The purpose of this study was to evaluate the potential associations between HLA-A, B, DRB1 gene and leukemia. A total of 1186 leukemic patients, including 326 patients with acute lymphoblastic leukemia (ALL), 545 patients with acute myeloid leukemia (AML), 315 patients with chronic myeloid leukemia (CML), and 1234 healthy unrelated donors were typed and were compared in a single centre by using same technique, then the Bonferroni correction method was used to correct the Type I error. The results indicated that as compared with the control,the frequency of HLA-DRB1(*)09 in ALL group significantly decreased (10.87% versus 16.08%; Pc = 0.014, OR = 0.637, 95% CI = 0.487-0.834), while in comparison with control, the frequency of HLA-B(*)18 in CML group was significantly higher (1.28% vs 0.20%; Pc = 0.039, OR = 6.336, 95% CI = 2.066-19.434). The positive and negative relation may exist between certain HLA molecules and leukemia. The negative relation between HLA-DRB1(*)09 and ALL indicated that DRB1*09 might play an important role by a restricted T-cell immune response in the early leukemogenic events, whereas the positive relation between HLA-B(*)18 and CML suggests that the B(*)18 molecules may not actively present leukemia-specific antigens resulting in immune escape. It is concluded that these findings can contribute to developing more appropriate method in leukemic immunotherapy.
Adolescent ; Adult ; Case-Control Studies ; Child ; Child, Preschool ; HLA-A Antigens ; genetics ; HLA-B Antigens ; genetics ; HLA-DRB1 Chains ; genetics ; Histocompatibility Testing ; Humans ; Infant ; Leukemia ; genetics ; immunology ; therapy ; Major Histocompatibility Complex ; genetics ; Middle Aged ; Retrospective Studies ; Tumor Escape ; Young Adult

We have assessed the relationships between immune trait (antibody titers of Sheep red blood cell, SRBC; Avian influenza, AI; Newcastle disease, ND) and varieties of MHC B-LBHII Gene in local chicken breeds (Wenshang Barred chicken, LH; Laiwu Black chicken, LWH; and Jining Bairi chicken, BR). We selected 300 chickens randomly from the three indigenous chicken populations. The variations of MHC B-L BII gene were detected by directly DNA sequencing and polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). The results indicated that there were about 19-22 nucleotide mutations in the three local breeds, which could affect 16-18 amino acid variations. Another results indicated that there was significantly relationship between seven to eight SNPs of the MHC B-LBII region and some immune traits (P < 0.05 or P < 0.01). Both locus G97A and locus T138A were found in the three species, which were significantly related to the antibodies of SRBC, ND and AI antibody titers (P < 0.05). Among them, the locus G97A was significantly associated with ND antibody titers (P < 0.05) in BR chicken, with SRBC antibody titers (P < 0.05) in LWH chicken, and with H9 antibody titers (P < 0.05) in LH chicken. Furthermore, locus T138A was significantly associated with H9 antibody titers in BR and LH chickens (P < 0.05). All those results suggest relationships among the different varieties of MHC B-LBII and immune traits in the three local breeds.
Animals ; Base Sequence ; Breeding ; Chickens ; genetics ; immunology ; Major Histocompatibility Complex ; genetics ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Polymorphism, Single-Stranded Conformational ; Sequence Analysis, DNA

BACKGROUNDDonor organ rejection continues to be a significant problem for patients receiving transplants. We therefore tested whether transferring a donor's major histocompatibility complex (MHC) gene to the recipient would mitigate the rejection of transplanted hearts in mice.

METHODSH-2K(k) gene from donor mice was amplified using nested polymerase chain reaction (PCR) and ligated into a mammalian expression vector, which was then transfected into thymus ground mass cells collected from the recipients. Clones stably expressing the transgene were then injected into the recipients' thymus visualized using ultrasound. Control mice were administered cells previously transfected with empty vector. Following heart transplantation, cardiac activity was monitored electrocardiographically. Recipient thymus cells were tested for MHC antigenicity using flow cytometry and spleen cells were subjected to mixed lymphocyte culture tests. Finally, the transplanted hearts were sectioned, stained and examined under light microscopy.

