Major Histocompatibility Complex
M.Tevfik Dorak, MD, PhD
The major histocompatibility complex (MHC) is a set of genes with immunological and non-immunological functions and present in all vertebrates studied so far 1;2. It was discovered during transplantation studies in mice (as the H-2 complex) by Peter A Issac Gorer in the Lister Institute in London in 1937 who later collaborated with George Snell of the Jackson Laboratories in Ben Harbor 3;4. Jean Dausset described the first human MHC antigen MAC (HLA-A2) as part of the Hu-1 system 5 followed by the discovery of the FOUR series 4a and 4b (HLA-Bw4 and -Bw6) by the Leiden group led by Jon van Rood in 1963 6;7. Rose Payne and Walter & Julia Bodmer identified the LA series (1964). Bernard Amos, who had originally worked with Gorer, organised the first International Histocompatibility Workshop in 1964 and the first WHO Nomenclature Committee Meeting in 1968 (see IHWG website; Marsh, 2004). See full references for early MHC-HLA work.
The function of the MHC can be described as pleiotropic, i.e., multiple unrelated ones 8-11. It is best known with its role in histocompatibility 12 and in immune regulation 13-17 with many other functions not much appreciated yet 2;18-22. The main function of the main MHC molecules is peptide binding and presentation of them to T lymphocytes. Among the non-immune functions, the noteworthy ones are interactions with other receptors on the cell surface 23;24, in particular with transferrin receptor (TfR), epidermal growth factor 25 and various hormone receptors 26-28, and signal transduction 29.
In nature, different taxa of multicellular organisms have unrelated compatibility systems such as the protozoan pheromone system 30;31, the fungal compatibility system 32-35, angiosperm (flowering plants) self-incompatibility system 33;36, and the invertebrate allorecognition systems 37-39. All of these systems are primarily involved in prevention of matings between genetically similar individuals to avoid the harmful effects of inbreeding. The MHC also prevents inbreeding through its influence on mate choice in mice 40;41 and humans 42;43; and on reproductive processes in rats 44, mice 45;46 and humans 47;48. The reproductive mechanisms are varied and range from selective fertilization to selective abortion. A major common feature of the compatibility systems is that they favour genetic dissimilarity between mates and the gametes (mate choice, selective fertilization); but similarity in co-operation (kin recognition, dual recognition, transplant matching) 49;50. All these functions are based on the provision of a phenotype for the genetic identity of the individual by the MHC: either cell surface molecules or chemosensory signals.
The MHC in humans is called Human Leukocyte Antigens (HLA). It is located on chromosome 6p21.31 and covers a region of about 3.6 Mbp depending on the haplotype 1;51. The longest haplotype is the HLA-DR53 group haplotypes because of the 110-160 kb extra DNA in their DR/DQ region 52-56. The HLA complex is divided into three regions: class I, II, and III regions as first proposed by Jan Klein in 1977 57. The telomeric region to the classical HLA complex is now called the class Ib region; and there has also been a suggestion for a class IV region located at the telomeric end of the class III region 2. The classical HLA antigens encoded in each region are HLA-A, -B, and -C in the class I region, and HLA-DR, -DQ and -DP in the class II region. All class I genes are between 3 and 6 kb, whereas, class II genes are 4-11 kb long 58. The 1998 Nomenclature Committee recognized more HLA genes all of which are in the class I and Ib regions: HLA-E, -F, -G, -H, -J, -K and -L 59. Among those, only HLA-E, -F and -G are expressed 60. The massive sequencing project of a human MHC haplotype has just been completed and the map positions of all of these genes are known 51. The class III region has the highest gene density but some of the genes are not involved in the immune system 2;61. Among the genes which are of interest, HSP70, TNF, C4A, C4B, C2, BF and CYP21 should be mentioned. The HSP70 genes encode cytosolic molecular chaperons and might have donated to the PBR region to the ancestor MHC gene 62. It has also been proposed that HSP70 may be the functional forerunners of MHC molecules because of their peptide binding and presenting abilities 63. By presenting intracellular contents of a cancer cells to the immune system, HSP70 behaves like a tumour rejection antigen 64-68 similar to the other molecular chaperons, calreticulin and grp94/gp96 67-69. An important feature of HSP70 alleles makes this locus a useful one in disease association studies. They show strong linkage disequilibrium (LD) with HLA-DR alleles 70-72. TNF(A) and TNFB (LTA) genes encode cachectin and lymphotoxin-a molecules, respectively 2;73. C2, C4A and C4B are the genes for some of the complement proteins, whereas, BF codes for factor B which is also involved in immune response 74;75. CYP21 is the gene for 21-hydroxylase which is an important enzyme in corticosteroid metabolism. Its complete deficiency causes congenital adrenal hyperplasia which was the first disease identified to be the result of a structural change in an HLA-linked gene 76. Other genes of interest in the class III region are the human homologue of the mouse mammary tumour integration site Int-3, NOTCH4, and the homologue of a homeobox gene similar to PBX1 involved in t(1;19) translocation in pre-B cell ALL encoded on chromosome 1q23, PBX2 (or HOX12) 2;77-79.
A highly relevant feature of the MHC antigens is their co-dominant expression. Since both alleles contribute to the phenotype equally, it is important to investigate the genotypes in disease association studies rather than the alleles on their own. If susceptibility to a disease is a recessive trait, allelic association studies may not yield a positive result. Also important is the fact that the MHC is inherited en bloc as a haplotype with the exception of the rare recombinational events. Recombination occurs at 1-3% frequency mostly at the HLA-A or HLA-DP ends, i.e., in 100 meiosis the haplotype will be broken and reconstituted in one to three of them. The large segment from HLA-B to HLA-DQB is almost always inherited as a whole. This also has important implications in disease associations. A haplotypical association is usually stronger and more meaningful than an allelic association.
