Early-Onset Ankylosing Spondylitis Is Associated With a Functional MICA Polymorphism

doi:10.1016/j.humimm.2005.09.004

Human Immunology

Volume 66, Issue 10, October 2005, Pages 1057-1061

https://doi.org/10.1016/j.humimm.2005.09.004 Get rights and content

Abstract

Major histocompatibility complex (MHC) class I chain–related A (MICA) molecules deliver activating signals through the NKG2D receptor expressed on the surface of natural killer (NK), CD8αβ and γδ T cells, and the MICA gene is polymorphic. The recently described MICA amino acid substitution at position 129 (MICA-129) seems to affect its binding to NKG2D. We investigated whether this dimorphism (MICA-129met [methionine] and MICA-129val [valine]) is associated with susceptibility to ankylosing spondylitis (AS) in a cohort of Algerian patients stratified according to their HLAB27 status and the age of onset of the disease. DNA from 129 patients and 76 healthy individuals were analyzed to determine the HLA-B generic type as well as MICA-129 polymorphism. Statistical analysis revealed: (1) a weaker association between AS and HLA-B27 in Algerians than in that reported for European patients (63% versus 80–90%), suggesting a possible influence of other genetic/environmental determinants in the studied population and (2) an association between MICA-129 met/met genotype and juvenile AS (p = 0.02) independent of HLA-B27 status. These data suggest a potential role for a functionally relevant MICA gene polymorphism in autoimmune/inflammatory disease susceptibility.

Introduction

Ankylosing spondylitis (AS) belongs to the spondyloarthropathies group, which also includes reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel diseases, and the so-called undifferentiated spondyloarthropathies. The development of this complex multifactorial disease is under the influence of the patient genetic background and environmentally related factors [1, 2]. Both can increase susceptibility by affecting the overall reactivity of the immune system. Indeed, even though three to nine loci, involving the worldwide recognized human leukocyte antigen (HLA)-B gene [1], play a significant role in the disease susceptibility, it is also admitted that reactive arthritis is triggered by gastrointestinal or genitourinary infections from Yersinia salmonella, Campylobacter, or Chlamydia [2].

Among the genetic loci that could constitute a potential link between the genetic and the environmental components of immune response, the major histocompatibility complex (MHC) class I chain–related A (MICA) gene is an attractive candidate. Belonging to an MHC multicopy gene family and neighbor to the HLA-B locus, the MICA gene codes for class I–like molecules. Displaying a limited tissue distribution, restricted to gastrointestinal epithelium and diverse epithelial tumors, MICA expression is induced by factors of cellular stress including cytomegalovirus [3] and bacterial infections [4, 5]. The MICA gene has no known role in antigen presentation but acts as a signal of cellular distress through the NKG2D-DAP10 activating receptor complex, expressed on effector cells. NKG2D engagement by MICA triggers natural killer (NK) cells and co-stimulate some of γδ T cells and antigen-specific αβ T cells leading to the adaptive immune response induction or enhancement.

The MICA gene exhibits a high rate of polymorphism, with more than 50 alleles so far described [6]. With the recent development of MICA genotyping schemes, an abundance of disease associations, especially those related to the common alleles of classical HLA–class I loci were explored. However, these studies provided controversial data concerning potential primary association of MICA allele, with the disease or association reflecting the linkage disequilibrium with the already known disease-associated HLA variants. Nevertheless, a recent report demonstrates that a single amino acid change, methionine to valine at position 129 of the α2-heavy chain domain, categorizes MICA alleles into strong (MICA-129met) and weak (MICA-129val) binders of NKG2D receptor, very likely affecting the thresholds of NK-cell activation and T-cell modulation [7].

Based on these data, we hypothesized that this functional polymorphism might influence the course of AS development. We have performed a case control study on a cohort of AS patients from Algeria (North Africa). HLA-B and MICA genotyping were performed and analyzed on the whole and with relation to age of clinical onset of the disease.

Section snippets

Patients and Controls

Genomic DNA was extracted from EDTA-treated peripheral blood samples using the standard proteinase K-phenol extraction method from both patients and healthy controls groups. A total of 129 unrelated AS patients attending the rheumatology department of the Douera University Hospital in Algiers, Algeria, who fulfilled the European Spondylarthropathy Study Group [8] and the 1984 New York–modified criteria [9] were included in this study. The sex ratio was 2.91 (96 males/33 females). The mean age

HLA-B Polymorphism

The distribution of HLA-B alleles for this case control study involving AS patients, as expected, revealed a statistically significant difference between patients and controls concerning the HLA-B27 specificity (89/129: 63% for AS group and 3/76: 4% for controls; Pc <10^–11 OR = 39.73; 95%CI = 11.87–132.98). Although HLA-B27 represents the predominant antigen among patients, the observed frequency (63%) is considerably less than the 80–90% commonly observed among European patient groups [1].

