Complement Receptor 1 Gene Research Articles

Association of leukocyte CR1 gene transcription with the disease severity and renal involvement in systemic lupus erythematosus

The reduced level of complement receptor 1 (CR1) on erythrocytes is speculated as a key mechanism contributing to immune complex (IC) overload and exaggerated complement (C) activation in systemic lupus erythematosus (SLE). Comparatively, fewer studies documented lower levels of CR1 on leukocytes and glomerular podocytes in this disease. The decline in E-CR1 is largely believed as an acquired phenomenon caused due to the proteolytic cleavage of CR1 from erythrocyte membrane. The mechanism underlying reduced CR1 expression on nucleated cells is under constant investigation. Recently, reduced leukocytes CR1 gene transcription had been demonstrated in SLE and was suggested as the main cause of decline in leukocyte CR1 (L-CR1). The relationship of L-CR1 gene transcription with severity and pathophysiology of disease needs to be elucidated. We determined the levels of L-CR1 in 30 active SLE patients and compared with normal healthy controls (n = 30). Patients were categorized into two groups i.e., with nephritis (n = 14) or without nephritis (n = 16). The expression of L-CR1 at transcriptional level was correlated with the levels of serum CIC, C3 and anti dsDNA antibodies. The levels of L-CR1 transcription were significantly reduced in all SLE patients as compared to controls (P < 0.001). This decline in L-CR1 however, was more marked in patients with nephritis than those without nephritis. In addition, the serum levels of CIC, anti dsDNA antibodies were higher and the levels of serum C3 were lower than the normal range in the patients. The difference was much more marked in SLE patients with nephritis than those without nephritis. The levels of L-CR1 transcription correlated negatively with the levels of CIC and anti dsDNA antibodies and positively with serum C3 levels. Thus, between SLE patients with and without nephritis, we found significant difference in the levels of L-CR1 transcription (P < 0.01), CIC (P < 0.05), anti dsDNA antibodies (P < 0.01) and C3 (P < 0.01). Our findings suggest that L-CR1 is drastically reduced in patients with severe form of SLE, i.e., lupus nephritis. Determination of L-CR1 expression at transcriptional level in addition to disease hallmarks like C3, CIC and anti-dsDNA antibodies may facilitate the assessment of severity of SLE and discrimination between patients with or without renal involvement.

A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria.

Parasitized red blood cells (RBCs) from children suffering from severe malaria often adhere to complement receptor 1 (CR1) on uninfected RBCs to form clumps of cells known as "rosettes." Despite a well documented association between rosetting and severe malaria, it is controversial whether rosetting is a cause or a correlate of parasite virulence. CR1-deficient RBC show greatly reduced rosetting; therefore, we hypothesized that, if rosetting is a direct cause of malaria pathology, CR1-deficient individuals should be protected against severe disease. In this study, we show that RBC CR1 deficiency occurs in up to 80% of healthy individuals from the malaria-endemic regions of Papua New Guinea. This RBC CR1 deficiency is associated with polymorphisms in the CR1 gene and, unexpectedly, with alpha-thalassemia, a common genetic disorder in Melanesian populations. Analysis of a case-control study demonstrated that the CR1 polymorphisms and alpha-thalassemia independently confer protection against severe malaria. We have therefore identified CR1 as a new malaria resistance gene and provided compelling evidence that rosetting is an important parasite virulence phenotype that should be a target for drug and vaccine development.

Complement receptor 1 gene polymorphisms in sarcoidosis.

Sarcoidosis is likely to result from exposure of genetically susceptible hosts to environmental agents. Erythrocyte (E) complement receptor 1 (CR1) is a membrane protein mediating the transport of immune complexes (ICs) to phagocytes, and at least three polymorphisms on the CR1 gene are related to erythrocyte surface density of CR1 molecules, in turn related to the rate of IC clearance from circulation. We hypothesized that sarcoidosis could be associated with increased frequency of the CR1 gene alleles coding for reduced CR1/E ratio. We studied 91 sarcoid patients and two control groups: 94 healthy volunteers and 71 patients with chronic obstructive pulmonary disease (COPD). Three polymorphic sites of CR1 gene, His1208Arg, intron 27 HindIII/RFLP, and Pro1827Arg, were analyzed. The three polymorphisms were in linkage disequilibrium. The GG genotype for the Pro1827Arg (C(5507)G) polymorphism was significantly associated with sarcoidosis in comparison to both control groups (odds ratio [OR] = 3.13; 95% confidence interval [CI] 1.49-6.69 versus healthy control subjects, and OR= 2.82, 95% CI 1.27-6.39 versus COPD control subjects). The same genotype was particularly associated to disease in females (OR = 7.05; 95% CI 3.10-16.61 versus healthy control subjects). These findings agree with speculations on the role of CR1 gene as a possible susceptibility factor.