The co-dominant expression and haplotypical transmission have an important consequence: within a family, HLA-identical sibling frequency should be 25% according to Mendelian expectations. This has been, however, found to be higher than that in leukaemia 80-84. This would suggest preferential transmission of leukaemia-associated HLA haplotypes 85. The fact that HLA-identical sibling frequency is higher than 25% in leukemic families should not be confused with the overall chance of having an HLA-identical sibling which is correlated with the family size (equal to [1 - (0.75)n] where n is the number of siblings). This probability may go up to 55% in areas where families are traditionally large 86.
Despite the enormous number of alleles at each expressed loci, the number of haplotypes observed in populations is much smaller than theoretical expectations. This is to say that certain alleles tend to occur together on the same haplotype rather than randomly segregating together. This is called linkage disequilibrium (LD) and quantitated by a D value 87;88.
The public specificities, also called supertypes and sometimes wrongly broad specificities, group a number of private specificities. In the HLA class I region, all HLA-B private specificities are grouped into two supertypical families: HLA-Bw4 and -Bw6. In recent years, the nature of HLA-B supertypes has been better understood. They are not encoded by a different gene. The antigens HLA-Bw4 and -Bw6 reside on a unique epitope on each HLA-B molecule and are distinctly different from the epitopes that determine the HLA-B specificity. Each HLA-B molecule expresses either the Bw4 or Bw6 supertype (residues 74 to 83 of the a 1 helix) in addition to a (private) HLA-B specificity. The amino acid residues 80 IALR 83 represent the Bw4 specificity, whereas, 80 NLRG 83 represent Bw6 (Ref 89).
Likewise, HLA-DR alleles are also associated with supertypes. However, the HLA-DR supertypes are not allelic with each other 90. They are encoded by separate genes (HLA-DRB3, -B4, -B5) and are distinct molecules (HLA-DR52, -DR53, -DR51, respectively). Only one or none of these genes occurs on a haplotype.
The private specificities in each supertypical family are as follows:
DR51 (DRB5): DR2 (DRB1*15/16)
DR52 (DRB3): DR3 (17/18; DRB1*03), DR5 (DRB1*11/12), DR6 (DRB1*13/14)
DR53 (DRB4): DR4 (DRB1*04), DR7 (DRB1*07), DR9 (DRB1*09)
Although all HLA-DR4 / 7 / 9 haplotypes carry the structural gene HLA-DRB4, not all of them express the HLA-DR53 molecule 91. The non-expression, however, is restricted to the HLA-(B57) : DR7 (Dw11): DQ9 haplotype 92 due to a G to A substitution in the acceptor splice site at the 3' end of the first intron, changing the normal AG dinucleotide to AA 93;94. In fact, the null allele of the HLA-DRB4 gene is expressed but it is an aberrant protein 95. An exception has been reported as an unexpected expression of HLA-DR53 in a DR7 (Dw11) : DQ9 - positive leukaemia patient 96. A difference between HLA-B and -DR supertypes is that not all DR alleles are associated with a supertype. These are HLA-DR1, -DR8 and -DR10. Thus, no supertypical gene is present on these haplotypes.
An interesting group of MHC haplotypes is the ancestral or extended haplotypes (also called supratypes). These are specific HLA-B, -DR, BF, C2, C4A and C4B combinations in significant linkage disequilibrium in chromosomes of unrelated individuals. They extend from HLA-B to DR and have been conserved en bloc 97-101. In some Caucasian populations, the extended haplotypes constitute 25-30% of all MHC haplotypes and together with recombinants between any two of them, they account for almost 75% of unselected haplotypes 97;98;100. Particular extended haplotypes are identical by descent. The evidence for this is that in one study, 22 of 26 unrelated extended-haplotype-matched subjects had similar mixed lymphocyte reactivity to HLA-identical siblings 99. Matching for extended haplotypes significantly improves survival in kidney transplantation 102. In Caucasians, there are 10 to 12 common extended haplotypes that show significant linkage disequilibrium. They are relatively population-specific 101;102 and are believed to represent the original MHC haplotypes of our ancestors which are still segregating unchanged. They are easily recognized from their characteristic class III polymorphisms called complotypes 100;102-104. Disease associations with extended haplotypes are generally stronger than allelic associations 100. The best examples of extended haplotype associations are those with rheumatoid arthritis 105, multiple sclerosis 106, insulin-dependent diabetes mellitus 100;107;108, and systemic lupus erythematosis 109.
One of the main characteristics of the MHC is its extreme polymorphism. Among the expressed loci, the MHC has the greatest degree of polymorphism in the human genome. The numbers of alleles recognized at the classical loci by December 1998 are presented in Table 1 (for the latest number of alleles, follow the link at the end).
Table 1. Number of alleles at the classical HLA loci (as of year 2000)
Data from Refs 59,91,110 (for an update, see: HLA Nomenclature)
This is at such a degree that it is theoretically possible for each human to possess a different set of MHC alleles. This feature of the MHC is shared by other compatibility systems in different taxa (such as the fungal mating types, invertebrate allorecognition system and plant self-incompatibility system). It is, however, important to recognise that within the allelic polymorphism at the DNA level which seems endless, there are ancient lineages which predate speciation and maintain themselves in closely related species. This is the basis of the trans-species polymorphism theory proposed by Jan Klein and has found widespread support 111. Allelic lineages may be shared by related species, such as human and apes 112;113 or even human and mice 114, having been present in their common ancestor. However, when primate and human HLA alleles are compared, there is no identical (private) class I allele in great apes and humans despite the similarities in polymorphic motifs 113;115-120. The only similarity is that the human class I supertypes Bw4 and Bw6 are cross-reactive with chimpanzees and gorillas (and even with rhesus monkeys) 113;117;121-123. This conservation throughout hominoid evolution is attributed to the functional importance of these two epitopes in CTL immunomodulation 89 and NK cell function 124-126.
