The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019

Associations of MICA Polymorphisms with Inflammatory Rheumatic Diseases



Qingwen Wang1, Xiaodong Zhou*, 2
1 Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, China
2 Department of Internal Medicine, The University of Texas Health Science Center at Houston, USA

Abstract

Inflammatory rheumatic diseases are characterized by inflammation resulting from the immune dysregulation that usually attacks joints, skin and internal organs. Many of them are considered as complex disease that may be predisposed by multiple genes and/or genetic loci, and triggered by environmental factors such as microbiome and cellular stress. The major histocompatibility complex class I chain-related gene A (MICA) is a highly polymorphic gene that encodes protein variants expressed under cellular stress conditions, and these MICA variants play important roles in immune activation and surveillance. Recently, accumulating evidences from both genetic and functional studies have suggested that MICA polymorphisms may be associated with various rheumatic diseases, and the expression of MICA variants may attribute to the altered immune responses in the diseases. The objective of this review is to discuss potential genetic associations and pathological relevance of MICA in inflammatory rheumatic diseases that may help us to understand pathogenesis contributing to the development of these diseases.

Keywords: MICA, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, systemic lupus erythematosus, Behçet’s disease, inflammatory bowel disease, ulcerative colitis, Crohn's disease.


Article Information


Identifiers and Pagination:

Year: 2015
Volume: 9
First Page: 94
Last Page: 100
Publisher Id: TORJ-9-94
DOI: 10.2174/1874312901409010094

Article History:

Received Date: 10/7/2015
Revision Received Date: 27/8/2015
Acceptance Date: 28/8/2015
Electronic publication date: 22/12/2015
Collection year: 2015

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© Wang and Zhou; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Department of Internal Medicine, University of Texas Medical School at Houston, 6431 Fannin Street, MSB5270, Houston Texas 77030, USA; Tel: 713-500-6900; Fax: 713-500-0580; E-mail: xiaodong.zhou@uth.tmc.edu




INTRODUCTION

The major histocompatibility complex class I chain-related gene A (MICA) is a non-classic HLA gene [1Bahram S, Bresnahan M, Geraghty DE, Spies T. A second lineage of mammalian major histocompatibility complex class I genes Proc Natl Acad Sci USA 1994; 91(14): 6259-63.
[http://dx.doi.org/10.1073/pnas.91.14.6259] [PMID: 8022771]
]. Similar to classic HLA genes, its DNA sequence is highly polymorphic [2Choy MK, Phipps ME. MICA polymorphism: biology and importance in immunity and disease Trends Mol Med 2010; 16(3): 97-106.
[http://dx.doi.org/10.1016/j.molmed.2010.01.002] [PMID: 20153697]
]. Two heavily investigated polymorphisms of the MICA are one single nucleotide polymorphism (SNP) at codon 129 leading to methionine (met) and valine (val) substitution, and a tri-nucleotide microsatellite (GCT)n starting at codon 293 named MICA-A(x), and an exceptional 5 repeats with an insertion of guanosine at codon 295 named MICA-A5.1. The former leads to a change of binding affinity to MICA receptor NKG2D [3Steinle A, Li P, Morris DL, et al. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family Immunogenetics 2001; 53(4): 279-87.
[http://dx.doi.org/10.1007/s002510100325] [PMID: 11491531]
], the latter causes structure alteration on MICA transmembrane (TM) domain [4Mizuki N, Ota M, Kimura M, et al. Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behçet disease Proc Natl Acad Sci USA 1997; 94(4): 1298-303.
[http://dx.doi.org/10.1073/pnas.94.4.1298] [PMID: 9037047]
]. In addition to individual polymorphisms, according to haplotypes of the exonic polymorphisms, about 100 MICA alleles have been identified [http://www.ebi.ac.uk/ipd/ imgt/hla/]. Although, the functional significance of these polymorphisms has not been fully defined, some have been associated with immune-mediated diseases.

