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PubMed1999

Toward an evolutionary genomics of the avian Mhc.

We review recent developments in the ongoing study of the evolution of the Mhc gene family in birds, with emphasis on class II B genes and results from songbirds obtained in our laboratory. Southern blots suggest a surprising diversity in Mhc class II gene number among various songbird species (Passeriformes). We have sequenced approximately 30 kb contigs from Mhc bearing cosmid clones from two species, red-winged blackbirds (Agelaius phoeniceus) and house finches (Carpodacus mexicanus), whose demography, lifetime reproductive success, epizootics, parasitology and mate choice are among the best studied for natural populations of birds. Of three genes cloned from these species, only one appears strongly polymorphic, and one (from the house finch) is likely a pseudogene. All are similar in structure to those in chickens, albeit with introns intermediate in length between chickens and mammals. Phylogenetic analysis of available class II B peptide-binding region exons suggests that the overwhelming long-term force operating on avian genes sampled thus far has been post-speciation gene duplication and/or concerted evolution. These and other results suggest that the evolution of class II B genes in birds conforms to a mixture of several models of multigene family evolution proposed for the mammalian Mhc, incorporating ongoing homogenization, duplication and pseudogene formation. Large-scale sequencing studies in these and other species, though still in their infancy, will prove invaluable for studying the comparative structures of avian Mhcs, as well as patterns of selection, mutation and linkage disequilibrium at several scales.

Animals↗
PubMed1991

DNA polymorphism of HLA class II genes in pauciarticular juvenile rheumatoid arthritis.

We investigated the DNA restriction fragment length polymorphism (RFLP) of the major histocompatibility complex (MHC) class II genes: HLA-DRB, -DQA, -DQB, DPA, and -DPB in 54 patients with pauciarticular juvenile rheumatoid arthritis (PJRA) and in healthy Danes. The frequencies of DNA fragments associated with the following HLA class II genes were increased in PJRA when compared to normal controls: DRB1*08 (DRw8) (35.2% vs 10.3%, RR = 4.6, p less than 10(-3), DRB3*01/02/03 (DRw52) (76.3% vs 48.1%, RR 3.5, p less than 10(-3)), DQA1*0401 (41.0% vs 7.4%, RR = 7.9, p less than 10(-3)), DQA1*0501 (55.6% vs 29.7%, RR = 3.0, p less than 10(-2), DQB1*0301 (DQw7) (46.2% vs 17.5%, RR = 4.0; p less than 10(-2)), DPA1*0201 (44.2% vs 7.9%, RR = 8.7, p less than 10(-5)), and DPB1*02 (DPw2) (40.7% vs 7.1%, RR = 8.5, p less than 10(-6)). The frequency of DRB1*11 was not significantly increased. The frequencies of DNA fragments associated with the following HLA class II genes were decreased in PJRA although not statistically significantly so after 'correction' of p values: DRB1*04 (14.8% vs 40.2%, RR = 0.27; p less than 10(-3)), DRB1*07 (0% vs 25.9%, RR = 0.04, p less than 10(-3)), DRB4*0101 (DRw53) (25.9% vs 53.6%, RR = 0.31, p less than 10(-3)), DQA1*0102 (11.6% vs 36.0%, RR = 0.25, p less than 10(-4)), and DQA1*0201 (2.6% vs 34.2%, RR = 0.05, p less than 10(-2)).(ABSTRACT TRUNCATED AT 250 WORDS)

Arthritis, Juvenile↗
PubMed1987

Mutant human B cell lines deficient in class II major histocompatibility complex transcription.

By mutagenesis and selection, two independent Ia- mutant cell lines derived from the Ia+ human B cell line Raji were isolated. One mutant failed to express detectable surface HLA-DR and HLA-DQ molecules, while the other expressed very low levels of these molecules. mRNA encoding Ia molecules was correspondingly absent or reduced in these cell lines. In contrast, levels of class I major histocompatibility complex (MHC) mRNA and protein were normal in these cells. The class II MHC genes of the mutant cells were grossly intact, suggesting that the defective expression of these genes was due to an absent or abnormal trans-acting regulatory factor. In vitro nuclear run-on transcription assays and measurement of class II MHC mRNA stability suggested that the specific defect in class II MHC gene expression in both mutant cell lines was at the level of transcription initiation.

B-Lymphocytes↗
PubMed1999

Analysis of the human HLA-DRA gene upstream region: evidence for a stem-loop array directed by nuclear factors.

Sequence analysis of the far-upstream region of the human HLA-DRA gene has revealed the presence of Y' and X' boxes, highly homologous to the well characterized Y and X boxes present within the proximal-promoter region. Comparison of Y, Y', X, and X' box sequences present within different class II MHC genes of different species demonstrates that these boxes are conserved during evolution, suggesting an important role in regulation of gene expression. The far-upstream region and the proximal promoter region of the class II MHC genes could be organized in secondary structures, as suggested for the EA gene, the murine counterpart of the human HLA-DRA gene. The essential feature of this model is a dimerization of the proteins binding to X and X' and/or Y and Y' boxes resulting in a loop-out of the intervening DNA and a rapprochement of the far-upstream and proximal-promoter regions, and consequently of any proteins binding to them. We set up an in vitro approach in order to determine whether proteins bound to sequences present within far-upstream and proximal-promoter regions of the human HLA-DRA gene could direct a secondary structure assembly of regulative regions. Moreover, by gel retardation and DNase I footprinting assays, we demonstrate that similar proteins bind to Y and Y' boxes and, among these proteins, NF-Y was unambiguously identified by antibody-super shift experiments. Taken together, the data presented in this paper provide evidence supporting the hypothesis that a stem-loop array of the 5'-upstream region of the human HLA-DRA gene could be directed by nuclear factors. In this manner, additional nuclear factors bound to the far region could be driven in close proximity of the transcription initiation site.

Base Sequence↗
PubMed2006

Major histocompatibility complex and kin discrimination in Atlantic salmon and brook trout.

Many species of salmonids can discriminate kin from unrelated conspecifics using olfactory cues. In this study, we determined the role of the major histocompatibility complex (MHC) in kin discrimination by juvenile Atlantic salmon (Salmo salar) and brook trout (Salvelinus fontinalis). Genetic variation at the highly polymorphic exon coding for peptide-binding region of an MHC class II gene was studied using polymerase chain reaction and denaturing gradient gel electrophoresis. Experiments compared discrimination ability based on MHC haplotypes both within and among kin and non-kin groups. Juveniles chose kin sharing both alleles over kin sharing no alleles. Juveniles also preferred non-kin sharing both alleles to non-kin sharing no alleles. These data suggest that the MHC class II gene influence kin discrimination in juvenile Atlantic salmon and brook trout. The influence of additional genes was also apparent in trials where juveniles were able to recognize kin sharing no alleles over non-kin sharing no alleles. However, the inability of juveniles to discriminate between kin sharing no alleles and non-kin sharing either one or both alleles indicates that MHC is as potent as the rest of the genome in producing distinguishable odours.

Alleles↗
PubMed1992

Monoclonal antibodies to NF-Y define its function in MHC class II and albumin gene transcription.

NF-Y is a sequence-specific DNA-binding protein which, as a heterodimer, recognizes CCAAT motifs in a variety of transcriptional promoters. We have generated a panel of monoclonal and affinity-purified polyclonal antibodies directed against various epitopes of NF-Y. These reagents are highly specific for either of the A or B subunits; we have mapped the epitopes recognized by the monoclonal antibodies to the glutamine-rich activation domain of NF-YA. The antibodies inhibit in vitro transcription from the promoters of the albumin gene and of Ea, a class II gene of the major histocompatibility complex. These data definitively demonstrate the role of NF-Y in regulating the transcription of two tissue-specific genes whose expression patterns do not overlap. Interestingly, the antibodies cannot inhibit a formed pre-initiation complex, but do block reinitiation of subsequent rounds of transcription from the same templates.

Albumins↗
PubMed1995

Aspartate at position 57 of nonobese diabetic I-Ag7 beta-chain diminishes the spontaneous incidence of insulin-dependent diabetes mellitus.

MHC class II genes have been shown to influence the development of the autoimmune disease insulin-dependent diabetes mellitus (IDDM) in the nonobese diabetic (NOD) mouse. In human IDDM it has been suggested that the presence of an aspartate at position 57 of the DQ beta-chain might be important in determining resistance to development of IDDM. The involvement of MHC class II genes in IDDM was investigated through the introduction of MHC encoding transgenes. We show that introduction of a mutated I-Ag7 Ab gene which encodes an aspartate at position 57 reduces the incidence of IDDM but does not prevent insulitis, sialadenitis, or the development of insulin and nuclear autoantibodies.

Amino Acid Sequence↗
PubMed1990

Effect of the AIR-1 locus on the activation of an enhancerless HLA-DQA1 promoter.