Similarly, in the HLA-DRB loci, while no private specificity has an equivalent in another species, the DRB3 / 4 / 5 loci seem to have remained as they are in all primates or even in rhesus monkeys 127;128. Interestingly, these loci encode the class II supertypes HLA-DR52, -53, and -51. The most ancient polymorphic class II locus appears to be HLA-DQA1 129;130. The polymorphism of this locus also correlates to the MHC class II supertypical groupings 131;132.
The haplotypical structure, phylogenetic analysis and sequence comparisons agree on the presence of five major haplotypical groups in the HLA class II region 59;128;133-135. These are HLA-DR1, HLA-DR51, HLA-DR52, HLA-DR8, and HLA-DR53. It appears that the oldest lineages are HLA-DRB1*04 (represented by the exon 2 motif 9 EQVKH 13) and HLA-DRB1*03 (the motif 9 EYSTS 13) 136. The analysis of intron sequences suggest that HLA-DRB1*03 first diverged from HLA-DRB1*04 more than 85 million years ago and later gave rise to HLA-DRB1*15 (Refs 133,137,138).
MHC class I and class II supertypes are biologically as functional as private specificities. MHC restriction of peptide presentation has been shown for HLA-Bw4 and -Bw6 139;140, HLA-DR52 141;142 and HLA-DR53 143-147. HLA-Bw4 appears to be more immunogenic than HLA-Bw6 judged by the antibody response in the case of mismatching in transplantation 148. Similar to the cross-reactive HLA-B supertypes between humans and chimpanzees 117, HLA-DR supertypes are cross-reactive with chimpanzee 142 and even with mouse class II supertypes 149. Particularly striking is the cross-reactions between HLA-DR53 and H-2Ek 145;150. Furthermore, HLA-DR53 has its own peptide binding motif 151;152. The most abundant peptide eluted from the DR53 molecule is derived from an intracellular protein, calreticulin, which is involved in MHC class I biosynthesis, heat shock response and tumour rejection 69;153-155.
1. Trowsdale J. "Both man & bird & beast": comparative organization of MHC genes [Review]. Immunogenetics 1995; 41: 1-17.
2. Gruen JR, Weissman SM. Evolving views of the major histocompatibility complex. Blood 1997; 90: 4252-4265.
3. Gorer PA. The genetic and antigenic basis of tumour transplantation. Journal of Pathology & Bacteriology 1937; 44 (3): 691-697. (link)
4. Gorer PA, Lyman S, Snell GD. Studies on the genetic and antigenic basis of tumour transplantation. Linkage between a histocompatibility gene and "fused" in mice. Proceedings of the Royal Society of London - Series B: Biological Sciences 1948; 135: 499-505.
5. Dausset J. Iso-leuco-anticorps. Acta Haematologica 1959; 20: 156-166 (see Commentary).
6. van Rood, J. J. Leukocyte Grouping: A Method and Its Application. PhD dissertation, 1962. University of Leiden, Netherlands.
7. van Rood JJ, van Leeuwen A. Leukocyte grouping. A method and its application. Journal of Clinical Investigation 1963; 42: 1382-1390.
8. Bodmer WF. Evolutionary significance of the HLA system [Review]. Nature 1972; 237: 139-145.
9. Meruelo D, Edidin M . The biological function of the major histocompatibility complex: hypotheses [Review]. Contemporary Topics in Immunobiology 1980; 9: 231-253.
10. Jonker M, Balner H . The major histocompatibility complex: a key to a better understanding of evolution. Transplantation Proceedings 1980; 12: 575-581.
11. Dausset J. The major histocompatibility complex in man. Science 1981; 213: 1469-1474.
12. Snell GD. Studies in histocompatibility. Science 1981; 213: 172-178.
13. Benacerraf B, McDevitt HO. Histocompatibility-linked immune response genes. Science 1972; 175: 273-279.
14. Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 1974; 248: 701-702.
15. Benacerraf B. Role of MHC gene products in immune regulation. Science 1981; 212: 1229-1238.
16. Doherty PC, Zinkernagel RM. A biological role for the major histocompatibility antigens. Lancet 1975; 1: 1406-1409.
17. Zinkernagel RM. Cellular immune recognition and the biological role of major transplantation antigens. Scandinavian Journal of Immunology 1997; 46: 421-436.
18. Bonner JJ. Major histocompatibility complex influences reproductive efficiency: evolutionary implications. Journal of Craniofacial Genetics and Developmental Biology 1986; Suppl 2: 5-11.
19. Lerner SP, Finch CE. The major histocompatibility complex and reproductive functions [Review]. Endocrine Reviews 1991; 12: 78-90.
20. Powis SH, Geraghty DE. What is the MHC? Immunology Today 1995; 16: 466-468.
21. Zavazava N, Eggert F. MHC and behavior. Immunology Today 1997; 18: 8-10.
22. Penn DJ, Potts WK. The evolution of mating preferences and major histocompatibility complex genes. American Naturalist 1999; 153: 145-164.
