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RIIb Alters Receptor Expression and Associates with Autoimmunity. I. Regulatory FCGR2B Polymorphisms and Their Association with Systemic Lupus Erythematosus1,2
* Division of Clinical Immunology and Rheumatology, Departments of Medicine and Microbiology, University of Alabama, Birmingham, AL 35294;
Epidemiology Branch, National Institute on Environmental Health Sciences, Research Triangle Park, NC 27709; and
Department of Public Health Sciences, Wake Forest University, Winston-Salem, NC 27157
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Abstract |
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RIIb, the immunoreceptor tyrosine-based inhibitory motif-containing receptor for IgG (Mendelian Inheritance in Man no. 604590), plays an important role in maintaining the homeostasis of immune responses. We have identified 10 novel single-nucleotide polymorphisms in the promoter region of human FCGR2B gene and characterized two functionally distinct haplotypes in its proximal promoter. In luciferase reporter assays, the less frequent promoter haplotype leads to increased expression of the reporter gene in both B lymphoid and myeloid cell lines under constitutive and stimulated conditions. Four independent genome-wide scans support linkage of the human FcR region to the systemic lupus erythematosus (SLE; Online Mendelian Inheritance in Man no. 152700) phenotype. Our case-control study in 600 Caucasians indicates a significant association of the less frequent FCGR2B promoter haplotype with the SLE phenotype (odds ratio = 1.65; p = 0.0054). The FCGR2B haplotype has no linkage disequilibrium with previously identified FCGR2A and FCGR3A polymorphisms, and after adjustment for FCGR2A and FCGR3A, FCGR2B showed a persistent association with SLE (odds ratio = 1.72; p = 0.0083). These results suggest that an expression variant of FCGR2B is a risk factor for human lupus and implicate FCGR2B in disease pathogenesis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RIIb (CD32B) is the only receptor that bears an immunoreceptor tyrosine-based inhibitory motif (ITIM)5 in its cytoplasmic domain (1). FcRIIb is expressed on B lymphocytes, myeloid cell lineages, and dendritic and mast cells. On B lymphocytes, coligation of FcRIIb with the B cell Ag receptor by IgG immune complexes down-regulates B cell Ag receptor signaling and modulates the threshold for B cell activation and proliferation (2, 3, 4, 5, 6). Coligation of FcRIIb also provides a negative-feedback mechanism for Ig production by B cells. On myeloid lineage cells, FcRIIb coclustering with the activating FcRs, such as FcRIa (CD64), FcRIIa (CD32A), and FcRIIIa (CD16A), down-modulates their function (2). Ab-mediated phagocytosis by macrophages is decreased by exaggerated FcRIIb coclustering and is enhanced by disruption of FcRIIb (7, 8, 9). On follicular dendritic cells (FDC), FcRIIb mediates the retention and conversion of immune complexes to a highly immunogenic form, which facilitate B cell recall responses (10, 11, 12, 13). Thus, FcRIIb plays multiple roles in modulating immune function and thus maintaining immune homeostasis. Indeed, studies in mouse models have highlighted the role of FCGR2B in the development of autoimmune diseases (14, 15, 16, 17, 18, 19). For example, targeted disruption of FCGR2B in the mouse leads to elevated serum Ig levels and, on the susceptible C57BL/6 background, leads to the development of lupus-like phenotypes (20, 21).
Human systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by production of antinuclear autoantibodies and tissue deposition of immune complexes (22, 23, 24, 25). This complex polygenic disease has strong genetic components (
s 
20) (26, 27). In humans, outside of MHC class II, genetic polymorphisms or defects in genes involved in Ag uptake and/or process and in immune complex clearance such as complement, FCGR2A and FCGR3A have been identified to contribute to SLE susceptibility (26, 28, 29, 30, 31, 32, 33). Recently, programmed cell death gene 1 (PDCD1) which regulates B cell activation has been identified as an autoimmunity candidate gene in the mouse (34, 35), and a single-nucleotide polymorphism (SNP) in a putative RUNX1 binding site in the promoter of human PDCD1 gene has been implicated as a risk allele for SLE (34, 35). However, potential variations in the regulatory regions of human FCGR2B as a disease susceptibility gene have not yet been characterized.
