Biomedical subjects
D J Schendel
Publications and source records attributed to D J Schendel.
Enhanced expression of HLA-class II molecules on activated human T lymphocytes following treatment with tumor necrosis factor alpha.
Many factors induce or enhance expression of major histocompatibility complex class I and class II molecules on various cell types. Human T lymphocytes are class II negative in the resting state but show expression of class II molecules following activation. We analyzed the modulating capacity of the lymphokines recombinant interferon gamma (rIFN-gamma), interleukin-4 (IL-4), and recombinant tumor necrosis factor alpha (rTNF-alpha) on class II expression in subsets of alloactivated human T lymphocytes. The activated CD4+ T cells expressed all three class II isotypes (DR, DQ, and DP), whereas the cytotoxic CD8+ T-cell lines expressed DR and DP molecules but failed to bind DQ-specific monoclonal antibodies significantly. Treatment with rIFN-gamma and IL-4 had no effect on class II expression on any of the T-cell lines or clones, whereas rTNF-alpha enhanced class II expression in both subsets. rTNF-alpha could modulate expression of all three class II isotypes but, in principle, it appears only to affect ongoing class II synthesis as de novo synthesis of class II molecules with a resultant change in the class II phenotype from DR+ DQ- DP+ to DR+ DQ+ DP+ in the CD8+ T lymphocytes was not observed. No synergic effects of rINF-gamma and rTNF-alpha were observed; this results from the fact that activated T cells express few, if any, receptors of rIFN-gamma.
HLA-Cw7-associated restriction fragment length polymorphism detected with an HLA-C locus-specific DNA probe.
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Genomic cloning and expression of HLA-B37 in the mouse mastocytoma cell line P815-HTR.
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On the peptide model of allorecognition: cytotoxic T lymphocytes recognize an alloantigen encoded by two HLA-linked genes.
The peptide model of allorecognition hypothesizes that alloreactive cytotoxic T lymphocytes recognize peptides associated with major histocompatibility complex (MHC) molecules. This study characterizes an unusual alloantigen that is recognized by two human cytotoxic T-cell lines and may represent a complex formed by the association of a naturally selected peptide with an MHC molecule. Family studies demonstrate that both components of the alloantigen are products of MHC-linked genes. One component is a class I molecule most likely encoded by the HLA-B locus. The second component is encoded by an MHC-linked gene that shows a limited polymorphism; whether it represents the product of a second class I gene or of some other MHC gene remains to be determined. These data provide experimental evidence supporting the peptide model of allorecognition in human beings and indicate that some naturally selected peptides involved in allorecognition may be derived from MHC-encoded proteins.
Differential surface expression of class II isotypes on activated CD4 and CD8 cells correlates with levels of locus-specific mRNA.
Class II molecules are encoded by genes located within the HLA-D region in man. Three major subregions (DR, DQ, and DP) have been identified, each containing several genes encoding the alpha- and beta-chains of the class II heterodimers. In man B lymphocytes constitutively express class II molecules, whereas T lymphocytes express class II molecules only after Ag activation. We have analyzed isotype-specific expression of class II on CD4+ and CD8+ T cell lines and clones derived from one donor after stimulation with allogeneic cells, with the soluble Ag (purified protein derivative of tuberculin), and with mitogen activation by PHA. Class II mRNA transcripts were analyzed in parallel by Northern blot hybridization with DR, DQ, and DP beta-chain-specific cDNA probes. Nearly all activated T lymphocytes expressed DR molecules and variable numbers of DP+ cells were detected in each T cell line or clone, regardless of the mode of Ag activation. DQ molecules were only found on T cell lines or clones of the CD4 phenotype. In contrast two CD8+ cytotoxic T cell lines did not bind DQ-specific mAb although they did express DR and DP molecules. The presence of DR, DQ, and DP mRNA transcripts correlated with the differential patterns of surface expression, indicating that variations in class II cell surface expression among activated T cells may relate to differential gene regulation in these cells.
Definition of HLA class I-associated DNA polymorphisms using an HLA-B locus-derived cDNA probe.
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Analysis of HLA-B35 variants and B35 haplotypes by isoelectric focusing and Southern blot analysis.
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The use of fusion proteins to study HLA-B27-specific allorecognition.