23. Svejgaard A, Ryder LP. Interaction of HLA molecules with non-immunological ligands as an explanation of HLA and disease association. Lancet 1976; ii: 547-549.
24. Edidin M. Function by association? MHC antigens and membrane receptor complexes. Immunology Today 1988; 9: 218-219.
25. Schreiber AB, Schlessinger J, Edidin M. Interaction between major histocompatibility complex antigens and epidermal growth factor receptors on human cells. Journal of Cell Biology 1984; 98: 725-731.
26. Phillips ML, Moule ML, Delovitch TL, Yip CC. Class I histocompatibility antigens and insulin receptors: evidence for interactions. Proceedings of the National Academy of Sciences USA 1986; 83: 3474-3478.
27. Solano AR, Cremaschi G, Sbnchez ML, Borda E, Sterin-Borda L, Podestb EJ. Molecular and biological interaction between major histocompatibility complex class I antigens and luteinizing hormone receptors or beta-adrenergic receptors triggers cellular response in mice. Proceedings of the National Academy of Sciences USA 1988; 85: 5087-5091.
28. Verland S, Simonsen M, Gammeltoft S, Allen H, Flavell RA, Olsson L. Specific molecular interaction between the insulin receptor and a D product of MHC class I. Journal of Immunology 1989; 143: 945-951.
29. Schafer PH, Pierce SK, Jardetzky TS. The structure of MHC class II: a role for dimer of dimers. Seminars in Immunology 1995; 7: 389-398.
30. Weiss MS, Anderson DH, Raffioni S, et al. A cooperative model for receptor recognition and cell adhesion: evidence from the molecular packing in the 1.6-A crystal structure of the pheromone Er-1 from the ciliated protozoan Euplotes raikovi. Proceedings of the National Academy of Sciences USA 1995; 92: 10172-10176.
31. Vallesi A, Giuli G , Bradshaw RA, Luporini P. Autocrine mitogenic activity of pheromones produced by the protozoan ciliate Euplotes raikovi. Nature 1995; 376: 522-524.
32. Metzenberg RL. The role of similarity and difference in fungal mating. Genetics 1990; 125: 457-462.
33. Hiscock SJ, Kues U , Dickinson HG. Molecular mechanisms of self-incompatibility in flowering plants and fungi - different means to the same end. Trends in Cell Biology 1996; 6: 421-428.
34. Wendland J, Vaillancourt LJ, Hegner J, et al. The mating-type locus B alpha 1 of Schizophyllum commune contains a pheromone receptor gene and putative pheromone genes. EMBO Journal 1995; 14: 5271-5278.
35. Kothe E. Tetrapolar fungal mating types: sexes by the thousands. FEMS Microbiological Reviews 1996; 18: 65-87.
36. Haring V, Gray JE, McClure BA, Anderson MA, Clarke AE. Self-incompatibility: a self-recognition system in plants [Review]. Science 1990; 250: 937-941.
37. Scofield VL, Schlumpberger JM, West LA, Weissman IL. Protochordate allorecognition is controlled by a MHC-like gene system. Nature 1982; 295: 499-502.
38. Grosberg RK. The evolution of allorecognition specificity in clonal invertebrates. Quarterly Review of Biology 1988; 63: 377-412.
39. Weissman IL, Saito Y, Rinkevich B. Allorecognition histocompatibility in a protochordate species: is the relationship to MHC somatic or structural? Immunological Reviews 1990; 113: 227-241.
40. Williams JR, Lenington S. Factors modulating preferences of female house mice for males differing in t-complex genotype: role of t-complex genotype, genetic background, and estrous condition of females. Behavior Genetics 1993; 23: 51-58.
41. Potts WK, Manning CJ, Wakeland EK. Mating patterns in seminatural populations of mice influenced by MHC genotype. Nature 1991; 352: 619-621.
42. Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu DD, Elias S. HLA and mate choice in humans. American Journal of Human Genetics 1997; 61: 497-504.
43. Wedekind C, Seebeck T, Bettens F, Paepke AJ. MHC-dependent mate preferences in humans. Proceedings of the Royal Society of London - Series B: Biological Sciences 1995; 260: 245-249.
44. Palm J. Maternal-Fetal histoincompatibility in rats: an escape from adversity. Cancer Research 1974; 34: 2061-2065.
45. Hamilton MS, Hellstrom I. Selection for histoincompatible progeny in mice. Biology of Reproduction 1978; 19: 267-270.
46. Wedekind C, Chapuisat M, Macas E, Rulicke T. Non-random fertilization in mice correlates with the MHC and something else. Heredity 1996; 77: 400-409.
47. Ober C, Elias S, Kostyu DD, Hauck WW. Decreased fecundability in Hutterite couples sharing HLA-DR. American Journal of Human Genetics 1992; 50: 6-14.
48. Jin K, Ho HN, Speed TP, Gill TJI. Reproductive failure and the major histocompatibility complex. American Journal of Human Genetics 1995; 56: 1456-1467.
49. Brown JL. Some paradoxical goals of cells and organisms: the role of the MHC. In: Pfaff DW, ed. Ethical Questions in Brain and Behavior: Problems and Opportunities, New York: Springer-Verlag, 1983: 111-124.
50. Jones JS, Partridge L. Tissue rejection: the price for sexual acceptance . Nature 1983; 304: 484-485.
51. The MHC sequencing consortium. Complete sequence and gene map of a human major histocompatibility complex. Nature 1999; 401: 921-923.
52. Dunham I, Sargent CA, Dawkins RL, Campbell RD. An analysis of variation in the long-range genomic organization of the human major histocompatibility complex class II region by pulsed-field gel electrophoresis. Genomics 1989; 5: 787-796.