RESULTSSouthern analysis following nested PCR revealed clear expression of H-2K(k) gene. Following transplantation, electrocardiosignals were detectable highly significantly longer in recipients administered thymal cells expressing donor H-2K(k) than in those receiving control cells. Flow cytometric analysis using an anti-H-2K(k) antibody confirmed its expression in H-2K(k) treated recipients but not in control mice. Mixed lymphocyte cultures containing H-2K(k) treated cells showed significantly less proliferation than those containing control cells. Hearts from control mice showed substantially greater lymphocyte infiltration than those from H-2K(k) treated mice and large areas of necrosis.

CONCLUSIONRejection of transplanted hearts can be mitigated substantially by introducing the donor's MHC into the recipient.

Animals ; Blotting, Southern ; Electrocardiography ; Female ; Flow Cytometry ; Graft Rejection ; genetics ; immunology ; Heart Transplantation ; immunology ; methods ; Major Histocompatibility Complex ; genetics ; immunology ; Male ; Mice ; Polymerase Chain Reaction

The present study aimed at analyzing the genetic variability of indigenous goat breeds (Capra hircus) using the MHC-associated microsatellite markers BF1, BM1818, BM1258, DYMS1, and SMHCC1. The following breeds were included: Chinese Xuhuai, Indian Changthangi and Pashmina, Kenyan Small East African (SEA) and Galla, and Albanian Vendi. To examine genetic variability, the levels of heterozigosity, degrees of inbreeding, and genetic differences among the breeds were analyzed. The mean number of alleles ranged from nine in the Galla to 14.5 in the Vendi breed. The mean observed heterozygosity and mean expected heterozygosity varied from 0.483 in the Vendi to 0.577 in the Galla breed, and from 0.767 in the SEA to 0.879 in the Vendi breed, respectively. Significant loss of heterozygosity (p < 0.01) indicated that these loci were not in Hardy-Weinberg equilibrium. The mean F IS values ranged from 0.3299 in the SEA to 0.4605 in the Vendi breed with a mean value of 0.3623 in all breeds (p < 0.001). Analysis of molecular variance indicated that 7.14% and 4.74% genetic variation existed among the different breeds and geographic groups, whereas 92.86% and 95.26% existed in the breeds and the geographic groups, respectively (p < 0.001). The microsatellite marker analysis disclosed a high degree of genetic polymorphism. Loss of heterozygosity could be due to genetic drift and endogamy. The genetic variation among populations and geographic groups does not indicate a correlation of genetic differences with geographic distance.
Alleles ; Animals ; DNA/genetics ; Female ; Genetic Variation ; Goats/*genetics ; Major Histocompatibility Complex/*genetics ; Male ; *Microsatellite Repeats ; Polymerase Chain Reaction/veterinary ; Polymorphism, Genetic

Using directed mutagenesis and phage display on a soluble fragment of the human immunoglobulin super-family receptor ILT2 (synonyms: LIR1, MIR7, CD85j), we have selected a range of mutants with binding affinities enhanced by up to 168,000-fold towards the conserved region of major histocompatibility complex (MHC) class I molecules. Produced in a dimeric form, either by chemical cross-linking with bivalent polyethylene glycol (PEG) derivatives or as a genetic fusion with human IgG Fc-fragment, the mutants exhibited a further increase in ligand-binding strength due to the avidity effect, with resident half-times (t(1/2)) on the surface of MHC I-positive cells of many hours. The novel compounds antagonized the interaction of CD8 co-receptor with MHC I in vitro without affecting the peptide-specific binding of T-cell receptors (TCRs). In both cytokine-release assays and cell-killing experiments the engineered receptors inhibited the activation of CD8(+) cytotoxic T lymphocytes (CTLs) in the presence of their target cells, with subnanomolar potency and in a dose-dependent manner. As a selective inhibitor of CD8(+) CTL responses, the engineered high affinity ILT2 receptor presents a new tool for studying the activation mechanism of different subsets of CTLs and could have potential for the development of novel autoimmunity therapies.
Amino Acid Sequence ; Antigens, CD ; chemistry ; genetics ; pharmacology ; Autoimmunity ; Biological Assay ; Cell Line ; Cytotoxicity, Immunologic ; genetics ; immunology ; Dose-Response Relationship, Immunologic ; Humans ; Immunoglobulins ; immunology ; metabolism ; Immunologic Factors ; chemistry ; genetics ; pharmacology ; Kinetics ; Leukocyte Immunoglobulin-like Receptor B1 ; Lymphocyte Activation ; genetics ; immunology ; Major Histocompatibility Complex ; genetics ; immunology ; Molecular Sequence Data ; Molecular Targeted Therapy ; Mutagenesis, Site-Directed ; Peptide Library ; Polyethylene Glycols ; Protein Binding ; genetics ; immunology ; Receptors, Immunologic ; chemistry ; genetics ; Recombinant Fusion Proteins ; genetics ; metabolism ; T-Lymphocytes, Cytotoxic ; immunology ; metabolism

