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Gene Review

HLA-C  -  major histocompatibility complex, class I, C

Homo sapiens

Synonyms: D6S204, HLA-JY3, HLC-C, PSORS1
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Disease relevance of HLA-C

  • The S gene (corneodesmosin), located 160 kb telomeric of HLA-C, is a strong candidate for psoriasis due to its reportedly exclusive expression in differentiating keratinocytes [1].
  • Jeg-3 choriocarcinoma cells constitutively express HLA-G and low levels of a novel HLA-C gene product [2].
  • The defects include a lower expression of all HLA class I antigens compared to EBV transformed normal B-blasts, and selective down-regulation of certain HLA-A and HLA-C alleles [3].
  • HLA-A, HLA-B, HLA-C, and HLA-D typing was performed in 47 mothers of patients suffering from ocular toxoplasmosis to investigate whether an immunogenetic predisposition exists for developing congenital toxoplasmosis in their offspring [4].
  • HLA-B and HLA-C alleles were resolved to four digits by a combination of molecular methods, and their respective associations with outcomes of HIV-1 infection were analyzed by statistical procedures appropriate for continuous or categorical data [5].
  • While the previously reported association between TNF*-238A and psoriasis seems to primarily reflect LD with PSORS1, TNF*-857T may represent a risk factor for PsA that is independent of the PSORS1 allele [6].

High impact information on HLA-C

  • Generation of allospecific natural killer cells by stimulation across a polymorphism of HLA-C [7].
  • Relationship between HLA-C locus and restenosis after coronary artery balloon angioplasty [8].
  • In addition, different arrangements of HLA-C are seen at inhibitory NK immune synapses, and these alter as NK synapses mature, but in a fashion distinct from that seen upon T cell activation [9].
  • After accumulation of target cell human leukocyte antigen (HLA)-C at inhibitory natural killer (NK) cell immune synapses, some HLA-C transfers from target cells to NK cell plasma membranes and cytoplasm [9].
  • This unexpected intercellular transfer of HLA-C is dependent on NK receptor recognition, since HLA-Cw6 or -Cw4 but not -Cw3 transfer to an NK transfectant expressing killer Ig-like receptor (KIR)2DL1 [9].

Chemical compound and disease context of HLA-C

  • Alanine at residue 73 (Ala-73) and aspartate at residue 9 (Asp-9) are characteristic to both Cw6 and Cw7 alleles of HLA-C gene and have been suggested as possible markers for psoriasis vulgaris (PsV) [10].
  • It is suggested that alanine at position 73 of HLA-C molecules can be a good marker for psoriasis vulgaris and that this residue may play an important role in determining susceptibility to this disease [11].

Biological context of HLA-C


Anatomical context of HLA-C

  • These results suggest that HLA-C molecules may deliver negative regulatory signals to some non-MHC-restricted T cells in a manner similar to that described previously for particular NK cells [13].
  • Similar patterns of HLA-C-mediated resistance were also found with two polyclonal T cell lines generated from the peripheral blood lymphocytes of unrelated donors [13].
  • Formation of MHC complexes with particular peptides did not appear to be essential to confer resistance, since a cell line with defective peptide transporter genes (TAP genes), when transfected with an appropriate HLA-C allele, was as resistant to lysis as HLA-C transfectant lines with normal TAP function [13].
  • Alloreactive cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and cellular glycosidases all recognize B*4601 as though it were an HLA-C allotype [16].
  • Eighty-five percent of the chondrocytes had strong representation of Class I molecules, and individual specificities for HLA-A, HLA-B, and HLA-C could be detected [17].

Associations of HLA-C with chemical compounds

  • In particular, conserved motifs in the alpha 1 helix and the conserved glycine at the base of the B pocket (position 45) provide a combination of features that is uniquely found in HLA-C molecules [12].
  • Fifty-two patients with PsA and 73 random matched controls from a Jewish population were selected and DNA typed by polymerase chain reaction-single-strand oligonucleotide probe (PCR-SSOP) (HLA-C), PCR sequence-specific primers (PCR-SSP) (HLA-B, -DR), radioactive PCR (MICA-TM polymorphism in the transmembrane region), and PCR-RFLP (TNF) [18].
  • This soluble receptor binds specifically to HLA-C alleles with serine 77 and asparagine 80 in cell adhesion assays [19].
  • Several other class I molecules, notably HLA-C antigens, are reactive in this system, and it may be capable of recognizing subtypes such as A*0207 which also carry free cysteine [20].
  • RESULTS: All patients possessed in their HLA-C antigens an alanine residue at position 73 (p < 0.002) [21].

Physical interactions of HLA-C


Regulatory relationships of HLA-C

  • For both types of effector cells, direct binding to HLA-C molecules was necessary to achieve inhibition since preincubation with mAb specific for class I molecules destroyed the protection from lysis of HLA-Cw7 expressing target cells. mAbs specific for CD3 and CD8 molecules had no influence on lysis or inhibition of the NK-like T cells [13].