53. Tokunaga K, Saueracker G, Kay PH, Christiansen FT, Anand R, Dawkins RL. Extensive deletions and insertions in different MHC supratypes detected by pulsed field gel electrophoresis. Journal of Experimental Medicine 1988; 168: 933-940.
54. Inoko H, Ando A, Kawai J, Trowsdale J, Tsuji K. Mapping of the HLA-D region by pulsed-field gel electrophoresis: size variation in subregion intervals. In: Silver J, ed. Molecular Biology of HLA Class II Antigens, Florida: CRC Press, 1990: 1-17.
55. Niven MJ, Hitman GA, Pearce H, Marshall B, Sachs JA. Large haplotype-specific differences in inter-genic distances in human MHC shown by pulsed field electrophoresis mapping of healthy and type 1 diabetic subjects. Tissue Antigens 1990; 36: 19-24.
56. Kendall E, Todd JA , Campbell RD. Molecular analysis of the MHC class II region in DR4, DR7, and DR9 haplotypes. Immunogenetics 1991; 34: 349-357.
57. Klein J. Evolution and function of the major histocompatibility complex: facts and speculations. In: Gotze D, ed. The Major Histocompatibility System in Man and Animals, New York: Springer-Verlag, 1976: 339-378.
58. Browning M, McMichael A. MHC and HLA: Genes, Molecules and Function. Oxford: Bios Scientific Publishers, 1996;
59. Bodmer JG, Marsh SG, Albert ED, et al. Nomenclature for the factors of the HLA system, 1998. European Journal of Immunogenetics 1999; 26: 81-116.
60. Le Bouteiller P. HLA class I chromosomal region, genes, and products: facts and questions. Critical Reviews in Immunology 1994; 14: 89-129.
61. Aguado B, Milner CM, Campbell RD. Genes of the MHC class III region and the functions of the proteins they encode. In: Browning M, McMichael A, eds. HLA and MHC: genes, molecules and function, Oxford: Bios Scientific Publishers, 1996: 39-76.
62. Flajnik MF, Canel C, Kramer J, Kasahara M. Which came first, MHC class I or class II? Immunogenetics 1991; 33: 295-300.
63. Srivastava PK, Heike M. Tumour-specific immunogenicity of of stress-induced proteins: convergence of two evolutionary pathways of antigen presentation? Seminars in Immunology 1991; 3: 57-64.
64. Srivastava PK. Peptide-binding heat shock proteins in the endoplasmic reticulum: role in immune response to cancer and in antigen presentation. Advances in Cancer Research 1993; 62: 153-177.
65. Srivastava PK, Menoret A, Basu S, Binder RJ, McQuade KL. Heat shock proteins come of age: primitive functions acquire new roles in an adaptive world. Immunity 1998; 8: 657-665.
66. Blachere NE, Li Z, Chandawarkar RY, et al. Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumour immunity. Journal of Experimental Medicine 1997; 186: 1315-1322.
67. Suto R, Srivastava PK. A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 1995; 269: 1585-1588.
68. Ishii T, Udono H, Yamano T, et al. Isolation of MHC class I-restricted tumour antigen peptide and its precursors associated with heat shock proteins hsp70, hsp90, and gp96. Journal of Immunology 1999; 162: 1303-1309.
69. Basu S, Srivastava PK. Calreticulin, a peptide-binding chaperone of the endoplasmic reticulum, elicits tumour- and peptide-specific immunity. Journal of Experimental Medicine 1999; 189: 797-802.
70. Partanen J, Milner C, Campbell RD, Maki M, Lipsanen V, Koskimies S. HLA-linked heat-shock protein 70 (HSP70-2) gene polymorphism and celiac disease. Tissue Antigens 1993; 41: 15-19.
71. Cascino I, D'Alfonso S, Cappello N, et al. Gametic association of HSP70-1 promoter region alleles and their inclusion in extended HLA haplotypes. Tissue Antigens 1993; 42: 62-66.
72. Cascino I, Sorrentino R, Tosi R. Strong genetic association between HLA-DR3 and a polymorphic variation in the regulatory region of the HSP70-1 gene. Immunogenetics 1993; 37: 177-182.
73. Webb GC, Chaplin DD. Genetic variability at the human tumour necrosis factor loci. Journal of Immunology 1990; 145: 1278-1285.
74. Campbell RD, Carroll MC, Porter RR. The molecular genetics of components of complement [Review]. Advances in Immunology 1986; 38: 203-244.
75. Campbell RD, Dunham I, Sargent CA. Molecular mapping of the HLA-linked complement genes and the RCA linkage group [Review]. Experimental & Clinical Immunogenetics 1988; 5: 81-98.
76. Levine LS, Zachmann M, New MI, et al. Genetic mapping of the 21-hydroxylase-deficiency gene within the HLA linkage group. New England Journal of Medicine 1978; 299: 911-915.
77. Sugaya K, Fukagawa T, Matsumoto K, et al. Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumour gene int-3. Genomics 1994; 23: 408-419.
78. Sugaya K, Sasanuma S, Nohata J, et al. Gene organization of human NOTCH4 and (CTG)n polymorphism in this human counterpart gene of mouse proto-oncogene Int3. Gene 1997; 189: 235-244.
79. Lu Q, Wright DD, Kamps MP. Fusion with E2A converts the Pbx1 homeodomain protein into a constitutive transcriptional activator in human leukemias carrying the t(1;19) translocation. Molecular & Cellular Biology 1994; 14: 3938-3948.
80. Chan KW, Pollack MS, Braun D, Jr., O'Reilly RJ , Dupont B. Distribution of HLA genotypes in families of patients with acute leukaemia. Implications for transplantation. Transplantation 1982; 33: 613-615.
81. De Moor P, Louwagie A. Distribution of HLA genotypes in sibs of patients with acute leukaemia. Scandinavian Journal of Haematology 1985; 34: 68-70.
82. De Moor P. Distribution of HLA genotypes in sibs of patients with acute lymphoblastic leukaemia. European Journal of Haematology 1989; 42: 317-318.
83. Carpentier NA, Jeannet M. Increased HLA-DR compatibility between patients with acute myeloid leukaemia and their parents: implication for bone marrow transplantation. Transplantation Proceedings 1987; 19: 2644-2645.
84. Dorak MT, Chalmers EA, Gaffney D, et al. Human major histocompatibility complex contains several leukaemia susceptibility genes. Leukaemia & Lymphoma 1994; 12: 211-222.
85. Dorak MT, Burnett AK. Major histocompatibility complex, t-complex, and leukaemia [Review]. Cancer Causes & Control 1992; 3: 273-282.
86. O'Riordan J, Finch A, Lawlor E, McCann SR. Probability of finding a compatible sibling donor for bone marrow transplantation in Ireland. Bone Marrow Transplantation 1992; 9: 27-30.
87. Mattiuz PL, Ihde D , Piazza A, Ceppelini R, Bodmer WF. New approaches to the population genetic and segregation analysis of the HL-A system. In: Terasaki P, ed. Histocompatibility Testing 1970, Copenhagen: Munksgaard, 1971: 193-205.
88. Begovich AB, McClure GR, Suraj VC, et al. Polymorphism, recombination, and linkage disequilibrium within the HLA class II region. Journal of Immunology 1992; 148: 249-258.
89. Nossner E, Goldberg JE, Naftzger C, Lyu SC, Clayberger C, Krensky AM. HLA-derived peptides which inhibit T cell function bind to members of the heat-shock protein 70 family. Journal of Experimental Medicine 1996; 183: 339-348.
90. Gorski J, Rollini P, Mach B. Structural comparison of the genes of two HLA-DR supertypic groups: the loci encoding DRw52 and DRw53 are not truly allelic. Immunogenetics 1987; 25: 397-402.
91. Schreuder GM, Hurley CK, Marsh SG, et al. The HLA dictionary 1999: A summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and -DQ antigens. Human Immunology 1999; 60: 1157-1181.
92. Knowles RW, Flomenberg N, Horibe K, Winchester R, Radka SF, Dupont B. Complexity of the supertypic HLA-DRw53 specificity: two distinct epitopes differentially expressed on one or all of the DR beta-chains depending on the HLA-DR allotype. Journal of Immunology 1986; 137: 2618-2626.
93. Sutton VR, Kienzle BK, Knowles RW. An altered splice site is found in the DRB4 gene that is not expressed in HLA-DR7,Dw11 individuals. Immunogenetics 1989; 29: 317-322.
94. Leen MP, Gorski J. DRB4 promoter polymorphism in DR7 individuals: correlation with DRB4 pre-mRNA and mRNA levels. Immunogenetics 1997; 45: 371-378.
95. Sutton VR, Knowles RW. An aberrant DRB4 null gene transcript is found that could encode a novel HLA-DR beta chain. Immunogenetics 1990; 31: 112-117.
96. Lardy NM, van der Horst AR, van de Weerd MJ, de Waal LP, Bontrop RE. HLA-DRB4 gene encoded HLA-DR53 specificity segregating with the HLA-DR7, -DQ9 haplotype: unusual association. Human Immunology 1998; 59: 115-118.
97. Alper CA, Awdeh Z, Yunis EJ. Conserved, extended MHC haplotypes [Review]. Experimental & Clinical Immunogenetics 1992; 9: 58-71.
98. Degli-Esposti MA, Leaver AL, Christiansen FT, Witt CS, Abraham LJ, Dawkins RL. Ancestral haplotypes: conserved population MHC haplotypes . Human Immunology 1992; 34 : 242-252.
99. Awdeh ZL, Alper CA , Eynon E, Alosco SM, Stein R, Yunis EJ. Unrelated individuals matched for MHC extended haplotypes and HLA-identical siblings show comparable responses in mixed lymphocyte culture. Lancet 1985; 2: 853-856.
100. Alper CA, Awdeh ZL, Yunis EJ. Complotypes, extended haplotypes, male segregation distortion, and disease markers. Human Immunology 1986; 15: 366-373.
101. Gaudieri S, Leelayuwat C, Tay GK, Townend DC, Dawkins RL. The major histocompatability complex (MHC) contains conserved polymorphic genomic sequences that are shuffled by recombination to form ethnic-specific haplotypes. Journal of Molecular Evolution 1997; 45: 17-23.
102. Wilton AN, Christiansen FT, Dawkins RL. Supratype matching improves renal transplant survival. Transplantation Proceedings 1985; 17: 2211-2216.
103. Christiansen FT, Witt CS, Dawkins RL. Questions in marrow matching: the implications of ancestral haplotypes for routine practice. Bone Marrow Transplantation 1991; 8: 83-86.
104. Degli-Esposti MA, Leelayuwat C, Daly LN, et al. Updated characterization of ancestral haplotypes using the Fourth Asia-Oceania Histocompatibility Workshop panel. Human Immunology 1995; 44: 12-18.
105. Fraser PA, Stern S, Larson MG, et al. HLA extended haplotypes in childhood and adult onset HLA-DR4-associated arthropathies. Tissue Antigens 1990; 35: 56-59.
