摘要:

The association between HLA‐DQ haplotypes and insulin‐dependent diabetes mellitus (IDDM) was studied in 48 children from 44 families ascertained from the high incidence area around Umeå, Sweden. Numerous hypotheses have been proposed to explain associations between HLA and IDDM, but comparisons of statistical models based on these hypotheses have not been attempted. The aim of the present study was to compare the goodness‐of‐fit and predictive abilities among different statistical models. A likelihood‐based analysis rather than a conventional analysis based on contingency tables was therefore adopted. We first used parental haplotype information in a conditional likelihood analysis (1) and then compared this analysis with that of an unaffected control group which used information on geographically matched controls. Under the analysis conditional on parental haplotype, a statistical model motivated by the hypothesis that the entire DQ heterodimer is involved in EDDM pathogenesis fit the data significantly better and had greater predictive ability than either a model motivated by the explanation that an IDDM gene is linked to DQB1 or that the DQB1 chain itself is involved in IDDM pathogenesis, or a model arising from the hypothesis that single amino acids at codon 57 of DQB1 and codon 52 of DQA1, respectively, confer susceptibility. Under the case‐control analysis, the identity of the best‐fitting or most predictive statistical model was not as clear, although both approaches to analyzing risk suggested that the single‐amino‐acids model had significantly poorer fit compared to the re

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02599.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

HLA Class I molecules on activated T cells are expressed as mAb W6/32 reactive heterodimers associated with β2‐microglobulin (β2‐m) and also as mAb LA45 reactive β2‐m free HLA Class I α‐chains. However, the regulation of free α‐chain expression remained enigmatic. Here we show, that the amount of cell surface expressed free heavy chains is influenced by two distinct mechanisms. Firstly, a proportion of expressed molecules are cleaved and give rise to a soluble pool of HLA Class I molecules. We provide evidence that, besides the previously described constitutive release of free alpha chains, a second phorbol ester inducible release mechanism involving activation of protein kinase C (PKC) does exist. We demonstrate that both the constitutive and the enhanced release of LA45 reactive HLA Class I α‐chains are the consequence of a cell membrane bound proteolytic activity with the characteristics of a 1, 10 phenanthroline sensitive metalloprotease. Secondly, we report that a distinct fraction of mAb tagged free a‐chains is internalized via an n‐ethylmaleimide sensitive pathway. Together, this data suggests that the expression of free α‐chains is regulated by pathways governing rel

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02600.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Based on previous studies in human melanoma leading to the molecular cloning of genes encoding peptide antigens recognized by MHC‐restricted cytotoxic T lymphocytes (CTL) we extended our efforts to renal cancer systems established in tissue culture. In two patients we obtained stable CD8+ CTL clones with high cytolytic activity for the corresponding autologous tumor cell linein vitro. Neither autologous EBV‐transformed B lymphocytes or PHA‐activated PBL nor natural killer targets K562 were lysed by these CTL clones. MZ1257‐RCC CTL5‐30 lysed autologous tumor cells as well as normal kidney cell cultures in an HLA‐A2 restricted fashion. Further specificity analysis showed cross reactivity with HLA‐A2 matched renal cancer cell lines, melanoma cell lines and tumor cell lines of other origins. HLA‐A2 negative target cells were not lysed. The restriction element for T cell recognition in another renal cancer system, MZ1973‐RCC, appeared to be HLA‐B8 as tested with CTL 5–10. Crossreactivity of CTL 5–10 was documented with one HLA‐B8 positive RCC line. Tumor cell lines of other origin were not lysed by CTL 5–10. For further study of CTL‐defined epitopes, peptides were extracted from tumor cell lines. Peptides from cultured cell lines were acid‐eluted and fractionated by reversed phase HPLC. The peptide fractions were tested in cytotoxicity assays for their ability to reconstitute RCC epitopes by addition to the HLA‐A2. 1 positive antigen processing mutant cell line 721.124xCEM.T2. One HPLC peak was identified containing an epitope for the HLA‐A2 restricted MZ1257‐RCC CTL 5–30. These peptide epitopes were present in the autologous renal cancer cell line MZ1257‐RCC as well as in an allogeneic HLA‐A2 positive RCC cell line MZ1973 and melanoma cell line SK29‐MEL, but were absent in peptides eluted from autologous EBV‐B cells. We conclude that renal cell carcinoma may induce autologous CTL. Epitopes recognized by MHC‐restricted CTL on RCC may be shared by HLA‐matched allogeneic renal cancer or even tumors of other origin, such as melanoma. The current challenge is the determination of the amino acid sequences of these CTL‐defined peptides as a step to further chara

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02601.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

The association of HLA class II DQB1 and DRB1 alleles with the development of cervical carcinoma was studied in 150 Swedish patients using PCR‐based HPV and HLA typing. The association of cervical carcinoma with alleles encoding the DQ3 antigen, previously found among German and Norwegian patients, was not observed in the Swedish patients. Five DQ‐DR haplotypes were indicated to be positively associated with development of cervical carcinoma in the Swedish patients. Two of these HLA associations were specific for HPV 18 infected patients, suggesting that the ability of the oncogenic HPV 18 to cause more rapid‐transit tumors than other high risk HPV types may be due to a deficiency in antigen presentation by the HLA molecules encoded by carried on these haplo

