Association between interleukin-18 polymorphisms and systemic lupus erythematosus: a meta-analysis

The aim of this study was to determine whether the three functional interleukin-18 (IL-18) promoter ?607 C/A (rs1946518), ?137 G/C (rs187238), and ?1297 C/T (rs360719) polymorphisms confer susceptibility to systemic lupus erythematosus (SLE) in ethnically different populations. Meta-analysis was conducted on the associations between these IL-18 polymorphisms and SLE using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 11 comparisons (nine studies) involving 8,453 subjects (2,928 SLE patients and 5,525 controls) were included in the meta-analysis. In all study subjects, meta-analysis showed no association between SLE and the IL-18 ?607 C allele (odds ratio [OR] = 1.065, 95 % confidence interval [CI] = 0.870–1.303, p = 0.541). However, stratification by ethnicity indicated a significant association between this allele and SLE in Europeans (OR = 0.864, 95 % CI = 0.757–0.986, p = 0.031), but not in Asians (OR = 1.230, 95 % CI = 0.902–1.676, p = 0.190). Meta-analyses showed the same pattern for the IL-18 ?607 C allele using the dominant and additive models. Meta-analysis of the IL-18 ?137 G/C polymorphism showed no association between SLE and the IL-18 ?137 G allele in all study subjects (OR = 0.916, 95 % CI = 0.836–1.003, p = 0.057), but stratification by ethnicity indicated a significant association between this allele and SLE in Asians (OR = 0.792, 95 % CI = 0.629–0.997, p = 0.047), but not in Europeans (OR = 0.930, 95 % CI = 0.839–1.032, p = 0.171). Furthermore, meta-analysis showed that the IL-18 ?1297 C allele was significantly associated with SLE in all study subjects and in Europeans (OR = 1.240, 95 % CI = 1.052–1.482, p = 0.010 and OR = 1.303, 95 % CI = 1.050–1.617, p = 0.016). This meta-analysis shows that the IL-18 ?607 C/A and ?1297 C/T polymorphism are associated with the development of SLE in Europeans, and the IL-18 ?137 G/C polymorphism is associated with SLE in Asians.     

Interleukin-6, interleukin-1 gene cluster and interleukin-1 receptor polymorphisms in Iranian patients with juvenile systemic lupus erythematosus

Background

Juvenile systemic lupus erythematosus (JSLE) is a polygenic, autoimmune disorder of unknown origin. As proinflammatory cytokines, including interleukin-6 (IL-6) and the interleukin-1 (IL-1) family, seem to contribute to the pathogenesis of JSLE, this investigation was performed to assess the associations of particular single nucleotide polymorphisms (SNPs) of IL-6 and IL-1 genes in a case-control study.

Methods

Fifty nine JSLE cases were recruited for this study as the patient group, and were compared against 140 healthy, unrelated, control subjects. Using the polymerase chain reaction with the sequence-specific primer method, genotyping was carried out for the IL-6 gene at positions ?174 and nt565, as well as the IL-1α gene at position ?889, the IL-1β gene at positions ?511 and +3962, the interleukin-1 receptor (IL-1R) gene at position Pst-I 1970, and the interleukin-1 receptor antagonist (IL-1Ra) gene at position Mspa-I 11100.

Results

Results of the analyzed data revealed a remarkable, positive association for the promoter sequence of the IL-1β gene at position ?511 for T/T in the patient group compared with healthy controls (P value, 0.03). Furthermore, a significant negative association was found between the T/C genotype at the same position on the IL-1β gene in juvenile SLE (P value, 0.03).

Conclusions

cytokine gene polymorphisms might play a role in the pathophysiology of JSLE. Particular IL-1 gene variants could affect individual susceptibility to JSLE.