106. Hauser SL, Fleischnick E, Weiner HL, et al. Extended major histocompatibility complex haplotypes in patients with multiple sclerosis. Neurology 1989; 39: 275-277.
107. Raum D, Awdeh Z, Yunis EJ, Alper CA, Gabbay KH. Extended major histocompatibility complex haplotypes in type I diabetes mellitus. Journal of Clinical Investigation 1984; 74: 449-454.
108. Christiansen FT, Saueracker GC, Leaver AL, Tokunaga K, Cameron PU, Dawkins RL. Characterization of MHC ancestral haplotypes associated with insulin-dependent diabetes mellitus: evidence for involvement of non-HLA genes. Journal of Immunogenetics 1990; 17: 379-386.
109. Welch TR, Beischel LS, Balakrishnan K, Quinlan M , West CD. Major histocompatibility complex extended haplotypes in systemic lupus erythematosus. Disease Markers 1988; 6: 247-255.
110. Marsh SG, Parham P, Barber LD. The HLA Facts Book. San Diego: Academic Press , 2000.
111. Klein J, Satta Y, O'hUigin C, Takahata N. The molecular descent of the major histocompatibility complex [Review]. Annual Review of Immunology 1993; 11: 269-295.
112. Kupfermann H, Mayer WE, O'hUigin C, Klein D, Klein J. Shared polymorphism between gorilla and human major histocompatibility complex DRB loci. Human Immunology 1992; 34: 267-278.
113. Lawlor DA, Warren E, Taylor P, Parham P. Gorilla class I major histocompatibility complex alleles: comparison to human and chimpanzee class I. Journal of Experimental Medicine 1991; 174: 1491-1509.
114. Lundberg AS, McDevitt HO. Evolution of major histocompatibility complex class II allelic diversity: direct descent in mice and humans. Proceedings of the National Academy of Sciences USA 1992; 89: 6545-6549.
115. Mayer WE, Jonker M, Klein D, Ivanyi P, van Seventer G, Klein J. Nucleotide sequences of chimpanzee MHC class I alleles: evidence for trans-species mode of evolution. EMBO Journal 1988; 7: 2765-2774.
116. Lawlor DA, Ward FE, Ennis PD, Jackson AP, Parham P. HLA-A and B polymorphisms predate the divergence of humans and chimpanzees. Nature 1988; 335: 268-271.
117. Lawlor DA, Warren E, Ward FE, Parham P. Comparison of class I MHC alleles in humans and apes [Review]. Immunological Reviews 1990; 113: 147-185.
118. Erlich HA, Gyllensten UB. Shared epitopes among HLA class II alleles: gene conversion, common ancestry and balancing selection. Immunology Today 1991; 12: 411-414.
119. Boyson JE, Shufflebotham C, Cadavid LF, et al. The MHC class I genes of the rhesus monkey. Different evolutionary histories of MHC class I and II genes in primates. Journal of Immunology 1996; 156: 4656-4665.
120. Parham P, Lawlor DA, Lomen CE, Ennis PD. Diversity and diversification of HLA-A,B,C alleles. Journal of Immunology 1989; 142 : 3937-3950.
121. Metzgar RS, Ward FE, Seigler HF. Study of the HL-A system in chimpanzees. In: Dausset J, Colombani J, eds. Histocompatibility Testing 1972, Copenhagen: Munksgaard, 1972: 55-61.
122. Bright S, Balner H. The antigens 4a and 4b in rhesus monkeys and stumptailed macaques. Tissue Antigens 1976; 8: 261-271.
123. Balner H. The major histocompatibility complex of primates: evolutionary aspects and comparative histogenetics. Philosophical Transactions of the Royal Society of London - Series B: Biological Sciences 1981; 292: 109-119.
124. Gumperz JE, Litwin V, Phillips JH, Lanier LL, Parham P. The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor. Journal of Experimental Medicine 1995; 181: 1133-1144.
125. Cella M, Longo A, Ferrara GB, Strominger JL, Colonna M. NK3-specific natural killer cells are selectively inhibited by Bw4-positive HLA alleles with isoleucine 80. Journal of Experimental Medicine 1994; 180: 1235-1242.
126. Lanier LL, Phillips JH. Inhibitory MHC class I receptors on NK cells and T cells. Immunology Today 1996; 17: 86-91.
127. Slierendregt BL, van Noort JT, Bakas RM, Otting N , Jonker M, Bontrop RE. Evolutionary stability of transspecies major histocompatibility complex class II DRB lineages in humans and rhesus monkeys. Human Immunology 1992; 35: 29-39.
128. Hickson RE, Cann RL. Mhc allelic diversity and modern human origins. Journal of Molecular Evolution 1997; 45: 589-598.
129. Gyllensten UB, Erlich HA. Ancient roots for polymorphism at the HLA-DQ alpha locus in primates. Proceedings of the National Academy of Sciences USA 1989; 86: 9986-9990.
130. Bergstrom T, Gyllensten U. Evolution of Mhc class II polymorphism: the rise and fall of class II gene function in primates [Review]. Immunological Reviews 1995; 143: 13-31.
131. Moriuchi J, Moriuchi T, Silver J. Nucleotide sequence of an HLA-DQ alpha chain derived from a DRw9 cell line: genetic and evolutionary implications. Proceedings of the National Academy of Sciences USA 1985; 82: 3420-3424.
132. Karr RW, Gregersen PK, Obata F, et al. Analysis of DR beta and DQ beta chain cDNA clones from a DR7 haplotype. Journal of Immunology 1986; 137: 2886-2890.
