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PubMed1989

Fine-needle aspiration biopsy sampling in renal transplantation: interstitial cellular infiltrates and major histocompatibility complex class-II antigen expression in renal tubular cells.

The dynamics of major histocompatibility complex (MHC) class-II (DR) antigen products in renal tubular cells and cellular infiltrations in the interstitium of the kidney following renal transplantation without immunosuppressive therapy are presented. DR antigen in 27 normal kidneys and in 18 of 19 kidneys transplanted as autograft showed no DR-antigen expression on their tubular cells. These DR-antigen-negative tubular cells could be induced to express the antigen during courses of untreated rejection both in primary (n = 6) and repeat (n = 4) allografts. Parallel to the increasing DR-antigen expression in the allograft, the autologous kidney expressed this antigen with the same time dependency and with the same intensity. Graft infiltrating cells were evaluated by daily fine-needle aspiration biopsy and core biopsy. Induction of DR antigen was associated with a significant infiltration of blastogenic cells and monocytes/macrophages in the allograft. During rejection of the allograft no cellular infiltrate was noted in the autograft, but during an initial time period after allograft removal cellular infiltrates were seen. Following both courses of rejection DR antigen returns to negative by 6-8 days as did blastogenic cells and monocytes/macrophages in the autograft interstitium. Inducible antigen expression in normally DR-antigen-negative allograft parenchymal cells during rejection is shown to depend on inflammatory cells in the graft. The antigen expression is not restricted to the tissue transplanted, but also affects autologous tissue of the host organism.

Animals↗
PubMed1990

Human major histocompatibility complex class II invariant chain is expressed on the cell surface.

Class II major histocompatibility complex antigens are intracellularly associated with a nonpolymorphic polypeptide referred to as the invariant chain. Before the class II heterodimer appears on the cell surface, the invariant chain dissociates but it has so far been unclear as to whether or not a proportion of the invariant chain also appears on the plasma membrane. We describe a study with three monoclonal antibodies which recognize an extracytoplasmic determinant present on all forms of the invariant chain and use them to demonstrate its presence on the surface of the intact cells. The determinants recognized by two of the antibodies were found to be located within the 60 amino acids at the extreme C-terminal (extracytoplasmic) end of the invariant chain. The invariant chain-specific monoclonal antibody, VIC-Y1, was found to bind a determinant located between amino acids 1 and 73, which correspond to mainly cytoplasmic residues. Using the C-terminal specific antibodies, the number of antibody binding sites on the surface of two B lymphoma lines was estimated to be 10(5) per cell. The results of this study appear to resolve the highly disputed question of whether or not the invariant chain can appear as a plasma membrane protein. The results are discussed in the context of a possible role for the invariant chain in antigen processing and presentation.

Antibodies, Monoclonal↗
PubMed1994

Protection against natural killer cells by interferon-gamma treatment of K562 cells cannot be explained by augmented major histocompatibility complex class I expression.

Prior study has revealed that the expression of certain major histocompatibility complex (MHC) class I molecules on the membranes of normal or transformed cells can prevent natural killer (NK)-cell-mediated killing. This has been explained by either (1) the target interference model, or (2) the effector inhibition model. In both cases, MHC class I molecules are concerned but the precise mechanisms are still unclear. The erythroleukaemia K562 cell is known as a NK-sensitive target. This sensitivity has been explained mostly as being due to lack of MHC class I antigens on the K562 membrane. However, several recent studies have indicated that the expression of MHC class I antigens on the cell does not solely explain the protection against NK cells. To elucidate the mechanism of NK-cell-mediated killing, we investigated the killing profiles of the K562 cells by NK cells. Previous studies indicated that the NK-sensitive K562 cells can express some MHC class I antigens on their surface, and become protective against NK-cell killing after treatment with human interferon-gamma (hIFN-gamma). In the present study, we show that this resistance is not rendered by MHC class I expression, because addition of anti-MHC class I monoclonal antibodies (mAb) in the killing assay of hIFN-gamma-treated K562 cells, which express MHC class I antigens as the target, did not restore the sensitivity to NK cells. Moreover, we show that spontaneously occurring K562 clones which could not express MHC class I antigens even after hIFN-gamma treatment, could be protected after treatment with the cytokine. Taken together, these results strongly suggest that the susceptibility of K562 cells to NK cell killing is due to some elements distinct from those related to MHC class I antigens.

Antibodies, Monoclonal↗
PubMed1993

Selectively down-regulated expression of major histocompatibility complex class I alleles in human solid tumors.