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02602.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

The limited availability of sera to human MHC‐linked transporters associated with antigen processing (TAP) has hampered the analysis of the role of these molecules in the reduced HLA Class I antigen expression by normal and transformed cells. To overcome these limitations, anti‐human TAP1 and anti‐human TAP2 xenoantisera have been generated and characterized. To this end rabbits have been immunized with TAP 1‐specific or TAP2‐specific peptides which correspond to nonhomologous, hydrophilic regions of each transporter subunit. The immunized rabbits developed high titer IgG antibodies which displayed specific reactivity with the immunizing peptides in ELISA. Both anti‐TAPl and anti‐TAP2 antisera immunoprecipitated the 70–76 kDa TAP complex from TAP1+‐TAP2+ cell lines WALK and Colo 38, but precipitated no component from TAP1+‐TAP2+ cell lines T2 and SK‐MEL‐19. Furthermore, in immunode‐pletion experiments anti‐TAPl and anti‐TAP2 antisera removed the molecules recognized by each of them in a lymphoid cell extract. Lastly, in Western blotting assays anti‐TAPl and anti‐TAP2 antisera reacted specifically with isolated TAP1 and TAP2, respectively. The latter results in conjunction with those of the immunodepletion experiments indicate thatTAPl and TAP2 are not detectable as isolated subunits in a cell extract and that TAP heterocomplex is the major, if not the only detectable molecular species in cells. Anti‐TAPl and anti‐TAP2 antisera were evaluated in immunohistochemical staining of both frozen and formalin fixed sections of skin and primary malignant melanoma lesions. Both antisera stained the cytoplasm of keratinocytes in normal skin and of melanoma cells in malignant lesions. The antisera we have elicited with TAP1‐ and TAP2‐specific peptides appear to be useful reagents to characterize the role of TAP in abnorm

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02603.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

αβ1 heterodimer is a member of the integrin receptor superfamily that has been described to be involved in cell‐matrix binding through its interaction with collagens, fibronectin and laminin. The αl integrin belongs to a subset of I‐domain containing integrins that includes αM, αL, αXand α2. In this study we describe an anti‐αl mAb (FBI2) that recognizes an epitope located in the human αl I‐domain, since the mAb can bind to human, but not to rat, recombinant I‐domain GST fusion protein. FBI2 mAb efficiently and specifically inhibits the binding of activated human lymphocytes to laminin, collagen and fibronectin. These data support the notion that the αl I‐domain itself has an important role in receptor‐ligand binding. In particular, we show that al inte‐grin‐dependent lymphocyte adhesion to fibronectin is I‐domain mediated, at variance with the RGD‐dependent adhesion which seems to be mediated by the βl rather than the αl integrin chain. Lastly, the overexpression of the αl‐integrin by stromal cells and blood vessels of solid tumors may suggest a rol

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02604.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02605.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02606.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

We have cloned and sequenced a genomic region centromeric of theHLA‐Blocus from different MHC ancestral haplotypes. These haplotypes are associated with several diseases. The sequences were analyzed for coding potential and their relevance to disease associations were assessed with respect to the level of polymorphism. Analysis of sequences located approximately 25kb centromeric ofHLA‐Breveals the existence of fibroblast growth factor receptor related sequences. These sequences designatedPERB1 (FGFR6) reveal 80% homology, at both nucleic acid and amino acid level, to the immunoglobulin domain 1 (Ig‐1) of the human fibroblast growth factor receptor 3 (FGFR3) gene. Amino acid comparison of the Ig‐1 domain of PERB1 to those of other FGFR molecules indicates thatPERB1is more closely related toFGFR3andFGFR5than toFGFR1,FGFR2orFGFR4. Genomic sequence analysis, however, reveals no consensus splice sites and indicates the existence of inframe premature stop codons in the putative coding sequences. The results suggest that these sequences may representFGFRgene fragments existing within the central MHC. Sequence analysis of theMhcin 6 chimpanzee and one orangutan indicates that the existence ofPERB 1predates the spe‐ciation of the three species. The fact that the MHC contains a mixture of functional and nonfunctional (pseudo) genes suggests that a functional copy ofPERB1 (FGFR6) may exist within or in close proximity t

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02607.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

CD69 is an early activation antigen of peripheral blood lymphocytes and is constitutively expressed on a wide variety of bone marrow‐derived cells. To further characterize the distribution and understand the potential biological role of the molecule in normal and malignant hematopoiesis, we used a novel high affinity anti‐CD69 mAb (UN6) and analyzed hematopoietic progenitor cells together with a panel of myeloid and lymphoid malignancies. We report that mobilized peripheral blood CD34+ cells display detectable levels of CD69 and that the density of membrane expression correlates with the immature phenotype CD34brightThy‐1brightcells. Furthermore, during cytokine‐induced differentiation, the expression of CD69 is moderately down‐regulated. Analysis of hematopoietic malignancies revealed that CD69 expression correlates with the immature myeloid phenotype. Taken together these data suggest a role of CD69 during the early phase of hematopoiesis and in the leukemic trans

ISSN:0001-2815    

DOI:10.1111/j.1399-0039.1996.tb02608.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY