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PubMed2006

The evolutionary ecology of the major histocompatibility complex.

The major histocompatibility complex (MHC) has become a paradigm for how selection can act to maintain adaptively important genetic diversity in natural populations. Here, we review the contribution of studies on the MHC in non-model species to our understanding of how selection affects MHC diversity, emphasising how ecological and ethological processes influence the tempo and mode of evolution at the MHC, and conversely, how variability at the MHC affects individual fitness, population dynamics and viability. We focus on three main areas: the types of information that have been used to detect the action of selection on MHC genes; the relative contributions of parasite-mediated and sexual selection on the maintenance of MHC diversity; and possible future lines of research that may help resolve some of the unanswered issues associated with MHC evolution.

Biological Evolution↗
PubMed2004

Comparative genomics of major histocompatibility complexes.

The major histocompatibility complex (MHC) is a gene dense region found in all jawed vertebrates examined to date. The MHC contains a high percentage of immune genes, in particular genes involved in antigen presentation, which are generally highly polymorphic. The region plays an important role in disease resistance. The clustering of MHC genes could be advantageous for co-evolution or regulation, and its study in many species is desirable. Even though some linkage of MHC genes is apparent in all gnathostomes, the genomic organization can differ greatly by species, suggesting rapid evolution of MHC genes after divergence from a common ancestor. Previous reviews of comparative MHC organization have been written when relatively fragmentary sequence and mapping data were available on many species. This review compares maps of MHC gene orders in commonly studied species, where extensive sequencing has been performed.

Animals↗
PubMedDate not supplied

Molecular organization of the canine major histocompatibility complex.

The major histocompatibility complex (MHC) is composed of a tightly linked cluster of genes; in dogs, this is referred to as the dog leukocyte antigen (DLA) region. The canine MHC is located on chromosome 12, and several genes within the DLA region have been identified that have significant sequence similarity to their human counterparts. However, in order to characterize other loci in the DLA region, DNA sequencing has begun using a canine bacterial artificial chromosome (BAC) library. Initially 135 BAC clones were isolated from a BAC library using a mixture of human and canine probes. These BAC clones were screened with locus-specific primers in polymerase chain reactions (PCRs). Fifty-six BAC clones were subjected to FingerPrinted Contig (FPC) analysis and several overlapping clones were identified. One BAC clone RP81-231-G24 has been sequenced. Preliminary sequence analysis of this 150 kb clone indicates that it contains the region where the class I and class III regions are joined and encompasses DLA-12a, DLA-53, DLA-12, DLA-64, TNF-alpha, and a canine gene that appears to resemble the HLA class III gene HSPA1A (HSP70-1).

Animals↗
PubMed2006

Interface-disrupting amino acids establish specificity between T cell receptors and complexes of major histocompatibility complex and peptide.

T cell receptors (TCRs) bind complexes of cognate major histocompatibility complex (MHC) and peptide at relatively low affinities (1-200 microM). Nevertheless, TCR-MHC-peptide interactions are usually specific for the peptide and the allele encoding the MHC. Here we show that to escape thymocyte negative selection, TCRs must interact with many of the side chains of MHC-peptide complexes as 'hot spots' for TCR binding. Moreover, even when the 'parental' side chain did not contribute binding affinity, some MHC-peptide residues contributed to TCR specificity, as amino acid substitutions substantially reduced binding affinity. The presence of such 'interface-disruptive' side chains helps to explain how TCRs generate specificity at low-affinity interfaces and why TCRs often 'accommodate' a subset of amino acids at a given MHC-peptide position.

Amino Acids↗
PubMed2003

A novel, alternative pathway of apoptosis triggered through class II major histocompatibility complex molecules.

Major histocompatibility complex class II (MHC-II) molecules, in addition to their role of presenting antigen to T lymphocytes, can serve as receptors triggering programmed cell death. MHC-II induced cell death affects activated/tumour transformed cells selectively, and it proceeds without the involvement of caspases, the major proteases of classical apoptosis. Caspase-independent programmed cell death can also be triggered, albeit less effectively, via a series of other cell surface molecules. Here, we discuss the major characteristics, physiological significance, and clinical relevance of caspase-independent apoptotic pathways with particular emphasis on the one induced by MHC-II ligation.

Apoptosis↗
PubMed2004

Considerable haplotypic diversity in the RT1-CE class I gene region of the rat major histocompatibility complex.