Unlike the SNPs in human FCGR2A and FCGR3A that affect the ligand-binding properties of the receptors (29, 36), we could not find any nonsynonymous SNPs encoding the extracellular domains of FcRIIb in >120 donors. However, we identified 10 polymorphic sites in the 2-kb promoter region of human FCGR2B and defined two SNP haplotypes in its proximal promoter. In luciferase reporter assays, the less frequent variant FCGR2B haplotype increases the promoter activity both constitutively and under inducible conditions. In our case-control study of 600 Caucasians, the variant FCGR2B haplotype is significantly associated with the SLE phenotype. This association is not due to the effects of previously identified FCGR2A or FCGR3A polymorphisms. Our observation not only provides evidence for the genetic association of FCGR2B with human lupus but also is the first study to characterize the functionally important promoter polymorphisms in FCGR2B, one of the key regulators in immune responses.
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Materials and Methods |
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Caucasian SLE patients and controls were recruited as part of the University of Alabama at Birmingham-based DISCOVERY cohort and as part of the Carolina Lupus Study (37), a population-based case-control study. The studies were reviewed and approved by the Institution Review Board, and all donors provided written informed consent.
FCGR2B genotyping
Long-range PCR was performed to specifically amplify FCGR2B from genomic DNA using Failsafe PCR system (Epicenter Technologies, Madison, WI). The sense primer (5'-CTCCACAGGTTACTCGTTTCTACCTTATCTTAC-3') anneals at both FCGR2B/C –2-kb promoters, and the antisense primer (5'-GCTTGCGTGGCCCCTGGTTCTCA-3') anneals at the FCGR2B-specific sequence in intron 6 between exons 6 and 7. The PCR conditions were 94°C for 2 min, 14 cycles of 98°C for 20 s and 68°C for 17 min, followed by 10 more cycles with the extension time increasing by 15 s each cycle, and a 7-min extension at 68°C. The resultant 15-kb PCR product was gel-purified and used as the template for the nested PCR to amplify the 2-kb promoter of FCGR2B with the sense primer (5'-GTTACTCGTTTCTACCTTATCTTAC-3') and the antisense primer (5'-TTGCAGTCAGCCCAGTCACTCTC-3'). The PCR conditions were 95°C for 5 min, 35 cycles of 94°C for 30 s, 56°C for 30 s, and 72°C for 2 min, and followed by a 7-min extension at 72°C. The nested-PCR product was then gel-purified and sequenced with BigDye terminator cycle sequencing on an ABI 377 (Applied Biosystems, Foster City, CA). The sequencing primer was 5'-ATTTCAAGAAGCATCCAGATTC-3'. The rare alleles were confirmed by sequencing from both directions.
For genotyping the FCGR2B promoter SNPs, pan-PCR was performed to amplify both FCGR2B/C promoters containing –120 or –386 SNP. For the PCR amplicon of 114 bp containing –120 SNP, the sense primer is 5'-AAAGAGGGTGGAAAGGGAGGAG-3' and the antisense primer is 5'-biotin-CTCTCAAAGCTTGGCGGATTCTAC-3'. For the PCR amplicon containing –386 SNP, the sense primer is 5'-TCAAGAAGCATCCAGATTCCAG-3' and the antisense primer is 5'-biotin-AAACTCAGCTCAGAACCTCCTGTT-3'. The PCR conditions were 95°C for 5 min, 40 cycles of 95°C for 30 s, 56°C for 30 s, and 72°C for 45 s, followed by a 7-min extension at 72°C. The PCR product was genotyped by pyrosequencing on a PSQ 96 system following the manufacturer’s instructions (Biotage, Westborough, MA). The pyrosequencing primers for –120 and –386 SNPs were 5'-CCTGTGATAAAACAGAACAT-3' and 5'-TGCTGGTGCACGCTGTCCT-3', respectively. For the donors who have the uncommon A or C allele at nt –120 or –386, FCGR2B-specific long PCR was then performed to assign the origin of these uncommon alleles by pyrosequencing.