Discussion

Three types of polymorphism constitute the MICA gene diversity: (1) polymorphisms (essentially base substitutions) within exons encoding the three α-domains, account for a total of 56 alleles (MICA*001 to MICA*051 representing both functional and silent variants); (2) a variable number of (GCT)n short tandem repeats (STRs) in the exon 5 and constitute five different alleles (termed MICA-A4, A5, A5.1, A6, and A9); and (3) a recently described functionally relevant dimorphism at codon 129,

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Additionally, the same author revealed MICA*019 as a supplemental AS risk factor in Chinese patients because independent of HLA- B27. Thus, these facts suggested the synergistic roles both MICA*019 and HLA-B27 could play in the etiology of AS [55]. In Taiwanese patients, MICA*019 homozygosity increased sMICA production; therefore, sMICA could be linked to AS development [74].
The Major Histocompatibility Complex class I chain-related molecule A (MICA) genes encode a highly polymorphic glycoprotein among the cell surface antigens that trigger an immune response after allograft transplantation. It is encoded by the MICA gene, a member of the glycosylated MIC genes. Discovered in 1994, the MICA gene is located within the MHC class I region. Moreover, its biological function is achieved through the interaction with the NKG2D receptor. Unlike the classical HLA molecules, MICA protein is not associated with β2- microglobulin nor binds peptides. MICA gene expression may result in a cytotoxic response and IFN-γ secretion through the up-regulation by heat shock proteins in response to infection (Human Cytomegalovirus HCMV), mediated by NKG2D-expressing cells. Anti-MICA antibodies were identified as significant risk factors for antibody mediated rejection after being detected in sera of patients with graft rejection. In addition, soluble MICA proteins (sMICA) has been detected in the serum of transplant recipients with cancers. Furthermore, the association of MICA polymorphisms with infectious diseases, various autoimmune diseases, cancer, and allograft rejection or graft-versus-host disease (GVHD) has been studied. Moreover, numerous advanced disease studies centered on MICA polymorphism are independent of HLA association. In this review, we discussed the up-to-date data about MICA and the association of MICA polymorphism with infections, autoimmune diseases, graft-versus-host disease, and cancer.
Influence of major histocompatibility complex class I chain-related gene A polymorphisms on cytomegalovirus disease after allogeneic hematopoietic cell transplantation
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Cytomegalovirus (CMV) infection and disease are common infectious complications after allogeneic hematopoietic cell transplantation (alloHCT). Major histocompatibility complex (MHC) class I chain-related gene A (MICA) is a ligand of the natural killer (NKG2D) receptor on immune effector cells that helps mediate NK cell alloreactivity. We hypothesized that MICA polymorphisms may influence CMV infection and disease incidence after alloHCT.
We conducted a retrospective analysis of 423 adults at the Cleveland Clinic with hematologic malignancies treated with a matched related or unrelated donor alloHCT. CMV cases analyzed included a compositive of instances of viral copy replication above detection limits as well as any biopsy-proven tissue invasive disease episodes. Genotypes at the MICA-129 position have been categorized as weak (valine/valine; V/V), intermediate (methionine/valine; M/V), or strong (methionine/methionine; M/M) receptor affinity.
In multivariable analysis, V/V donor MICA-129 genotype was associated with CMV infection and disease (hazard ratio [HR] = 1.40; 95% confidence interval [CI], 1.00–1.96; p = .05), but not MICA mismatch (HR = 1.38; 95% CI, 0.83–2.29; p = .22). There was no association of acute or chronic GVHD with MICA donor–recipient mismatch (HR = 1.05; 95% 95% CI, 0.66–1.68; p = .83 and HR = 0.94; 95% CI, 0.51–1.76; p = .85, respectively) or V/V donor MICA-129 genotypes (HR = 1.02; 95% CI, 0.79–1.31; p = .89 and HR = 0.89; 95% CI, 0.65–1.22; p = .47, respectively).
These findings suggest that the donor MICA-129 V/V genotype with weak NKG2D receptor binding affinity is associated with an increased risk of CMV infection and disease after alloHCT.
Genetics of Axial Spondyloarthritis
2019, Axial Spondyloarthritis
Ankylosing spondylitis (AS) is among the most heritable of common human diseases. While the major susceptibility gene for the disease, HLA-B27, has among the strongest genetic effects for any common genetic variant, it contributes only ∼20% of the genetic risk of the disease, and only a small minority (∼5%) of HLA-B27 carriers develop the disease. Much progress has been made identifying further genetic variants involved in the disease, which have highlighted novel pathways previously unreported to be involved in human disease as influencing risk of AS. This information presents valuable clues as to potential therapeutic targets for AS and related conditions.
MICA-129 A/G dimorphism, its relation to soluble mica plasma level and spontaneous preterm birth: A case-control study
