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PubMed1980

Regulation of the anti-inulin antibody response by a nonallotype-linked gene.

The antibody response to the inulin [(In), beta-(2 leads to 1) fructosan] determinant of bacterial levan [(BL), a beta-(2 leads to 6) polyfructosan that contains beta-(2 leads to 1) branch points] requires the presence of the a haplotype of the Igh gene complex. BALB/c (Igh a) mice immunized with BL produce IgG anti-In antibodies of a single spectrotype by isoelectric focusing analysis. C57BL/6 mice, which possess the b haplotype of the Igh gene complex and which fail to produce anti-In antibodies, nevertheless possess a gene, spectrotype regulation gene 1 (Sr-1), that regulates the isoelectric focusing (IEF) pattern of anti-In antibodies in mice of the a haplotype. Thus, the IEF patterns of anti-In antibodies of (BALB/c x C57BL/6)F1 mice and of B.C8 mice (C57BL/Ka . Igh-Ca) are considerably more complex than those of BALB/c. Backcross analysis indicates that Sr-1 is not linked to the Igh complex, the major histocompatibility complex, or to the genes that code for coat color. Studies of the heterogeneity of anti-In antibodies in recombinant inbred lines and their progeny from matings to BALB/c and C.B20 (BALB/c . Igh-Cb) suggest the existence of other regulatory genes.

Animals↗
PubMed1989

Modulation of HLA class II antigen expression by transfection of sense and antisense DR alpha cDNA.

In the human there are three isotypic forms of MHC class II gene products (HLA-DR, -DQ, and -DP). The isotype-matched alpha-beta dimers are predominant but isotype-mismatched dimers can also be expressed (DR alpha-DQ beta). Here it is shown that the expression of the DR alpha-DQ beta dimer can be correlated to a high ratio of DR alpha/DR beta mRNA. The DR alpha chain expression was modulated by transfection of a sense and antisense DR alpha cDNA. Overexpression of DR alpha promoted the appearance of the DR alpha-DQ beta dimer. On the other hand, pre-existing DR alpha-DQ beta dimer expression was suppressed after antisense DR alpha cDNA transfection. Therefore, imbalanced expression of the alpha and beta chain from a given isotype could lead to the modification of HLA class II phenotype.

B-Lymphocytes↗
PubMed2002

Peptide scanning for thyrotropin receptor T-cell epitopes in mice vaccinated with naked DNA.

Vaccinating mice with DNA encoding the thyrotropin receptor (TSHR), the major autoantigen in Graves' disease, induces memory T cells that secrete interferon-gamma (IFN-gamma) in response to TSHR antigen. We used a panel of 29 synthetic TSHR peptides encompassing the ectodomain and three extracellular loops to identify T-cell epitopes after TSHR-DNA vaccination of BALB/c, NOD.H-2h4, and AKR/N mice. These strains were chosen because of their previous use in animal models of thyroid autoimmunity. In initial studies, challenge of splenocytes with TSHR protein induced IFN-gamma and tumor necrosis factor-alpha (TNF-alpha) production in all three strains of mice. BALB/c mice recognized three peptides, all in the TSHR A subunit. These peptides differed from the four peptides recognized by nonobese diabetic (NOD mice NOD H-2h4). Three of the latter were also in the A subunit. The fourth was within the intervening C peptide region excised on TSHR cleavage into A and B subunits. Because of high and erratic responses in AKR/N mice, their TSHR T-cell epitopes could not be determined. In summary, we report that TSHR DNA vaccination of BALB/c and NOD.H-2h4 mice, with different major histocompatibility complex (MHC) class II genes (I-Ad and I-Ak, respectively), recognize restricted, nonoverlapping TSHR T-cell epitopes, nearly all in the TSHR A subunit.

Amino Acid Sequence↗
PubMed1983

Cloning the heavy chain of human HLA-DR antigen using synthetic oligodeoxyribonucleotides as hybridization probes.

The recent development of the amino acid microsequence technique allows us to obtain partial sequence information using an extremely small amount of protein. Two sets of mixed oligonucleotide probes were chemically synthesized using the amino acid sequence information for the heavy chain of human HLA-DR antigen obtained by the microsequence technique. These two hybridization probes were used to screen cDNA clones constructed from cytoplasmic poly(A)+ mRNA from a human B lymphoblastoid homozygous cell line (LG-2). Of the 10,000 clones screened, two clones hybridized with the probes. DNA sequence analysis showed that the longer one of the two cDNA clones was 1183 nucleotides long, including the entire coding region, the signal peptide region, and the complete 3'-noncoding region. The deduced amino acid sequence of the HLA-DR alpha chain is identical to that of other cell lines with a different HLA-DR typing. However, several nucleotide differences are found in the 3'-untranslated region compared with that of other DR haplotypes.