We studied the expression of major histocompatibility complex (MHC) class I molecule in 52 ex-vivo tumor samples comprising 29 ovarian, 15 lung, 1 breast, and 4 colon carcinomas; 1 midgut carcinoid; and 2 malignant mesenchymal tumors obtained from surgical specimens or from malignant effusions. The allelic products were visualized in untreated and interferon gamma + tumor necrosis factor alpha treated aliquots of tumor cells and in the patient's blood lymphocytes by the one-dimensional isoelectric focusing method. Generally, the tumor cells contained lower amounts of MHC class I molecules compared to the lymphocytes. In vitro exposure to interferon gamma and tumor necrosis factor alpha elevated the level of MHC class I expression in 24 of 52 tumors and corrected the assembly defect seen in 2 cases. In 20 tumors one or several human leukocyte antigen alleles were undetectable even after cytokine treatment. Correlation was seen with the grade of differentiation; the proportion of tumors with selective losses in poorly, moderately, or well differentiated tumors were 16 of 30, 3 of 13, and 1 of 9, respectively. Selective losses occurred in ovarian carcinoma cells collected from malignant effusions (12 of 22, 54%) but not in 7 primary tumors. In primary lung carcinomas the frequency was 36% (5 of 14 cases). Thirty-nine patients were serologically typed; thus the MHC alleles on the tumor cells could be identified. In this panel of tumors 30 human leukocyte antigen alleles were represented. Among these the expression of 15 was found to be down-regulated in some but not all tumors of the same histology.

Alleles↗
PubMed1984

Resistance of metastatic tumor variants to tumor-specific cytotoxic T-lymphocytes not due to defects in expression of restricting major histocompatibility complex molecules in murine cells.

Metastases of ESb lymphoma cells in syngeneic DBA/2 animals frequently are selectively immunoresistant to lysis by syngeneic cytotoxic T-lymphocytes (CTL). This immunoresistance of tumor cells to CTL lysis could be due to a defect in either of two structures: (a) tumor-associated transplantation antigens; or (b) mouse major histocompatibility complex (H-2) antigens serving as restricting elements. In this study, we have analyzed the possible involvement of major histocompatibility complex Class I antigens in the immunoresistance of ESb tumor variant cells. Syngeneic anti-ESb CTL appeared to be H-2Kd restricted since only antibodies to Kd but not D,Ld molecules could inhibit CTL lysis. Comparison of H-2 antigens expressed on immunosensitive and resistant ESb sublines by immunofluorescence and flow cytofluorography, alloreactive CTL, two-dimensional gel analysis did not reveal any differences either qualitatively or quantitatively. Southern blotting of tumor-derived DNA with H-2-specific probes did not reveal differences either. Serologically detectable cell surface differentiation antigens were expressed very similarly on immunosensitive and resistant tumor lines, and only minor differences were noted by biochemical analysis of plasma membrane proteins. C-Type viral Mr 70,000 glycoprotein antigens were also similar in both types of cells. We conclude that cell surface changes on immunoresistant ESb variant cells are very selective and involve only CTL-defined tumor-associated transplantation antigen determinants.

Animals↗
PubMed1993

Human class I major histocompatibility complex transgene prevents virus-induced demyelination in susceptible mutant B10.D2dml mice.

Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelination in susceptible strains of mice, providing an excellent model for multiple sclerosis. Class I genes within the major histocompatibility complex locus (H-2D region) play a major role in determining whether strains of mice develop chronic demyelination and TMEV persistence. B10.D2dml mice with deletion in the 3' end of Dd and the 5' end of Ld genes develop the most prominent demyelination in comparison with resistant B10.D2 mice with normal complementation of H-2D region genes. We tested whether expression of a class I human transgene (HLA-B27) would modulate virus-induced demyelination in mutant B10.D2dml mice. Transgenic B10.D2dml (HLA-B27+) mice infected with virus showed dramatic decrease in the extent of demyelination (p < 0.0001) and virus antigen expression in spinal cord compared with littermate controls without the human class I transgene. These experiments demonstrate that transgenic expression of a human class I major histocompatibility complex locus molecule can prevent demyelination induced by a virus in mutant mice.

Animals↗
PubMed1993

Endothelial activation by hydrogen peroxide. Selective increases of intercellular adhesion molecule-1 and major histocompatibility complex class I.

