Structure, Function, and Genetics of Human Class II Molecules

Giles, Robert C.; Capra, J. Donald

doi:10.1016/s0065-2776(08)60337-5

Cited by 105 publications

(29 citation statements)

References 163 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HLA-DQw2 is in tight linkage disequilibrium with HLA-DR3 and DRw52, which are usually carried on HLA-B8-bearing haplotypes. HLA-DQw2 is also found on DR7 haplotypes (42,43). Charron et a1 (44) and Giles et a1 (45) have shown that DQa chains from one chromosome can combine with DQP chains from another chromosome, thus forming new "hybrid" molecules that are not present in either parent.…”

Section: Discussionmentioning

confidence: 99%

Two ro (ss‐a) autoantibody responses in systemic lupus erythematosus

Hamilton

Harley

Bias

et al. 1988

Arthritis & Rheumatism

176

View full text Add to dashboard Cite

Sdnuclear RNP were quantitated by enzyme-linked immunosorbent assay in 106 white patients with systemic lupus erythematosus. Two Ro autoantibody subgroups were identified that differed quantitatively, genetically, and clinically. The subgroup having anti-Ro only demonstrated significantly lower mean anti-Ro levels than did the subgroup with concomitant anti-La and showed a strong association with the linked HLA alleles DR2 and DQwl. The anti-Ro with anti-La sub- group was associated with the linked HLA alleles B8, DR3, DRw52, and DQw2 (DR3 was primary), and this subgroup consisted of patients with older ages at disease onset, sicca complex, and less renal involvement. Overall, the relative risk (RR) for having anti-Ro was highest in HLA-DR21DR3 heterozygotes compared with non-DR2/DR3 heterozygotes (RR 15) and all other DR combinations (RR 7), suggesting a compound effect of 2 immune responses. Heterozygotes for HLA-DQwl/ DQw2 demonstrated significantly higher mean levels of anti-Ro, which may be indicative of trans gene interaction at HLA-DQ. These data suggest the hypothesis that HLA genes exert their major effects on Ro/La autoantibody subsets of systemic lupus erythematosus.Genetic predisposition to systemic lupus erythematosus (SLE) has been associated with several alleles of the major histocompatibility complex (MHC). Those most consistently reported include HLA-B8, DR2, DR3, and DQwl, as well as null alleles of the HLA-linked second and fourth components of complement (1-8). When autoantibody subsets of SLE are considered, certain HLA antigen correlations become stronger. Most notably, in patients with SLE and in patients with other autoimmune diseases expressing anti-Ro and anti-La, HLA-DR3 andlor DR2 are found in the majority (4,5,9-13). Thus, MHC control of these immune responses, either qualitatively or quantitatively, has been suggested. Recently, enzyme-linked immunosorbent assays (ELISA) have been developed to measure anti-Ro, anti-La, and the anti-Sdnuclear RNP (anti-SmhRNP) complex (14)(15)(16)(17)(18)(19)(20). By virtue of being more sensitive and quantitative, these assays may provide greater insight into the role

show abstract

Section: Discussionmentioning

confidence: 99%

Two ro (ss‐a) autoantibody responses in systemic lupus erythematosus

Hamilton

Harley

Bias

et al. 1988

Arthritis & Rheumatism

176

View full text Add to dashboard Cite

show abstract

“…Each antigen consists of an a and a /3 chain. The allelic sequence diversity resides mainly in the second exon, which encodes the amino-terminal domain (1)(2)(3)(4). Eight allelic variants have been found at the HLA-DQa locus (also known as DQA1) (3,5,6), and these alleles have been classified into four major types, designated Al-A4.…”

mentioning

confidence: 99%

Ancient roots for polymorphism at the HLA-DQ alpha locus in primates.

Gyllensten¹,

Erlich²

1989

Proc. Natl. Acad. Sci. U.S.A.

135

View full text Add to dashboard Cite

The genes encoding the human histocompatibility antigens (HLA) exhibit a remarkable degree of polymorphism as revealed by immunologic and molecular analyses. This extensive sequence polymorphism either may have been generated during the lifetime of the human species or could have arisen before speciation and been maintained in the contemporary human population by selection or, possibly, by genetic drift. These two hypotheses were examined using the polymerase chain reaction method to amplify polymorphic sequences from the DQa locus, as well as the DXa locus, an homologous but nonexpressed locus, in a series of primates that diverged at known times. In general, the amino acid sequence of a specific human DQa allelic type is more closely related to its chimpanzee or gorilla counterpart than to other human DQa alleles. Phylogenetic analysis of the silent nucleotide position changes shows that the similarity of allelic types between species is due to common ancestry rather than convergent evolution. Thus, most of the polymorphism at the DQa locus in the human species was already present at least 5 million years ago in the ancestral species that gave rise to the chimpanzee, gorilla, and human lineages. However, one of the DQa alleles may have arisen after speciation by recombination between two ancestral alleles.The human histocompatibility class II genes encode three cell-surface antigens, designated HLA-DR, HLA-DQ, and HLA-DP. Each antigen consists of an a and a /3 chain. The allelic sequence diversity resides mainly in the second exon, which encodes the amino-terminal domain (1-4). Eight allelic variants have been found at the HLA-DQa locus (also known as DQA1) (3,5,6), and these alleles have been classified into four major types, designated Al-A4. An homologous and nonexpressed locus denoted DXa (also known as DQA2) has also been found (7), and appears to be monomorphic (3). With polymerase chain reaction primers designed for the polymorphic second exon of the HLA-DQa locus (5, 8) we have amplified the homologous DNA segment from nine chimpanzees (Pan troglodytes), four gorillas (Gorilla gorilla), and two individuals each of baboon (Papio leucophaeus), rhesus (Macaca mulatta), langur (Presbytis entellus), capuchin monkey (Cebus capucinus), and marmoset (Callithrix spp.). These species are a set of primates whose divergence times from the human lineage, estimated from fossil data as well as from molecular comparisons, rise gradually from the -5 million years (Myr) ago for Pan and Gorilla to nearly 40 Myr ago for the New World species (Cebus and Callithrix) (9)(10)(11)(12)(13)(14)(15). This set of species allowed us to test hypotheses concerning the age of the polymorphism at the DQa locus, as well as to study the mechanism primarily responsible for generating variation at these loci. MATERIALS AND METHODSOne microgram of genomic DNA was subjected to 30 cycles of polymerase chain reaction (16)(17)(18) by using the primers and amplification conditions previously described for human DNA samples (5,8). By cont...

