Distinctive polymorphism at the HLA-C locus: implications for the expression of HLA-C.

Abstract

SummaryThe HLA-C locus remains an enigma. The serological polymorphism is poorly defined, HLA-C molecules are expressed at the cell surface at about 10% the levels of HLA-A and -B, and their importance for antigen presentation to either CDS-bearing T cells or natural killer cells is undear. Our understanding of HLA-C polymorphism has also lagged behind that of HLA-A and -B. We have applied the polymerase chain reaction to the characterization of eDNA encoding HLA-C antigens. Combining the recent results with previously characterized HLA-C alleles gives a data base of 26 sequences, which was used to analyze the nature of HLA-C polymorphism and compare it to the variation seen in HLA-A and -B. The sequences form 10 families of alleles that correlate well with the patterns of serological crossreactivity, including the C blanks, and all major HLA-C allelic families appear to have been sampled. The families further divide into two groups of HLA-C alleles defined on the basis of linked substitutions in the 3' exons. 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. In particular, the helix of the (xl domain of HLA-C molecules is unusually conserved. Despite the reduced diversity in the antigen recognition site, it is evident that HLA-C genes have been the target of past selection for polymorphism. Within the antigen recognition site, it is the ol1 domain that is most diagnostic of HLA-C, whereas the o~2 domain is similar to that of HLA-B, the locus to which HLA-C is most closely related. In particular, conserved motifs in the or1 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. We hypothesize that these features restrict the peptides bound by HLA-C molecules and in this manner reduce the efficiency of HLA-C assembly and expression at the cell surface. The overall picture of HLA-C polymorphism obtained from this sampling of HLA-C alleles is unlikely to change as further alleles are characterized.

Human leukocyte antigen–C in short- and long-term liver graft acceptance

“…Nonetheless, HLA-C molecules show a more limited polymorphism in their putative binding sites than HLA-A, -B, and -DR molecules, suggesting a likely restricted role of HLA-C in antigen presentation. 34 It is possible that subtle structural changes in HLA-Cw6 molecules differentiate them from other HLA-C mole- cules, leading to greater specificity for peptide engagement, causing increased alloreactivity and risk for AR. 35 In fact, HLA-Cw6 has been associated with some autoimmune diseases, such as psoriasis vulgaris, although it is unclear whether HLA-Cw6 itself is the cause of this disease or whether its association is mediated by the Ala-73 residue shared with other HLA-C alleles.…”

A Tumor-Infiltrating Lymphocyte from a Melanoma Metastasis with Decreased Expression of Melanoma Differentiation Antigens Recognizes MAGE-12

“…High avidity of the epitope/F001-TCR interaction was suggested by the picomolar range in which MAGE-12:170 -178 could induce recognition of F001-EBV-B cells. This might explain why the reported low surface expression of HLA-Cw alleles (52) was not a factor limiting the recognition of melanoma cells by F001-TIL. Thus, the identification of MAGE-12:170 -178 adds a new epitope in the context of HLA class I alleles different from HLA-A that could be used for Ag-specific vaccination.…”

“…It is not clear why in the context of HLA-A*0201 MART-1/MelanA and gp100/ PMel17 exert an immunodominant role. Given the predominant expression of HLA-A over HLA-Cw alleles (52), it is possible that a MA associated with the latter might most commonly remain cryptic. Furthermore, immune dominance might depend on previous individual exposure to endogenous or environmental Ags mimicking MDA epitopes (53).…”

Characteristics, Detection, and Clinical Relevance of Alloantibodies in Kidney Transplantation

“…One of the features of this MHC antigen is its low (~10%) cell membrane expression in comparison to HLA-A and HLA-B proteins. In addition, the products of HLA-C locus genes are not expressed on platelets (Zemmour & Parham, 1992). During the last decade, several reports have addressed their role in clinical transplantation.…”