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PubMed1980

Influence of the mouse major histocompatibility complex, H-2, on liver adenylate cyclase activity and on glucagon binding to liver cell membranes.

The major histocompatibility complex of mice, the H-2 complex, regulates the steady-state level of adenosine cyclic 3',5'-monophosphate (cAMP) in liver. This effect of H-2 may be due to an effect on hormone binding to receptors. Here we show that liver membranes from animals of different H-2 types differ in their sensitivity to glucagon stimulation of adenylate cyclase and in the affinity of their receptors for glucagon. No H-2-associated differences are seen in basal, NaF-stimulated, or GMP-PNP-stimulated adenylate cyclase.

Adenylyl Cyclases↗
PubMed1984

Subdivision of the S region of the mouse major histocompatibility complex by identification of genomic polymorphisms of the class III genes.

The S region of the mouse major histocompatibility complex (MHC) encodes the class III proteins, the second (C2) and fourth (C4) components of complement, and factor B. Previously, the assignment of S-region haplotypes was based on analysis of protein polymorphisms. The recent availability of C2, C4, and factor B cDNA probes prompted a search for restriction fragment length polymorphisms which would serve as additional genetic markers for these loci. DNA was isolated from livers of mice of all standard inbred H-2 haplotypes and of haplotypes pz and bs. These DNA samples were digested with restriction endonucleases and analyzed by Southern blot. By the pattern of restriction fragment length polymorphism observed, specific markers have been identified in factor B of haplotypes f, u, z, bs, r, and v, and in C4 of haplotypes b,q,f,j,p,s,pz,r, and v. These genetic markers were used in the analysis of S-region composition in strains B10.TFR5(H-2ap5) and C3H.LG(H-2dx), and a possible intra-S-region recombinant was revealed in the H-2dx haplotype. The genetic markers identified here subdivide the S region and will be of value in defining further the composition of the complement gene complex of the mouse MHC.

Alleles↗
PubMed1999

Interactions between the class II transactivator and CREB binding protein increase transcription of major histocompatibility complex class II genes.

Class II major histocompatibility (class II) genes are regulated in a B-cell-specific and gamma interferon-inducible fashion. The master switch for the expression of these genes is the class II transactivator (CIITA). In this report, we demonstrate that one of the functions of CIITA is to recruit the CREB binding protein (CBP) to class II promoters. Not only functional but also specific binding interactions between CIITA and CBP were demonstrated. Moreover, a dominant negative form of CBP decreased the activity of class II promoters and levels of class II determinants on the surface of cells. Finally, the inhibition of class II gene expression by the glucocorticoid hormone could be attributed to the squelching of CBP by the glucocorticoid receptor. We conclude that CBP, a histone acetyltransferase, plays an important role in the transcription of class II genes.

Animals↗
PubMed1988

Class I and II major histocompatibility complex gene product expression by a rat insulinoma cell line in vitro following exposure to gamma interferon.

A study of Class I and II major histocompatibility complex gene product expression by a rat insulinoma cell line (RINm5F) was performed using monoclonal antibodies and immunoperoxidase techniques. RINm5F cells were incubated with different concentrations of gamma interferon. RINm5F cells exhibit low levels of Class I molecules and are normally devoid of Class II gene products. Upon exposure to gamma interferon, RINm5F cells showed a dramatic increase in Class I expression. This expression was homogenous and could be detected on all cells after 18 h of incubation with as little as 1 unit/ml of interferon. In contrast, de novo Class II expression was not homogeneous and required 36 h of incubation with 10 units/ml of interferon. The number of RINm5F cells expressing Class II antigens was dose- and time-dependent. Interferon treatment did not affect the morphology of RINm5F cells as determined by ultrastructural analysis. Withdrawal of interferon from the culture medium for as long as 78 h diminished but did not abolish the expression of Class I and Class II molecules already induced. The ability of interferon to enhance expression of Class I gene products and induce de novo expression of Class II molecules on B-cell-derived RINm5F cells supports the hypothesis that aberrant expression of major histocompatibility complex gene products on pancreatic B cells may be an important factor in triggering the immune response in Type 1 (insulin dependent) diabetes mellitus.

Adenoma, Islet Cell↗
PubMed1993

Differential expression of interleukin-6, intracellular adhesion molecule 1, and major histocompatibility complex class II molecules in renal carcinoma cells stimulated with S fimbriae of uropathogenic Escherichia coli.