Studies on the regulation of a major histocompatibility complex (MHC) class II gene, HLA-DQA1, in Ia-positive cells (Raji, a human B-lymphoma cell line) and in isogenic Ia-negative cells (RJ2.2.5, a mutant of Raji altered at the AIR-1 locus) are reported. As previously found, AIR-1 is required in its entirety for the activity of an enhancer factor, the absence of which abolishes transcription of MHC class II genes. In this paper, we show that HLA-DQA1 gene expression can be directed by an enhancerless promoter. The fact that this promoter is inactive in the RJ2.2.5 mutant suggests that the trans-acting element determined by the AIR-1 locus is not only an enhancer factor as previously described, but also acts at the MHC class II promoter level.

Base Sequence↗
PubMed1999

Positive selection of thymocytes induced by gene transfer: MHC class II-mediated selection of CD8 lineage cells.

Recombinant adenovirus vectors are powerful tools for inducing de novo gene expression in vivo. Here we have exploited them to study the specificity of CD4/CD8 lineage commitment during thymocyte positive selection, transferring MHC class II genes directly into thymi of mice deficient in both class I and II molecules. Expression of class II molecules was induced on cortical stroma, provoking the selection of a large population of mature CD4(+)CD8(-) cells, as expected, but also of a significant number of CD4(-)CD8(+) cells. The latter constituted a diverse population, containing both immature precursors and, though less frequent, cells that were mature according to several criteria. CD4(-)CD8(+) cells appeared with the same kinetics as their CD4(+)CD8(-) counterparts, but tended to be more prevalent at early times or when thymocyte reconstitution was only modest. These observations, derived from a dynamic selection system, indicate that CD4/CD8 lineage commitment is not irredeemably linked to the class of MHC molecule driving positive selection, a conclusion most compatible with selective models of commitment.

Adenoviridae↗
PubMed1987

Biochemical and molecular analysis of sheep MHC class II molecules.

A panel of monoclonal antibodies was used for structural and immunodepletion analysis of sheep MHC class II molecules. The results indicate the antibodies recognize molecules of molecular weight 32-34,000 (alpha chain) and 26-28,000 (beta chain). Immunodepletion analysis indicates that the antibodies may recognize up to four distinct class II molecules some of which are structurally distinguishable using SDS-PAGE. Southern blot analysis using HLA-D region DR, DQ, DP, DO and DZ cDNA probes showed that a number of the cDNA probes hybridized specifically to sheep DNA indicating the presence of closely related genes in sheep. Together the results suggest that the sheep MHC class II region contains distinct MHC class II genes similar to those found in man.

Animals↗
PubMed1993

Structure and evolution of the promoter regions of the DQA genes.

HLA-DQ antigens are unique among the class II antigens in that their alpha chains are highly polymorphic. In the present study, we characterized the general structure of the promoter regions of the DQA genes derived from different DR haplotypes and defined their nucleotide sequence polymorphisms. The promoter of each DQA1 allele contains three sequence motifs which are not present in non-DQA related class II genes: one identical to a tumor necrosis factor (TNF alpha) response element, one similar to an NF kappa B binding element, and one similar to a W motif. All DQA alleles lack TATA and CCAAT boxes in the proximal promoter region but carry other sequence elements characteristic of MHC class II genes, including S, X, X2, and Y boxes, and a pyrimidine-rich tract upstream of the X box. Nucleotide sequence polymorphisms among the various DQA1 alleles were noted within the promoter region, with some of the differences mapping within, or close to, regulatory elements that are important for the expression of MHC class II genes. All DQA1 alleles carry an unrearranged, full length, Alu-Sx related repeat immediately upstream of the proximal promoter region. This repeat was not present in the DQA2 (DXA) genes analyzed, confirming that DQ locus duplication probably occurred before integration of the Alu repeat into the primordial DQA1 locus, some 31-43 million years (myr) ago. The DQA2 promoter region is highly conserved between DR4 and DR3 haplotypes, with the degree of conservation exceeding that expected from the neutral mutation rate.

Alleles↗
PubMed1987

Activation of an encephalitogenic T lymphocyte line with a cellfree supernatant containing basic protein and I region gene products.