Products of activated leukocytes may alter vascular endothelial cell (EC) function. For example, ECs respond to leukocyte-derived cytokines, such as tumor necrosis factor (TNF) or interleukin-1, by reversibly altering levels of expression of specific gene products that promote inflammation. In contrast, hydrogen peroxide, a product of TNF-activated neutrophils, can produce irreversible EC injury and death. In this study, we have investigated the effects of subinjurious concentrations of hydrogen peroxide on EC inflammatory functions. Treatment with 50 to 100 mumol/L hydrogen peroxide selectively increases surface expression of intercellular adhesion molecule-1 and major histocompatibility complex class I, but not endothelial leukocyte adhesion molecule-1 (also known as E-selectin), vascular cell adhesion molecule-1, or gp96, a constitutively expressed EC surface protein. Increased major histocompatibility complex class I and intercellular adhesion molecule-1 surface expression is associated with specifically increased messenger RNA levels, suggesting selective endothelial gene activation. Hydrogen peroxide does not activate the transcription factor Nuclear Factor kappa B, an important mediator of TNF-induced gene expression. Co-treatment with hydrogen peroxide inhibits TNF-induced gene expression at 4 hours, an effect which can be attributed to reversible inhibition of TNF binding to EC surface receptors. Hydrogen peroxide also antagonizes the actions of interleukin-1. At 24 hours, TNF and hydrogen peroxide produce, at most, additive increases in intercellular adhesion molecule-1 and major histocompatibility complex class I. These results suggest that subinjurious concentrations of hydrogen peroxide can activate endothelium and that the effects of hydrogen peroxide on ECs differ from those of inflammatory cytokines.

Antigens, Surface↗
PubMed1996

Invariant chain and DM edit self-peptide presentation by major histocompatibility complex (MHC) class II molecules.

We have studied the consequences of invariant chain (Ii) and DM expression on major histocompatibility complex (MHC) class II function. Ii has a number of discrete functions in the biology of class II, including competitive blocking of peptide binding in the endoplasmic reticulum and enhancing localization in the endocytic compartments. DM is thought to act primarily in endosomes to promote dissociation of the Ii-derived (CLIP) peptide from the class II antigen-binding pocket and subsequent peptide loading. In this study, we have evaluated the functional role of Ii and DM by examining their impact on surface expression of epitopes recognized by a large panel of alloreactive T cells. We find most epitopes studied are influenced by both Ii and DM. Most strikingly, we find that surface expression of a significant fraction of peptide-class II complexes is extinguished, rather than enhanced, by DM expression within the APC. The epitopes antagonized by DM do not appear to be specific for CLIP. Finally, we found that DM was also able to extinguish recognition of a defined peptide derived from the internally synthesized H-2Ld protein. Thus, rather than primarily serving in the removal of CLIP, DM may have a more generalized function of editing the array of peptides that are presented by class II. This editing can be either positive or negative, suggesting that DM plays a specifying role in the display of peptides presented to CD4 T cells.

Animals↗
PubMed1996

Physical mapping of the Ring1, Ring2, Ke6, Ke4, Rxrb, Col11a2, and RT1.Hb genes in the rat major histocompatibility complex.

A contig of cosmids containing the Ring1, Ring2, Ke6, Ke4, Rxrb, and Col11a2 genes in the rat major histocompatibility complex has been established and aligned to the class II cluster (RT1.Hb). The relative order and the transcriptional orientations of these rat genes are the same as in their human and mouse homologues. The distances are also similar, except for the Col11a2 - class II interval, which is clearly shorter in rat and mouse compared with human. The previously defined Ke5 probe could be shown to map into the large Col11a2 gene.

Amino Acid Sequence↗
PubMed1992

Major histocompatibility complex, t-complex, and leukemia.

In experimental models, leukemia was the first disease shown to have an association with the major histocompatibility complex (MHC) genes. In humans, several allelic human-leukocyte antigen (HLA) associations also have been recognized. In addition to allelic associations, atypical HLA segregation patterns have been observed in leukemic families. These include a higher frequency of HLA-identical unaffected siblings, increased HLA homozygosity and increased maternal HLA-DR identity. These observations suggest preferential transmission of disease-associated haplotypes and a male transmission bias in leukemic families. The lack of disease-specific segregation, however, supports the idea that the HLA system is not directly relevant in leukemogenesis. Therefore, the existence of another genetic region linked to the MHC, causing segregation distortion, and containing recessive leukemia susceptibility genes may be postulated. The mouse t-complex would fit this model. This gene complex has recessive (semi-) lethal genes, is transmitted preferentially through fathers, and both the mouse t-complex and its rat homolog, growth and reproduction complex grc, confer susceptibility to carcinogenesis. This model could also explain the increased spontaneous abortion rate in mothers of leukemic patients, epidemiologic associations of leukemia with oral clefts and neuroectodermal tumors, and the transmission of a radiation-induced leukemia risk through fathers. Such segregation distortion might be the reason behind the maintenance of a gene(s) with a lethal effect in the population.