The major histocompatibility complex (MHC) class I region extending between the Bat1 and Pou5f1 genes shows considerable genomic plasticity in mouse and rhesus macaque but not in human haplotypes. In the rat, this region is known as the RT1-CE region. The recently published rat MHC sequence gave rise to a complete set of class I gene sequences in a single MHC haplotype, namely the RT1(n) haplotype of the widely used BN inbred strain. To study the degree of genetic diversity, we compared the RT1-CE region-derived class I genes of the RT1(n) haplotype with class I sequences of other rat haplotypes. By using phylogenetic tree analyses, we obtained evidence for extensive "presence and absence" polymorphisms of single loci and even small subfamilies of class I genes in the rat. Alleles of RT1-CE region class I genes could also be identified, but the rate of allelic nucleotide substitutions appeared rather low, indicating that the diversity in the RT1-CE region is mainly based on genomic plasticity.

Animals↗
PubMed2000

HIV-1 Nef protein binds to the cellular protein PACS-1 to downregulate class I major histocompatibility complexes.

Major-histocompatibility-complex (MHC) proteins are used to display, on the surface of a cell, peptides derived from foreign material - such as a virus - that is infecting that cell. Cytotoxic T lymphocytes then recognize and kill the infected cell. The HIV-1 Nef protein downregulates the cell-surface expression of class I MHC proteins, and probably thereby promotes immune evasion by HIV-1. In the presence of Nef, class I MHC molecules are relocalized from the cell surface to the trans-Golgi network (TGN) through as-yet-unknown mechanisms. Here we show that Nef-induced downregulation of MHC-I expression and MHC-I targeting to the TGN require the binding of Nef to PACS-1, a molecule that controls the TGN localization of the cellular protein furin. This interaction is dependent on Nef's cluster of acidic amino acids. A chimaeric integral membrane protein containing Nef as its cytoplasmic domain localizes to the TGN after internalization, in an acidic-cluster- and PACS-1-dependent manner. These results support a model in which Nef relocalizes MHC-I by acting as a connector between MHC-I's cytoplasmic tail and the PACS-1-dependent protein-sorting pathway.

Animals↗
PubMed1994

Is antigen processing guided by major histocompatibility complex molecules?

Major histocompatibility complex class I (MHC-1) molecules bind peptide fragments derived from cytosolic antigens, and class II (MHC-2) molecules bind fragments of proteins that enter the endocytic pathway. How peptides of the right affinity and size are generated in vivo is still the focus of intense research. Current data are consistent with the view that precursor peptides of varying length are produced in the cytosol and transported into the endoplasmic reticulum lumen where nascent MHC-1 could sample the peptides for their affinity. High-affinity peptides would form stable complexes with MHC-1, which are resistant to proteolysis by luminal enzymes; peptides unable to bind to MHC-1 presumably undergo proteolysis in the lumen. On the other hand, multiple mechanisms are probably used to load MHC-2. Some proteins denatured in the acidic and reducing environment of the endosomes most likely bind to MHC-2 through the antigen's immunodominant region, and the exposed portions of the antigen are degraded by endosomal proteases. Other antigens must first be proteolysed into peptide fragments, which compete among themselves for binding to MHC-2, whereas heat shock proteins could also contribute peptides for MHC-2 loading. Because of their respective loading modes, there is a partial correlation between the MHC-2 binding affinity of the protein fragments and their in vivo immunodominance, which may not necessarily be the case for MHC-1.

Antigen Presentation↗
PubMed1987

Persistence and selectivity of the immune phagocytosis inhibition by major histocompatibility complex antibodies.

Major histocompatibility complex (MHC) antibodies induce immune phagocytosis inhibition (IPI) which lasts for at least 7 days. IPI-inducing antibodies do not inhibit the phagocytosis mediated by the beta-glucan receptor. This corresponds well to recent findings that these antibodies do not interfere with the phagocytosis of deactivated saccharomyces, mediated by the mannose-fucose receptor, or polyacrylic acid particles, also mediated by non-Fc receptors. Substances that interact with certain MHC antigens or with Fc receptors, certain toxins that inhibit surface molecule mobility, and ciclosporin do not cause IPI and do not suppress the induction of IPI by MHC antibodies. These substances are: opioid peptides, insulin, penicillin G, immune complexes, aggregated IgG, Fc fragments, ciclosporin, botulinum C2 toxin, sodium azide. Some lectins and EDTA are inhibitory in a non-selective fashion, since the Fc receptor independent phagocytosis is also abrogated.

Antibodies, Monoclonal↗
PubMed1978

The unity of genes in the major histocompatibility complex.

The major histocompatibility complex (MHC) of the mouse can be genetically divided into several regions specialized to performing specific functions. Thus the class I regions (K and D) code for antigens that activate effector (killer) T cells, class II region (I) for antigens causing T-cell proliferation, and class III regions (s) for complement components. A strong case is made for the theory that the division of labor within the MHC is not absolute. Evidence is presented that class I antigens can sometimes cause as strong T-cell proliferation as class II antigens; that class II antigens can generate effector T cells; and that class I antigens may be involved in the immune response to some antigens. The fact that different regions can perform similar functions argues for the unity of the MHC genes.