The production of interleukin-6, intracellular adhesion molecule 1, and major histocompatibility complex class II molecules by a renal carcinoma cell line (ACHN) in response to S fimbriae of uropathogenic Escherichia coli was studied. S fimbriae adhered to ACHN cells and stimulated the production of interleukin-6 and intercellular adhesion molecule 1 but did not affect major histocompatibility complex class II expression by renal carcinoma cells. Our data demonstrate that S fimbriae of E. coli display immunomodulating properties on kidney-derived epithelial cells.

Carcinoma, Renal Cell↗
PubMed2006

Major histocompatibility complex haplotype is associated with postherpetic pain in mice.

BACKGROUND: Postherpetic neuralgia is one of the major complications of herpes zoster caused by the reactivation of varicella-zoster virus and is characterized by severe pain. The authors previously showed the association of a human major histocompatibility complex (MHC) haplotype with postherpetic neuralgia. This study was performed to experimentally confirm the role of MHC haplotype in the development of postherpetic pain using a mouse model of postherpetic pain, which corresponds to postherpetic neuralgia. METHODS: BALB/c mice (MHC haplotype: H-2), C57BL/6 mice (MHC haplotype: H-2), and BALB/b mice, a congenic BALB/c strain with H-2, were used. Herpes simplex virus type I was transdermally inoculated on the hind paw. Unilaterally zosteriform skin lesion and pain-related responses (acute herpetic pain) were caused, and some mice showed pain-related responses (postherpetic pain) after the cure of skin lesions. Herpes simplex virus type I antigen and CD3-positive cells were immunostained in the dorsal root ganglion in the acute phase. RESULTS: The incidence (78%) of postherpetic pain in C57BL/6 mice was significantly higher than that (35%) in BALB/c mice (P = 0.004, odds ratio = 6.7). Furthermore, the incidence of postherpetic pain in BALB/b (H-2) was similar to that in C57BL/6. Herpes simplex virus type I antigen-positive cells were less in the dorsal root ganglion of C57BL/6 mice than that of BALB/c mice. CD3-positive T cells were more in the dorsal root ganglion of C57BL/6 mice than BALB/c mice. CONCLUSIONS: These results suggest that the MHC haplotype (H-2) is involved in the incidence of postherpetic pain, and CD3-positive T cells may play a role in its pathogenesis.

Animals↗
PubMed2005

The non-major histocompatibility complex quantitative trait locus Cia10 contains a major arthritis gene and regulates disease severity, pannus formation, and joint damage.

OBJECTIVE: To construct rats congenic for the chromosome 2 arthritis-regulatory quantitative trait locus Cia10, originally identified in a (DA x ACI)F(2) intercross rat strain that had been assessed for collagen-induced arthritis (CIA), and to determine the effect of this congenic interval on arthritis severity, joint histologic structure, and cytokine transcription in rats with pristane-induced arthritis (PIA). METHODS: A 52.6-MB interval derived from the ACI (CIA- and PIA-resistant) strain and containing the Cia10 interval was introgressed into the DA (arthritis-susceptible) background through genotype-guided congenic breeding. Homozygous male and female DA.ACI(Cia10) congenic rats were studied for their susceptibility to and severity of PIA, and were compared with same-sex DA rats. Histologic analyses were done on hind paws collected on day 32 following the pristane injection. Levels of interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) messenger RNA (mRNA) were measured with real-time polymerase chain reaction on synovial tissues from day-32 ankles. RESULTS: Both male and female DA.ACI(Cia10) congenic rats developed a significantly milder form of arthritis, with a 95% and 92% reduction in the arthritis severity index compared with DA male and female controls, respectively (males P < or = 0.001 and females P = 0.003). DA.ACI(Cia10) congenic rat synovial tissue was more likely to preserve its normal histologic architecture, including minimal to no cartilage and bone erosions, synovial hyperplasia, and pannus formation, and reduced numbers of vessels (angiogenesis), when compared with DA synovial tissue. There was a 2.7- and 2.4-fold reduction in the amount of IL-1beta and TNFalpha mRNA, respectively, in the synovial tissue of DA.ACI(Cia10) congenic rats compared with DA rats. Sequencing analyses of complementary DNA for the Cia10-predicted candidate gene Ptpn8, the rat homolog of the rheumatoid arthritis (RA)-susceptibility gene PTPN22, revealed no polymorphisms between the DA and ACI strains. CONCLUSION: This study determined that Cia10 harbors a major autoimmune arthritis-regulatory gene. This gene regulates clinical disease severity, histologic damage, and the levels of at least two central proinflammatory cytokines. We are in the process of narrowing down the critical region for positional cloning of the Cia10 gene. The identification of this gene will provide novel targets or pathways for focused candidate-gene studies in RA.