Animals↗
PubMed1989

Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes.

IgA deficiency and common variable immunodeficiency are heritable disorders that can occur within the same family. Both immunodeficiencies are characterized by arrests in B-cell differentiation that vary in the extent of the immunoglobulin isotypes involved. A high frequency of major histocompatibility complex supratypes associated with a null allele of the gene encoding the C4A isotype of complement component C4 has been observed in IgA-deficient individuals. In search of a genetic linkage between the two immunodeficiencies, we examined the major histocompatibility complex (MHC) class III genes encoding complement components C2, C4A, and C4B and steroid 21-hydroxylase in addition to the HLA serotypes in individuals with either common variable immunodeficiency or IgA deficiency. Twelve of 19 patients with common variable immunodeficiency (63%, P less than 0.001) and 9 of 16 patients with IgA deficiency (56%, P less than 0.01) had rare C2 alleles and/or C4A and 21-hydroxylase A deletions, whereas these gene features were seen in only 5 of 34 healthy individuals (15%) in the control group. Nine of 11 patients with C4A deletion had an HLA haplotype consistent with the MHC supratype HLA-A1, Cw7, B8, C4AQ0, C4B1, BfS, DR3 previously found to be associated with IgA deficiency. The data support the hypothesis that common variable immunodeficiency and IgA deficiency are related disorders, susceptibility to which is determined by a gene(s) within or near the MHC class III gene region on chromosome 6.

Alleles↗
PubMed1991

Immunoglobulin variable-region-like domains of diverse sequence within the major histocompatibility complex of the chicken.

The highly polymorphic B-G antigens are considered to be part of the major histocompatibility complex (MHC) of the chicken, the B system of histocompatibility, because they are encoded in a family of genes tightly linked with the genes encoding MHC class I and class II antigens. To better understand these unusual MHC antigens, full-length B-G cDNA clones were isolated from B21 embryonic erythroid cell cDNA library, restriction-mapped, and sequenced. Five transcript types were identified. Analysis of the deduced amino acid sequences suggests that the B-G polypeptides are composed of single extracellular domains that resemble immunoglobulin domains of the variable-region (V) type, single membrane-spanning domains typical of integral membrane proteins, and long cytoplasmic tails. Sequence diversity among the five transcript types was found in all domains, notably including the B-G immunoglobulin V-like domains. The cytoplasmic tails of the B-G antigens are made up entirely of units of seven amino acid residues (heptads) that are typical of an alpha-helical coiled-coil conformation. The heptads vary in number and sequence between the different transcripts. The presence within B-G polypeptides of polymorphic immunoglobulin V-like domains warrants further investigations to determine the degree and nature of variability within this domain in these unusual MHC antigens.

Amino Acid Sequence↗
PubMed1992

Empty and peptide-containing conformers of class I major histocompatibility complex molecules expressed in Drosophila melanogaster cells.

Transfected Drosophila melanogaster cells can express large quantities of class I major histocompatibility complex molecules. Such molecules lack endogenous peptides because the Drosophila cells are devoid of proteins necessary for intracellular peptide loading. The empty molecules are efficiently expressed on the cell surface and can acquire extracellular peptides. The conformation and stability of empty murine class I molecules are determined by the source of beta 2-microglobulin. All beta 2-microglobulin-induced conformers of empty heavy chains seem to be unified in a common rigid conformation on peptide binding.

Amino Acid Sequence↗
PubMed1996

Limited polymorphism at major histocompatibility complex (MHC) loci in the Swedish moose A. alces.

The Swedish moose was analysed for genetic variability at major histocompatibility complex (MHC) class I and class II DQA, DQB and DRB loci using restriction fragment length polymorphism (RFLP) and single strand conformation polymorphism (SSCP) techniques. Both methods revealed limited amounts of polymorphism. Since the SSCP analysis concerned an expressed DRB gene it can be concluded that the level of functional MHC class II polymorphism, at least at the DRB locus, is low in Swedish moose. DNA fingerprinting was used to determine if the unusual pattern of low MHC variability could be explained by a low degree of genome-wide genetic diversity. Hybridizations with two minisatellite probes gave similarity indices somewhat higher than the average for other natural population, but the data suggest that the low MHC variability cannot be explained by a recent population bottleneck. However, since minisatellite sequences evolve more rapidly than MHC sequences, the low levels of MHC diversity may be attributed to a bottleneck of more ancient origin. The selection pressure for MHC variability in moose may also be reduced and we discuss the possibility that its solitary life style may reduce lateral transmission of pathogens in the population.