Amino Acid Sequence↗
PubMed1991

Autoreactive T cells from normal mice recognize mycobacterial 65 kd heat-shock protein from Mycobacterium bovis.

We established a TCR V beta 6+ CD4+ autoreactive T cell line from lymph node cells of unprimed BALB/c mice bred in a specific pathogen-free condition. The T cell line proliferated in the presence of irradiated spleen cells expressing MHC class II I-Ad and/or I-Ed molecules. The proliferative response of the autoreactive T cell line was significantly enhanced in response to 65 kd heat-shock protein (hsp) from Mycobacterium bovis, a member of the hsp60 family, which is highly conserved in both prokaryotes and eukaryotes. Our results suggest that the autoreactive T cells in normal mice may recognize endogenous peptides of self-hsp60 bound to MHC class II gene products and are cross-reactive to mycobacterial 65 kd hsp. The autoreactive hsp-specific T cells may therefore play an important role in the immune surveillance against invasion of various pathogens and tumors by recognizing infected and transformed autologous cells that express high levels of endogenous hsp60.

Animals↗
PubMed1992

Structural analysis of human anti-mouse H-2E xenorecognition: T cell receptor bias and impaired CD4 interaction contribute to weak xenoresponses.

T lymphocyte responses to the MHC of an evolutionarily distant species are known to be weak compared with responses against allogeneic MHC products within a species. This fact was used to examine the regions of human MHC class II molecules required for the stimulation of strong primary immune responses against MHC alloantigens. A panel of mouse DAP.3 transfectants expressing the products of wild-type and recombinant DR1/H-2Ek MHC class II genes paired to either DR alpha or H-2E alpha genes was generated, and tested as stimulator cells for purified human T cells. A strong proliferative response to DAP.3 transfectants expressing allogeneic HLA-DR molecules was seen. In contrast, weak or absent responses were recorded against DAP.3 cells expressing H-2E molecules. Substitution of the DR1 beta chain with H-2E beta k led to a dramatic loss of recognition; alpha chain substitution had a less marked effect. Furthermore, replacement of the beta 2 domain of DR1 with H-2E sequence caused 90% inhibition, whereas introduction of the beta 2 domain of DR1 into H-2Ek led to a 10-fold increase in T cell response. These results are most readily explained if the beta 2 domain contributes to the interaction site for the CD4 molecule. Substitution of either half of the beta 1 domain led to a marked loss of response. This was more impressive following substitution of the TCR-contacting alpha-helical region of the domain.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2004

T cell expression of CIITA represses Th1 immunity.

Despite the fact that major histocompatibility complex class II transactivator (CIITA) has been known to be involved in Th1/Th2 balance in addition to its major role as a master regulator for the expression of MHC class II genes, the exact role of CIITA in Th1/Th2 balance is still controversial. To investigate whether the Th1/Th2 balance could be modulated by T cell specific expression of CIITA, we generated CIITA-transgenic mice, in which the CIITA expression is controlled by the distal promoter of p56lck, resulting in constitutive expression of CIITA predominantly in peripheral T cells. Naive CD4+ T cells from CIITA-transgenic mice exhibited a low level of IFN-gamma secretion as well as impaired Th1 polarization in vitro, while IL-4 secretion was enhanced under Th2 condition. In addition, the development of experimental autoimmune encephalomyelitis (EAE), a prototype of Th1-mediated disease, was repressed in CIITA-transgenic mice. Resistance to EAE was correlated with reduced production of IFN-gamma in response to MOG35-55, while the proliferation of MOG35-55 -specific T cells was not affected in CIITA-transgenic mice. Together, these data demonstrate that overexpression of CIITA in T cells inhibits Th1 differentiation and function, suggesting that the expression of CIITA in T cells might play a role in the regulation of the Th1/Th2 balance during the T cell lineage commitment.

Animals↗
PubMed1995

Identification of transcriptional activation domain of TREB5, a CREB/ATF family protein that binds to HTLV-1 enhancer.