Animals↗
PubMed2002

An efficient and versatile mammalian viral vector system for major histocompatibility complex class I/peptide complexes.

We report a Sendai virus (SeV) vector system for expression of major histocompatibility complex (MHC) class I/peptide complexes. We cloned the extracellular domain of a human MHC class I heavy chain, HLA-A*2402, and human beta-2 microglobulin (beta2m) fused with HLA-A*2402-restricted human immunodeficiency virus type 1 (HIV-1) cytotoxic T-lymphocyte (CTL) epitopes (e-beta2m) in separate SeV vectors. When we coinfected nonhuman mammalian cells with the SeVs, naturally folded human MHC class I/peptide complexes were secreted in the culture supernatants. Biotin binding peptide sequences on the C terminus of the heavy chain were used to tetramerize the complexes. These tetramers made in the SeV system recognized specific CD8-positive T cells in peripheral blood mononuclear cells of HIV-1-positive patients with a specificity and sensitivity similar to those of MHC class I tetramers made in an Escherichia coli system. Solo infection of e-beta2m/SeV produced soluble e-beta2m in the culture supernatant, and cells pulsed with the soluble protein were recognized by specific CTLs. Furthermore, when cells were infected with e-beta2m/SeV, these cells were recognized by the specific CTLs more efficiently than the protein pulse per se. SeV is nonpathogenic for humans, can transduce foreign genes into nondividing cells, and may be useful for immunotherapy to enhance antigen-specific immune responses. Our system can be used not only to detect but also to stimulate antigen-specific cellular immune responses.

Animals↗
PubMed1991

Mouse major histocompatibility complex and lung development: haplotype variation, H-2 immunolocalization, and progressive maturation.

The association of the mouse major histocompatibility complex (H-2), lung maturation, and corticosteroid responsiveness has recently been demonstrated in congenic B10 (H-2b) and B10.A (H-2a) mice (Hu et al.: American Journal of Medical Genetics 35:126-131, 1990). We have investigated additional haplotypes [B10.BR (H-2k) and B10.D2 (H-2d)] to confirm that there is a strong association between H-2 haplotype variation and the degree of pulmonary maturation. Lungs of B10.D2, B10.BR, B10, and B10.A congenic mice achieve haplotypic specific maturation: B10.D2 lungs greater than B10 lungs = B10.BR lung greater than B10.A lungs. It appears that the expression of these developmental potentials is under corticosteroid regulation. Further, to test the hypothesis that H-2 antigens would be expressed earlier in embryonic lungs with the H-2b (B10) or H-2k (B10.BR) haplotype than with the H-2a (B10.A) haplotype, we investigated the spatiotemporal patterns of H-2 antigen localization in B10, B10.BR, and B10.A congenic mouse strains with and without corticosteroid treatment. The spatial patterns of H-2 antigen localization was similar in the B10, B10.BR, and B10.A mouse lungs; however, these patterns appeared earlier in both untreated and treated B10 and B10.BR mice as compared with untreated B10.A mice, suggesting an H-2 haplotype associated rate of pulmonary maturation. Following corticosteroid treatment, all congenic strains had a temporally comparable spatial distribution of H-2 antigens. Our results provide preliminary evidence suggesting that both a lung "developmental gene(s)" and a "glucocorticoid responsiveness gene(s)" are most likely outside the K-D subregions of the H-2 complex. A model of the H-2 regulation of lung maturation and corticosteroid responsiveness is discussed.

Animals↗
PubMed1993

Interference with major histocompatibility complex class II-restricted antigen presentation in the brain by herpes simplex virus type 1: a possible mechanism of evasion of the immune response.