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The aim of this case- control study was to investigate the association between preterm birth (PTB), MICA-129 A/G dimorphism and sMICA levels. Fifty pregnant women with singleton pregnancy and previous PTB, or clinic diagnostic of threatened preterm labor in the actual pregnancy, or cervical length less than 25 mm and 50 healthy pregnant women were enrolled. DNA was extracted for genotyping for MICA-129 A/G by real-time PCR and sMICA plasma level was quantified by sandwich ELISA assay. Clinical and socioeconomic characteristics, results of TaqMan® genotyping and ELISA quantification were compared between the groups using qui-square, Fisher´s exact or Mann-Whitney test. A binary logistic regression model was used to predict PTB. The correlation between MICA-129 A/G genotypes and sMICA levels was investigated. There were not statistically significant differences between MICA-129 A/G polymorphism and sMICA plasma level.There was found a correlation between MICA-129 val/val genotype and higher levels of sMICA (ρ: -0.342; p:0.001). The presence of MICA-129  val/val genotype may be influencing sMICA expression.
Association Between Major Histocompatibility Complex Class I Chain-Related Gene Polymorphisms and Susceptibility of Systemic Lupus Erythematosus
2017, American Journal of the Medical Sciences
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Extensive studies on MICA-129 have been conducted and showed that the MICA-129 Met allele was positively associated with SLE19,20 and psoriatic disease.21 Additionally, there is an association of the MICA-129 Met/Met genotype with juvenile ankylosing spondylitis 22 and inflammatory bowel disease.23 The frequency of the MICA-129 Val allele was higher in individuals with autoimmune diabetes.24
Major histocompatibility complex class I chain-related gene (MIC) polymorphisms have been associated with many autoimmune diseases. To explore the correlation between MIC polymorphisms and systemic lupus erythematosus (SLE), we compared the sequence of the MIC gene in Han Chinese patients with SLE from Hainan Island, China, with healthy individuals.
In this study, the MIC polymorphisms in 296 subjects (159 patients with SLE and 137 healthy volunteers) of Han ethnicity from Hainan Island were characterized. A chi-square test was performed to evaluate the differences in the allelic frequency of the MIC genes between patients with SLE and the control subjects.
The genotyping results indicated that the frequencies of the MICA*010, MICB*014, and MICB*002 alleles were significantly higher in the control subjects than the patients with SLE. Additionally, the results also indicated that the frequency of the MICB*009N in the SLE group was significantly increased compared to that in the matched control subjects.
The results of this study suggested that the MICB*009N allele might be a risk factor for SLE, whereas the MICB*014, MICA*010 and MICB*002 alleles were associated with reduced incidence of SLE in the study population.
MHC Class I Chain-Related Gene A (MICA) Donor-Recipient Mismatches and MICA-129 Polymorphism in Unrelated Donor Hematopoietic Cell Transplantations Has No Impact on Outcomes in Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, or Myelodysplastic Syndrome: A Center for International Blood and Marrow Transplant Research Study
2017, Biology of Blood and Marrow Transplantation
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Therefore, limiting inclusion to a subset of remarkably matched pairs would result in a higher than expected level of HLA haplotype homogeneity with lower MICA mismatch rate. In our study population, the incidence aGVHD III and IV was 16% for VV and 17% for VM/MM, compared with 1% and 26% reported in the prior publication [16]. In the current cohort, the largest studied to date, none of the investigated outcomes were significantly associated with MICA mismatching and the MICA-129 polymorphism VV, with the exception of an unexpected finding of significantly higher relapse in association with MICA mismatches in 10/10 patients.
Single-center studies have previously reported associations of MHC Class I Chain-Related Gene A (MICA) polymorphisms and donor-recipient MICA mismatching with graft-versus-host disease (GVHD) after unrelated donor hematopoietic cell transplantation (HCT). In this study, we investigated the association of MICA polymorphism (MICA-129, MM versus MV versus VV) and MICA mismatches after HCT with 10/10 HLA–matched (n = 552) or 9/10 (n = 161) unrelated donors. Included were adult patients with a first unrelated bone marrow or peripheral blood HCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome that were reported to the Center for International Blood and Marrow Transplant Research between 1999 and 2011. Our results showed that neither MICA mismatch nor MICA-129 polymorphism were associated with any transplantation outcome (P < .01), with the exception of a higher relapse in recipients of MICA-mismatched HLA 10/10 donors (hazard ratio [HR], 1.7; P = .003). There was a suggestion of association between MICA mismatches and a higher risk of acute GVHD grades II to IV (HR, 1.4; P = .013) There were no significant interactions between MICA mismatches and HLA matching (9/10 versus 10/10). In conclusion, the findings in this cohort did not confirm prior studies reporting that MICA polymorphism and MICA mismatches were associated with HCT outcomes.

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HA and HD contributed equally to this work and are considered first authors.

Supported by EUROAS BMH4-CT98-3605 and EUROAS Genomic Bank (QLRI-CT-2002-02276). Grant coordinator: Dr. S. Laoussadi.

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Early-Onset Ankylosing Spondylitis Is Associated With a Functional MICA Polymorphism

Abstract

Introduction

Section snippets

Patients and Controls

HLA-B Polymorphism

Discussion

Best Pract Res Clin Rheumatol

Immunity

Hum Immunol

Immunity

Pathogenesis of spondylarthropathies. Persistent bacterial antigen, autoimmunity, or both?

Arthritis Rheum

Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells

Nat Immunol

Binding of Escherichia coli adhesin AfaE to CD55 triggers cell-surface expression of the MHC class I-related molecule MICA

Proc Natl Acad Sci U S A