Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two-dimensional gel electrophoretic analyses of immunoprecipitates of the HLA-D region antigens revealed three beta (Mr 28 X 10(3) to 30 X 10(3) structurally polymorphic polypeptides. Analyses of the nonglycosylated beta polypeptides indicated that their polymorphism is most probably due to variations in amino acid structure. The polymorphism has been examined using lymphoblastoid cell lines that were derived from different geographical populations (North European and Italian) and that expressed various HLA-DR alloantigenic specificities. The results confirm that the positional variation of one beta polypeptide (namely beta-1) correlated with the HLA-DR allospecificity and was not influenced by the ethnic origin of the individual donating the cells. The positional variation of a second beta polypeptide (namely beta-2) was consistent with strong linkage dis-equilibrium between the corresponding genetic locus and the HLA-DR locus. Further, the association with a particular HLA-DR allospecificity was population-dependent; that is, different beta-2 polypeptides were associated with the same HLA-DR specificity in different geographical populations. In contrast, the position of the third beta polypeptide (namely, beta-3) which corresponds to the HLA-DC locus, did not necessarily vary with the HLA-DR specificity; that is, apparently the same beta-3 polypeptide was associated with different HLA-DR specificities provided the cells were of the same ethnic origin. The data indicate that lymphoblastoid cells express at least three sets of HLA-D region antigens that are encoded by different loci including HLA-DR and DC.
Mol Biol Med 1983 Jul
PMID:Biochemical analysis of the polymorphism of three HLA-D region antigens. 659 60

We describe an approach to the cloning of cell surface proteins that is independent of messenger RNA isolation. Mouse Ltk- cells are cotransformed with the thymidine kinase gene from Herpes Simplex Virus and total human DNA. Transformants expressing the human surface antigens of interest are isolated by two selection steps, consisting of treatment with hypoxanthine/aminopterin/thymidine and fluorescence-activated cell sorting. Using this procedure, we isolated seven transformants expressing HLA-A,B,C antigens and 12 transformants expressing the 4F2 antigen. We have so far failed to identify any OKT-10 antigen expressing L-cell transformants. Three independent secondary 4F2 transformants were obtained after identical cotransformation of fresh Ltk- cells with DNA from primary transformants. Analysis of their genome by hybridization with human DNA revealed a shared set of human restriction fragments in all three cell lines. This 32 X 10(3) base-pair segment of DNA codes for the human 4F2 antigen, thereby offering the opportunity to clone the gene. To substantiate this hypothesis, we analyzed the seven HLA-expressing cell lines, and we found that all of them had acquired an HLA-coding sequence concomitant to its expression.
Mol Biol Med 1983 Oct
PMID:An approach to the cloning of cell surface protein genes. Selection by cell sorting of mouse L-cells that express HLA or 4F2 antigens after transformation with total human DNA. 668 Jan 52

The shedding of the mobile Fc receptor (FcR1) and the depletion of the immobile Fc receptor (FcR11) bearing human lymphocytes revealed that human natural killer cells belong to the FcR11-bearing population. Anti-beta-2-microglobulin treatment of the effector cells decreased natural cytotoxicity against some target cells and the detectability of HLA antigens, indicating that histocompatibility antigens or related structures may be involved in natural cytotoxicity. Using a panel of 29 autologous and allogenic PHA-stimulated target cells and peripheral lymphocytes from the same donors as the effector cells, distinct cytotoxic responses against allogeneic and autologous target cells were observed. A computer analysis of selective natural cytotoxicity distinguished seven different groups of target cells that may represent common structures for NK recognition.
Mol Immunol 1982 Oct
PMID:Recognition of autologous and allogeneic lymphocytes and tumor cells by human natural killer cells. 675 25