     

Polymorphisms of interleukin-1 and interleukin-6 genes on the risk of ischemic stroke in a meta-analysis

Many epidemiological studies have investigated the associations between polymorphisms of interleukin-1 (IL1) and interleukin-6 (IL6) genes and risk of ischemic stroke (IS), but no conclusions are available because of conflicting results. The aim of this study was to assess the relationships by meta-analysis. The databases of Pubmed, Embase and Wangfang, updated to August 1st, 2011, were retrieved. Odds ratio (OR) and corresponding 95% confidence interval (95% CI) as effect size were calculated by a fixed- or random-effect model. In total, three case-control studies for IL1α-889C/T, eight studies for IL1β-511C/T, eight studies for IL1-Ra and seven studies for IL6-147G/C were included in this meta-analysis. Combined analysis indicated that IL1β-511C/T polymorphism was not overall associated with risk of IS [OR (95% CI)=1.22 (0.85-1.87) for TT vs. CC]. However, when subgroup analyses for countries were conducted, the results indicated that T allele was associated with increased risk of IS for Polish and associated with a trend of increased risk of IS for Chinese although it did not reach statistical significance [TT vs. CC: OR (95% CI)=1.97 (1.22-3.17) for Polish and 1.40 (0.99-1.99) for Chinese]. In addition, overall and subgroup analyses indicated that IL1α-889C/T, IL1-Ra and IL6-147G/C polymorphisms were also not associated with risk of IS [OR (95% CI)=1.21 (0.86-1.70) for TT vs. CC of IL1α-889C/T, 1.22 (0.85-1.75) for RN2/RN2 vs. RN1/RN1 for IL1-Ra and 1.09 (0.84-1.40) for G carriers vs. C carriers for IL6-147G/C]. This study inferred that IL1β-511C/T polymorphism might be moderately associated with increased risk of IS, but no sufficient evidence was available to support any associations between IL1-Ra and IL6-147G/C polymorphisms and IS. We could not draw a conclusion between IL1α-889C/T polymorphism and risk of IS based on the limited data, and further large sample-sized studies were required.     

Associations between vitamin D receptor polymorphisms and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis

The aim of this study was to determine whether the vitamin D receptor (VDR) polymorphisms confer susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematous (SLE). A meta-analysis was conducted on the associations between the BsmI, TaqI, FokI, and ApaI polymorphisms of VDR and RA or SLE using: (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) additive model. A total of ten studies, six RA and four SLE studies, were considered in the meta-analysis. Meta-analysis of the VDR BsmI and TaqI polymorphisms showed no association between RA in all subjects, or in European or Asian subjects. In contrast, meta-analysis of the F allele, the FF genotype, and the FF vs. the ff genotype of the FokI polymorphism showed significant associations with RA in Europeans. The overall OR of the association between the F allele and RA was 1.502 (95% CI = 1.158–1.949, P = 0.002). Meta-analysis of the B allele, BB + Bb genotype, and BB genotype (additive model) of the BsmI polymorphism showed significant associations with SLE and LN in Asians. The overall ORs of the associations between the B allele and SLE and LN were 3.584 (95% CI = 1.407–9.130, P = 0.007) and 3.652 (95% CI = 1.347–9.902, P = 0.011). This meta-analysis demonstrates that the VDR FokI polymorphism may confer susceptibility to RA in Europeans. Furthermore, associations were found between the VDR BsmI polymorphism and susceptibilities to SLE and LN in Asians.     

CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis

The aim of this study was to summarize results on the association of cytotoxic T-lymphocyte antigen-4 (CTLA-4) promoter exon-1 +49 and 1722T/C polymorphism with systemic lupus erythematosus (SLE) susceptibility by using the meta-analysis. We searched all the publications about the association between CTLA-4) promoter exon-1 +49 and 1722T/C polymorphism and SLE from PubMed, Elsevier Science Direct, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), and Wanfang (Chinese). Previous CTLA-4 association studies with SLE, however, have produced inconsistent results. We have performed a meta-analysis to better assess the purported associations. A total of 17 independent studies (to June 2012) testing association between one or more CTLA-4 polymorphisms and SLE were used in this analysis. We have compared allele and genotype frequencies at two polymorphic sites found in exon-1 (at +49) and the promoter region (at ?1722). The data demonstrate that the exon-1 +49 polymorphism is associated with SLE susceptibility in Asian population. The overall risk, measured by odds ratio (OR), stratification by ethnicity indicates the exon-1 +49 GG+GA genotype is associated with SLE, at least in Asians (OR = 0.85, 95 % CI = 0.73–0.99, P = 0.04 for GG+GA vs. AA; OR = 0.85, 95 % CI = 0.72–1.00, P = 0.05 for AG vs. AA). Similar trends are found in allele-specific risk estimates and disease association. Overall, there was significant association between the 1722T/C polymorphism and overall SLE risks (OR = 0.78, 95 % CI = 0.63–0.97, P = 0.04 for GG+GA vs. AA, OR = 0.87, 95 % CI = 0.76–0.99, P = 0.04 for G vs. A) in Asian population.In summary, this meta-analysis demonstrates that the CTLA-4 promoter +49A/G and promoter ?1722C/T polymorphism may confer susceptibility to SLE, especially in Asian-derived population.     

CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis

Several reports demonstrate association between variants of the cytotoxic T lymphocyte antigen-4 (CTLA-4) and autoimmune diseases. CTLA-4 may generate autoimmunity by immune dysregulation, making CTLA-4 an attractive candidate gene for systemic lupus erythematosus (SLE) susceptibility. Previous CTLA-4 association studies with SLE, however, have produced inconsistent results. We have performed a meta-analysis to better assess the purported associations. A total of 14 independent studies (to July 2004) testing association between one or more CTLA-4 polymorphisms and SLE were used in this analysis. We have compared allele and genotype frequencies at four polymorphic sites found in exon-1 (at +49), the promoter region (at –318 and –1722), and the 3 untranslated region (3UTR) (dinucleotide repeat). We have evaluated both fixed and random effect models, depending on the presence of between-study heterogeneity. The data demonstrate that the exon-1 +49 polymorphism is significantly associated with SLE susceptibility. The overall risk, measured by odds ratio (OR), for exon-1 +49 GG genotype is 1.287 [95% confidence interval (CI)=1.031–1.562, P=0.011]. Stratification by ethnicity indicates the exon–1 +49 GG genotype is associated with SLE, at least in Asians (OR=1.293, 95% CI=1.031–1.620, P=0.026). European-derived populations have an effect of similar magnitude (OR=1.268, 95% CI=0.860–1.870, P=0.230), though not significant. Similar trends are found in allele-specific risk estimates and disease association. The OR for the exon-1 +49 risk allele (G) in Asians is 1.246 (95% CI=1.057–1.469, P=0.009), while Europeans have no evidence of allelic association (OR=0.978, 95% CI=0.833–1.148, P=0.780). In conclusion, this meta-analysis supports the CTLA-4 exon-1 +49 (A/G) polymorphism influencing the risk for developing SLE, especially in Asians.     

Association of RANTES and MBL gene polymorphisms with systemic lupus erythematosus: a meta-analysis

The RANTES (regulated on activation normal T cell expressed and secreted) and MBL (mannose binding lectin) single-nucleotide polymorphisms have been repeatedly associated with systemic lupus erythematosus (SLE), but the findings are not consistent across studies. The aim of this study was to determine whether the functional RANTES-28, -403 and MBL2 A/O polymorphisms confer susceptibility to SLE in multiple ethnic populations. A meta-analysis was conducted (allelic contrast, the additive model, the dominant model and the recessive model) on RANTES with seven studies (four studies for RANTES-28: three Asian and one American studies; three studies for RANTES-403: two Asian and one European studies), MBL with eight studies (five European and three American studies). OR is used as a measure of the effect of the association in a fixed/random effects model. The meta-analysis indicated that none of the two polymorphisms in gene of the RANTES showed any significant association with SLE risk, respectively, except for the recessive model (OR = 1.24, 95 % CI: 1.01–1.52, P = 0.04) in all study subjects combined with the two polymorphisms. According to the MBL2 A/O polymorphism, the results indicated a significant association between the polymorphism and SLE in allelic contrast (OR = 0.83, 95 % CI: 0.73–0.93, P = 0.002). While stratified by ethnicity in European, no significant association was found. In summary, the present study suggests that the RANTES-28, -403 polymorphisms do not associate with SLE, but the MBL2 A/O polymorphism might associate with SLE.     