The MICA gene encodes a protein that expresses on the surface of selective cells such as gut epithelial, fibroblasts and endothelial cells [5Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium Proc Natl Acad Sci USA 1996; 93(22): 12445-50.
[http://dx.doi.org/10.1073/pnas.93.22.12445] [PMID: 8901601]
, 6Zwirner NW, Dole K, Stastny P. Differential surface expression of MICA by endothelial cells, fibroblasts, keratinocytes, and monocytes Hum Immunol 1999; 60(4): 323-30.
[http://dx.doi.org/10.1016/S0198-8859(98)00128-1] [PMID: 10363723]
], and it plays unique roles in immune activation and surveillance [7Salih HR, Rammensee HG, Steinle A. Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding J Immunol 2002; 169(8): 4098-102.
[http://dx.doi.org/10.4049/jimmunol.169.8.4098] [PMID: 12370336]
, 8Kriegeskorte AK, Gebhardt FE, Porcellini S, et al. NKG2D-independent suppression of T cell proliferation by H60 and MICA Proc Natl Acad Sci USA 2005; 102(33): 11805-10.
[http://dx.doi.org/10.1073/pnas.0502026102] [PMID: 16091471]
]. Under cellular stress conditions, such as infections, tissue injury, pro-inflammatory signals, and malignant transformation [9González S, López-Soto A, Suarez-Alvarez B, López-Vázquez A, López-Larrea C. NKG2D ligands: key targets of the immune response Trends Immunol 2008; 29(8): 397-403.
[http://dx.doi.org/10.1016/j.it.2008.04.007] [PMID: 18602338]
-15Tieng V, Le Bouguénec C, du Merle L, et al. Binding of Escherichia coli adhesin AfaE to CD55 triggers cell-surface expression of the MHC class I-related molecule MICA Proc Natl Acad Sci USA 2002; 99(5): 2977-82.
[http://dx.doi.org/10.1073/pnas.032668099] [PMID: 11830641]
], MICA interacts with its receptor NKG2D found on natural killer (NK) cells, NK T cells, γδ T cells, αβ CD8+ T cells,

and a minor immune-regulatory subset of CD4+ T cells [14Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells Nat Immunol 2001; 2(3): 255-60.
[http://dx.doi.org/10.1038/85321] [PMID: 11224526]
-22González S, Groh V, Spies T. Immunobiology of human NKG2D and its ligands Curr Top Microbiol Immunol 2006; 298: 121-38.
[http://dx.doi.org/10.1007/3-540-27743-9_6] [PMID: 16329186]
]. Binding of MICA (membrane-bound MICA) with NKG2D triggers cell-mediated cytotoxicity and cytokine release from NK and T cells [13Das H, Groh V, Kuijl C, et al. MICA engagement by human Vgamma2Vdelta2 T cells enhances their antigen-dependent effector function Immunity 2001; 15(1): 83-93.
[http://dx.doi.org/10.1016/S1074-7613(01)00168-6] [PMID: 11485740]
, 14Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells Nat Immunol 2001; 2(3): 255-60.
[http://dx.doi.org/10.1038/85321] [PMID: 11224526]
, 23Rincon-Orozco B, Kunzmann V, Wrobel P, Kabelitz D, Steinle A, Herrmann T. Activation of V gamma 9V delta 2 T cells by NKG2D J Immunol 2005; 175(4): 2144-51.
[http://dx.doi.org/10.4049/jimmunol.175.4.2144] [PMID: 16081780]
, 24André P, Castriconi R, Espéli M, et al. Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors Eur J Immunol 2004; 34(4): 961-71.
[http://dx.doi.org/10.1002/eji.200324705] [PMID: 15048706]
]. On the other hand, the proteolytic cleavage of MICA proteins from expressing cells, termed MICA shedding produces soluble MICA that may control the immune process by down-modulating NKG2D expression [25Salih HR, Rammensee HG, Steinle A. Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding J Immunol 2002; 169(8): 4098-102.
[http://dx.doi.org/10.4049/jimmunol.169.8.4098] [PMID: 12370336]
, 26Raneros AB, Suarez-Álvarez B, López-Larrea C. Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention Oncoimmunology 2014; 25(3 ): e28497.], and facilitate expansion of an immunosuppressive CD4+ T-cell subset [19Groh V, Smythe K, Dai Z, Spies T. Fas-ligand-mediated paracrine T cell regulation by the receptor NKG2D in tumor immunity Nat Immunol 2006; 7(7): 755-62.
[http://dx.doi.org/10.1038/ni1350] [PMID: 16732291]
]. In addition, MICA can be excreted in exosomes which can also down-regulate NKG2D activity [27Ashiru O, Boutet P, Fernández-Messina L, et al. Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes Cancer Res 2010; 70(2): 481-9.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1688] [PMID: 20068167]
]. Therefore, the balance between membrane-bound MICA and soluble MICA/exosomal MICA may control the outcome of immune function via NKG2D regulation.