Other interactions of HLA-C

  • In comparison with HLA-A and -B, HLA-C alleles are more closely related to each other, there being less variation in residues of the antigen recognition site and more variation at other positions [12].
  • All MM cell lines constitutively expressed class I, but not class II, surface antigen, and all three class I loci (HLA-A, HLA-B, and HLA-C) were expressed [23].
  • The possible role of carbohydrate in the interaction of HLA-C with a human inhibitory natural Killer cell Immunoglobulin-like Receptor with two Ig domains, KIR2DL1, was investigated [24].
  • Our present data indicate that a single amino acid difference greatly influences the p58.1/p50.1 affinity for their HLA-C ligand and suggests a possible role of position 70 as a contact site in the natural killer cell receptor/major histocompatibility complex class I interaction [25].
  • Distinctive features of the alpha 1-domain alpha helix of HLA-C heavy chains free of beta 2-microglobulin [26].

Analytical, diagnostic and therapeutic context of HLA-C

  • For bone marrow transplantation the HLA-C and -DQ alleles are also considered [27].
  • Molecular cloning of HLA-C- and HLA-B-specific receptors has revealed new members of the immunoglobulin superfamily with two or three Ig-like domains, respectively, in their extracellular portion [28].
  • The data thus indicate that HLA-C-restricted CTLs may have an under-appreciated antiviral role in the setting of Nef in vivo and suggest a benefit of promoting HLA-C-restricted CTLs for immunotherapy or vaccine development [29].
  • The frequency distribution of the 14-HLA-A, 18 HLA-B, 5 HLA-C and 10 HLA-D antigens, which were tested, was similar in patients with obstructive, provocable obstructive or non-obstructive HCM to that of a control group of 800 normal persons [30].
  • At present, the possible involvement of HLA-C antigen in liver transplantation is still unexplored [31].