TLR9 polymorphisms and systemic lupus erythematosus risk in Asians: a meta-analysis study

The results from previous studies on association of TLR9 polymorphisms with the risk of systemic lupus erythematosus (SLE) remained contradictory. Therefore, a meta-analysis was performed to assess the association between TLR9 polymorphisms and SLE susceptibility. A literature-based search was conducted to identify all relevant studies. Pooled data were estimated by fixed- and random-effects models when appropriate. We examined seven publications, showing that there were only three polymorphisms (-1486C/T, +1174A/G and +1635C/T) existing in Asian populations. The meta-analysis indicated that none of these three polymorphisms showed any significant association with SLE risk in Asian populations. In conclusion, the present study indicates that TLR9 polymorphisms are not candidates for susceptibility to SLE, at least, in eastern Asian population. Furthermore, a large number of studies should be performed to explore the association of TLR9 polymorphisms with the risk of SLE in other populations, such as Europeans, Americans and Africans.     

Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility

Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P _meta = 6.6×10⁻⁸, OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P _meta = 2.9×10⁻⁷, OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ∼146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (P _meta = 3.2×10⁻⁷, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (P _meta = 3.5×10⁻⁴, OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.     

Clinical associations of serum interleukin-17 in systemic lupus erythematosus

Introduction

Serum interleukin (IL)-17 concentrations have been reported to be increased in systemic lupus erythematosus (SLE), but associations with clinical characteristics are not well understood. We characterized clinical associations of serum IL-17 in SLE.

Methods

We quantified IL-17 in serum samples from 98 SLE patients studied cross-sectionally, and in 246 samples from 75 of these patients followed longitudinally over two years. Disease activity was recorded using the SLE Disease Activity Index (SLEDAI)-2k. Serum IL-6, migration inhibitory factor (MIF), and B cell activating factor of the tumour necrosis factor family (BAFF) were also measured in these samples.

Results

Serum IL-17 levels were significantly higher in SLE patients compared to healthy donors (P <0.0001). No correlation was observed between serum IL-17 and SLEDAI-2k, at baseline or during longitudinal follow-up. However, we observed that SLEDAI-2k was positively correlated with IL-17/IL-6 ratio. Serum IL-17 was significantly increased in SLE patients with central nervous system (CNS) disease (P = 0.0298). A strong correlation was observed between serum IL-17 and IL-6 (r = 0.62, P <0.0001), and this relationship was observed regardless of disease activity and persisted when integrating cytokine levels over the period observed (r = 0.66, P <0.0001). A strong correlation of serum IL-17 was also observed with serum BAFF (r = 0.64, P <0.0001), and MIF (r = 0.36, P = 0.0016).

Conclusions

Serum IL-17 concentration correlates poorly with SLE disease activity but is significantly elevated in patients with CNS disease. IL-17/IL-6 ratio may be more useful than IL-17 or IL-6 alone to characterize Th17-driven disease, such as SLE. The association of other cytokines with serum IL-17 suggests that IL-17 may drive activation of diverse immune pathways in SLE.     

Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms (SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes—the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes—we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P<10^-7) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.     

Association of the − 1082G/A polymorphism in the interleukin-10 gene with systemic lupus erythematosus: A meta-analysis