show abstract

“…1). They are of key importance in the immune system, since they restrict recognition of foreign antigen to T-helper lymphocytes sharing the appropriate Ta phenotypes.…”

mentioning

confidence: 99%

“…Thus, the detailed structure of several a and (8 chains from many haplotypes has been deduced from their respective genes, and the organization of the MHC class II gene family in mouse and man is almost entirely known. Expression ofthese genes by DNA-mediated transfer is yielding important information on the structure-function relationship of Ia a and (3 chains (1,11).…”

mentioning

confidence: 99%

Structure of the human Ia-associated invariant (gamma)-chain gene: identification of 5' sequences shared with major histocompatibility complex class II genes.

O’Sullivan¹,

Larhammar²,

Wilson³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The human gene encoding the Ia-associated y (or invariant) chain was isolated by screening a genomic library in phage X with cDNA probes. The frequency of positive clones in the library, the overlapping restriction maps of the cloned fragments, and the patterns of genomic hybridization suggested that the y-chain gene exists as a single copy per haploid genome. The gene consists of 8 exons, spanning approximately 12 kilobases of DNA. All exon sequences were in an open reading frame, contained appropriate splice junction sequences, and encompassed the entire sequence of full-length V-chain mRNA, suggesting that the gene we isolated is most likely functional. Furthermore, "CAAT"-type and "TATA"-type promoter sequences were found at the expected positions upstream from the proposed cap site. The organization of the V-chain gene has none of the distinctive features of the immunoglobulin superfamily of genes, of which la a and (3 chains are members. Therefore, the evolutionary origins, and perhaps the functions, of the la y chains are distinct from those of the other two Ia subunits a and (3. Despite the unrelatedness of these genes, consensus sequences found approximately 150 base pairs upstream from all the Ta a-and E8-chain genes sequenced to date were also found in analogous positions in the V-chain gene, suggesting a possible role in the coregulation of expression of these genes.Ia molecules are polymorphic cell surface glycoproteins expressed primarily by antigen-presenting cells and B lymphocytes (reviewed in ref. 1). They are of key importance in the immune system, since they restrict recognition of foreign antigen to T-helper lymphocytes sharing the appropriate Ta phenotypes. Ia molecules are formed by three noncovalently bound transmembrane glycoproteins, the highly polymorphic a and 8 chains, encoded by the major histocompatibility complex (MHC) class II genes, and the nonpolymorphic y (or invariant) chain (reviewed in ref. 2). At the cell surface, they comprise only a-(3 dimers, as y chains dissociate from Ia oligomers during Golgi processing (3,4). The expression of a, ,3, and y chains is strictly coregulated during development, most likely at the level of gene transcription (5, 6), as indicated by their virtually identical tissue distribution (7,8) and their parallel induction by y-interferon (5). An understanding of the regulatory mechanisms of Ta expression is of great interest, since expression of Ia molecules by immune cells is a key requirement for recognition of foreign antigens by T lymphocytes (9), and since Ia expression by nonimmune cells has been involved in the pathogenesis of autoimmune diseases (10). The cloning of a-and (-chain genes (reviewed in ref. 11) has provided necessary tools for studying the molecular basis for Ia function and expression. Thus, the detailed structure of several a and (8 chains from many haplotypes has been deduced from their respective genes, and the organization of the MHC class II gene family in mouse and man is almost entirely known. Expression ofthese ...

show abstract

Structure, Function, and Genetics of Human Class II Molecules

Cited by 105 publications

References 163 publications

Two ro (ss‐a) autoantibody responses in systemic lupus erythematosus

Two ro (ss‐a) autoantibody responses in systemic lupus erythematosus

Ancient roots for polymorphism at the HLA-DQ alpha locus in primates.

Structure of the human Ia-associated invariant (gamma)-chain gene: identification of 5' sequences shared with major histocompatibility complex class II genes.

Contact Info

Product

Resources

About