Given its complex gene sequence and protein expression features, as well as unique functions in immune process, studies of MICA in order to understand pathogenesis of various immune-mediated diseases are important. Accumulating evidences have supported that MICA and its signaling pathway are useful biomarker for the measurement of disease susceptibility, evaluation of disease progression and/or development of therapeutic approaches. This review will focus on recent reports of MICA in association with inflammatory rheumatic diseases.

MICA IN RHEUMATOID ARTHRITIS (RA)

The first report of MICA in association with RA was based on a study of fifty-four Spanish families of affected son and daughter and 211 consecutive RA patients, in which MICA-A6 was suggested to be protective against RA in the shared epitope (SE) positive RA patients [28Martinez A, Fernandez-Arquero M, Balsa A, et al. Primary association of a MICA allele with protection against rheumatoid arthritis Arthritis Rheum 2001; 44(6): 1261-5.
[http://dx.doi.org/10.1002/1529-0131(200106)44:6<1261::AID-ART217>3.0.CO;2-L] [PMID: 11407684]
]. This result was immediately replicated by a small Caucasian case/control cohort (90/85) [29Singal DP, Li J, Zhang G. Microsatellite polymorphism of the MICA gene and susceptibility to rheumatoid arthritis Clin Exp Rheumatol 2001; 19(4): 451-2.
[PMID: 11491503]
]. However, studies of a larger RA tri-families of French Caucasian along with an independent 100 RA trio families and a German Caucasian case-control (90/182) cohort did not confirm such an association. Instead, the evidence from the studies showed a MICA SNP rs1051794 corresponding to MICA codon 129 (MICA-129) in association with RA, and it was suggested that this SNP was in complete linkage disequilibrium (LD) with another functional SNP, rs1051792 that contributes differential binding affinity of MICA protein to its receptor NKG2D [30Kirsten H, Petit-Teixeira E, Scholz M, et al. Association of MICA with rheumatoid arthritis independent of known HLA-DRB1 risk alleles in a family-based and a case control study Arthritis Res Ther 2009; 11(3): R60.
[http://dx.doi.org/10.1186/ar2683] [PMID: 19409079]
].

Although functional studies of these RA-associated MICA alleles have not been reported, MICA and NKG2D signaling appeared to be aberrant in RA patients [31Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis Proc Natl Acad Sci USA 2003; 100(16): 9452-7.
[http://dx.doi.org/10.1073/pnas.1632807100] [PMID: 12878725]
]. In particular, substantial amount of synoviocyte-derived soluble MICA was observed in peripheral blood serum samples of RA patients [31Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis Proc Natl Acad Sci USA 2003; 100(16): 9452-7.
[http://dx.doi.org/10.1073/pnas.1632807100] [PMID: 12878725]
]. However, it failed to induce down-modulation of NKG2D on T cells by overcoming opposing activity of tumor necrosis factor alpha (TNF-α) and IL-15 [31Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis Proc Natl Acad Sci USA 2003; 100(16): 9452-7.
[http://dx.doi.org/10.1073/pnas.1632807100] [PMID: 12878725]
]. Increased NKG2D activity in RA patients was observed, and that may cause autoreactive T cell stimulation which may be responsible to the self-perpetuating pathology in RA [31Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis Proc Natl Acad Sci USA 2003; 100(16): 9452-7.
[http://dx.doi.org/10.1073/pnas.1632807100] [PMID: 12878725]
].