A great many studies have investigated the − 1082G/A polymorphism (rs1800896) in the interleukin-10 gene (IL10) with SLE susceptibility, but the results are inconsistent and inconclusive. The aim of this meta-analysis was in order to more precisely estimate the relationship. The databases of Pubmed and Web of Science updated to Oct, 2012 were retrieved. Odds ratio (OR) and corresponding 95% confidence interval (95%CI.) as effect size were calculated by fixed-effect model. Analysis for allele contrast of stratification by ethnicity in either Asian or Caucasian, as well as in overall population indicated no significant association (Overall: OR 1.096, 95%CI. 0.995–1.207; Asian: OR 1.204, 95%CI.: 0.944–1.535; Caucasian: OR 1.075, 95%CI.: 0.961–1.202). Analysis for recessive model showed no association in overall populations and in Caucasian (Overall: OR 1.135, 95%CI.: 0.945–1.362; Caucasian: OR 1.069, 95%CI.: 0.882–1.296), but significant association in Asian (OR: 2.848; 95%CI.: 1.194–6.791). Analysis for dominant model indicated that the variant G allele carriers (GG + GA) may have increased the risk of SLE when compared with the homozygote AA in overall populations and in Caucasian (Overall: OR 1.203, 95%CI.: 1.029–1.407; Caucasian: OR 1.233, 95%CI.: 1.014–1.499), but not in Asian (OR: 1.154; 95%CI.: 0.856–1.557). Significant association was found by using homozygote contrast model in overall populations and Asian (Overall: OR 1.303, 95%CI.: 1.031–1.648; Asian: OR 3.206, 95%CI.: 1.241–8.284), while no association was found in Caucasian (OR: 1.209; 95%CI.: 0.940–1.556). The results provided evidence for the association between the IL10 − 1082G/A polymorphism and the risk of SLE. To confirm these findings, more case–control studies with subtle study design based on adequately sized populations are required.     

Clearance of dying cells and systemic lupus erythematosus: the role of C1q and the complement system

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of unknown etiology characterized by the presence of pathogenic high-titer autoantibodies to a diverse group of autoantigens. In 88% of patients, autoantibodies are present an average of 3.3 years before diagnosis. Antinuclear, anti-Ro, anti-La, and anti-phospholipid antibodies appear first, followed by anti-DNA, anti-Smith and anti-ribonucleoprotein. These autoantibodies have features of an antigen-driven, T-cell-dependent immune response. Once present, the course of SLE is characterized by disease flares and autoimmune dysregulation. Programmed cell death (PCD), an essential developmental and homeostatic mechanism, is the preferred physiological death processes for cells as well as an important immune response regulator. Appropriate clearance of apoptotic material completes the PCD process, and is essential for regulating of inflammation and maintaining self-tolerance. Early complement proteins are important in protecting humans against the development of SLE and the protective role of C1q and complement in SLE is mainly related to their role in clearance of dying cells. However, the complement system is also an important ingredient in inflammation, which mediates SLE pathogenesis. Thus, the question remains whether complement factors have either a protective or a destructive role, or a combination of both.     

EBV and systemic lupus erythematosus: a new perspective

We have proposed that EBV uses mature B cell biology to access memory B cells as a site of persistent infection. A central feature of this model is that EBV adapts its gene expression profile to the state of the B cell it resides in and that the level of infection is stable over time. This led us to question whether changes in the behavior or regulation of mature B cells would alter the state of EBV persistence. To investigate this, we studied the impact of systemic lupus erythematosus (SLE), a disease characterized by immune dysfunction, on EBV infection. We show that patients with SLE have abnormally high frequencies of EBV-infected cells in their blood, and this is associated with the occurrence of SLE disease flares. Although patients with SLE have frequencies of infected cells comparable to those seen in immunosuppressed patients, in SLE the effect was independent of immunosuppressive therapy. Aberrant expression of viral lytic (BZLF1) and latency (latency membrane proteins 1 and 2a) genes was also detected in the blood of SLE patients. We conclude that the abnormal regulation of EBV infection in SLE patients reflects the sensitivity of the virus to perturbation of the immune system.     

三氧化二砷对系统性红斑狼疮患者外周血淋巴细胞凋亡和IL-10分泌的影响

目的观察不同浓度三氧化二砷（As2O3）对活动期系统性红斑狼疮（SLE）患者外周血淋巴细胞凋亡及白介素10（IL-10）分泌的影响。方法收集15例未曾用过激素及免疫抑制剂治疗并排除其它类型的自身免疫性疾病及感染性疾病的初诊SLE患者和同期15例健康体检者（健康对照组）的外周血,分别于不同浓度As2O3干预培养后12h和24h采用VnnexinV＼PI染色定量分析外周血淋巴细胞凋亡率,采用酶联免疫吸附法（ELISA）检测培养上清液中IL-10的含量。结果SLE组患者和健康对照组在不同As2O3浓度下12h和24h的凋亡率均增加（P〈0．05）;不同浓度As2O3诱导SLE患者在12h和24h淋巴细胞凋亡率明显高于健康对照组（P〈0．05）;且随As2O3干预浓度的增加,两组外周血淋巴细胞凋亡率均增加（P〈0．05）。SLE组患者外周血淋巴细胞在体外培养后分泌IL-10水平明显高于健康对照组（P〈0．05）,且As2O3能显著抑制其分泌,As2O3对健康对照组无影响（P〉0．05）。结论As2O3能诱导外周血淋巴细胞凋亡,并且具有时间和浓度依赖性,提示As2O3通过引起淋巴细胞凋亡发挥治疗作用;As2O3抑制SLE患者外周血淋巴细胞分泌IL-10可能是其发挥治疗作用的重要机制之一。     

