recognized by HB57. Three other mAb (1G6, XG9, and P24) induced little or no proliferation. 1G6 bound to a unique epitope on the IgM molecule, whereas XG9 shared a determinant with VIIIE11 mAb. Regulatory influences of Fc receptor binding cannot account for all the diversity in proliferation observed with the individual anti-IgM mAb. Markedly augmented proliferation was obtained when B cells were cultured with certain combinations of anti-IgM mAb in the presence of exogenous T cell supernatant. The proliferation induced in the absence of T cell supernatant by high concentrations of mAb mixtures that included 1G6 approached that observed for the same mixtures in the presence of T cell supernatant. The data suggest that certain signals delivered through membrane IgM can bypass the need for T cell supernatant in the activation of human B lymphocytes.

Animals↗
PubMed1985

Identification, at the genomic level, of an HLA-DR restriction element for cloned antigen-specific T4 cells.

Two T4 cell clones (TLC) specific for antigenic epitopes on Chlamydia trachomatis were studied. Using a panel of allogeneic antigen-presenting cells (APC), both TLC were found to be restricted by HLA class II elements closely associated with, but not identical to the DRw5S specificity, as determined by highly selected alloantisera, a monoclonal antibody (mAb), 109d6, and confirmed on the DNA level by determination of restriction fragment length polymorphisms (RFLP) with a DR beta probe. Furthermore, HLA-DR-specific mAb, including 109d6, but not other HLA class II- or class I-specific antibodies inhibited the two TLC, strongly suggesting that the restriction element is expressed by a DR molecule. Using digestion with Hind III restriction enzyme and a DR beta probe, we found a complete concordance between the appearance of a 9.3 kilobase band and the ability of allogeneic APC to restimulate the T cell clones. Thus, the restriction element for these T cell clones appear to be expressed by DR molecules, but can, at present, only be detected at the genomic level.

Antibodies, Monoclonal↗
PubMed1985

Definition of a possible genetic basis for susceptibility to acute myelogenous leukemia associated with the presence of a polymorphic Ia epitope.

The polymorphic Ia epitope recognized by monoclonal antibody 109d6 is detectable on the leukemic cells of a significantly increased number of individuals with acute myelogenous leukemia, compared with its frequency in normal healthy control individuals. In control individuals, the presence of the 109d6 epitope is closely correlated with but not identical to the DRw53 allo-specificity. However, the frequency of particular conventional Ia allodeterminants, including DRw53, is not significantly elevated in the leukemia group. Considerable evidence supports the conclusion that the high frequency of the 109d6 epitope reflects an inherited basis for susceptibility to the development of acute myelogenous leukemia and not a differentiation event occurring in the leukemic lineage. The 109d6 determinant is expressed by leukemic myeloblasts as well as by homologous normal B cells and monocytes obtained from the same individuals during remission of the leukemia. Furthermore, in healthy family members the 109d6 epitope is encoded by Ia haplotypes that are shared with the patient. Of special interest, certain of these haplotypes have combinations of the 109d6 epitope and Ia specificities not commonly seen in normal individuals; here, also, healthy family members share these haplotypes.

Antibodies, Monoclonal↗
PubMed1984

Molecular localization of human class II MT2 and MT3 determinants.

The specificities of the monoclonal antibodies I-LR2 and 109d6, which recognize MT2- and MT3-like serologic determinants, respectively, have been confirmed by panel testing. In addition, the relationships of these antibodies to other monoclonal antibodies and alloantisera have been studied by means of cell surface fluorescence, complement-dependent cytotoxicity and immunoprecipitation. Using these monoclonal antibodies, molecules encoded by the HLA-D region have been isolated and characterized by amino acid sequencing and peptide mapping. By these criteria, the major populations of molecules bearing MT2- and MT3-like determinants are indistinguishable from DR molecules.

Amino Acid Sequence↗
PubMed1984

Definition of AML susceptibility and classification using monoclonal antibodies.