MICA IN ANKYLOSING SPONDYLITIS (AS)

Studies of MICA in AS was first reported in a small case-control Caucasian cohort (48/50) [32Goto K, Ota M, Ohno S, et al. MICA gene and ankylosing spondylitis: linkage analysis via a transmembrane-encoded triplet repeat polymorphism Tissue Antigens 1997; 49(5): 503-7.
[http://dx.doi.org/10.1111/j.1399-0039.1997.tb02786.x] [PMID: 9174144]
], in which the four-repetition GCT of the MICA gene (MICA-A4) was found at significantly higher frequency in AS [32Goto K, Ota M, Ohno S, et al. MICA gene and ankylosing spondylitis: linkage analysis via a transmembrane-encoded triplet repeat polymorphism Tissue Antigens 1997; 49(5): 503-7.
[http://dx.doi.org/10.1111/j.1399-0039.1997.tb02786.x] [PMID: 9174144]
]. However, another study of AS case-control cohort (162/103) indicated that the frequency of the MICA-A4 allele was not significantly higher in the B27-positive and B27-negative patient groups, as compared to the B27-positive and B27-negative control groups, respectively [33Yabuki K, Ota M, Goto K, et al. Triplet repeat polymorphism in the MICA gene in HLA-B27 positive and negative caucasian patients with ankylosing spondylitis Hum Immunol 1999; 60(1): 83-6.
[http://dx.doi.org/10.1016/S0198-8859(98)00092-5] [PMID: 9952031]
]. Therefore, the MICA-A4 was considered in strong linkage disequilibrium (LD) with HLA-B27. This result was contradictive to a report from the studies of Sardinia AS (case/control: 82/139), in which a high frequency of MICA-A4 (80%) was found in HLA-B27-negative AS patients, and that was associated with AS [34Ricci-Vitiani L, Vacca A, Potolicchio I, et al. MICA gene triplet repeat polymorphism in patients with HLA-B27 positive and negative ankylosing spondylitis from Sardinia J Rheumatol 2000; 27(9): 2193-7.
[PMID: 10990233]
]. Following MICA-A4 studies, Amroun et al. reported an association between MICA-129 met/met genotype and juvenile AS independent of HLA-B27 positivity in a case-control Algerian cohort (129/760) [35Amroun H, Djoudi H, Busson M, et al. Early-onset ankylosing spondylitis is associated with a functional MICA polymorphism Hum Immunol 2005; 66(10): 1057-61.
[http://dx.doi.org/10.1016/j.humimm.2005.09.004] [PMID: 16386647]
]. Recently, a sequencing study of the exonic haplotypes of the MICA alleles was performed in two large case-control cohorts of US Caucasian (1070/1003) and Chinese Han (473/536) [36Zhou X, Wang J, Zou H, et al. MICA, a gene contributing strong susceptibility to ankylosing spondylitis Ann Rheum Dis 2014; 73(8): 1552-7.
[http://dx.doi.org/10.1136/annrheumdis-2013-203352] [PMID: 23727634]
]. From the studies, the haplotype allele MICA*007:01 was identified as a significant risk allele for AS in both Caucasian and Han populations, and MICA*019 was a major risk allele in Han AS patients. Conditional analysis of MICA alleles on HLA-B27 that unshielded LD effect supported independent associations of the MICA*007 and *019 with AS [36Zhou X, Wang J, Zou H, et al. MICA, a gene contributing strong susceptibility to ankylosing spondylitis Ann Rheum Dis 2014; 73(8): 1552-7.
[http://dx.doi.org/10.1136/annrheumdis-2013-203352] [PMID: 23727634]
]. Of note, MICA*007 contains both MICA-A4 and MICA-129-met, MICA*019 with MICA-A5 and MICA-129-val compared to the common allele MICA*008 with A5.1 and MICA-129-val.