Transient transfection and luciferase reporter assays
For BJAB cells, the FCGR2B-promoter reporter plasmid (40 µg) was cotransfected with 300 ng of the reference plasmid pRL-SV40 into 10 x 106 cells by electroporation at 200 V and 960 µF. For U937 cells, the FCGR2B-promoter reporter plasmid (1 µg) was cotransfected with 100 ng of the reference plasmid into 5 x 105 cells using 3 µl of FuGENE 6 reagent according to the manufacturer’s instructions (Roche Molecular Biochemicals, Indianapolis, IN). The cells were recovered overnight and treated with 0.5 mM dibutyryl cAMP, or 400 U/ml IFN-, or nonstimulated for additional 24 h. The cells were then lysed and measured for luciferase activities using the Dual Luciferase Reporter Assay System (Promega, Madison, WI). The firefly luciferase activity was normalized by Renilla luciferase activity to yield the relative luciferase activity (RLA).
Statistical analysis
Data for comparison of mean values among samples were analyzed by Student’s t test or Kruskal-Wallis test. To test for an association between FCGR2B and human SLE, we computed four separate logistic regression models. The four models contained only the FCGR2B haplotype and were sequentially partitioned into two degree of freedom tests for general association and three a priori genetic models (i.e., dominant, additive, and recessive). We estimated the degree of linkage disequilibrium among FCGR loci using the D and D' statistics (38). In the joint analysis and the conditional tests of association, to adjust for the effects of FCGR2A and FCGR3A on our FCGR2B tests of association, we computed a parallel set of logistic regression models that contain the effects of all three genes with tests of FCGR2B conditional on the FCGR2A/3A genotypes viewed as a priori tests.
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Results |
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To identify functional SNPs in the human FCGR2B gene, cDNA from >120 donors was amplified and sequenced. We did not find any nonsynonymous SNPs in the IgG-binding extracellular domains of FcRIIb (39). However, we found that the expression levels of FcRIIb is variable among individuals (data not shown). Therefore, we searched for SNPs in the regulatory region of FCGR2B gene. Study of polymorphisms in the noncoding regions of FCGR2B is complicated by the extremely high homology between the FCGR2B and FCGR2C genes, which reflects gene duplication and crossover events during evolution of FcR cluster (40, 41, 42). To characterize the promoter region of FCGR2B, we screened a bacterial artificial chromosome library, identified the FCGR2B and FCGR2C genes, and sequenced a 12-kb region of the 5' portion of each gene (42). FCGR2B and FCGR2C are nearly 100% identical within the first 3.4 kb of the 5' flanking region and regions through exon 3. However, a stretch of 31 nt in the intron 6 (between exons 6 and 7) of FCGR2B is unique to the FCGR2B gene (41, 42). Based on this information, we developed a long-range PCR to specifically amplify the 15 kb of FCGR2B from –2 kb to intron 7 from genomic DNA and a subsequent nested PCR using the long PCR product as a template to amplify the FCGR2B promoter for genotyping.
Among 66 non-SLE controls and 66 SLE patients, we found 10 SNPs in the first 2-kb promoter of FCGR2B (Fig. 1). We did not identify any deletions or insertions in this FCGR2B promoter region. The gene specificity of the nested-PCR strategy was verified by gene-specific SNPs in the FCGR2C exon 3 (42).
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In the mouse, key elements regulating FCGR2B expression are located within the first several hundred base pairs of the 5' promoter. To focus on potential functionally important polymorphisms in the human FCGR2B promoter, we made a series of 5' deletion promoter-reporter constructs and transfected them into BJAB cells, a B-lymphoid cell line. Luciferase reporter assays showed that 1.0-kb promoter of FCGR2B retains 100% activity as compared with 4.3-, 2.0-, and 1.4-kb promoter (Fig. 2). There may be a repressor element between –0.6 and –1.0 kb, because deletion of this promoter fragment leads to a 1.9-fold increase of the luciferase activity (Fig. 2). We obtained similar results using the same 5'-promoter constructs in U937 cells, a myeloid cell line. Therefore, we focused our further study on the three SNPs in the proximal 1.0-kb promoter of human FCGR2B.