Of 112 patients with acute leukemia 13 exhibited terminal deoxyribonucleotidyl transferase activity (TdT) with a cell phenotype characterized by the presence of early or mature monocyte differentiation antigens detected by monoclonal antibodies and elevated serum lysozyme. These cells were either unclassifiable by cytochemical analysis or fell into the M2 or M5 categories by the French-American-British classification. These leukemias appear to form a distinct nosologic entity representing a malignant transformation among early cells in the monocyte lineage. Among 60 patients with acute myelogenous leukemia 87% expressed the polymorphic Ia antigen detected by monoclonal antibody 109d6 compared to an incidence of 40.5% in the control population, relative risk 9.2. Evidence was obtained that this antigen was present in healthy family members and remission B-cells and monocytes of patients, and that its presence was associated with a genetically defined susceptibility state for the development of acute myelogenous leukemia.

Antibodies, Monoclonal↗
PubMed1984

Evidence for the separate molecular expression of four distinct polymorphic Ia epitopes on cells of DR4 homozygous individuals.

The monoclonal antibodies 109d6 and IVD12 reacted with separate polymorphic Ia epitopes in immunofluorescent studies. Using a panel of lymphoblastoid B cell lines, antibody 109d6 reacted with all HLA-DR4 or DR7 positive lines in a pattern resembling the MT3 specificity recognized by human alloantisera. The antibody IVD12 reacted with all HLA-DR4 and two of three DR5 positive B cell lines suggesting that it recognized a specificity similar to MB3. The intensity of fluorescence was greater on DR5(+) cell lines than on DR4(+) cell lines relative to the amount of a nonpolymorphic Ia determinant. Among 45 unrelated control individuals reactivity with antibody 109d6 was correlated most closely with (r = 0.724) but not identical in occurrence to the MT3 specificity. Cocapping experiments demonstrated that the 109d6 epitope and the IVD12 epitope were present on independently redistributed cell surface molecules of DR4 homozygous lymphoblastoid cell lines. Furthermore, the DR4 alloantigens detected by an absorbed polyclonal human alloserum were similarly identified on molecules that were independent from those bearing either the 109d6 epitope or the IVD12 epitope. Taken together, these data indicate the existence of at least four distinct, serologically defined Ia molecular species.

Animals↗
PubMed1984

Loss of suppressor T-cells in active inflammatory bowel disease.

The proportions and absolute numbers of helper and suppressor T-cells in 40 patients with inflammatory bowel disease and 22 control subjects were determined, using the monoclonal antibodies OKT 4 and OKT 8. There were no significant differences in helper or suppressor cell proportions among 15 steroid treated patients with active inflammatory bowel disease, 10 patients with inactive inflammatory bowel disease, 10 patients with other gastrointestinal diseases, or 12 normal control subjects. In contrast, 15 patients with active inflammatory bowel disease not treated with corticosteroids manifested increased proportions of helper cells and decreased proportions of suppressor cells (p less than 0.001), compared with all other patient groups and to normal controls. When absolute numbers of helper and suppressor subsets were measured, these alterations in proportions of helper and suppressor cells were primarily attributable to decreased counts of suppressor T-cells both in patients with active Crohn's disease and in those with ulcerative colitis (p less than 0.01). In four patients undergoing serial study, the helper/suppressor ratios appeared to rise and fall respectively with clinical exacerbations and remissions of disease. These data provide additional evidence for the involvement of cellular immune systems in these disease processes.

Adolescent↗
PubMed1983

Structural analysis of a human I-A homologue using a monoclonal antibody that recognizes an MB3-like specificity.

