The association of high levels of IL-10 with autoimmune diseases suggests that this cytokine plays an important role in the disease pathogenesis. Family studies of first-degree relatives and analysis of twins indicate that heritable genetic factors underlie inter-individual differences in quantitative IL-10 production. Genome wide scans have shown an association between the chromosomal region containing the IL-10 locus and autoimmune diseases, and studies of the IL-10 gene have identified both single nucleotide polymorphisms (SNP) and short tandem repeat polymorphisms (STRP) in the promoter. Susceptibility to and manifestations of autoimmune diseases have reported associations with SNPs, SNP haplotypes and STRPs in the IL-10 promoter region, but results have varied. Since the total numbers of affecteds studied in different ethnic groups have been small, further studies with greater power will be necessary to uncover the genetic basis of dysregulated IL-10 production in autoimmune diseases.

Introduction

Autoimmune diseases are characterized by the presence of dysregulated cytokine expression that plays a role in the maintenance of autoreactive lymphocytes. Genetic polymorphisms that alter the function or expression of these cytokine genes are likely candidates as factors either predisposing to disease or modulating disease manifestations, and are the subject of intense research.

Interleukin-10 (IL-10), a cytokine that exhibits multiple modulatory effects on the immune system, has altered expression in many autoimmune diseases. The expression of IL-10 appears to be influenced by polymorphisms in its promoter, which may be associated with autoimmune disease. However, the definition of which of the many currently identified promoter polymorphisms are involved in disease pathogenesis, and whether new, as yet unidentified polymorphisms might also play a role in IL-10 dysregulation, is still a subject of continued investigation.

Interleukin-10 is produced by CD4 and CD8T cells, activated B lymphocytes, monocytes, macrophages, and keratinocytes.^1,2 As an anti inflammatory cytokine IL-10 down-regulates the expression of Th1 cytokines, MHC class II and costimulatory molecules on macrophages. However, IL-10 also stimulates FcγR expression on the same cells,^1,2 and has been shown to prolong B cell survival, to induce B cell differentiation, and to enhance B cell proliferation and antibody production.^1-5 The effects of IL-10 on B cells, particularly on the stimulation and survival of autoreactive B cells are believed to be of great importance in autoimmune diseases. ^2,5 Additionally, IL-10 may play an important role in influencing the balance of Th1 versus Th2 cytokines, which can influence the progression of autoimmune diseases.^6-8

Association of IL-10 Production with Autoimmune Diseases

A number of studies of both mouse and human models of autoimmune diseases have documented altered IL-10 serum levels, suggesting a direct link between IL-10 levels and disease.^1,2 Evidence from mouse models suggest that IL-10 production may play a protective role in organ-specific autoimmune disease and alter the balance between pathogenic Th1 cells and protective anti-inflammatory Th2 cells.² However, while some studies show that administration of IL-10 could result in improvement of the disease phenotype, other studies have shown that IL-10-deficient mice fail to develop an autoimmune syndrome, and the expression of an IL-10 transgene resulted in earlier disease onset or exacerbated disease rather than in protection.²

High serum levels of IL-10 have been documented in human autoimmune diseases. In systemic lupus erythematosus (SLE) patients, high IL-10 levels have been shown to correlate with disease activity,^9,10 and studies indicate that cultured PBMC from lupus patients spontaneously produce high levels of IL-10.¹ Production of high levels of IL-10 has also been demonstrated in synovial T-lymphocytes of rheumatoid arthritis patients, in the serum of systemic sclerosis, Kawasaki disease, and ALPS patients, as well as in the cultured cells of polymyositis and dermatomyositis patients.² High IL-10 levels have been found in the blister fluid of pemphigus vulgaris and bullous pemphigoid patients and in the mucosal T cells in ulcerative colitis.^2,11-16 Increased expression of IL-10 mRNA by PBMCs and/or various other tissues was associated with Sjogren's syndrome, Grave's disease, myasthenia gravis, psoriasis and autoimmune lymphoproliferative syndrome (ALPS).^1,2,8,16,17 Taken together, these studies indicate that dysregulated expression of IL-10 plays a significant role in autoimmune diseases. While the disease association with IL-10 levels is clear, the degree to which IL-10 production precedes disease onset, as opposed to resulting from disease activity, is less clear. In addition, while autoimmune disease progression may play a role in altering the levels of IL-10 and other cytokines, evidence from family studies suggest that, to a large extent, heritable genetic differences determine IL-10 production and thus contribute to autoimmune disease phenotype.^18,19 The association of high levels of IL-10 mRNA and protein with early stages of Grave's disease and Hashimoto's thyroiditis also suggests a role for IL-10 in the early stages of some diseases.⁸