Activation of antigen-specific T lymphocyte lines requires presentation of the relevant antigen by syngeneic accessory cells (AC) that express Class II MHC gene products. To determine if the T cell activation signal was AC associated or was shed into the medium, supernatants from rat thymic AC populations pulsed with guinea pig basic protein (GP-BP) or PPD were used to stimulate resting BP- or PPD-reactive T cell lines derived from Lewis or BN rats. Cellfree supernatants were found to stimulate the T cell lines in an antigen-specific, strain-restricted manner, reflecting the pattern of stimulation observed with intact AC used. The activity of the cellfree supernatant could be enhanced five to 20 times in the presence of activated T lymphocytes, the optimal production occurring over a 6-hr period. The cellfree T lymphocyte activation signal produced in the presence of activated T cell products contained both an antigen-specific, MHC-restricted component (85%) and an antigen-independent, mitogenic component (15%). Supernatants containing GP-BP but not bovine BP or PPD induced highly significant proliferation of the Lewis rat-derived BP-1 T lymphocyte line, and transfer of these supernatant-activated cells produced clinical signs of experimental autoimmune encephalomyelitis (EAE) and DTH reactions to GP-BP. The GP-BP component was not inhibited by either of two monoclonal antibodies directed at determinants on either side of the epitope(s) recognized by BP-1 cells. However, stimulation was inhibited by an anti-I-A but not an anti-I-E monoclonal antibody, suggesting the involvement of a Class II MHC gene product on the T cell activation signal. The supernatant activity could be separated by ultracentrifugation at 100,000 X G for 4 hr into a microsomal pellet and an ultrasupernatant, and both fractions had greatly reduced activity on resting T cells until they were reconstituted by vigorous mixing. These results suggest that T effector cells can be activated by AC-derived microsomal fragments bearing Class II antigens that associate noncovalently with processed antigen. This cellfree signal is sufficient to activate encephalitogenic T lymphocytes to transfer clinical EAE and DTH reactions without need for a direct T cell-AC interaction.

Animals↗
PubMed1989

Association of class I, II, and III MHC gene products with systemic lupus erythematosus. Results of a Central European multicenter study.

Class I, II, and III MHC gene products were examined in 248 Central European SLE patients. The previously reported association with HLA-A1, -B8 and -DR3, and C4AQ0 alleles was confirmed. The frequency of HLA-DR2 was also slightly elevated in SLE patients, while no increase in C4BQ0 alleles was observed. Additional findings were a significantly increased frequency of HLA-B13 and a significant decrease of HLA-B44.

Alleles↗
PubMed1998

MHC haplotype-dependent regulation of MOG-induced EAE in rats.

Experimental autoimmune encephalomyelitis (EAE) induced in the rat by active immunization with myelin-oligodendrocyte-glycoprotein (MOG) is mediated by synergy between MOG-specific T cells and demyelinating MOG-specific antibody responses. The resulting disease is chronic and displays demyelinating central nervous system (CNS) pathology that closely resembles multiple sclerosis. We analyzed major histocompatibility complex (MHC) haplotype influences on this disease. The MHC haplotype does not exert an all-or-none effect on disease susceptibility. Rather, it determines the degree of disease susceptibility, recruitment of MOG-specific immunocompetent cells, clinical course, and CNS pathology in a hierarchical and allele-specific manner. Major haplotype-specific effects on MOG-EAE map to the MHC class II gene region, but this effect is modified by other MHC genes. In addition, non-MHC genes directly influence both disease and T cell functions, such as the secretion of IFN-gamma. Thus, in MOG-EAE, allelic MHC class II effects are graded, strongly modified by other MHC genes, and overcome by effects of non-MHC genes and environment.

Animals↗
PubMed1988

Antiviral immunity induced by recombinant nucleoprotein of influenza A virus. I. Characteristics and cross-reactivity of T cell responses.

The gene for the nucleoprotein of the A/NT/60/68 influenza virus was expressed in bacteria and the recombinant protein purified. Lymph node cells from mice immunized with recombinant nucleoprotein proliferated in response to in vitro stimulation with a range of type A influenza viruses. Proliferation was inhibited by mAb to CD4 and class II MHC gene products. IFN-gamma was produced and type-specific CTL were generated in stimulated cultures of immune lymph node cells. These CTL were CD4+ and restricted to class II MHC gene products. Immunization with recombinant nucleoprotein generated Th cells in vivo as measured by the ability to generate an accelerated response to hemagglutinin after challenge with inactivated virus. The results are discussed with reference to a cross-reactive vaccine against influenza.

Animals↗
PubMed1988

Characterization of cells comprising murine thymocyte multicellular complexes.