Multiple sclerosis (MS) is a chronic central nervous system disease of considerable medical and social impact. It is characterized by destruction of the myelin, the axon proteolipid sheath, or demyelination. While the etiology of MS remains unknown, one of the most well-grounded theories of its pathogenesis postulates that immunomediated inflammatory processes play the main role in myelin damage. The leading role in the autoimmune disturbance development belongs to T-cell system, however, B-cells also participate in the pathological process. Both genetical predisposition and environmental influence are involved in MS development. Correlations were found between MS and numerous environmental factors, including ecology and different infectious agents. However, no single environmental factor and no single infection was confirmed to be the primary cause of MS. The predisposition to MS seems to depend on several genes. Alleles and haplotypes of HLA genes which are the main human immune-response genes are undoubtedly associated with MS. Serological methods have shown weak association of MS with A3 and B7 loci of HLA class I. Stronger association was found for HLA class II haplotype specified to DR2(DR15), DQ6(DQ1) in serology typing nomenclature or DRB1*1501, DQA1*0102, DQB1*0602 in sequence-based genotyping terminology. Besides, MS was found to be associated with alleles of genes of T-cell receptors, cytokines, myelin components and some others, although these results are sometimes contradictory. The analysis of genetical predisposition factors and of possible mechanisms of their involvement in demyelination process on molecular and cellular levels should enlighten the MS pathogenesis and provide new ways of medical treatment and prevention of MS.
Mol Biol (Mosk)
PMID:[Multiple sclerosis: molecular and cellular mechanisms]. 747 40

Affinity-purified major histocompatibility complex (MHC) class II molecules are known to bind antigenic peptides in vitro. The percentage of MHC class II molecules occupied with such peptides is usually very low and varies significantly depending upon the sequence and size of a given antigenic peptide. The present study describes a method by which complete saturation of affinity-purified MHC class II with antigenic peptide can be achieved by simply incubating purified MHC class II molecules at neutral pH in the presence of several 100-fold molar excess of antigenic peptide. Complexes of human HLA-DR2 and a peptide analog from human myelin basic protein MBP (83-102)Y83 were selected for this study. The on-rate kinetic results showed saturation of MHC class II occupancy at 300-500-fold molar excess peptide concentrations. The specificity of the MBP (83-102)Y83 peptide binding to HLA-DR2 at higher peptide concentration was demonstrated by incubating an equivalent amount of another epitope from myelin basic protein [MBP (1-14) peptide] as well as by competitive binding assays. The quantitation of bound peptide was carried out using biotinylated-MBP (83-102)Y83 peptide which showed 100-125% occupancy of HLA-DR2 with a recovery of 100%. The presence of a single peptide entity in purified complexes was confirmed by reverse-phase narrowbore HPLC analysis of the acid extracted supernatant and by mass spectrometry analysis. Two-dimensional gel electrophoresis (IEF/SDS) of purified HLA-DR2 and DR2.MBP (83-102)Y83 complexes showed the absence of various endogenous polypeptides in 100% loaded complexes. These results demonstrate that higher peptide concentrations can be useful in generating MHC class II-peptide complexes of defined composition. Such complexes of MHC class II occupied with a single peptide may have significant clinical relevance for antigen-specific therapy of various autoimmune diseases and may provide better understanding of MHC-peptide-TCR interactions.
Mol Immunol 1994 Oct
PMID:Antigenic peptide binding to MHC class II molecules at increased peptide concentrations. 752 70