133. Satta Y, Mayer WE , Klein J. HLA-DRB intron 1 sequences: implications for the evolution of HLA-DRB genes and haplotypes. Human Immunology 1996; 51: 1-12.
134. Svensson AC, Setterblad N, Pihlgren U, Rask L, Andersson G. Evolutionary relationship between human major histocompatibility complex HLA-DR haplotypes. Immunogenetics 1996; 43: 304-314.
135. Gongora R, Figueroa F, Klein J. The HLA-DRB9 gene and the origin of HLA-DR haplotypes. Human Immunology 1996; 51: 23-31.
136. Klein J, O'hUigin C. Class II B Mhc motifs in an evolutionary perspective [Review]. Immunological Reviews 1995; 143: 89-111.
137. Figueroa F, O'hUigin C, Tichy H, Klein J. The origin of the primate Mhc-DRB genes and allelic lineages as deduced from the study of prosimians. Journal of Immunology 1994; 152: 4455-4465.
138. Satta Y, Mayer WE , Klein J. Evolutionary relationship of HLA-DRB genes inferred from intron sequences. Journal of Molecular Evolution 1996; 42: 648-657.
139. Clayberger C, Rosen M, Parham P, Krensky AM. Recognition of an HLA public determinant (Bw4) by human allogeneic cytotoxic T lymphocytes. Journal of Immunology 1990; 144: 4172-4176.
140. Arnett KL, Huang W, Valiante NM, Barber LD, Parham P. The Bw4/Bw6 difference between HLA-B*0802 and HLA-B*0801 changes the peptides endogenously bound and the stimulation of alloreactive T cells. Immunogenetics 1998; 48: 56-61.
141. Decary F, L'Abbe D, Tremblay L, Chartrand P. The immune response to the HPA-1a antigen: association with HLA- DRw52a. Transfusion Medicine 1991; 1: 55-62.
142. Bontrop RE, Elferink DG, Otting N, Jonker M, de Vries RR. Major histocompatibility complex class II-restricted antigen presentation across a species barrier: conservation of restriction determinants in evolution. Journal of Experimental Medicine 1990; 172: 53-59.
143. Qvigstad E, Gaudernack G, Thorsby E. Antigen-specific T cell clones restricted by DR, DRw53 (MT), or DP (SB) class II HLA molecules. Inhibition studies with monoclonal HLA-specific antibodies. Human Immunology 1984; 11: 207-217.
144. Paulsen G, Qvigstad E, Gaudernack G, Rask L, Winchester R, Thorsby E. Identification, at the genomic level, of an HLA-DR restriction element for cloned antigen-specific T4 cells. Journal of Experimental Medicine 1985; 161: 1569-1574.
145. Waters SJ, Winchester RJ, Nagase F, Thorbecke GJ, Bona CA. Antigen presentation by murine and human cells to a murine T-cell hybridoma: demonstration of a restriction element associated with a major histocompatibility complex class II determinant(s) shared by both species. Proceedings of the National Academy of Sciences USA 1984; 81: 7559-7563.
146. Mustafa AS, Deggerdal A, Lundin KE, Meloen RM, Shinnick TM, Oftung F. An HLA-DRw53-restricted T-cell epitope from a novel Mycobacterium leprae protein antigen important to the human memory T-cell repertoire against M. leprae. Infection & Immunity 1994; 62: 5595-5602.
147. Mustafa AS. Identification of mycobacterial peptide epitopes recognized by CD4+ T cells in association with multiple major histocompatibility complex class II molecules. Nutrition 1995; 11: 657-660.
148. Fuller TC, Fuller A. The humoral immune response against an HLA class I allodeterminant correlates with the HLA-DR phenotype of the responder. Transplantation 1999; 68: 173-182.
149. Pierres M, Mercier P, Madsen M, Mawas C, Kristensen T. Monoclonal mouse anti-I-Ak and anti-I-Ek antibodies cross-reacting with HLA-DR supertypic and subtypic determinants rather than classical DR allelic specificities. Tissue Antigens 1982; 19: 289-300.
150. Matsuyama T, Schwenzer J, Silver J, Winchester R. Structural relationships between the DR beta 1 and DR beta 2 subunits in DR4, 7, and w9 haplotypes and the DRw53 (MT3) specificity. Journal of Immunology 1986; 137: 934-940.
151. Kobayashi H, Kokubo T, Abe Y, et al. Analysis of anchor residues in a naturally processed HLA-DR53 ligand. Immunogenetics 1996; 44: 366-371.
152. Kinouchi R, Kobayasi H, Sato K, Kimura S, Katagiri M. Peptide motifs of HLA-DR4/DR53 (DRB1*0405/DRB4*0101) molecules. Immunogenetics 1994; 40: 376-378.
153. Max H, Halder T, Kalbus M, Gnau V, Jung G, Kalbacher H. A 16mer peptide of the human autoantigen calreticulin is a most prominent HLA-DR4Dw4-associated self-peptide. Human Immunology 1994; 41: 39-45.
154. Verreck FA, Elferink D, Vermeulen CJ, et al. DR4Dw4/DR53 molecules contain a peptide from the autoantigen calreticulin. Tissue Antigens 1995; 45: 270-275.
155. Harris MR, Yu YY, Kindle CS, Hansen TH, Solheim JC. Calreticulin and calnexin interact with different protein and glycan determinants during the assembly of MHC class I. Journal of Immunology 1998; 160: 5404-5409.
Please update your bookmark: http://www.dorak.info/mhc/mhc.html
Last edited on 13 August 2013