TREB5 (hXBP-1) protein is a transcription factor that recognizes the CRE-like element in enhancers of human T-cell leukemia virus and MHC class II gene and activates their transcription. TREB5 is a member of the CREB/ATF family, containing a basic amino acid region and leucine zipper structure (b-Zip structure). To characterize the key domain of TREB5 for transcriptional activation, mutational analysis was carried out. The C-terminal region of 148-221 amino acids was identified as an activation domain and was also active when fused to Gal4 DNA binding domain. This domain contains three unique regions rich in glutamic acid, glutamine, or serine/threonine and is active in both osteosarcoma (HOS) and T (Jurkat) cell lines. All of these three regions are essential; however, a part of the serine/threonine region was dispensable in Jurkat, but not in HOS cells. In addition to the activation domain, the N-terminal region showed activity in conjunction with the b-Zip structure, but not with the Gal4 DNA binding domain. Furthermore, this region showed activity in Jurkat cells, but not in HOS cells. These results suggest that TREB5 has two activational functions in transcription and may provide diversity in cell-type-specific transcriptional activation, possibly through dimerization with other b-Zip proteins and phosphorylation.

Amino Acid Sequence↗
PubMed1997

Major histocompatibility complex class II DNA polymorphisms in chicken strains selected for Marek's disease resistance and egg production or for egg production alone.

The objective of this study was to investigate frequencies of major histocompatibility complex (MHC) class II restriction fragments in two groups of White Leghorn strains. Each group consisted of an unselected control, a strain selected for egg production traits, and a strain selected for egg production traits and Marek's disease (MD) resistance. PvuII-digested genomic DNA was hybridized with a chicken genomic MHC class II probe. The MHC class II DNA fragment frequencies in the selected strains differed from those in the related unselected control and in the strain selected using the same criteria from a different base population. Based on the sizes of the breeding populations, particularly those in the control strain and in the strain selected for egg production, it was considered unlikely that the observed changes of the MHC class II fragment frequencies were due to random genetic drift. The data suggested that some MHC class II bands are associated with production traits or with MD resistance, and that these associations tend to be unique to each genetic background. Hence, MHC class II genes are likely candidates for the investigation of quantitative trait loci in egg production and disease resistance traits such as those for which the studied strains were selected.

Animals↗
PubMed1991

Quantitative assessment of HIV-1 DNA load by coamplification of HIV-1 gag and HLA-DQ-alpha genes.

We developed an assay for simultaneous amplification, detection and quantitation of HIV-1 gag gene and the DQ-alpha locus of the histocompatibility (HLA) region of the human genome by polymerase chain reaction (PCR). Crude cell lysates from control cell lines and peripheral blood mononuclear cells (PBMC) from HIV-1-infected and control individuals were coamplified using optimized concentrations of primers directed at both loci, followed by simultaneous hybridization with radioactively labeled HIV-1-gag and HLA-DQ-alpha probes. Simultaneous quantitation of the 242-base-pair HLA and 115-base-pair HIV products was accomplished by both end-point dilution analysis and image analysis of autoradiographs relative to standard curves derived from infected cell lines. We observed good agreement between input cell counts on fresh samples and the HLA-DQ-alpha target copy number values determined by both end-point dilution analysis and comparison of band intensities with standard curves. HIV-1 proviral load in symptomatic patients ranged from 200 to 4000 HIV-PCR-units per 1 x 10(6) PBMC (mean of 1245 copies), whereas asymptomatic patients had levels ranging from two to 1000 HIV-PCR-units per 1 x 10(6) PBMC (mean of 213 copies). This HIV/HLA coamplification approach should be particularly useful for analysis of frozen repository samples from natural history studies, and may facilitate wider application of quantitative PCR analysis.

Base Sequence↗
PubMed2001

Familial lupus erythematosus. Clinical and immunologic features of 125 multiplex families.

Evidence for a genetic susceptibility to systemic lupus erythematosus (SLE) in humans is based on the high concordance rate observed in identical twins and on the relatively high incidence of familial cases. Although recent genetic studies have lead to significant advances in the identification of new susceptibility genes in SLE, no large clinico-pathologic study of familial SLE has been reported to date. In the present study, we describe the main clinical and immunologic features of 125 lupus multiplex families including at least 2 cases of SLE and/or discoid lupus erythematosus (DLE), recruited through a French national survey starting in July 1997. Medical records of all affected members were reviewed by the same investigator, all available family members were interviewed using the same standardized procedure, and blood was drawn for autoantibodies typing. Clinical and immunologic features of 90 probands from multiplex SLE families were compared with those of 100 sporadic SLE patients sharing the same French Caucasian origin. The 125 lupus multiplex families included 282 affected members (2.3 patients per family); of the 125 families, 96 were of French Caucasian origin. One hundred multiplex families included 2 affected relatives, while 25 included 3 or more affected individuals. The relationship between affected members was sibs (45%), parent-offspring (31%), and second-degree (24%). An autosomal dominant mode of inheritance was strongly suggested in 1 extended pedigree with 6 clinically affected members, and a recessive pattern was suspected in 5 other families. No obvious mode of inheritance could be suspected in most of the remainder. Among French Caucasians, sex ratio, mean age at onset, and clinical and biologic SLE-related manifestations were not significantly different in multiplex compared with sporadic SLE cases. The analysis of these 125 multiplex families suggests a genetic heterogeneity that should be considered for ongoing genomic screening.