Potential antigenic regions of the various external domains of the HLA-B27 antigen were expressed as fusion proteins in bacterial hosts and analyzed for their ability to induce humoral and cellular responses. Monoclonal antibodies directed against the proteins recognized monomorphic determinants of denatured HLA-antigens, but not B27-antigens expressed by intact lymphocytes. T-cell proliferation and IL-2 secretion were induced with a fusion protein representing regions of the first and second domains around amino acid residue 114. None of the fusion proteins stimulated cytotoxic T-lymphocytes (CTL) in an HLA-specific manner, although several included those amino acid sequences thought to be important for CTL recognition.
Serological and biochemical characterization of HLA-A molecules bearing a public epitope.
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Major histocompatibility complex markers in patients with nomifensine-induced immune hemolytic anemia.
To evaluate a possible role of major-histocompatibility-complex (MHC)-related immune-response genes for the selective production of drug-induced antibodies, HLA class I (ABC), class II (DR, DQ), class III (BF, C2, C4A, C4B) as well as glyoxalase-1 allotypes were investigated in 26 patients with nomifensine-induced immune hemolytic anemia. No statistically significant deviations of MHC antigen frequencies were noted. The possible implications of these findings are discussed.
Possible male segregation distortion of DR2 haplotypes in narcolepsy patients.
Segregation of disease-associated DR2-linked haplotypes from patients with narcolepsy was studied in 18 German families. Of these, 13 were informative, as transmission could be traced from DR2 heterozygous patients to their healthy offspring. Although the composition of extended haplotypes was equal in males and females, DR2 was transmitted to 78.6% of the offspring by diseased fathers but only to 57.1% by diseased mothers. Compared to an expected 1:1 ratio according to Mendelian segregation this means a statistically significant deviation (p less than or equal to 0.03) for male but not for female patients. In contrast, transmission distortion was not observed with 30 DR2 haplotypes in 27 healthy families. These data represent a new example of male segregation distortion in an HLA-associated disorder.
Triggering of the lethal hit in human cytotoxic T lymphocytes: a functional role for a 103-kDa T cell-specific activation antigen.
A monoclonal antibody (CB.1) is described that defines a new triggering signal for human cytotoxic T lymphocytes (CTL). The antibody precipitates a 103-kDa surface antigen from activated normal human T cells. The antigen is undetectable or present in only low amounts on resting T lymphocytes but its expression increases strongly after activation and proliferation on T4+ and T8+ T lymphocytes. Binding of antibody CB.1 to CTL results in triggering of the lethal hit. This induction of cytotoxicity is dependent on cross-linking of CTL and an Fc receptor-bearing target cell with CB.1 and requires Ca2+ like antigen-specific triggering. CB.1-induced triggering can be specifically inhibited by binding of antibodies to the T8 or T4 molecules on T8+ or T4+ CTL.
HLA and narcolepsy in a German population.
In this paper the first MHC data including HLA-A, B, C, DR, DQ and complement BF, C4A, C4B determinants in German narcoleptics are presented together with the first family studies in European Caucasoids. 57 out of 58 unrelated patients (98.3%) were positive for DR2 and DQw1, respectively. In contrast to all other reports, one patient with typical signs of narcolepsy was found to be DR2/DQw1 negative. Data showing significant increase in the frequency of B7, and normal frequencies of B35 were discordant with data from Japanese patients. Definition of the extended DR2 linked haplotypes, deduced from 6 families, revealed that 5 out of 12 were DQw1, DR2, BFS, C4B1, C4A3, B7 (Cw7), while 11/12 had DR2, DQw1, BFS, C4A3, C4B1 in common. In one multiple case family two genotypically different DR2 haplotypes were identified in affected siblings. Results from the family study were concordant with a dominant mode of inheritance with incomplete penetrance of a hypothetical disease susceptibility gene.
T cells specific for different antigens express different HLA-D region products.