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7%) was about equally represented in both the –386G-120T and –386C-120A haplotypes. To determine whether the variant alleles affect the promoter activity, we performed luciferase reporter assays using constructs containing the 1.0-kb FCGR2B promoter incorporating different alleles in front of the luciferase gene. The –893 "C/G" alleles did not influence promoter activity in the context of both –386G-120T and –386C-120A haplotypes in BJAB and U937 cells (Fig. 3, A and B). However, the FCGR2B promoter with the –386C-120A haplotype showed a 1.8-fold greater expression of the luciferase reporter, compared with the –386G-120T haplotype, in both BJAB and U937 cells (Fig. 3, A and B). This difference is apparent in the context of either common "C" or uncommon "G" allele at nt –893. This result showed clearly that the two proximal FCGR2B promoter haplotypes differentially affect constitutive promoter activity.
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RIIb is regulated by cytokines and hormones (7, 8, 43, 44, 45). We next examined whether the two FCGR2B promoter haplotypes have differential activity under stimulated conditions. BJAB and U937 cells were transfected with the reporter plasmid containing –893C-386G-120T or –893C-386C-120A haplotype for 16 h and then stimulated with dibutyryl cAMP or IFN- for 24 h. In BJAB cells, cAMP up-regulated FCGR2B promoter activity by 1.5-fold, and IFN- slightly down-regulated FCGR2B promoter in the context of both –386G-120T and –386C-120A haplotypes (Fig. 3C). In U937 cells, for both the FCGR2B promoter haplotypes, cAMP slightly up-regulated the promoter activity, and IFN- down-regulated the promoter by 50% (Fig. 3D). These data indicate that the less frequent variant –386C-120A haplotype has greater promoter activity than the more common –386G-120T haplotype under both constitutive and stimulated conditions.
We have examined the FcRIIb expression levels on primary cells, and in agreement with our in vitro luciferase assay, the donors with the –386C-120A haplotype express more receptor on B lymphocytes and monocytes than donors homozygous for the –386G-120T haplotype (46). The differential promoter activity of the two FCGR2B haplotype is due to their differential binding capacity for transcription factors GATA4 and YY1 (46).
The association of FCGR2B haplotype with SLE
To investigate the relationship of the two functionally important FCGR2B promoter haplotypes to an autoimmune phenotype, we developed a strategy to genotype the two SNPs at nt –386 and –120 in a larger collection of samples. PCR was performed to amplify 114-bp promoter regions containing the –120 SNP of both FCGR2B and FCGR2C genes from genomic DNA. The pan-PCR products were applied to quantitative pyrosequencing in a 96-well format which gave 100, 75, 50, or 25% allele distributions reflecting the four chromosomes from both FCGR2B and FCGR2C genes that were amplified. For the donors with the variant –120A allele, FCGR2B-specific long PCR, followed by nested PCR, was performed and applied to pyrosequencing to determine the allele frequency in the FCGR2B gene. By this method, the frequency of the variant –120A allele in the FCGR2C gene was also determined. A similar strategy was also used for –386 G/C SNPs. For the FCGR2B gene in our Caucasian population, we have found that the frequency of the common haplotype –386G-120T (named 2B.1 haplotype) is 91%, the uncommon –386C-120A (2B.4) haplotype is 
9% (Fig. 4). The –386C-120T (2B.2) haplotype is very rare, and the frequency is 0.41%. We have not observed the –386G-120A (2B.3) haplotype in the FCGR2B gene from our populations. For the FCGR2C gene, however, the haplotype frequencies are distinct from FCGR2B. The –386C-120T (2B.2) haplotype occurs much more frequently than in the FCGR2B gene (12 vs 0.4% haplotype frequency), and the –386C-120A (2B.4) haplotype is much more rare than in the FCGR2B gene (1 vs 9%) (Fig. 4). As with FCGR2B, we have not observed the –386G-120A (2B.3) haplotype in the FCGR2C gene. Having established these haplotype frequencies, we focused our further association studies on the common –386G-120T and variant –386C-120A haplotype.