Age of Onset↗
PubMed1984

Induction of H-2-restricted contact hypersensitivity by hapten-derivatized skin grafts. Evidence that the immunogenic signal includes H-2 determinants derived from the skin.

Contact hypersensitivity has been induced in mice grafted with skin derivatized with dinitrofluorobenzene. At optimal concentration of epicutaneously applied hapten (0.02%), it was found that syngeneic, but not allogeneic, skin grafts induced sensitivity. Genetic identity of graft donors and recipients at class I or class II loci of H-2 was essential and sufficient for induction of sensitization. The fact that Ia antigens on haptenated grafts restricted the response indicates that Langerhans cells, the only Ia-bearing cells of the normal murine epidermis, function as antigen presenting cells. Nonvital syngeneic, but not allogeneic, grafts were able to induce contact hypersensitivity, so it is proposed that the immunogenic signal derived from haptenated skin grafts consists of hapten and a class I or class II MHC gene product, but need not necessarily be delivered on a viable cell.

Animals↗
PubMed1999

Human papillomavirus type 16 E6 variants in cervical carcinoma: relationship to host genetic factors and clinical parameters.

Infection with human papillomavirus type 16 (HPV-16) confers a high risk for the development of cervical neoplasia. Variants of this virus may interact differentially with host genetic factors, possibly altering the disease course. Thus, HPV-16 E6 variants may differ in their ability to degrade p53 whereas the polymorphic p53 alleles may provide more or less susceptible substrates for the viral oncogene product. Also, E6 variants may differ in immunogenicity by generating different peptides for presentation by polymorphic HLA molecules to specific T cells. This study examines HPV-16 E6 sequence variation in cervical carcinomas from the UK and its relationship to polymorphism of HLA and p53 and to clinical parameters. Sequence analysis of the HPV-16 E6 ORF from 77 tumour biopsies detected the viral prototype sequence in 38% of cases. The most common variation detected was a T to G transition at base pair 350, resulting in an amino acid change from a leucine to a valine. Overall, the frequencies of 350T and 350G sequences were similar (49. 4% and 50.6% respectively). Other mutations of lower frequencies were detected together with and independently of 350G. HPV-16 E6 sequence variation at base pair 350 did not correlate with HLA genotype or clinical outcome. There was no difference in the distribution of p53 proline and arginine alleles between HPV-16-positive cervical carcinoma patients and local controls, and no influence on clinical outcome; however, there was a trend for an increased frequency of p53 arginine homozygotes among the 350T carcinoma patients.

Adult↗
PubMed1997

Significantly increased occurrence of HLA-DQB1*0301 allele in patients with ocular cicatricial pemphigoid.

To determine the immunogenetic characteristics of patients with immune-mediated subepithelial blistering diseases of mucous membranes, we performed HLA-typing for the class II MHC gene DQB1*0301 allele using a direct method. Genomic DNA extracted from Caucasian patients was amplified by polymerase chain reaction using primer pairs specific for the DQB loci followed by Southern blotting with a peroxidase-conjugated sequence-specific oligonucleotide probe. Seventy-six percent (16/21) of patients with ocular mucosal disease (with or without oral mucosal and skin diseases) carried the DQB1*0301 allele; by contrast, only 33% (14/42) of race-, age-, and geography-matched normal individuals carried the DQB1*0301 allele (p < 0.005). The relative risk for ocular disease if DQB1*0301 allele is present is 6.4, similar to the relative risk of 8 for patients with ocular but no oral disease (pure ocular cicatricial pemphigoid, p < 0.025). In patients with oral mucosal disease (with or without ocular mucosal and skin diseases), 68% (15/22) carried the DQB1*0301 allele (p < 0.025). When patients with ocular disease were excluded, however, the increased occurrence of the DQB1*0301 allele in patients with oral disease was not statistically significant (64%, 7/11, p < 0.25). In patients with subepidermal blistering skin disease but no oral or ocular disease, there was no increase in the occurrence of the DQB1*0301 allele (38%, 5/13, p > 0.5). The significantly increased occurrence of the DQB1*0301 allele in patients with ocular mucosal disease may point to a distinct immunogenetic factor that predisposes patients to develop an ocular scarring process.