MICA IN PSORIATIC ARTHRITIS (PSA) AND PSORIASIS

Studies of MICA in PsA and psoriasis appeared more complex. A Spanish study of 65 patients with PsA, 5 psoriasis, and 177 healthy controls was the first to show MICA-A9 as a risk to PsA [37Gonzalez S, Martinez-Borra J, Torre-Alonso JC, et al. The MICA-A9 triplet repeat polymorphism in the transmembrane region confers additional susceptibility to the development of psoriatic arthritis and is independent of the association of Cw*0602 in psoriasis Arthritis Rheum 1999; 42(5): 1010-6.
[http://dx.doi.org/10.1002/1529-0131(199905)42:5<1010::AID-ANR21>3.0.CO;2-H] [PMID: 10323458]
]. This observation was replicated in a case-control study (110/110) of another Spanish cohort [38Queiro R, Alperi M, Alonso-Castro S, et al. Patients with psoriatic arthritis may show differences in their clinical and genetic profiles depending on their age at psoriasis onset Clin Exp Rheumatol 2012; 30(4): 476-80.
[PMID: 22510299]
]. Further studies in Jewish (Caucasian) cases and controls (52/73) suggested that a higher frequency of MICA-A9 in PsA patients is in LD with HLA-B alleles (B*5701, B*3801), but the latter were not increased in PsA [39González S, Brautbar C, Martínez-Borra J, et al. Polymorphism in MICA rather than HLA-B/C genes is associated with psoriatic arthritis in the Jewish population Hum Immunol 2001; 62(6): 632-8.
[http://dx.doi.org/10.1016/S0198-8859(01)00242-7] [PMID: 11390038]
]. Two studies of Chinese populations including each of the case-control studies of PsA (102/210) and psoriasis (105/160) indicated no association [40Chang YT, Tsai SF, Lee DD, et al. A study of candidate genes for psoriasis near HLA-C in Chinese patients with psoriasis Br J Dermatol 2003; 148(3): 418-23.
[http://dx.doi.org/10.1046/j.1365-2133.2003.05166.x] [PMID: 12653732]
, 41Chang YT, Chou CT, Yu CW, et al. Cytokine gene polymorphisms in Chinese patients with psoriasis Br J Dermatol 2007; 156(5): 899-905.
[http://dx.doi.org/10.1111/j.1365-2133.2007.07820.x] [PMID: 17388919]
].

Considering ethnic heterogeneity in genetics, Song et al. performed a meta-analysis using 10 studies involving 2,002 cases and 1,933 controls of European and Asian [42Song GG, Kim JH, Lee YH. Associations between the major histocompatibility complex class I chain-related gene A transmembrane (MICA-TM) polymorphism and susceptibility to psoriasis and psoriatic arthritis: a meta-analysis Rheumatol Int 2014; 34(1): 117-23.
[http://dx.doi.org/10.1007/s00296-013-2849-2] [PMID: 23974432]
]. The results showed that MICA-A9 was significantly associated with PsA and psoriasis patients in the entire study population, and with PsA in Europeans and psoriasis in Asian populations [42Song GG, Kim JH, Lee YH. Associations between the major histocompatibility complex class I chain-related gene A transmembrane (MICA-TM) polymorphism and susceptibility to psoriasis and psoriatic arthritis: a meta-analysis Rheumatol Int 2014; 34(1): 117-23.
[http://dx.doi.org/10.1007/s00296-013-2849-2] [PMID: 23974432]
].