  1. S gene (Corneodesmosin) diversity and its relationship to psoriasis; high content of cSNP in the HLA-linked S gene. Enerbäck, C., Enlund, F., Inerot, A., Samuelsson, L., Wahlström, J., Swanbeck, G., Martinsson, T. J. Invest. Dermatol. (2000) [Pubmed]
  2. The role of MHC class I expression in developmental tumours. Stern, P.L., Rinke de Wit, T.F. Semin. Cancer Biol. (1991) [Pubmed]
  3. Cell phenotype dependent expression of MHC class I antigens in Burkitt's lymphoma cell lines. Masucci, M.G., Klein, E. Semin. Cancer Biol. (1991) [Pubmed]
  4. HLA typing in congenital toxoplasmosis. Meenken, C., Rothova, A., de Waal, L.P., van der Horst, A.R., Mesman, B.J., Kijlstra, A. The British journal of ophthalmology. (1995) [Pubmed]
  5. Human leukocyte antigen B58 supertype and human immunodeficiency virus type 1 infection in native Africans. Lazaryan, A., Lobashevsky, E., Mulenga, J., Karita, E., Allen, S., Tang, J., Kaslow, R.A. J. Virol. (2006) [Pubmed]
  6. TNF polymorphisms in psoriasis: association of psoriatic arthritis with the promoter polymorphism TNF*-857 independent of the PSORS1 risk allele. Reich, K., Hüffmeier, U., König, I.R., Lascorz, J., Lohmann, J., Wendler, J., Traupe, H., Mössner, R., Reis, A., Burkhardt, H. Arthritis Rheum. (2007) [Pubmed]
  7. Generation of allospecific natural killer cells by stimulation across a polymorphism of HLA-C. Colonna, M., Brooks, E.G., Falco, M., Ferrara, G.B., Strominger, J.L. Science (1993) [Pubmed]
  8. Relationship between HLA-C locus and restenosis after coronary artery balloon angioplasty. Watanabe, Y., Yamada, N., Yokoi, H., Fujiwara, Y., Mokuno, H., Daida, H., Yamaguchi, H. JAMA (1997) [Pubmed]
  9. Intercellular transfer and supramolecular organization of human leukocyte antigen C at inhibitory natural killer cell immune synapses. Carlin, L.M., Eleme, K., McCann, F.E., Davis, D.M. J. Exp. Med. (2001) [Pubmed]
  10. Study of alanine-73 and aspartate-9 of HLA-C locus in Saudi psoriasis patients, using sequence-specific primers (PCR-SSP). Abanmi, A., Al Harthi, F., Al Agla, R., Khan, H.A., Tariq, M. J. Biochem. Mol. Biol. (2005) [Pubmed]
  11. Specific nucleotide sequence of HLA-C is strongly associated with psoriasis vulgaris. Asahina, A., Akazaki, S., Nakagawa, H., Kuwata, S., Tokunaga, K., Ishibashi, Y., Juji, T. J. Invest. Dermatol. (1991) [Pubmed]
  12. Distinctive polymorphism at the HLA-C locus: implications for the expression of HLA-C. Zemmour, J., Parham, P. J. Exp. Med. (1992) [Pubmed]
  13. Expression of HLA-C molecules confers target cell resistance to some non-major histocompatibility complex-restricted T cells in a manner analogous to allospecific natural killer cells. Falk, C.S., Steinle, A., Schendel, D.J. J. Exp. Med. (1995) [Pubmed]
  14. Isolation and characterization of yeast artificial chromosome clones linking the HLA-B and HLA-C loci. Bronson, S.K., Pei, J., Taillon-Miller, P., Chorney, M.J., Geraghty, D.E., Chaplin, D.D. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  15. CpG islands and HTF islands in the HLA class I region: investigation of the methylation status of class I genes leads to precise physical mapping of the HLA-B and -C genes. Pontarotti, P., Chimini, G., Nguyen, C., Boretto, J., Jordan, B.R. Nucleic Acids Res. (1988) [Pubmed]
  16. The inter-locus recombinant HLA-B*4601 has high selectivity in peptide binding and functions characteristic of HLA-C. Barber, L.D., Percival, L., Valiante, N.M., Chen, L., Lee, C., Gumperz, J.E., Phillips, J.H., Lanier, L.L., Bigge, J.C., Parekh, R.B., Parham, P. J. Exp. Med. (1996) [Pubmed]
  17. The expression of major histocompatibility antigens on human articular chondrocytes. Lance, E.M., Kimura, L.H., Manibog, C.N. Clin. Orthop. Relat. Res. (1993) [Pubmed]
  18. Polymorphism in MICA rather than HLA-B/C genes is associated with psoriatic arthritis in the Jewish population. González, S., Brautbar, C., Martínez-Borra, J., López-Vazquez, A., Segal, R., Blanco-Gelaz, M.A., Enk, C.D., Safriman, C., López-Larrea, C. Hum. Immunol. (2001) [Pubmed]
  19. Human natural killer cell inhibitory receptors bind to HLA class I molecules. Döhring, C., Colonna, M. Eur. J. Immunol. (1996) [Pubmed]
  20. Chemical reactivity of an HLA-B27 thiol group. Whelan, M.A., Archer, J.R. Eur. J. Immunol. (1993) [Pubmed]
  21. Do specific pockets of HLA-C molecules predispose Jewish patients to psoriasis vulgaris? Roitberg-Tambur, A., Friedmann, A., Tzfoni, E.E., Battat, S., Ben Hammo, R., Safirman, C., Tokunaga, K., Asahina, A., Brautbar, C. J. Am. Acad. Dermatol. (1994) [Pubmed]
  22. Definition of polymorphic residues on killer Ig-like receptor proteins which contribute to the HLA-C binding site. Richardson, J., Reyburn, H.T., Luque, I., Valés-Gómez, M., Strominger, J.L. Eur. J. Immunol. (2000) [Pubmed]
  23. HLA antigen expression and malignant mesothelioma. Christmas, T.I., Manning, L.S., Davis, M.R., Robinson, B.W., Garlepp, M.J. Am. J. Respir. Cell Mol. Biol. (1991) [Pubmed]
  24. N-linked carbohydrate on human leukocyte antigen-C and recognition by natural killer cell inhibitory receptors. Baba, E., Erskine, R., Boyson, J.E., Cohen, G.B., Davis, D.M., Malik, P., Mandelboim, O., Reyburn, H.T., Strominger, J.L. Hum. Immunol. (2000) [Pubmed]
  25. Role of amino acid position 70 in the binding affinity of p50.1 and p58.1 receptors for HLA-Cw4 molecules. Biassoni, R., Pessino, A., Malaspina, A., Cantoni, C., Bottino, C., Sivori, S., Moretta, L., Moretta, A. Eur. J. Immunol. (1997) [Pubmed]
  26. Distinctive features of the alpha 1-domain alpha helix of HLA-C heavy chains free of beta 2-microglobulin. Setini, A., Beretta, A., De Santis, C., Meneveri, R., Martayan, A., Mazzilli, M.C., Appella, E., Siccardi, A.G., Natali, P.G., Giacomini, P. Hum. Immunol. (1996) [Pubmed]
  27. Pyrosequencing(R)-based strategies for improved allele typing of human leukocyte antigen Loci. Ringquist, S., Styche, A., Rudert, W.A., Trucco, M. Methods Mol. Biol. (2006) [Pubmed]
  28. Receptors for HLA class-I molecules in human natural killer cells. Moretta, A., Bottino, C., Vitale, M., Pende, D., Biassoni, R., Mingari, M.C., Moretta, L. Annu. Rev. Immunol. (1996) [Pubmed]
  29. Nef interference with HIV-1-specific CTL antiviral activity is epitope specific. Adnan, S., Balamurugan, A., Trocha, A., Bennett, M.S., Ng, H.L., Ali, A., Brander, C., Yang, O.O. Blood (2006) [Pubmed]
  30. HLA complex and hypertrophic cardiomyopathy in a European population. Beckers, J., Vandeputte, R., Geboers, J., DeGeest, H. Eur. Heart J. (1985) [Pubmed]
  31. Human leukocyte antigen-C in short- and long-term liver graft acceptance. Moya-Quiles, M.R., Muro, M., Torío, A., Sánchez-Bueno, F., Miras, M., Marín, L., García-Alonso, A.M., Parrilla, P., Dausset, J., Alvarez-López, M.R. Liver Transpl. (2003) [Pubmed]
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