Major histocompatibility complex (MHC) class II molecules are cell surface glycoproteins and are known to display processed antigens on the surface of antigen presenting cells (APC). Within the APC, the loading of processed antigenic peptides to MHC class II molecules is known to take place in the endosomal compartment at acidic pH environment. The present study describes the in vitro effect of pH on binding of four biotinylated myelin basic protein (MBP) peptides to affinity purified HLA-DR2 containing a mixture of DRB1*1501 and DRB5*0101 beta chain. The binding affinity of the selected peptides are in the order of MBP(83-102)Y83 > MBP(124-143) > MBP(143-168) > MBP(1-14). Most of these peptides in association with HLA-DR2 are considered as immunodominant epitopes for human multiple sclerosis autoimmune disorder. One epitope, MBP(1-14), had almost no affinity to purified HLA-DR2 and was used as a control peptide in all binding assays. The quantitation of the bound peptide at various pH was carried out by antibody capture of complexes followed by avidin-alkaline phosphatase detection system. Among four peptides tested, only the highest affinity MBP(83-102)Y83 peptide showed maximum binding to purified HLA-DR2 at acidic pH. Two other epitopes, MBP(124-143) and MBP(143-168), showed maximum binding at basic and neutral pH values, respectively. The binding of only high affinity peptides, MBP(83-102)Y83 and MBP(124-143), was significantly affected by changing the pH of the binding buffer. Such alteration in pH of the binding buffer resulted in 100% occupancy of DR2 with both high affinity MBP peptides. In contrast, no significant increase in binding of the low affinity MBP(143-168) peptide was observed at altered pH values. The specificity of the increased binding of high affinity peptides to HLA-DR2 at optimum pH was demonstrated by competitive binding assays using non-biotinylated peptides. Finally, the stability of various MBP peptide bound complexes was tested at 4 degrees, 25 degrees and 37 degrees C which correlates well with their affinity to HLA-DR2. These results suggest that pH plays an important role in in vitro binding of antigenic peptides and such manipulation of binding conditions can be utilized in generating 100% loaded MHC class II with high affinity antigenic peptides. Since high affinity peptides are generally considered as major immunodominant epitopes, the in vitro pH dependent binding can be utilized in screening immunodominant epitopes of various autoantigens and generating complexes of defined composition.
Mol Immunol 1995 Jun
PMID:pH dependent binding of high and low affinity myelin basic protein peptides to purified HLA-DR2. 754 90

Recently, we defined the antigenic epitope recognized by the human monoclonal antibody L94 to be a protein with a C-terminal sequence of alanine-proline (AP). An antigenic peptide no. 707 (RVAALARDAP), which was identified by the use of cDNA libraries of an antigen positive melanoma cell line M14, was evaluated for cellular immune responses in melanoma patients. PBMC from 16 of 19 melanoma patients were shown to lyse autologous B lymphoblastoid cell lines (BCL) pulsed with synthetic peptide no. 707 (hereafter no. 707). This specific cytotoxicity to the peptide significantly increased in 84% of melanoma patients after in vivo immunization with a melanoma cell vaccine (MCV). In contrast, peptide specific cytotoxicity was observed in only one of 19 normal volunteer donors. In vitro restimulation of MCV treated patients' PBMC with no. 707 augmented cytotoxicity against autologous no. 707-pulsed BCL. This cytotoxicity was specific to the C-terminal sequence AP, since the removal of C-terminal AP completely abolished the specific lysis. no. 707 restimulation of PBMC enhanced cytotoxicity against autologous melanomas. Autologous melanoma and peptide-pulsed BCL targets were lysed by CD8+CTL in a HLA class I-restricted manner. The strong cytotoxicity was obtained from patients of HLA A24. CTL lysis of autologous no. 707-pulsed BCL was partially blocked by unlabeled autologous melanomas in a cold target inhibition test. This suggested that the epitope identical or cross-reactive to no. 707 may be presented on the melanoma cell surface by HLA class I antigens. Our findings suggest that peptide no. 707 presented on human melanoma cells is recognized by CTL and that C-terminal AP plays a critical role in both antibody and T cell recognition.
Mol Immunol 1995 Jun
PMID:Cytotoxic T cell recognition of a human melanoma derived peptide with a carboxyl-terminal alanine-proline sequence. 754 91

We have recently described a method based on Artificial Neural Networks to cluster protein sequences into families. The network was trained with Kohonen's unsupervised-learning algorithm using, as inputs, matrix patterns derived from the bipeptide composition of the proteins. We show here the application of that method to classify 1758 protein sequences, using as inputs a limited number of principal components of the bipeptidic matrices. As a result of training, the network self-organized the activation of its neurons into a topologically ordered map, in which proteins belonging to a known family (immunoglobulins, actins, interferons, myosins, HLA histocompatibility antigens, hemoglobins, etc.) were usually associated with the same neuron or with neighboring ones. Once the topological map has been obtained, the classification of new sequences is very fast.
Proc Int Conf Intell Syst Mol Biol 1993
PMID:Protein classification using neural networks. 758 28