The association between systemic lupus erythematosus and deficiencies of the complement system.

Systemic lupus erythematosus (SLE), an autoimmune disease characterized by chronic nephritis, arthritis or dermatitis and the presence of antinuclear autoantibodies is associated with deficiencies of complement factors of the classical activation pathway. Results accumulated over the past few years with the use of complement gene deficient mice made it possible to update the conventional hypothesis for this association in regard to the etiology of the disease, whereby the early events leading to induction of autoimmunity can be explained by various functions of complement. As a conclusion, a new model for the etiology of the SLE based on the reduced elimination of apoptotic cells, the increased uptake of IgM containing immune complexes into the spleen and the CD21/CD35 dependent B cell toleration in the periphery demonstrates the importance of complement in the prevention of autoimmunity whereas the inflammatory reactions occurring in later stages of the disease are relatively independent from complement. The results obtained with complement deficient mice contribute to a better understanding of tolerance-inducing mechanisms and offers the option to develop new therapeutic procedures for autoimmune diseases.     

Characterization of human complement receptor type 2 (CR2/CD21) as a receptor for IFN-alpha: a potential role in systemic lupus erythematosus

Human complement receptor type 2 (CR2/CD21) is a B lymphocyte membrane glycoprotein that plays a central role in the immune responses to foreign Ags as well as the development of autoimmunity to nuclear Ags in systemic lupus erythematosus. In addition to these three well-characterized ligands, C3d/iC3b, EBV-gp350, and CD23, a previous study has identified CR2 as a potential receptor for IFN-alpha. IFN-alpha, a multifunctional cytokine important in the innate immune system, has recently been proposed to play a major pathogenic role in the development of systemic lupus erythematosus in humans and mice. In this study, we have shown using surface plasmon resonance and ELISA approaches that CR2 will bind IFN-alpha in the same affinity range as the other three well-characterized ligands studied in parallel. In addition, we show that IFN-alpha interacts with short consensus repeat domains 1 and 2 in a region that serves as the ligand binding site for C3d/iC3b, EBV-gp350, and CD23. Finally, we show that treatment of purified human peripheral blood B cells with the inhibitory anti-CR2 mAb 171 diminishes the induction of IFN-alpha-responsive genes. Thus, IFN-alpha represents a fourth class of extracellular ligands for CR2 and interacts with the same domain as the other three ligands. Defining the role of CR2 as compared with the well-characterized type 1 IFN-alpha receptor 1 and 2 in mediating innate immune and autoimmune roles of this cytokine should provide additional insights into the biologic roles of this interaction.     

Complement and systemic lupus erythematosus

Complement is implicated in the pathogenesis of systemic lupus erythematosus (SLE) in several ways and may act as both friend and foe. Homozygous deficiency of any of the proteins of the classical pathway is causally associated with susceptibility to the development of SLE, especially deficiency of the earliest proteins of the activation pathway. However, complement is also implicated in the effector inflammatory phase of the autoimmune response that characterizes the disease. Complement proteins are deposited in inflamed tissues and, in experimental models, inhibition of C5 ameliorates disease in a murine model. As a further twist to the associations between the complement system and SLE, autoantibodies to some complement proteins, especially to C1q, develop as part of the autoantibody response. The presence of anti-C1q autoantibodies is associated with severe illness, including glomerulonephritis. In this chapter the role of the complement system in SLE is reviewed and hypotheses are advanced to explain the complex relationships between complement and lupus.