Animals↗
PubMed1998

Inactivation of a defined active site in the mouse 20S proteasome complex enhances major histocompatibility complex class I antigen presentation of a murine cytomegalovirus protein.

Proteasomes generate peptides bound by major histocompatibility complex (MHC) class I molecules. Avoiding proteasome inhibitors, which in most cases do not distinguish between individual active sites within the cell, we used a molecular genetic approach that allowed for the first time the in vivo analysis of defined proteasomal active sites with regard to their significance for antigen processing. Functional elimination of the delta/low molecular weight protein (LMP) 2 sites by substitution with a mutated inactive LMP2 T1A subunit results in reduced cell surface expression of the MHC class I H-2Ld and H-2Dd molecules. Surface levels of H-2Ld and H-2Dd molecules were restored by external loading with peptides. However, as a result of the active site mutation, MHC class I presentation of a 9-mer peptide derived from a protein of murine cytomegalovirus was enhanced about three- to fivefold. Our experiments provide evidence that the delta/LMP2 active site elimination limits the processing and presentation of several peptides, but may be, nonetheless, beneficial for the generation and presentation of others.

Animals↗
PubMed1983

Specificity of T cell clones for antigen and autologous major histocompatibility complex products determines specificity for foreign major histocompatibility complex products.

We have analyzed a panel of T cell clones that corecognize defined epitopes of the insulin molecule in association with Ia for their patterns of recognition of alloantigens. A striking correlation is observed between recognition of the I-Ab gene product and cow insulin alpha loop and recognition of I-Eu of the PL/J haplotype. These results are consistent with the notion that reactions to foreign major histocompatibility complex (MHC) products reflect molecular mimicry by foreign class II antigens of 'physiologic' complexes formed by autologous class II MHC molecules and antigen.

Animals↗
PubMed2001

Effects of lipofectin-antigen complexes on major histocompatibility complex class I-restricted antigen presentation pathway in murine dendritic cells and on dendritic cell maturation.

We previously reported that exogenous antigens complexed with the cationic liposome lipofectin (LF) were efficiently presented via major histocompatibility complex (MHC) class I molecules on pulsed dendritic cells (DCs) in vitro. In the present study, we demonstrated that MHC class I-restricted antigen presentation on DC2.4 cells, a murine immature DC line, treated with LF-antigen complexes was remarkably suppressed through the inhibition of endocytosis, proteasome catalysis, and Golgi transport. We also found that LF did not influence expression of interleukin-12 p40 mRNA, MHC molecules, or co-stimulatory molecules in DC2.4 cells. These findings suggest that an antigen-loading procedure using LF could enhance delivery of exogenous antigens to the classical MHC class I pathway in DCs, but it does not initiate DC maturation.

Acetylcysteine↗
PubMed2005

Resistance to chlamydial lung infection is dependent on major histocompatibility complex as well as non-major histocompatibility complex determinants.

Our previous work has shown that C3H/HeN and C57BL/6 mice have differential susceptibility to Chlamydia trachomatis mouse pneumonitis (C. muridarum) lung infection. C3H/HeN (H-2(k)) mice were found to be highly susceptible to C. muridarum infection with higher mortality and more severe morbidity compared to C57BL/6 (H-2(b)) mice. To examine the role of major histocompatibility complex (MHC) genes on host resistance to chlamydial lung infection, we compared MHC congenic mice, B6.H2k [C57BL/6 background, C3H MHC (H-2(k))] and C3H.H2b [C3H/HeN background, C57BL/6 MHC (H-2(b))] and their corresponding wild type C57BL/6 mice and C3H/HeN mice, respectively, in susceptibility to C. muridarum infection. We found that B6.H2k, C3H.H2b and C3H/HeN mice are more susceptible to chlamydial lung infection compared to the wild type C57BL/6 mice by showing more serious body weight loss, higher in vivo chlamydial growth and more severe pathologic changes. Congenic B6.H2k mice showed significantly lower levels of IL-12 and IFN-gamma production compared to C57BL/6 as well as C3H/HeN and C3H.H2b mice. One the other hand, although congenic C3H.H2b mice displayed similar cytokine response to C57BL/6 mice, they were highly susceptible to C. muridarum infection. Overall, the results suggest that protection against chlamydial lung infection is both MHC and non-MHC gene dependent, and that the interaction between MHC and non-MHC elements may contribute to host resistance to chlamydial infection.

