The Complement Components Coded in the Major Histocompatibility Complexes and their Biological Activities

Porter, Roy

doi:10.1111/j.1600-065x.1985.tb01142.x

Cited by 37 publications

(14 citation statements)

References 32 publications

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“…Class I11 gene products are involved in the clearance of immune complexes and the activation of inflammation-mediating molecules (14). Traditionally, factor B and the second and fourth complement components (BF, C2, and C4A and C4B) have been detected by protein electrophoresis (15)(16)(17).…”

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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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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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“…Human C4 is coded by tandem genes located in the HLA class III region [3]. Both genes are highly polymorphic.…”

Section: Introductionmentioning

confidence: 99%

Structural Basis of the Binding Specificity of the Thioester-Containing Proteins, C4, C3 and Alpha-2-Macroglobulin

Aw¹,

Sk²

1988

Complement

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We have previously noted a large difference in the specificity of the covalent binding reaction of human C4-A and C4-B. Here we report data on three other thioester- containing proteins. Human C3 is unreactive with glycine but its reactivity with glycerol (kˊko = 23.0 M–1) is similar to that of human C4-B (kˊko = 15.5 M–1). Human a2-macro- globulin reacts with glycine (kˊko = 206 M–1) in a manner similar to C4-B (kˊko = 119 M–1 ) but its reactivity with glycerol (kˊ/ko = 1.2 M–1) is C4-A like (kˊ/ko = 1.3 M–1). Mouse C4 is C4-B like in its reaction with both glycine (kˊko = 136 M–1) and glycerol (k'/ko = 26.0 M–1). Of these proteins, only C4-A shows a very high rate of reaction with glycine (kˊko = 13,400 M–1). The comparison of the primary structures of these proteins has allowed us to propose the Leu Asp:lie His substitutions at positions 1105 and 1106 in the human pro-C4 molecule as the residues largely responsible for the binding specificities of these proteins. The Leurlle change would not markedly affect the reactivity of these proteins, but may be necessary for allosteric reasons. The Asp in C4-A and His in C4-B seem likely to be the major specificity-defining residues.

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“…A number of complement factor polymorphisms were investigated in the 1970s and 1980s in small groups of patients using older techniques (e.g., migration of DNA fragments on electrophoretic gels) to identify genetic variants (4,15,69,83,114,252,294). C2, C4, and CFB are located on chromosome 6 in close linkage to HLA-B loci (229). Those early studies did not adequately address the possible effects of linkage disequilibrium with nearby MHC loci, and future studies of this region will need to address the potential confounding impact of LD with MHC variants.…”

Section: Other Candidate Gene Studiesmentioning

confidence: 99%

Leprosy and the Human Genome

Misch¹,

Berrington²,

Vary

et al. 2010

Microbiol Mol Biol Rev

116

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SUMMARY Despite the availability of effective treatment for several decades, leprosy remains an important medical problem in many regions of the world. Infection with Mycobacterium leprae can produce paucibacillary disease, characterized by well-formed granulomas and a Th1 T-cell response, or multibacillary disease, characterized by poorly organized cellular infiltrates and Th2 cytokines. These diametric immune responses confer states of relative resistance or susceptibility to leprosy, respectively, and have well-defined clinical manifestations. As a result, leprosy provides a unique opportunity to dissect the genetic basis of human in vivo immunity. A series of studies over the past 40 years suggests that host genes influence the risk of leprosy acquisition and the predilection for different clinical forms of the disease. However, a comprehensive, cellular, and molecular view of the genes and variants involved is still being assembled. In this article, we review several decades of human genetic studies of leprosy, including a number of recent investigations. We emphasize genetic analyses that are validated by the replication of the same phenotype in independent studies or supported by functional experiments demonstrating biological mechanisms of action for specific polymorphisms. Identifying and functionally exploring the genetic and immunological factors that underlie human susceptibility to leprosy have yielded important insights into M. leprae pathogenesis and are likely to advance our understanding of the immune response to other pathogenic mycobacteria. This knowledge may inform new treatment or vaccine strategies for leprosy or tuberculosis.

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The Complement Components Coded in the Major Histocompatibility Complexes and their Biological Activities

Cited by 37 publications

References 32 publications

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus

Structural Basis of the Binding Specificity of the Thioester-Containing Proteins, C4, C3 and Alpha-2-Macroglobulin

Leprosy and the Human Genome

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