Monoclonal antibody IVD12 was used to isolate and characterize a human Ia molecule present on B cells that generally display DR4 or DR5 phenotypes. The specificity of binding of IVD12 to human peripheral blood B cells from 75 normal individuals and 19 homozygous human lymphoblastoid B cell lines was identical to the supertypic specificity MB3 previously defined. Furthermore, IVD12-reactivity was shown to segregate with HLA in three informative families. In each family, individuals positive for IVD12 binding were also positive for DR4 or DR5. Using IVD12, a molecule has been isolated from the homozygous cell line PRIESS (DR4/4) and has been shown by amino acid sequence analysis to be homologous to the murine I-A and human HLA-DS molecules. These findings suggest that the MB3 specificity is found on a molecule encoded by loci distinct from those loci which encode HLA-DR molecules. This molecule represents the third family of HLA-D region molecules isolated from the cell line PRIESS. Both HLA-DR and HLA-SB molecules from this cell line were previously shown by amino acid sequence analysis to be I-E-like but distinct from one another. Collectively, these data provide evidence that the HLA-D region contains at least six loci encoding distinct alpha and beta chains for the HLA-SB, HLA-DR, and HLA-DS molecules.

Amino Acid Sequence↗
PubMed1983

HLA-DS molecules and their relation to supertypic specificities.

We have analyzed the structures of HLA-DS molecules from DR1, 2, 3, 4, 5, and 7 cell lines by two-dimensional gel electrophoresis and examined the relationship of HLA-DS molecules to those expressing the supertypic specificities MT1, MB3, and MT3. These studies have allowed us to conclude that the HLA-DS locus is as polymorphic as HLA-DR and that the MT1 and MB3 supertypic specificities reside on DS molecules. Furthermore, MT1 molecules from DR1, DR2, and DRw6 cell lines are structurally different as are MB3 molecules from DR4 and DR5 cell lines. In addition, studies using two MT3 specific reagents, a monoclonal antibody, 109d6, and an alloantiserum, Hon, suggest that MT3 is a cross-reactive determinant present on products of two different loci: a DS4 molecule and a DR7-like molecule.

Antibodies, Monoclonal↗
PubMed1983

Association of susceptibility to certain hematopoietic malignancies with the presence of Ia allodeterminants distinct from the DR series; utility of monoclonal antibody reagents.

The Ia antigen allospecificities of individuals with either B type chronic lymphocytic leukemia or hairy cell leukemia resembled one another and differed significantly from those of a control population. In contrast, the Ia alloantigens of individuals with non-Hodgkin's lymphoma were distinctly different from those of the leukemic group but differed little from the control group. A monoclonal antibody, IVD12, directed to an MB3-like determinant reacted with the greatest proportion of the leukemic individuals and yielded the highest positive relative risk. A lower degree of positive association was found with the presence of the MT2 determinant. In contrast, the low observed frequency of the MT1/MB1 determinant among leukemic individuals was associated with the most significant negative relative risk. The relative risk associated with the presence of DR5 was positive, while among patients with chronic lymphocytic leukemia the relative risk associated with DR2 was negative. Among patients with Hodgkin's Disease the relative risk associated with the presence of DR5 was significantly increased.

Antibodies, Monoclonal↗
PubMed1982

Association of certain Ia allotypes with the occurrence of chronic lymphocytic leukemia. Recognition by a monoclonal anti-Ia reagent of a susceptibility determinant not in the DR series.

The Ia antigen allospecificities of individuals with B type chronic lymphocytic leukemia differed significantly from those of a control population. A monoclonal antibody, IVD12, directed to a MB3-1ike determinant, reacted with 92.5 percent of the individuals with leukemia and yielded the greatest positive relative risk, 13.5. A lower degree of positive association was found with the presence of the MT2 determinant. In contrast, the low observed frequency of the MT1/MB1 determinant among leukemic individuals was associated with the most significant negative relative risk, -8.1. Among HLA- DR specificities, the relative risk associated with the presence of DR5 was positive while that with DR2 was negative.

Adult↗
PubMed1982

The human HLA-DR antigens are encoded by multiple beta-chain loci.

Monoclonal antibodies have been used to isolate and characterize human HLA-DR antigens from human B cell lines. Using sequential immunodepletion experiments, several subsets of DR antigens have been identified. Partial amino-terminal amino acid sequencing has identified these subsets as DR molecules with sequences homologous to the murine I-E alloantigens. In addition, sequence data provide evidence for primary structural differences in the DR beta-chains of two of the subsets. These results provide primary structural evidence for the presence of multiple DR beta-chain loci.

Amino Acid Sequence↗