Psoriasis is a common autoimmune and hyper proliferative skin disease, characterized by thick, silvery scale patches. Numerous family studies have provided compelling evidence of a genetic predisposition to psoriasis, although the inheritance pattern is unclear. However, few of these studies have achieved consistent results, except for the MHC locus, a problem frequently encountered in the investigation of complex disease. Using high-throughput techniques to genotype hundreds of thousands of single nucleotide polymorphisms explore their relationship with phenotypes, genome-wide association studies (GWAS) are now proven to be a powerful approach for screening the susceptibility genes (loci) of complex disease. Recently, three GWAS on psoriasis published in Nature Genetics have provided us with many novel clues concerning disease pathogenesis, in both immune and non-immune pathways. The MHC locus (HLA-Cw6 and other MHC variance), the major locus involved in the immune reactions of human immune disease, has consistently been shown to be associated with psoriasis, both in previous linkage and present GWAS. IL-12B and IL23R, which are the two non-MHC genes with highly associated evidence with psoriasis in multiple studies performed so far and potent cytokines with complex biological activities, should be of great importance in the pathogenesis of psoriasis. Recent clinical trials, in which anti-IL-12p40 antibodies were used for the treatment of psoriasis, have provided further evidence of the role of IL-12/23 in the pathophysiology of psoriasis,and highlighted a new road of treatment for psoriasis. In 2008,we performed the first large GWAS in the Chinese population and identified a novel susceptibility locus within the late cornified envelope (LCE) gene cluster: LCE3A and LCE3D on chromosome 1q21, with conclusive evidence (rs4085613, p(combined)=6.69*10(-30); odds ratio=0.76). Meanwhile, another group also identified a deletion comprising and LCE gene cluster of LCE3B and LCE3C, which is significantly associated with a risk of psoriasis in Spain, Netherland, Italy and USA. Both of these independent studies provided substantial association evidence for the LCE genes involved in the pathogenesis of psoriasis. The LCE genes encode the stratum-corneum proteins of the cornified envelope, which plays an important role in epidermal terminal differentiation. As we know, psoriasis is a disease of interfollicular epidermis and rapid keratinocyte proliferation may cause the production of parakeratotic keratinocytes in psoriatic skin and, thus, the formation of poorly adherent stratum corneum, which in turn results in the characteristic scale or flakes of psoriasis lesions. Although some of the highlighted genes are already targeted by effective psoriasis therapies, others could become future targets for treatments,especially for the LCE genes, which will be very useful for unlocking new drug targets and tailored treatments for this painful, disfiguring skin disease. Meanwhile larger samples and improved strategy for identification of other susceptibility variants to psoriasis and downstream functional study to elucidate the underlying mechanisms of diseases are also needed. Taken together, unremitting efforts of the basic research on psoriasis will lead us to achieve a better treatment and diagnosis for psoriasis in the near future.
Autoimmunity ; genetics ; Cornified Envelope Proline-Rich Proteins ; genetics ; Genetic Predisposition to Disease ; Genome, Human ; genetics ; Genome-Wide Association Study ; Humans ; Interleukin-12 Subunit p40 ; genetics ; Major Histocompatibility Complex ; genetics ; Psoriasis ; genetics ; immunology ; Receptors, Interleukin ; genetics

BACKGROUNDProliferation, cell migration and phenotypic modulation of airway smooth muscle cells (ASMCs) are important features of airway remodelling in asthma. The precise cellular and molecular mechanisms that regulate ASMCs proliferation, migration and phenotypic modulation in the lung remain unknown. Basic fibroblast growth factor (bFGF), a highly specific chemotactic and mitogenic factor for many cell types, appears to be involved in the development of airway remodelling. Our study assessed whether bFGF directly stimulates the proliferation, migration and phenotypic modulation of ASMCs.