T cell lines and clones were analyzed for surface expression of Ia antigens using monoclonal antibodies (mAb) that detect monomorphic and polymorphic epitopes on Ia molecules encoded by the HLA-DR and HLA-DQ gene clusters. All mAb bound to B lymphocytes or lymphoblastoid cell lines of the same individuals from whom the T cells were derived. Three mAb detecting monomorphic epitopes, primarily associated with HLA-DR, bound to all T cells showing that each clone or line expressed some type of Ia. Three other mAb defining polymorphic epitopes associated with HLA-DR products showed differential binding patterns. Two reagents, R3 and E15/4 recognizing the supertypic specificity DRw52 (formerly MT2), bound to every alloreactive clone, whereas the 16.23 mAb, detecting a private DR3-associated epitope, failed to bind to any clone. In contrast, the 16.23 epitope was detected on high percentages of T cells specific for purified protein derivative of tuberculin (PPD) or tetanus toxoid (TT). Biochemical studies showed that the 16.23 and DRw52-like epitopes can be present on distinct DR molecules on B cell lines and this may also be the case for T cells. Three other mAb, detecting epitopes associated with HLA-DQ, also revealed differential binding patterns when tested on various T cells. Two failed to bind to any alloreactive clone and to only low numbers of PPD- or TT-specific T cell lines, whereas the third bound distinctly to a CD4+/CD8+ alloreactive clone. Biochemical analyses have shown that these DQ epitopes can be present on different molecules. Combined, these observations indicate that differential expression of Ia molecules encoded by both HLA-DR and DQ occurs between B and activated T cells as well as among T cell populations of the same individual. Whether these differences reflect quantitative variations in expression of given DR or DQ molecules or, alternatively, are due to differential class II gene expression in activated T cells remains to be determined.
Immunogenicity of and immune response to the human platelet antigen Zwa is strongly associated with HLA-B8 and DR3.
In a prospective study the immunogenicity of the Zwa antigen during gestation was investigated. Twenty-six out of 1,211 pregnant women were Zwa negative (2.15%). In 2 out of 23 Zwa negative mothers who delivered Zwa positive children, an antibody to Zwa was detected. To determine the relationship between the immune response of pregnant women towards Zwa and the MHC, the phenotype frequencies of HLA-A, B, C, DR, and complement BF, C2, C4A, C4B allotypes of "non-responders" without detectable Zwa antibodies (N = 20) were compared with a group of "responders", i.e. Zwa negative mothers giving birth to Zwa positive children with typical neonatal alloimmune thrombocytopenia (NAIT; N = 39) and with a normal control population. When compared to the normal control group, "non-responders" showed a significant increase of the DRw6 frequency, whereas in the "responders" group HLA-A1, B8, DR3, and C4A*QO were significantly elevated. If "non-responders" and "responders" were directly compared, only B8 and DR3 remained significantly different. The strongest association with a hypothetical immune response gene appeared to exist with DR3.
C4 phenotypic variation suggests an unusual class III gene organization.
The class III gene markers, C4A, C4B, C2 and BF were determined in 26 HLA genotyped families. In 6 of these families the inheritance of the C4A electrophoretic phenotype, C4A 3, A 2 could not be explained assuming the genetic model that the C4A component is controlled by only one locus (C4A) and suggests that both C4A 3 and C4A 2 are encoded by the same chromosome. This apparently duplicated C4A locus haplotype is common in Northern Europeans occurring at a frequency of at least 6%. In 4 families the C4A 3, A 2 'variant' occurred together with HLA-Bw35 and in 2 together with HLA-Bw55. Furthermore, it was striking that in each family the C4A 3, A 2 'variant' was found exclusively with the complotype FC3/20 which encodes no phenotypically expressed C4B locus product.
Possible association between HLA-DR5 and superficial spreading melanoma (SSM).
Previous analyses of possible associations between MHC determinants and cutaneous malignant melanoma (MM) have been inconclusive. We have investigated 98 patients with special emphasis on histologically determined subtypes of MM, and 5 multiple-case families. In addition to HLA-ABC and DR typing, complement allotypes of C2, C4A, C4B, BF were determined. Among the unrelated patients HLA-DR5 and, secondarily, B49 were observed to be associated with superficial spreading (SSM) but not with nodular (NM) or lentigo maligna melanoma (LMM). In families with MM, no definite segregation of the disease according to HLA and complement haplotypes was discernible. Moreover, no coincidence of haplotypes occurred in patients of the different families. HLA region recombinations including B/DR and/or DR/GLO were found in all the families investigated.