To identify genes that contribute to the manifestation of rheumatoid arthritis we performed association studies via microsatellite analyses of immunorelevant loci (HLA-DRB, 5 T cell receptor loci, TNFa IL1, IL2, IL5R and CD40L). A total of 183 patients and 275 healthy controls were typed in terms of HLA and grouped according to the known predisposing HLA-DRB1 genes (DRB1*04; relative risk approx. 5; DRB1*01, relative risk approx. 2; a third group carried neither allele). Microsatellite polymorphisms characterizing the TCRBV6S3, CD3D, IL1A, IL2, and IL5R genes did not show significant associations with rheumatoid arthritis, whereas TCRBV6S1, TCRBV6S7, TNFa, and CD40L genes may influence relative protection or risk in certain groups of patients. Analysis of a microsatellite marker adjacent to the transcription element alpha (TEA) in the T cell receptor alpha delta complex indicates that in the cohort carrying neither the DRB1*04 nor the DRB1*01 allele the relative risk to acquire rheumatoid arthritis is increased (> 13) or decreased (< 0.07), depending on the inherited microsatellite allele adjacent to the TEA locus. Sequence analysis of the closely linked TEA region from patients and controls revealed a novel dimorphism. Only the newly identified TEA allele leads to binding of a nuclear protein that may be involved in the regulated expression of the TCRDA genes. Subsequent typing of rheumatoid arthritis patients and controls revealed, however, that the association of the microsatellite marker is largely independent of the TEA allele, confirming incomplete linkage in the 2 kb region of the TCRDA locus. These results are discussed in the context of hot spots of recombination in this genomic region and other linked candidate sequences that predispose to develop rheumatoid arthritis.
J Mol Med (Berl) 1995 Jan
PMID:Immunoprinting: various genes are associated with increased risk to develop rheumatoid arthritis in different groups of adult patients. 763 38

DNA sequence polymorphism in the genes encoding HLA class II proteins accounts for allelic diversity in antigen recognition and presentation and, thus, in the role of these cell surface glycoproteins as determinants of the scope of the T-cell repertoire. In addition, sequence polymorphism in the promoter-proximal transcriptional regulatory regions of these genes has been described, particularly for the HLA-DQB1 locus, where these differences may contribute to variation in locus- and allele-specific expression. In this study, we measured the effect of such regulatory sequence polymorphism on the expression of endogenous alleles of DQB1 in heterozygous cells. Quantitative reverse transcriptase-mediated PCR analysis showed that expression of the DQB1*0301 allele responded more rapidly to gamma interferon induction than that of DQB1*0302. We have analyzed functional effects of a prominent allelic polymorphism that consists of a TG dinucleotide present between the W and X1 consensus elements in the DQB1*0302 allele but missing in the DQB1*0301 allele. The dominant effect of this polymorphism was to introduce a variation in the spacing between the W and X1 elements of these two alleles. A secondary compensatory effect was specific for the TG dinucleotide itself, which was essential for the binding of a nuclear protein complex to the *0302 regulatory region immediately 5' of the X1 element. Derivatives of the DQB1 5' regulatory region were used to drive expression of the chloramphenicol acetyltransferase gene in transient transfections of human B-lymphoblastoid and gamma interferon-treated melanoma cell lines, demonstrating that the additional spacing between the W and X1 elements caused by the presence of the TG dinucleotide in the *0302 allele resulted in reduced expression compared with that driven by the *0301 fragment; this difference overshadowed an up-regulating effect on expression which corresponded to the binding of the TG-dependent nuclear protein complex. The presence of this polymorphism in multiple HLA-DQB1 alleles and in several species suggests selection for two alternative transcriptional regulatory mechanisms influencing expression of alleles of the same HLA locus.
Mol Cell Biol 1995 Sep
PMID:Functional effects of a natural polymorphism in the transcriptional regulatory sequence of HLA-DQB1. 765 94


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