Animals↗
PubMedDate not supplied

Susceptibility to Eimeria tenella of chickens and chicken embryos of partly inbred lines possessing homozygous major histocompatibility complex haplotypes.

Susceptibility to Eimeria tenella infection of chicken embryos and chickens of partly inbred lines possessing different major histocompatibility complex haplotypes was investigated. Chicken embryos of line H-B2 possessing B2 homozygous haplotype showed lower mortality and higher oocyst production than embryos of line H-B15 possessing B15 homozygous haplotype. Embryos of line H-B2 chickens were considered more resistant to E. tenella infection than those of line H-B15. Seven days after 10-day-old chickens were infected with E. tenella, the two lines showed no significant differences in percent bodyweight gain, cecal lesion score, and oocyst production; they differed significantly only in cecal shrinkage. Results suggest that the B system affects chicken embryos and chickens differently in susceptibility to E. tenella infection.

Animals↗
PubMed1996

Targeted infection of human cells via major histocompatibility complex class I molecules by Moloney murine leukemia virus-derived viruses displaying single-chain antibody fragment-envelope fusion proteins.

As an approach to cell targeting by retroviruses, the lack of which constitutes one major limitation of retroviral vector technology, we engineered the Moloney murine leukemia virus ecotropic envelope glycoprotein. When inserted between amino acids 6 and 7 of the latter, a single-chain antibody fragment (ScFv) specific for human major histocompatibility complex class I molecules was shown to be able to redefine the tropism of ecotropic Moloney murine leukemia virus-derived retroviral particles by allowing infection of major histocompatibility complex class I-positive human cells. At variance with other recently described experimental systems, the type of modification adopted here allowed targeted infection in the absence of coexpressed wild-type env-encoded protein molecules. Interestingly, the chimeric ScFv-env protein also retained the ability to recognize the ecotropic receptor and allowed infection of murine cells, albeit at a reduced efficiency.

3T3 Cells↗
PubMed1999

Gene conversion of major histocompatibility complex genes is associated with CpG-rich regions.

We examined 32 DNA sequences of mouse and human major histocompatibility complex (MHC) genes believed to have been subjected to gene conversion events. All regions of the mouse H2 genes as well as the human HLA genes which have been implied to be involved in gene conversion events had elevated levels of CpG dinucleotides, whereas the rest of the genes showed extensive CpG suppression. Mouse MHC genes which have been suspected but not directly implied to be involved in gene conversion events also showed elevated levels of CpG dinucleotides. Moreover, both mouse and human MHC genes which have never been suspected of undergoing gene conversion had low levels of CpG throughout the genes. These results indicate that high CpG levels are correlated with gene conversion rather than with polymorphism, as non-polymorphic genes that have been implicated as gene conversion donors also have elevated levels of CpG dimers in the involved regions, whereas polymorphic genes which have never been considered to undergo gene conversion events have a low level of CpG dinucleotides. We also studied the methylation pattern of CpG dimers in the Abk gene by restriction enzyme digestion of mouse testis DNA followed by Southern blot and hybridization to an Abk-specific probe. The examined CpG dimers in prepubescent mice, where the latest germline stages are spermatogonia, leptene, or pachytene, are respectively non-methylated. Accordingly, the CpG dimers appear to be non-methylated in germline DNA from the testis of prepubescent mice, where gene conversions have been reported to occur.

Animals↗
PubMedDate not supplied

Response to Eimeria tenella of chickens selected for high or low antibody response and differing in haplotypes at the major histocompatibility complex.

Sublines of chickens selected for high antibody (HA) or low antibody (LA) response that differed at the major histocompatibility complex (MHC) were tested for response to Eimeria tenella. In Expt. 1, the first exposure to E. tenella was natural (in floor pens), and chicks were challenged orally 21 days later with 0, 928, or 1855 oocysts. In Expt. 2, chicks were reared in wire-floored batteries, vaccinated orally with 928 oocysts, and challenged orally 12 days later with 15,844 oocysts. Corticosterone (20 mg/kg) was mixed with feed from 24 hr before vaccination to 120 hr after vaccination in Expt. 2. In Expt. 1, LA chicks had more-severe cecal lesions but gained relatively more body weight after challenge than did HA chicks. In Expt. 2, cecal lesions were least severe in HA chicks that had been fed corticosterone, most severe in LA chicks fed corticosterone, and intermediate in chicks that were not fed corticosterone. No differences in response to E. tenella occurred as a result of haplotypes at the MHC.

Animals↗