In studies of the association between PsA clinical forms and MICA [43Mameli A, Cauli A, Taccari E, et al. Association of MICA alleles with psoriatic arthritis and its clinical forms. A multicenter Italian study Clin Exp Rheumatol 2008; 26(4): 649-52.
[PMID: 18799098]
]. Two hundred and twenty-six patients were classified as asymmetric oligoarthritis (AO), symmetric poly-arthritis (PA) and spondylitis (SP), or combinations (PA/SP, OA/SP). Compared to 225 normal controls, only the combined PA/SP subset showed a significantly positive association with MICA-A9 [43Mameli A, Cauli A, Taccari E, et al. Association of MICA alleles with psoriatic arthritis and its clinical forms. A multicenter Italian study Clin Exp Rheumatol 2008; 26(4): 649-52.
[PMID: 18799098]
]. Another study in Canadian Caucasian with 745 patients and 547 controls indicated that MICA-129-met/met was a marker of skin manifestations of PsA that was independent of HLA-B and -C [44Pollock RA, Chandran V, Pellett FJ, et al. The functional MICA-129 polymorphism is associated with skin but not joint manifestations of psoriatic disease independently of HLA-B and HLA-C Tissue Antigens 2013; 82(1): 43-7.
[http://dx.doi.org/10.1111/tan.12126] [PMID: 23611695]
].

A common concern of these genetic studies is relatively small sample sizes [45Chen ML, Huang J, Xie ZF. Comment on Song et al.: associations between the major histocompatibility complex class I chain-related gene A transmembrane (MICA-TM) polymorphism and susceptibility to psoriasis and psoriatic arthritis: a meta-analysis Rheumatol Int 2014; 34(2): 297.
[http://dx.doi.org/10.1007/s00296-013-2867-0] [PMID: 24043263]
]. Recently, a large-scale fine-mapping study of psoriasis vulgaris (PsV) risk in the HLA region in 9,247 PsV patients and 13,589 controls of European descent was performed by imputing HLA-class I and II and MICA genes from SNP genotype data. HLA-C*06:02, *12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53 showed significant association with PsV, but not MICA [46Okada Y, Han B, Tsoi LC, et al. Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes Am J Hum Genet 2014; 95(2): 162-72.
[http://dx.doi.org/10.1016/j.ajhg.2014.07.002] [PMID: 25087609]
].

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

In a study of case-control cohort (48/158) of Italian population, the positive associations of MICA-A5 and MICA-A5.1 and negative association of MICA-A9 with SLE were observed, and which appeared independently from HLA-DR3 and DQ2 [47Gambelunghe G, Gerli R, Bocci EB, et al. Contribution of MHC class I chain-related A (MICA) gene polymorphism to genetic susceptibility for systemic lupus erythematosus Rheumatology (Oxford) 2005; 44(3): 287-92.
[http://dx.doi.org/10.1093/rheumatology/keh459] [PMID: 15522921]
]. The increased MICA-A5.1 in SLE was also reported in Czech population (case/control: 123/96) [48Fojtíková M, Novota P, Cejková P, Pešičková S, Tegzová D, Cerná M. HLA class II, MICA and PRL gene polymorphisms: the common contribution to the systemic lupus erythematosus development in Czech population Rheumatol Int 2011; 31(9): 1195-201.
[http://dx.doi.org/10.1007/s00296-010-1431-4] [PMID: 20352225]
]. Recently, a GWAS (case/control: 183/1288) of Central European population reported an association of cutaneous lupus erythematosus with SNP rs2844559 that is located 27 kb proximal of the MICA gene [49Kunz M, König IR, Schillert A, et al. Genome-wide association study identifies new susceptibility loci for cutaneous lupus erythematosus Exp Dermatol 2015; 24(7): 510-5.
[http://dx.doi.org/10.1111/exd.12708] [PMID: 25827949]
].