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C encoding Ile187Thr187, was found in only several donors with the 2B.4 promoter haplotype, and the variant Thr187 is not associated with SLE in a Caucasian population (39). Combined analysis of FCGR2B, FCGR2A, FCGR3A polymorphisms
Functional polymorphisms in the extracellular domains of FcRIIa and FcRIIIa have been shown to associate with SLE in a number of studies (26). Because FCGR2B is located 200 kb telomeric to FCGR2A/3A within the classical FcR cluster, we next examined the potential linkage disequilibrium among the polymorphisms of these three genes in our collection of Caucasians. Analyses of the SNP genotyping data show that there is no linkage disequilibrium of FCGR2B promoter haplotypes with FCGR2A and FCGR3A polymorphisms, because the calculated D' was low (D' = 0.221 and D' = 0.486, respectively), and there is no statistical interaction between FCGR2B and FCGR3A loci under a dominant-additive genetic model (p = 0.6629). We also computed the three conditional association tests for FCGR2A, FCGR3A, and FCGR2B polymorphisms. Logistic regression, adjusted for FCGR2A and FCGR3A, showed a persistent effect for FCGR2B (Table II; p = 0.0083; odds ratio = 1.72; 95% confidence interval = 1.15–2.58). After adjusting for FCGR2B polymorphisms, FCGR3A is also significantly associated with SLE (Table II; p = 0.0288; odds ratio = 0.65; 95% confidence interval = 0.44–0.96). This lack of substantial linkage disequilibrium from FCGR2B to FCGR2A/3A is consistent with the physical distance of 250 kb across this cluster, which is larger than the median haplotype block in Caucasians (42, 48). Therefore, FCGR2B and FCGR3A may contribute to SLE independently and, perhaps, synergistically.
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Discussion |
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RIIb is widely expressed on immune cells and plays an important role in maintaining immune response homeostasis. FCGR2B-deficient mice have elevated Ig levels in response to both thymus-dependent and -independent Ags, and, on a susceptible genetic background, FCGR2B-deficient mice develop a lupus-like autoimmune disease (20, 21). Polymorphisms in the mouse homolog of the human FCGR2B gene have been identified in several autoimmune-prone strains (14, 16). Taken together, these observations have focused attention on FcRIIb both as a disease susceptibility gene and as a potential therapeutic target for autoimmunity.
To assess the role of FcRIIb in human autoimmunity, we identified the functional genetic variations in the FCGR2B gene and assessed their association with the SLE phenotype. We characterized the two FCGR2B proximal promoter haplotypes which were found in >99% of all 600 donors studied. The two FCGR2B haplotypes have differential promoter activity in cell lines of lymphoid and myeloid lineages under both constitutive and stimulated conditions. The less frequent, variant gain-of-function promoter haplotype of FCGR2B is significantly enriched in SLE patients in our case-control study of Caucasians with an odds ratio of 1.65. This disease association is not due to linkage disequilibrium with other FcR family genes (FCGR2A or FCGR3A).
The association of the gain-of-function promoter variant of FCGR2B with human SLE might be considered a surprise. However, the effect of the homozygous FCGR2B knockout mouse is background dependent, and the repertoire of FcRs in mouse is different from that in humans. Mouse has a single CD32 gene (the ITIM-containing FCGR2B), whereas humans have two additional CD32 genes, the immunoreceptor tyrosine-based activation motif-containing activation receptors, FCGR2A and FCGR2C. FcRIIb is expressed on multiple cell types and may have distinct function(s) depending on its cell context. For example, expressed on mononuclear phagocytes, FcRIIb can decrease the phagocytosis of immune complexes, a process important for the in vivo clearance of immune complex. On FDC, FcRIIb promotes the maturation of FDC reticulum and mediates the uptake and conversion of immune complexes on FDCs to potentially more highly immunogenic forms (10, 11, 12, 13, 49). In contrast, on B cells, FcRIIb down-modulates B cell activation and Ab production. Thus, FcRIIb may play distinct roles according to the disease stage and the cell types involved in the development of autoimmunity. In considering modulation of FcRIIb as a therapeutic target, it may be important to consider cell type-specific targeting according to the disease characteristics and its developmental stage.