METHODSConfluent and growth arrested human ASMCs were treated with human recombinant FGF. Proliferation was measured by BrdU incorporation and cell counting. Migration was examined using Boyden chamber apparatus. Expressions of smooth muscle (sm)-alpha-actin and sm-myosin heavy chain (MHC) isoform 1 were determined by RT-PCR and Western blot analysis.

RESULTSIt was found that hrbFGF (10 ng/ml), when added to ASMCs, induced a significant increase in BrdU uptake and cell number by ASMCs as compared to controls and a significant increase in ASMCs migration with respect to controls. The mRNA and protein expressions of sm-alpha-actin and sm-MHC in ASMCs that were stimulated with hrbFGF decreased with respect to controls.

CONCLUSIONIt appears that bFGF can directly stimulate proliferation and migration of ASMCs, however, the expressions of cells' contractive phenotype decreased.

Actins ; analysis ; genetics ; Bronchi ; cytology ; drug effects ; physiology ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Cells, Cultured ; Fibroblast Growth Factor 2 ; pharmacology ; Humans ; Major Histocompatibility Complex ; Myocytes, Smooth Muscle ; drug effects ; Phenotype ; RNA, Messenger ; analysis

This study was purposed to investigate the inhibitory effect of anti-C II TA M1-RNA on MHC II expression. The M1-RNA with guide sequences (GS) recognizing C II TA at 3408 site (M1-3408-GS) and C II TA target RNA (3176 - 3560) were constructed, then cloned into the pUC19 and pGEM-7zf (+) vector respectively. The recombinant M1-RNA and its target RNA were incubated in cell-free conditions. It showed that M1-3408-GS could exclusively cleave target RNA, then it was cloned into the psNAV vector. Stable transfectants of Jurkat cells with M1-3408-GS were analyzed for classical MHC II (HLA-DR, -DP, -DQ) induction in response to IFN-gamma by flow cytometry. The level of C II TA mRNA was measured by RT-PCR. The results showed that after IFN-gamma treatment, the expression of HLA-DR, HLA-DP, HLA-DQ on M1-3408-GS positive Jurkat cells decreased 83.17%, 94.12% and 84.31% respectively as compared with control. At the same time the mRNA contents of C II TA also markedly decreased (P < 0.05, t = 4.89). It is concluded that anti-C II TA M1-RNA (M1-3408-GS) inhibits C II TA, decreases itself mRNA content and so suppresses expression of MHC II molecules regulated by C II TA.
Down-Regulation ; Histocompatibility Antigens Class II ; metabolism ; Humans ; Jurkat Cells ; Major Histocompatibility Complex ; genetics ; Nuclear Proteins ; metabolism ; RNA, Messenger ; metabolism ; Ribonuclease P ; metabolism ; Trans-Activators ; metabolism

Asthma ; drug therapy ; immunology ; Diagnosis, Differential ; Drugs, Chinese Herbal ; therapeutic use ; Humans ; Major Histocompatibility Complex ; genetics ; immunology ; Medicine, Chinese Traditional ; Phytotherapy

The profound graft-versus-leukemia (GVL) effect presented after allogeneic hematopoietic cell transplantation (allo-HSCT) has been evidenced. In contrast to T cell mediated GVL, natural killer (NK) cells recognize target cells and introduce GVL effect by using an integration of activating and inhibitory receptors. This review has summarized current literatures from 2001 - 2003 on human killer cell immunoglobulin receptors (KIR) and other NK cell receptors involved in recognition of tumor targets and the polymorphism of KIR genes of donor/recipient pairs of related and unrelated Allo-HSCT. KIR epitope mismatch may facilitate engraftment and reduce leukemia relapse post transplant by mediating lysis of recipient's cells and introducing GVL effect under the condition of KIR epitope mismatch. Clinical roles of KIR in Allo-HSCT and immunotherapy are discussed. Technologic approach in allogeneic reactive NK cells introduction, identification and selection in vitro, development of inhibitory receptor blockade as well as up-regulation of activating NK cells may significantly enhance GVL immune response. Further investigation on the regulation of KIR inhibitory receptors enables to design novel strategy in cancer immunotherapy over the forthcoming decade.
Graft vs Host Disease ; immunology ; Hematopoietic Stem Cell Transplantation ; Humans ; Immune Tolerance ; Killer Cells, Natural ; immunology ; Major Histocompatibility Complex ; Receptors, Immunologic ; chemistry ; genetics ; physiology ; Receptors, KIR ; Transplantation, Homologous