Alleles↗
PubMed1993

Clonality of T lymphocytes expanded with IL-2 from rheumatoid arthritis peripheral blood, synovial fluid and synovial membrane.

The association of rheumatoid arthritis (RA) with particular MHC class II genes suggests that autoantigen-specific T cell clones present in joints could be central to the pathogenesis of the disease. Previous investigations on the clonal diversity of T cells infiltrating the rheumatoid synovial membrane have yielded conflicting results. With the use of Southern blot analysis, we investigated the clonality of rheumatoid T cell lines expanded from peripheral blood, synovial fluid and synovial tissue. From peripheral blood lymphocyte (PBL) of RA patients and healthy normal controls, we also checked the consequences of two different culture conditions on the clonality of these cell lines. From control PBL, we found that in vitro non-specific expansion of non-clonal T cell populations does not create artefactual clonal selection. However, growing T cells in vitro with IL-2 seems to be able to lead to preferential expansion of cells bearing IL-2 receptor (IL-2R). We identified such in vivo activated IL-2-sensitive T cell clones frequently in RA synovial tissue (8/13) and more rarely in synovial fluid and peripheral blood (3/12). One patient presents the same T cell receptor gene rearrangements in synovial membrane of two affected joints. In RA synovial tissue, the frequency of these IL-2-responsive T cells is most prevalent among actively inflamed membranes removed early in the disease process. The role and the relevance to the disease of these IL-2-responsive T cells remain to be elucidated.

Adult↗
PubMed1983

Population genetic analyses of insulin dependent diabetes mellitus using HLA allele frequencies.

In order to try to detect heterogeneity within insulin dependent diabetes mellitus (IDDM) and to distinguish a mode of inheritance of IDDM, population genetic analyses were performed using HLA allele frequencies. HLA-A and -B typing performed on 231 IDDM individuals and 268 controls from the southeastern U.S. showed significant increases with IDDM in A2, B8, B15 and B18, and significant decreases in Aw23, B7, B14 and B17. The combination of HLA-B8/B15 showed a greatly increased risk (RR = 25.5). Between the 120 IDDM individuals and 123 controls HLA-DR typed, HLA-DR3 and -DR4 were significantly increased among the IDDM group and DR2 and DR7 were decreased. The risk for DR3/4 was 29.2. It appeared that the B15 association was secondary to the DR4, but the B8/DR3 association showed no difference. Using the method of Curie-Cohen, no significant increases in risk were found for the B8/B15 or DR3/DR4 heterozygotes when compared to the respective homozygotes. Using the method of Thomson and Bodmer, the dominant mode of inheritance was excluded for DR4 only. There was a significant increase in B15 and DR4 in those with onset before age 20. No significant differences were found among the DR phenotypes with respect to season.

Age Factors↗
PubMed1983

Investigation of the mode of inheritance of the HLA associated diseases by the method of antigen genotype frequencies among diseased individuals.

Statistical features of the method of antigen genotype frequencies among the diseased, for single and multiple disease associations at a locus, will be presented. A methodology to determine when a true intermediate mode of inheritance can be distinguished from strict recessive or additive inheritance will be developed. The effect of sporadics and ascertainment bias on the observed antigen genotype frequencies will be investigated. Data on ankylosing spondylitis, multiple sclerosis and dermatitis herpetiformis are very close to expectations for an additive (or dominant) mode of inheritance for the HLA-linked disease-predisposing gene, and data on hemochromatosis, insulin dependent diabetes mellitus and celiac disease are close to recessive expectations. If an intermediate model does apply in any of these cases, it must be an intermediate model that is fairly close to a strict recessive or dominant model; as appropriate. DR data for insulin dependent diabetes mellitus (IDDM) strongly indicate that there are two separate "disease" alleles, which exhibit negative complementation, predisposing individuals to IDDM, where the mode of inheritance of the "disease" alleles considered separately is close to recessive. In general, this method cannot rule out the existence of sporadics or a second disease-predisposing gene, when the penetrance values over the two disease-predisposing genes are strictly additive, for diseases showing agreement with additive (or dominant) modes of inheritance.

Arthritis, Juvenile↗