A hypothetical model of the foreign antigen binding site of Class II histocompatibility molecules

Brown, Jerry H.; Jardetzky, Theodore S.; Saper, Mark A.; Samraoui, B.; Björkman, Pamela J.; Wiley, Don C.

doi:10.1038/332845a0

Cited by 1,122 publications

(575 citation statements)

References 62 publications

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“…DR2,DQPl.AZH and DRw6,DQP1.9 are both quite rare in the normal Caucasian population (normal haplotype frequency -1% and -4%, respectively [ 12, and have been found to be associated with other autoimmune disorders: I .AZH with insulindependent diabetes mellitus (20,26) and 1.9 with pemphigus vulgaris (27,28). Residues 28 and 30 are at the bottom of the antigen-binding cleft, pointing upwards into the site, according to the hypothesized 3-dimensional model of the class I1 molecule (55); this implicates involvement of the first HVR in antigen interaction. Polymorphic residues 70 and 71 point upwards and, presumably, interact with a specific T cell receptor.…”

Section: Discussionmentioning

confidence: 99%

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus

Fronek

Timmerman

Alper

et al. 1990

Arthritis & Rheumatism

114

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Susceptibility to systemic lupus erythematosus is associated with major histocompatibility complex (MHC)-encoded genes. We have used nucleotide sequence analysis to better define the disease-associated MHC alleles. HLA-DR2, DQwl, and especially the rare allele DQPl.AZH confer high relative risk (RR = 14) for lupus nephritis in a Caucasian population of patients. Pilot studies using historical controls suggest that these genes also confer a high risk in non-Caucasian ethnic groups (RR = 24-78). We have found that DR4 is significantly decreased in patients with lupus nephritis. Fifty percent of the patients with lupus nephritis had either the DQP1.1, the DQPl.AZH, or the DQP1.9 alleles. These alleles share amino acid residues that have been predicted to be the contact points for antigen and the T cell receptor. These HLA alleles appear to have a direct role in the predisposition to lupus nephritis, whereas DR4 may have a "protective" effect.Systemic lupus erythematosus (SLE) is a complex autoimmune disorder that involves the skin, joints, serosal surface, kidneys, central nervous system, and blood elements. It is characterized by abnormalities in B cell activation, with resultant autoantibody production, and by dysregulation of T cells, the complement cascade, and the clearing of immune complexes. Genetic factors in SLE have been implicated by results of studies of family aggregation of the disease ( l ) , increased concordance of SLE among monozygotic versus dizygotic twins (2), Gm markers (3), decreased red cell CRl receptors (4), abnormal T cell suppressor function in healthy relatives of SLE patients (3, and associations with several major histocompatibility complex (MHC) loci (summarized in refs. 6 and 7).Population studies have shown an increased association between SLE and class I1 MHC DR2 and/or DR3 antigen alleles, as well as an association with class 111 MHC C2 and C4A deficiencies (8,9). The strengths of these associations vary from study to study, and they can vary in ethnically different populations (7-10). The relative risk (RR) of SLE in a person positive for any 1 of these markers has been reported to be 3 or less. However, the RR is significantly increased if multiple alleles are present, such as homozygosity of C4A null (RR = 16) or C4A null and DR2 (RR = 25) (9), which supports the notion that susceptibility to this disease may be polygenic. The class 11 loci of the human major histocompatibility complex encode the HLA-D cell-surface

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Section: Discussionmentioning

confidence: 99%

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus

Fronek

Timmerman

Alper

et al. 1990

Arthritis & Rheumatism

114

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“…The validity of such modelling was previously established for HLA-DR, prior to crystallization. Investigators used molecular modelling to predict the class II HLA-DR structure based on crystal coordinates of the class I HLA-A molecules [37,38]. When the HLA-DR1 molecule was later crystallized and compared with the computer models, which were based on two different HLA-A alleles, the hypothetical models were correct for the overall tertiary structure with the exception of the region composed of a37 to a43 [17,38].…”

Section: Hla-dq Pocket Change and Iddm Resistance 199mentioning

confidence: 99%

Molecular Modelling of HLA‐DQ Suggests a Mechanism of Resistance in Type 1 Diabetes

Hoover

Marta

1997

Scand J Immunol

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Genetic resistance and susceptibility to insulin-dependent diabetes mellitus (IDDM) have been associated with the HLA class II region on chromosome 6. In many races, the DQB1*0602 allele has been observed at a decreased frequency in IDDM, suggesting a protective role. A DNA sequence analysis of five patients, previously typed as having allele DQB1*0602, revealed sequence variation: one is DQB1*0603 and four possess unique sequences related to DQB1*0602 (one patient) or DQB1*0603 (three patients). Samples from four unaffected controls possessed normal DQB1*0602 sequences, and all patients and controls have normal DQA1 sequences. Each of the four unique patient sequences yields predicted amino acid sequences differing from the more common DQB1 alleles by variation at codons 9, 38 (silent), 59, and/or 62. Molecular modelling of the predicted protein sequence of these permissive variants reveals an HLA-DQ structure from diabetic patients that differs in the surface contour of the peptide-binding groove from normal DQB1*0602 sequence. In all the models of permissive molecules, the surface area corresponding to the HLA-DR pockets 6, 7 and 9 are modified. These pockets accommodate side chains of the bound peptide; thus modification of this region could alter peptide specificity. This 'pocket change' suggests that the normal allele could confer dominant protection against the development of IDDM by affecting peptide and/or T cell receptor (TCR) binding. This could regulate the deletion or suppression of T cell clones inappropriately recognizing the beta cells of the pancreas.

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“…Modeling of the HLA-DR molecule predicts that a discrete antigen-binding groove is surrounded on both sides by an a-helical loop (49). In this model the shared epitope in rheumatoid arthritis forms one of the a-helical loops.…”

Section: Immunogenetic Cluesmentioning

confidence: 99%

Pathogenesis of giant cell arteritis

Hunder

Lie

Goronzy

et al. 1993

Arthritis & Rheumatism

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The actinic hypothesis generates more heat than lightIn a recent Current Comment published in Arthritis and Rheumatism (l), O'Brien and Regan review their concept of the pathogenesis of giant cell arteritis (GCA) and emphasize their commitment to the ''actinic hypothesis." This hypothesis proposes that the primary causative lesion in GCA is an alteration or degeneration of the elastic lamina of the temporal artery caused by solar radiation. O'Brien and Regan believe the degenerated elastin then triggers the development of the arteritis, and cannot understand why others do not share their enthusiasm for this idea.For many years elastic tissues of the aorta and its proximal branches have been thought to be somehow involved in the development of GCA (2). Various investigators have noted that the inflammatory reactions in positive biopsy specimens often appear more intense around the internal elastic lamina of the temporal artery (2-4). Multinucleated giant cells, which are characteristic of the disease, are often in direct

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A hypothetical model of the foreign antigen binding site of Class II histocompatibility molecules

Cited by 1,122 publications

References 62 publications

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus

Molecular Modelling of HLA‐DQ Suggests a Mechanism of Resistance in Type 1 Diabetes

Pathogenesis of giant cell arteritis

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