A Japanese study of cases and controls (SLE/RA/control: 716/327/351) indicated that the MICA129Met;A9 haplotype was associated with SLE, and there was an additive genetic effect between the MICA129Met;A9 haplotype and HLA-DRB1*15:01 [50Yoshida K, Komai K, Shiozawa K, et al. Role of the MICA polymorphism in systemic lupus erythematosus Arthritis Rheum 2011; 63(10): 3058-66.
[http://dx.doi.org/10.1002/art.30501] [PMID: 21702010]
]. However, the associations were not replicated in a Spanish study (case/control: 333/361) [51Sánchez E, Torres B, Vilches JR, et al. No primary association of MICA polymorphism with systemic lupus erythematosus Rheumatology (Oxford) 2006; 45(9): 1096-100.
[http://dx.doi.org/10.1093/rheumatology/kel058] [PMID: 16537577]
].

An increased expression of MICA was observed in SLE patients' kidneys [52Spada R, Rojas JM, Pérez-Yagüe S, et al. NKG2D ligand overexpression in lupus nephritis correlates with increased NK cell activity and differentiation in kidneys but not in the periphery J Leukoc Biol 2015; 97(3): 583-98.
[http://dx.doi.org/10.1189/jlb.4A0714-326R] [PMID: 25583577]
]. The MICA 129Met;A9 was shown to suppress NK cell-mediated cytotoxicity, but it stimulated the release of IFNγ [50Yoshida K, Komai K, Shiozawa K, et al. Role of the MICA polymorphism in systemic lupus erythematosus Arthritis Rheum 2011; 63(10): 3058-66.
[http://dx.doi.org/10.1002/art.30501] [PMID: 21702010]
]. In addition, increased NKG2D(+) CD4(+) T cells were inversely correlated with disease activity in juvenile-onset systemic lupus erythematosus (SLE) [53Dai Z, Turtle CJ, Booth GC, et al. Normally occurring NKG2D+CD4+ T cells are immunosuppressive and inversely correlated with disease activity in juvenile-onset lupus J Exp Med 2009; 206(4): 793-805.
[http://dx.doi.org/10.1084/jem.20081648] [PMID: 19289577]
].

MICA IN BEHÇET’S DISEASE (BD)

Association between the MICA gene and BD appeared also controversial. Mizuki et al. first reported a significantly higher frequency of MICA-A6 in BD patients of Japanese cohort (case/control: 77/103) [54Mizuki N, Ota M, Kimura M, et al. Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behçet disease Proc Natl Acad Sci USA 1997; 94(4): 1298-303.
[http://dx.doi.org/10.1073/pnas.94.4.1298] [PMID: 9037047]
], which was independently supported by several other studies including a Greek (case/control: 38/40) [55Yabuki K, Mizuki N, Ota M, et al. Association of MICA gene and HLA-B*5101 with Behçet’s disease in Greece Invest Ophthalmol Vis Sci 1999; 40(9): 1921-6.
[PMID: 10440244]
] and a Korean cohort (108/204) [56Park SH, Park KS, Seo YI, et al. Association of MICA polymorphism with HLA-B51 and disease severity in Korean patients with Behcet’s disease J Korean Med Sci 2002; 17(3): 366-70.
[http://dx.doi.org/10.3346/jkms.2002.17.3.366] [PMID: 12068141]
], as well as a study of juvenile BD (jBD) of Italian cohort (18/20) [57Picco P, Porfirio B, Gattorno M, et al. MICA gene polymorphisms in an Italian paediatric series of juvenile Behçet disease Int J Mol Med 2002; 10(5): 575-8.
[PMID: 12373294]
]. However, the follow-up studies by Mizuki et al. indicated that the previously reported MICA-A6 association was due to LD effect of HLA-B51 [58Mizuki N, Yabuki K, Ota M, et al. Analysis of microsatellite polymorphism around the HLA-B locus in Iranian patients with Behçet’s disease Tissue Antigens 2002; 60(5): 396-9.
[http://dx.doi.org/10.1034/j.1399-0039.2002.600506.x] [PMID: 12492815]
-60Mizuki N, Ota M, Yabuki K, et al. Localization of the pathogenic gene of Behçet’s disease by microsatellite analysis of three different populations Invest Ophthalmol Vis Sci 2000; 41(12): 3702-8.
[PMID: 11053265]
], and this notion was in consistent with the studies of Spanish case-control cohort (58/194) [61González-Escribano MF, Rodríguez MR, Aguilar F, Alvarez A, Sanchez-Roman J, Núñez-Roldán A. Lack of association of MICA transmembrane region polymorphism and Behçet’s disease in Spain Tissue Antigens 1999; 54(3): 278-81.
[http://dx.doi.org/10.1034/j.1399-0039.1999.540309.x] [PMID: 10519365]
] and Italian (69/130) [62Salvarani C, Boiardi L, Mantovani V, et al. Association of MICA alleles and HLA-B51 in Italian patients with Behçet’s disease J Rheumatol 2001; 28(8): 1867-70.
[PMID: 11508592]
].