Characterization of complexes between thymocytes and thymic stromal cells was facilitated in the present study by demonstrating that complexes would reform if cells were incubated for 1.5 to 2 h in vitro at ambient temperature. Several immunologic approaches were used to determine the phenotype of complexed cells. Bound T cells were 97% double-positive (CD4 and CD8), 3% double-negative and greater than 99% CD3 positive by using immunoperoxidase immunohistology on cytospins. Five percent expressed the TCR beta-chain and 1 to 2% were IL-2R positive. The percentages were the same whether complexes were preformed in vivo or formed in vitro. Despite the apparent absence of single positive cells in complexes, when isolated CD4 or CD8 positive cells were tested for their ability to bind to adherent thymic macrophages, each subpopulation contained some cells which were capable of complex formation. When thymocytes were fractionated by density, steroid sensitivity or peanut agglutinin positivity then allowed to form complexes, cells with an immature phenotype had a greater propensity for complex formation. Central stromal cells all were class II MHC gene product (I-A and I-E) positive, expressed macrophage-associated Ag (B23.1 and MAC-1), were negative for cytokeratin but positive for vimentin, were reactive with a polyclonal antimacrophage serum, but did not express dendritic cell Ag (33D1). The data demonstrate that immature thymocytes bind exclusively to class II MHC gene product positive thymic macrophages. This binding step may play a role in the acquisition of T cell function in the thymus.

Animals↗
PubMed2003

DEK binding to class II MHC Y-box sequences is gene- and allele-specific.

Using electrophoretic mobility shift assays, we examined sequence-specific binding of DEK, a potential autoantigen in juvenile rheumatoid arthritis, to conserved Y-box regulatory sequences in class II MHC gene promoters. Nuclear extracts from several cell lines of different phenotypes contained sequence-specific binding activity recognizing DRA, DQA1*0101, and DQA1*0501 Y-box sequences. Participation of both DEK and NF-Y in the DQA1 Y-box binding complex was confirmed by 'supershifting' with anti-DEK and anti-NF-Y antibodies. Recombinant DEK also bound specifically to the DQA1*0101 Y box and to the polymorphic DQA1*0501 Y box, but not to the consensus DRA Y box. Measurement of the apparent dissociation constants demonstrated a two- to fivefold difference in DEK binding to the DQA1 Y-box sequence in comparison with other class II MHC Y-box sequences. Residues that are crucial for DEK binding to the DQA1*0101 Y box were identified by DNase I footprinting. The specific characteristics of DEK binding to these related sequences suggests a potential role for DEK in differential regulation of class II MHC expression, and thus in the pathogenesis of juvenile rheumatoid arthritis and other autoimmune diseases.

Alleles↗
PubMed1984

Thymus dictates major histocompatibility complex (MHC) specificity and immune response gene phenotype of class II MHC-restricted T cells but not of class I MHC-restricted T cells.

Athymic H-2b nude mice received grafts from C57BL/6 (Sendai virus and H-Y antigen cytotoxic T lymphocyte [CTL] responder type), bm1 (H-2Kb mutant, Sendai CTL nonresponder type), or bm12 (H-21-A mutant, H-Y CTL nonresponder type) neonates. In observations of the CTL response to H-Y, both recipients and thymus donors were female. All types of thymus engraftment resulted in mature H-2b splenic T lymphocyte surface phenotype in nude hosts. T cell immunocompetence (as measured by major histocompatibility complex [MHC] CTL responses to allogeneic cells) was restored, and induced nonresponsiveness to the MHC determinants of the engrafted thymus in the nude host. The CTL reaction to Sendai virus in both responder type C57BL/6 and nonresponder type bm1 neonatal thymuses allowed maturation of Sendai-specific, H-2Kb-restricted CTL. For the CTL reaction to H-Y, only responder type C57BL/6 thymuses restored the CTL response, whereas this was not achieved with thymuses from nonresponder type bm12 neonatal females. Results of double thymus (B6 and bm12) engraftment excluded the possibility that this latter effect was caused by suppression. In addition, athymic bm1 mice were engrafted with thymuses from either B6 (Sendai CTL responder type) or syngeneic bm1 neonates (Sendai CTL nonresponder type). Again, both types of neonate thymuses restored T cell competence as measured by MHC/CTL responses to allogeneic cells. However, neither responder B6 nor nonresponder bm1 neonate thymus grafts allowed maturation of Sendai-specific CTL. In conclusion, the thymus dictates MHC specificity and immune response gene phenotype of T cells restricted to class II MHC molecules but not of T cells restricted to class I MHC molecules.

Animals↗