Animals↗
PubMed2004

Modulation of major histocompatibility complex Class I molecules and major histocompatibility complex-bound immunogenic peptides induced by interferon-alpha and interferon-gamma treatment of human glioblastoma multiforme.

OBJECT: Little is known about the quantitative modulation of major histocompatibility complex (MHC) Class I expression on human gliomas that is effected by interferons; even less is known about the immunogenic peptides that are accommodated in the peptide-binding motifs of MHC Class I alleles in these brain tumors. In this article the authors investigated the ability of interferon (IFN)alpha and IFNgamma to upregulate MHC Class I expression and to modulate acid-eluted Class I-bound peptides on human glioblastoma multiforme (GBM) cells in vitro. METHODS: Early-passage primary human GBM cell cultures and U87MG GBM cells were incubated with varying doses of INFalpha or IFNgamma ranging between 0 and 2000 U/ml. Upregulation of MHC Class I expression was assayed by immunocytochemical analysis, flow cytometry, and Western blot analysis. Modulation of acid-eluted MHC Class I-bound peptides from the IFN-treated GBM cells was examined with the aid of mass spectroscopy. The in vitro expression of the MHC Class I molecule was upregulated by both IFNalpha and IFNgamma in a dose-dependent manner. Interferon-gamma exhibited a more potent effect on MHC Class I upregulation, peaking at 10 U/ml; whereas the effect of IFNalpha was less marked, reaching a plateau at 500 U/ml. In addition, a native peptide eluted from MHC Class I molecules of human GBM cells was identified and found to be consistently upregulated by IFN treatment. CONCLUSIONS: Interferon-alpha and IFN-gamma can significantly upregulate the MHC Class I molecules that are expressed on the cell surface of human GBM cells as well as the potentially immunogenic peptides bound to the MHC. These results may help explain the molecular basis for increased immunogenicity with IFN treatment of human GBMs and might provide added insight into the design of future antitumor vaccines for human brain tumors.

Cell Line, Tumor↗
PubMed1987

Aberrant expression of class II major histocompatibility complex molecules by B cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in type 1 (insulin-dependent) diabetes mellitus.

Twenty-three patients with recent onset Type 1 (insulin-dependent) diabetes in whom residual insulin secreting B cells were present and 12 patients with disease of more prolonged duration (maximum 9 years), 8 of whom had residual B cells, were studied. Aberrant expression of Class II major histocompatibility complex molecules was demonstrated immunohistochemically on insulin secreting B cells in 21 out of 23 patients with recent onset disease and 6 of the patients with more prolonged disease. No such expression was seen on glucagon secreting A cells or somatostatin secreting D cells. Islets where there was marked hyperexpression of Class I major histocompatibility complex molecules on islet endocrine cells were seen in all cases in which residual B cells were present. Ninety-two per cent of insulin containing islets but only 1% of insulin deficient islets exhibited this phenomenon (p less than 0.001, Chi-squared test). There was evidence to suggest that both these abnormalities of major histocompatibility complex expression preceded insulitis within a given islet. They also appeared to be unique to Type 1 diabetes, being absent in pancreases of patients with Type 2 (non-insulin-dependent) diabetes, chronic pancreatitis, cystic fibrosis, graft-versus-host disease and Coxsackie B viral pancreatitis. The development of autoimmunity to B cells in Type 1 diabetes may be a "multistep" process in which abnormalities of major histocompatibility complex expression on islet endocrine cells are crucial events.

Adolescent↗
PubMed1989

Embryonal carcinoma cells express Qa and Tla class I genes of the major histocompatibility complex.

The murine major histocompatibility complex encodes H-2K and H-2D transplantation antigens and other class I-like proteins called Qa and Tla molecules; the functions of the Qa/Tla molecules are not known. That they may participate in embryonic cell-cell interactions and/or play a role in immune responses against tumors has been speculated. We have studied two murine embryonal carcinoma tumors, 402AX and PCC4, that are rejected in vivo immunologically, although they do not express H-2K or H-2D antigens. Transplantation studies with these cells suggest that rejection is mediated by class-I-like major histocompatibility complex antigens. As a first step in evaluating Qa/Tla function(s), we have characterized expression of class I-like genes and proteins in 402AX and PCC4 cells. Northern (RNA) blot hybridizations, polymerase chain reaction studies, and cDNA cloning experiments demonstrate that EC lines transcribe genes allelic to the Tla region gene "37", Qa-2 region gene "Q7", and another, previously uncharacterized, class I-like gene. Immunoprecipitation studies show that the embryonal carcinoma tumor cells contain low levels of beta 2-microglobulin expressed in association with non-H-2K, non-H-2D class I-like proteins.

Amino Acid Sequence↗