Host survival of herpes simplex virus type 1 (HSV-1) infection depends on the establishment of latent infections in both peripheral and central nervous systems. Strains of HSV-1 that are successful in escaping the immune response produce a lethal infection. We now report a possible mechanism of immune response evasion used by HSV-1. After intraocular inoculation of mice, HSV-1 strain F established a latent infection in the brain, whereas strain KOS did not. The immune response to HSV-1 infection (strains KOS and F) in the brain was characterized by induction of major histocompatibility complex class II expression and recruitment of CD4+ and CD8+ cells to highly restricted sites of intracerebral viral infection. Major histocompatibility complex class II antigen expression was primarily intracellular in strain KOS infection centers and at the cell surface in strain F infection centers. We propose that major histocompatibility complex class II-restricted viral-antigen presentation to T cells is interrupted during strain KOS infections, thereby allowing KOS infection to evade T-cell-mediated events that would normally protect the host from a lethal infection. Immunocompromised mice (athymic or irradiate mice) could not survive strain F infections; however, latent F infections were established in irradiated mice reconstituted with naive lymph node and spleen cells. These data suggest that class II-restricted presentation of viral antigens is required for the control of HSV-1 infections in the nervous system.

Animals↗
PubMed1981

Genes within the major histocompatibility complex of the guinea pig influence susceptibility to Trichostrongylus colubriformis infection.

The influence of genes in the major histocompatibility complex (MHC) of the guinea pig on the susceptibility to infection with the parasitic nematode Trichostrongylus colubriformis was investigated. Back-cross analysis of 2 lines of guinea pigs suggests that genes that map in or near the I region of the guinea pig MHC influence susceptibility to infection by the parasite. However, other genes, possibly not linked to the guinea pig MHC, may also be required for the full expression of susceptibility.

Animals↗
PubMed1997

Role of the major histocompatibility complex class II Ea gene in lupus susceptibility in mice.

The gene(s) encoded within major histocompatibility complex (MHC) act as one of the major genetic elements contributing to the susceptibility of murine systemic lupus erythematosus (SLE). We have recently demonstrated that lupus susceptibility is more closely linked to the I-E- H-2(b) haplotype than to the I-E+ H-2(d) haplotype in lupus-prone BXSB and (NZB x BXSB)F1 hybrid mice. To investigate whether the reduced susceptibility to SLE in H-2(d) mice is related to the expression of the MHC class II Ea gene (absent in H-2(b) mice), we determined the possible role of the Ea gene as a lupus protective gene in mice. Our results showed that (i) the development of SLE was almost completely prevented in BXSB (H-2(b)) mice expressing two copies of the Ead transgene at the homozygous level as well as in BXSB H-2(k) (I-E+) congenic mice as for H-2(d) BXSB mice, and (ii) the expression of two functional Ea (transgenic and endogenous) genes in either H-2(d/b) (NZB x BXSB)F1 or H-2(k/b) (MRL x BXSB)F1 mice provided protection from SLE at levels comparable to those conferred by the H-2(d/d) or H-2(k/k) haplotype. In addition, the level of the Ea gene-mediated protection appeared to be dependent on the genetic susceptibility to SLE in individual lupus-prone mice. Our results indicate that the reduced susceptibility associated with the I-E+ H-2(d) and H-2(k) haplotypes (versus the I-E- H-2(b) haplotype) is largely, if not all, contributed by the apparent autoimmune suppressive effect of the Ea gene, independently of the expression of the I-A or other MHC-linked genes.

Animals↗
PubMed1984

Class I, II and III major histocompatibility complex gene polymorphisms in BB rats.

The BB rat spontaneously develops insulin-dependent diabetes mellitus of autoimmune aetiology. From breeding studies, one of the genes necessary for the development of diabetes in these animals is linked to RT1, the rat's major histocompatibility complex. To study further the RT1 linked diabetogenic gene of the BB rat, we have studied restriction fragment length polymorphism using 32P-labelled DNA probes of the major histocompatibility complex genes. As we have previously reported, an I-A alpha probe (mouse class II gene) defines four chromosome types in the control BBN population, only one of which is found among diabetes prone BB rats. All BB rats we have studied are homozygous for the type IIa chromosome. Here we examine restriction fragment length polymorphisms using three other DNA probes. Using a DC beta-probe (human class II), the same pattern of polymorphisms (though different molecular weights) is found as with the I-A alpha probe. An H-2d C4 (fourth component of complement, mouse class III) defines no polymorphisms among or between BB and BBN rats. Using H-2 LdC-2 domain probe (mouse class I) many polymorphisms are apparent and in a limited series distinguishes I-A alpha defined IIa/IIa BBN rats from IIa/IIa BB rats. These studies provide the basis to subtype the RT1u identical BB and BBN animals and should aid in the localization and characterization of the RT1 linked diabetogenic gene of the BB rat.