IL-10 Promoter Polymorphisms and IL-10 Production

IL-10 production is regulated at the transcriptional level, and studies suggest that heritable genetic differences that associate with inter-individual differences in gene expression may differentially regulate IL-10 production.^19-21 There is also evidence that suggests the existence of post-transcriptional regulation by RNA-destabilizing, AU-rich elements within the 3'-untranslated of IL-10 mRNA.²²

Inter-individual differences in IL-10 production is heritable.²³ First degree relatives of SLE patients produce high levels of IL-10 compared with unrelated controls,²⁴ and first-degree relatives of nonsurvivors of fatal meningococcal disease produce significantly lower levels of IL-10 than relatives of survivors.^23,25 The implication of a heritable genetic basis for IL-10 production is also supported by the concordance of IL-10 production in monozygotic twins, which suggests that genetics could account for up to 75% of IL-10 production.²³ Therefore, high IL-10 production associated with autoimmune diseases may represent a risk factor for disease susceptibility or severity, and the genetic polymorphisms that regulate IL-10 production represent genetic risk factors for autoimmune diseases.^{1,9,10,18,19,24,26}

Promoter-reporter studies have identified several positive and negative regulatory promoter sequences within the 1.3 kb region upstream of the transcription start site, and a transcription factor binding site search of the immediate 4kb promoter region has identified more than 74 potential binding sites.^27,28 Three functional NF-κB and a Stat3 binding site, and four cAMP-responsive elements have been identified in the 2kb promoter region of the human IL-10 promoter.^29-31 However, none of these elements appear to be polymorphic. Functional Sp1 and Sp3 transcription factor binding sites have similarly been identified in the murine IL-10 promoter.³²

The human IL-10 promoter is highly polymorphic. Two (CA) short tandem repeat polymorphisms (STRP), IL-10.R and IL-10.G, have been identified at -4 kb and -1.1 kb, respectively, and three single nucleotide polymorphisms (SNP), -1082G/A, -819C/T and -597C/A, which form three predominant haplotypes (GCC, ACC, ATA), had been identified previously in the 1.0 kb promoter region.^33-36 A fourth haplotype, GTA, was seen only in a Chinese population.³⁷ The G allele at -1082 and haplotypes containing this allele have been associated with high IL-10 production, while the A allele and the ATA haplotype have been associated with low IL-10 production.^35,38

Resequencing within the 8kb promoter region by various groups has identified at least 23 additional SNPs (Fig. 1),^19,39,40 and four novel SNPs have been identified recently in the 3' untranslated region ( 3' UTR).⁴¹ Significant differences in the allele frequencies of some promoter SNPs have been seen in different ethnic or geographic populations, underscoring the need for appropriate stratification in disease association studies (Table 1).⁴² Haplotypes defined by proximal and distal SNPs ^19,35,43 and by SNPs and STRP alleles associate with IL-10 production.^39,44 However, because of variable, inconsistent associations between IL-10 production and different SNP alleles, SNP haplotypes and STRP alleles, it is currently unclear which promoter polymorphisms are causal in determining differences in IL-10 production. Data from our group, which showed an association between distal SNP haplotypes and IL-10 production suggest that SNPs in the distal promoter may play a role in IL-10 production.¹⁹

Figure 1

Schematic representation of the IL-10 promoter region: A) SNPs identified within putative transcription factor binding sites using the TESS search tool (http://www.cbil.upenn.edu/tess/); B) Novel SNPs identified in the distal promoter (AWG, unpublished (more...)

Table 1

SNP allele frequencies in different ethnic group.