The association of the C-A promoter haplotype with the SLE phenotype suggests human FCGR2B as a candidate gene for autoimmune susceptibility. Human SLE is a complex, polygenic genetic trait with a strong genetic component (26). Four independent genome-wide scans support linkage of chromosome 1q21–23, which encompasses the FcR cluster, with SLE (50, 51, 52, 53). SNPs in FCGR2A and FCGR3A have shown linkage and association with SLE in both family-based and case control-based studies (odds ratio 1.5–2.2 for FCGR3A) (28, 29, 30, 31, 32). According to the linkage disequilibrium analysis and conditional tests of association within the FcR cluster, the association of FCGR2B with SLE does not represent disequilibrium with FCGR2A or FCGR3A. FCGR2B and FCGR3A contribute to autoimmunity independently. This association of FCGR2B promoter polymorphisms with the SLE phenotype must be confirmed in both family-based and further case control studies, and it will be of great interest to determine whether an extended haplotype including both promoter and the nonsynonymous exon 5 (transmembrane) SNPs will explain the proposed association of the FCGR2B transmembrane polymorphism with SLE in Japanese patients. Such studies will need to take care to differentiate the promoters of human FCGR2B and FCGR2C, which have exceptionally high homology, and to consider the contribution of other genes as suggested in the mouse (21). As with susceptibility genes in other complex diseases, one can anticipate that the contribution of each gene will have a modest odds ratio (54). Nonetheless, identification of single-gene variants will help characterize pathologic pathways for these complex autoimmune disorders, and combined multigene analysis will be important for the ultimate understanding of the disease pathogenesis.
Most importantly, our data demonstrate the occurrence of two functionally distinct FCGR2B promoter haplotypes that affect promoter activity in both lymphoid and myeloid cell lines. The two FCGR2B promoter haplotypes have differential binding capacity for transcription factors GATA4 and YY1 and lead to differential expression levels of the endogenous FcRIIb on primary cells (46). Identification of the FCGR2B promoter variants as a disease risk factor also supports the notion that duplicated regions within the genome are likely the hot spots of genomic instability and are associated with genetic diseases (55). Furthermore, apart from autoimmunity, FCGR2B promoter genotypes may also play an important role in the variations of human Ab responses to vaccines as predicted by its function on B cells and studies in the mouse (56).
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Acknowledgments |
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Footnotes |
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2 The authors declare that they have no competing financial interests.
3 Current address: Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA 52242.
4 Address correspondence and reprint requests to Dr. Robert P. Kimberly, Tinsley Harrison Tower 429, 1900 University Boulevard, University of Alabama, Birmingham, AL 35294-0006. E-mail address: rpk{at}uab.edu
5 Abbreviations used in this paper: ITIM, immunoreceptor tyrosine-based inhibitory motif; FDC, follicular dendritic cell; SLE, systemic lupus erythematosus; SNP, single-nucleotide polymorphism; RLA, relative luciferase activity.
Received for publication November 26, 2003. Accepted for publication March 26, 2004.
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Z. S. M. Rahman and T. Manser Failed Up-Regulation of the Inhibitory IgG Fc Receptor Fc{gamma}RIIB on Germinal Center B Cells in Autoimmune-Prone Mice Is Not Associated with Deletion Polymorphisms in the Promoter Region of the Fc{gamma}RIIB Gene J. Immunol., August 1, 2005; 175(3): 1440 - 1449. [Abstract] [Full Text] [PDF]
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Y. Hitomi, N. Tsuchiya, A. Kawasaki, J. Ohashi, T. Suzuki, C. Kyogoku, T. Fukazawa, S. Bejrachandra, U. Siriboonrit, D. Chandanayingyong, et al. CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B Hum. Mol. Genet., December 1, 2004; 13(23): 2907 - 2917. [Abstract] [Full Text] [PDF]
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K. Su, X. Li, J. C. Edberg, J. Wu, P. Ferguson, and R. P. Kimberly A Promoter Haplotype of the Immunoreceptor Tyrosine-Based Inhibitory Motif-Bearing Fc{gamma}RIIb Alters Receptor Expression and Associates with Autoimmunity. II. Differential Binding of GATA4 and Yin-Yang1 Transcription Factors and Correlated Receptor Expression and Function J. Immunol., June 1, 2004; 172(11): 7192 - 7199. [Abstract] [Full Text] [PDF]
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), or stimulated with 0.5 mM dibutyryl cAMP (
) or 400 U/ml IFN-
) for an additional 24 h. The firefly luciferase activity was measured and normalized by Renilla luciferase levels to yield RLA. The results represent the mean ± SEM from three independent experiments.