The class I histocompatibility antigen from human cell membranes has two structural motifs: the membrane-proximal end of the glycoprotein contains two domains with immunoglobulin-folds that are paired in a novel manner, and the region distal from the membrane is a platform of eight antiparallel beta-strands topped by alpha-helices. A large groove between the alpha-helices provides a binding site for processed foreign antigens. An unknown 'antigen' is found in this site in crystals of purified HLA-A2.

Structure of the human class I histocompatibility antigen, HLA-A2.

Analysis of membrane and surface protein sequences with the hydrophobic moment plot.

Over half of the inherited predisposition to insulin-dependent diabetes mellitus maps to the region of chromosome 6 that contains the highly polymorphic HLA class II genes which determine immune responsiveness. Analysis of DNA sequences from diabetics indicates that alleles of HLA-DQ beta determine both disease susceptibility and resistance, and that the structure of the DQ molecule, in particular residue 57 of the beta-chain, specifies the autoimmune response against the insulin-producing islet cells.

HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus.

We have cloned and sequenced a human mRNA specific for mammalian T-lymphoid cells The message was found to be expressed in human and murine T lymphoblasts, thymocytes and phytohaemagglutinin-stimulated T lymphocytes The protein deduced from the cDNA sequence has a molecular weight of 34,938 and shows extensive similarity to the entire length of the variable, joining and constant regions of mammalian immunoglobulin light chains In addition, the relative positions of the cysteine residues are similar to those of the light chains of murine and human immunoglobulin molecules These properties suggest that the cDNA clone may correspond to a message that specifies part of the human T-cell receptor

A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains

Cold Spring Harbor Symposia on Quantitative Biology.: Vol. LII. Evolution of Catalytic Functions. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1987, ISBN 0-87969-054-2, xix + 955 pp., US $150.00.

A comparison of seven human DR and DC class II histocompatibility antigen beta-chain amino acid sequences indicates that the allelic variation is of comparable magnitude within the DR and DC beta-chain genes. Silent and replacement nucleotide substitutions in six DR and DC beta-chain sequences, as well as in seven murine class II sequences (three I-A beta and four I-A alpha alleles) were analyzed. The results suggest that the mutation rates are of a comparable magnitude in the nucleotide sequences encoding the first and second external domains of the class II molecules. Nevertheless, the allelic amino acid replacements are predominantly located in the first domains. We conclude that a conservative selective pressure acts on the second domains, whereas in many positions in the first domains replacement substitutions are selectively neutral or maybe even favoured. Thus, the difference between the first and second domains as regards the number of amino acid replacements is mainly due to selection.

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Mutations and selection in the generation of class II histocompatibility antigen polymorphism.

UNLIKE the classical transplantation antigens, called HLA-A,B,C in man and H-2K,D in mouse, the HLA-DR (la) antigens have a restricted tissue distribution1. Primarily cells belonging to the immune system express Ia antigens whose only known biological role is to participate in cell-to-cell cooperation events involving lymphocytes and macrophages2–4. However, cells of the immune system do not only interact among themselves but they also associate physically with other types of cells like epithelial cells of the intestine and the lactating mammary gland5 and with reticuloepithelial cells of the thymus6. The possibility that all such interactions are under la antigen control is raised by indirect immunofluorescence analyses which show that la antigens are expressed on a great variety of epithelia. We report here our examination of several cryostat sections of guinea pig tissues for the presence of la antigens by indirect immunofluorescence. To obtain staining patterns that were reproducible and significantly different from the controls it proved necessary to use immunosorbent-purified heteroantibodies (see legend to Fig. 1 for description of the antibodies).

Occurrence of Ia antigens on tissues on non-lymphoid origin

At least three class II antigens, all composed of an alpha and a beta subunit, are encoded in the human major histocompatibility complex, i.e., DR, DC and SB. Two cDNA clones, encoding a DC alpha and a DC beta chain, respectively, were isolated from a cDNA library of the lymphoblastoid cell line Raji (DR3,w6). The two polypeptides predicted from the nucleotide sequences of these clones are each composed of a signal peptide, two extracellular domains, a hydrophobic transmembrane region and a short cytoplasmic tail. Comparison of the DC alpha sequence with two previously published partial sequences shows that the majority of the differences is located in the amino-terminal domain. The differences are not randomly distributed; a cluster of replacements is present in the central portion of the amino-terminal domain. Likewise, the allelic polymorphism of the DC beta chains occurs preferentially in the amino-terminal domain, where three minor clusters of replacements can be discerned. The non-random distribution of the variability of DC alpha and beta chains may be due to phenotypic selection against replacement substitutions in the second domains of the polypeptides.

/pdf/both-alpha-and-beta-chains-of-hla-dc-class-ii-52cyyhgzfn.pdf

Both alpha and beta chains of HLA-DC class II histocompatibility antigens display extensive polymorphism in their amino-terminal domains.

https://www.cell.com/cell/pdf/0092-8674(82)90021-6.pdf

Alpha chain of HLA-DR transplantation antigens is a member of the same protein superfamily as the immunoglobulins

The HLA-D locus in the major histocompatibility complex controls the expression of the genetically polymorphic HLA-DR antigens. mRNA coding for the beta chains of these antigens was partially purified from the human lymphoblastoid cell line Raji. The mRNA was copied into double-stranded cDNA and cloned in Escherichia coli. One clone, pDR-beta-1, obtained by hybrid selection, carries a 1070-base-pair insert comprising all of the coding region except the signal sequence and a substantial portion of the untranslated region. To identify pDR-beta-1, highly purified HLA-DR antigen beta chains derived from Raji cells were subjected to NH2-terminal amino acid sequence determination. This sequence displayed extensive homology with that deduced from the nucleotide sequence at the 5' end of the pDR-beta-1 coding region. Taken together, the amino acid and nucleotide sequences strongly argue in favor of Raji cells containing at least two beta-chain loci.

https://www.pnas.org/content/pnas/79/6/1703.full.pdf

K. Wiman

Papers

Mutations and selection in the generation of class II histocompatibility antigen polymorphism.

Occurrence of Ia antigens on tissues on non-lymphoid origin

Both alpha and beta chains of HLA-DC class II histocompatibility antigens display extensive polymorphism in their amino-terminal domains.

Alpha chain of HLA-DR transplantation antigens is a member of the same protein superfamily as the immunoglobulins

Isolation and identification of a cDNA clone corresponding to an HLA-DR antigen beta chain.