Animals↗
PubMed1983

Partial purification and characterization of chicken immune-associated antigen in serum coded for by the major histocompatibility complex.

Chicken serum contains 3 molecular species of immune-associated (Ia) antigen coded for by the major histocompatibility complex (MHC). These molecules are named B-L alloantigens [1]. They vary in electrophoretic migration velocity and molecular size [2]. The aim of this study was to characterize one of the antigen species - the low molecular size form. Therefore, we performed a partial purification by: (i) affinity chromatography; and (ii) ammonium sulfate precipitation of serum B-L antigen from the chicken plasma. Since the MHC-antigens were known to be glycoproteins, the purification was based on lectin affinity chromatography, as previously used for the membrane-bound MHC-antigens [3]. Electro-immunochemical analysis using rabbit antibodies against the chicken lymphocyte plasma membrane and the partially purified antigen were employed to monitor the purification and to characterize the different molecular forms of the Ia molecules. The partially purified preparation was then analyzed to elucidate the biochemical structure of the serum B-L antigen. Finally, rabbit antiserum was raised against this preparation to evaluate its level of purity and to follow further purification of this molecule.

Animals↗
PubMed1991

The "adjuvant effect" of the polymorphic B-G antigens of the chicken major histocompatibility complex analyzed using purified molecules incorporated in liposomes.

The polymorphic B-G region of the chicken major histocompatibility complex has previously been shown to mediate an "adjuvant effect" on the humoral response to other erythrocyte alloantigens. We demonstrate here that B-G molecules purified with monoclonal antibodies exert this adjuvant effect on the production of alloantibodies to chicken class I (B-F) molecules, when the two are in the same liposome. The adjuvant effect may in part be mediated by antibodies, since the antibody response to B-G molecules occurs much faster than the response to B-F molecules, and conditions in which antibodies to B-G are present increase the speed of the response to B-F molecules. We also found that the presence of B-G molecules in separate liposomes results in a lack of response to B-F molecules. In the light of this and other data, we consider the possible roles for the polymorphic B-G molecules, particularly for the generation of B cell diversity, in the immune systems of birds and other animals.

Adjuvants, Immunologic↗
PubMed1991

Major histocompatibility complex antigen expression on lymphocytes from aging strain A mice.

Molecules encoded by the major histocompatibility complex (MHC) are crucial for the proper functioning of the immune response. In this study, the levels of class I and class II major histocompatibility antigens on lymphocytes from strain A mice were measured as a function of age. Class I protein levels increased significantly on both peripheral blood and spleen (T cells and B cells) lymphocytes with age. This increase in MHC class I protein levels was accompanied by an increase in class I mRNA levels. On the other hand, class II protein levels did not show a significant change with age. Moreover, while the percentage of class I-expressing spleen lymphocytes stayed at a steady-state level of 100% with age, the percentage of class II-expressing spleen lymphocytes decreased from 85% in young animals to 70% in old animals. This decrease was due to a decrease in the relative proportion of B cells compared to T cells in the spleen lymphocyte population of old mice. When class II mRNA levels were measured, it was found that these levels decreased markedly with age. Overall, it is clear that the regulation of MHC class I and class II expression changes with age in A strain mice. Since optimal levels of MHC expression are crucial for the proper functioning of cellular and humoral immune responses, it will be most interesting to understand how the control of MHC gene expression changes with age and whether MHC gene expression can be modulated in old individuals to restore better immune function.

Aging↗
PubMed2005

Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor.

Autoimmune diseases are caused by self-reactive lymphocytes that have escaped deletion. Here we have determined the structure of the trimolecular complex for a T cell receptor (TCR) from a patient with multiple sclerosis that causes autoimmunity in transgenic mice. The structure showed a TCR topology notably different from that of antimicrobial TCRs. Rather than being centered on the peptide-major histocompatibility complex, this TCR contacted only the N-terminal peptide segment and made asymmetrical interactions with the major histocompatibility complex helices. The interaction was dominated by the hypervariable complementarity-determining region 3 loops, indicating that unconventional topologies are possible because of the unique complementarity-determining region 3 sequences created during rearrangement. This topology reduces the interaction surface with peptide and alters the geometry for CD4 association. We propose that unusual TCR-binding properties can permit autoreactive T cells to escape deletion.

Amino Acid Sequence↗