Serum Regulates the Expression of Complement Receptor 2 on Human B Cell Lines

Complement receptor 2 (CR2) participates in the regulation of B cell responses to antigen. In this study we report that treatment of IM-9 B lymphoblastoid cells or Raji Burkitt's lymphoma cells with 10% heat-inactivated fetal bovine serum for 24 hr increased both the CR2 mRNA level and CR2 surface protein expression more than twofold. No change in the CR2 expression level was observed if cells were cultured in serum-free medium. The CD 19 mRNA level decreased after 24 hr independently of the presence of serum. The serum-stimulated increase in CR2 expression was not due to changes in the proliferative capacity of the cells and could not be mimicked by various cytokines. However, IFN-γ as well as OKB7, a CR2-specific monoclonal antibody, blocked the serum-induced increase in CR2 expression at the mRNA level. Our data show for the first time that factors in serum induce the expression of the CR2 gene and that signals initiated by IFN-γ and OKB7 interfere with the serum-induced changes. Because stimuli that alter CR2 expression can influence the extent of the B cell response to antigen-C3d complexes, serum factors may play a role in regulating the responsiveness of B cells.

Heterogeneous nuclear ribonucleoprotein D0B is a sequence-specificDNA-binding protein

Complement receptor 2 (CR2) is important in the regulation of the B lymphocyte response; the regulation of its expression is therefore of central importance. We recently reported that a 42 kDa heterogeneous nuclear ribonucleoprotein (hnRNP) is involved in the transcriptional regulation of the human CR2 gene [Tolnay, Lambris and Tsokos (1997) J. Immunol. 159, 5492-5501]. We cloned the cDNA encoding this protein and found it to be identical with hnRNP D0B, a sequence-specific RNA-binding protein. By using a set of mutated oligonucleotides, we demonstrated that the recombinant hnRNP D0B displays sequence specificity for double-stranded oligonucleotide defined by the CR2 promoter. We conducted electrophoretic mobility-shift assays to estimate the apparent Kd of hnRNP D0B for the double-stranded DNA motif and found it to be 59 nM. Interestingly, hnRNP D0B displayed affinities of 28 and 18 nM for the sense and anti-sense strands of the CR2 promoter-defined oligonucleotide respectively. The significantly greater binding affinity of hnRNP D0B for single-stranded DNA than for double-stranded DNA suggests that the protein might melt the double helix. The intranuclear concentration of sequence-specific protein was estimated to be 250-400 nM, indicating that the protein binds to the CR2 promoter in vivo. Co-precipitation of a complex formed in vivo between hnRNP D0B and the TATA-binding protein demonstrates that hnRNP D0B interacts with the basal transcription apparatus. Our results suggest a new physiological role for hnRNP D0B that involves binding to double- and single-stranded DNA sequences in a specific manner and functioning as a transcription factor.

Variability of CR2 gene products is due to alternative exon usage and different CR2 alleles.

The gene encoding human complement receptor 2 (CR2) lies within a cluster of genes on human chromosome 1. Polymorphisms have been described for several of these genes or gene products. To examine any possible polymorphisms in the CR2 gene product we have analyzed the CR2 transcriptional products for variations via alternative exon usage and for the presence of different CR2 alleles within the human population. This analysis has suggested that an exon encoding a 60 amino acid short consensus repeat can be alternatively spliced. Evidence for two transcriptional products has been found in a variety of transformed human B cells and two human tonsils. Interestingly the ratio of the two forms of mRNA, that which includes the alternative exon and that which does not, is not constant when examining the RNA from these sources. In addition to the variation introduced by the alternatively spliced product, there appears to exist in the human population at least three different alleles for CR2. These alleles have been defined by multiple nucleotide changes which are not silent but which alter the amino acid encoded at that site. However, we have not identified allelic variants of CR2 which would produce a product varying in the number of long homologous repeats, as has been identified for the various alleles of the closely related protein, human complement receptor 1.