IL-10 Promoter Polymorphisms and Automimmune Disease

Genome wide scans have shown linkage of disease susceptibility to the region on chromosome 1 that encompasses the IL-10 locus. The IL-10 gene has been localized at 1q31-1q32 region, and several genome scans have identified regions of chromosome 1 (1q21-23, 1q31-32, 1q42-44) which may contain susceptibility loci for SLE and other autoimmune diseases.^45-51

Using case-control approaches to look at the distribution of promoter SNP or STRP alleles, several studies have found an association between IL-10 promoter polymorphisms and autoimmune disease susceptibility or disease manifestations (Tables 2 and 3)^{19,37,38,41,43,52-65,74} In each autoimmune disease examined, some studies have failed to find associations between promoter polymorphisms and susceptibility or manifestations.^{37,43,61,63-73} For example, Lazarus et al (1997) have found an association between -1082G, -1082G-containing haplotypes and the presence of anti-Ro autoantibodies and nephritis in Caucasian SLE.⁵³ A study by Crawley et al (1999) also used a Caucasian group, but failed to find a similar association, and Mok et al (1998) have found an association between the ATA haplotype and lupus nephritis in a Chinese population.^37,68 Therefore, currently it is not clear which of the 26 identified SNPs, which haplotypes or which STRP alleles are relevant in the disease process. In reviewing these studies several observations are clear: 1) the total number of affecteds that have been studied is small (Table 2); 2) different genetic markers, either SNPs or STRPs, have been screened; 3) different ethnic populations have been used in different studies; and 4) different genotyping techniques have been used, often without delineation of error rates. Since there are clear differences in the allele frequencies in different ethnic and geographic groups, appropriate stratification by ethnicity will be important. In support of this, our group has found an association between the promoter SNP (-2763A/T) in African Americans with SLE 19 but not in a Dutch Caucasian cohort of 98 affecteds compared with 128 controls (-2763AA = 0.37 in affecteds vs 0.36 in controls; Gibson and Huizinga, unpublished results). Others have failed to find a similar association in an Italian SLE group.⁴¹

Table 2

Association studies of IL-10 polymorphisms and autoimmune disease susceptibility.

Table 3

Association studies of IL-10 polymorphisms and autoimmune disease manifestations.

Variable associations between IL-10 STRP alleles and autoimmune disease have also been documented. In different studies, different IL-10G STRP alleles associated with SLE in a UK Caucasian cohort, an Italian Caucasian cohort and in Mexican Americans, while IL-10R alleles associated with RA in two different UK Caucasian cohorts, and in an African American group.^{41,52,54,55,58} Data from our group did not show an association between the IL-10R STRP and SLE in three ethnic groups (Caucasians, African Americans or Mexican Americans). However, we found significant association between SLE and IL-10.G8 and IL-10.G9 in Caucasians, and IL-10.G8, IL-10.G9 and IL-10.G11 in African Americans (Table 4). We have not replicated the association in Mexican Americans observed by Mehrian and colleagues, but our cohort numbers were not adequately powered to provide a definitive result (Table 4).

Table 4

IL-10G allele frequencies in African American, Caucasian and Mexican American SLE populations.

Of particular interest is a recent study that examined distal SNPs in the -8kb promoter region, and extended haplotypes in the 4kb region in an Italian SLE cohort.⁴¹ While the authors found no association between SLE and distal SNPs or SNPs in the 3'UTR, a meta-analysis of four IL-10.G STRP association studies found significant association with STRPs containing larger numbers of (CA) repeats. IL-10.G alleles containing 21 (CA) repeats or more (IL-10.G9 and up), and extended SNP-STRP haplotypes that included these longer repeat alleles were associated significantly with SLE.⁴¹ This study suggests that the disease association might not be with a particular STRP allele, but with a larger stretch of (CA) repeats. The biologic basis for this observation is not clear at present.

In summary, associations between IL-10 promoter polymorphisms, IL-10 production and autoimmune diseases have been documented. However, while association studies have yielded inconsistent results, the total number of affecteds from each of the various ethnic groups studied has not been large. Additionally, adequate numbers of studies have not been done in all ethnic groups. Recent resequencing efforts have uncovered a more complex promoter structure, and additional SNPs are being discovered in the promoter and in the 3'UTR^41,75 (and Gibson, unpublished results). This raises the possibility that other, more complex SNP associations with disease phenotypes might be uncovered in future studies.

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