An imputation with SNPs and meta-analysis of the extended HLA locus in 2 independent BD cohorts (case/control Turkish: 503/504 and Italian: 144/1270) showed that a SNP (rs116799036) between the HLA-B51 and the MICA was strongly associated with BD, and that influenced HLA-B*51 [63Hughes T, Coit P, Adler A, et al. Identification of multiple independent susceptibility loci in the HLA region in Behçet’s disease Nat Genet 2013; 45(3): 319-24.
[http://dx.doi.org/10.1038/ng.2551] [PMID: 23396137]
]. However, this observation was not replicated in a large case-control cohort (1,190/1,257), which instead verified HLA-B51 as a primary BA allele [64Ombrello MJ, Kirino Y, de Bakker PI, Gül A, Kastner DL, Remmers EF. Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity Proc Natl Acad Sci USA 2014; 111(24): 8867-72.
[http://dx.doi.org/10.1073/pnas.1406575111] [PMID: 24821759]
]. Recently, a study of Iranian BD reported that the HLA-B51 allele and the rs76546355/rs116799036 MHC SNP are independent genetic risk factors for BD [65Xavier JM, Davatchi F, Abade O, et al. Characterization of the major histocompatibility complex locus association with Behçet’s disease in Iran Arthritis Res Ther 2015; 17: 81.
[http://dx.doi.org/10.1186/s13075-015-0585-6] [PMID: 25889189]
].

While the association of single polymorphisms of the MICA with BD appeared inconsistent in different reports, increased haplotype alleles of the MICA*009 and/or *019 were associated with BD in two independent studies including case-control European Caucasian (56/90) and Spanish (42/165) cohorts [66Hughes EH, Collins RW, Kondeatis E, et al. Associations of major histocompatibility complex class I chain-related molecule polymorphisms with Behcet’s disease in Caucasian patients Tissue Antigens 2005; 66(3): 195-9.
[http://dx.doi.org/10.1111/j.1399-0039.2005.00465.x] [PMID: 16101830]
, 67Muñoz-Saá I, Cambra A, Pallarés L, et al. Allelic diversity and affinity variants of MICA are imbalanced in Spanish patients with Behçet’s disease Scand J Immunol 2006; 64(1): 77-82.
[http://dx.doi.org/10.1111/j.1365-3083.2006.01780.x] [PMID: 16784494]
].

There are limited studies of pathological importance of MICA in BD. In a study with 27 patients and 21 controls, soluble MICA in serum and NKG2D expression on CD8+ T cells were not significantly increased in BD [68Clemente A, Cambra A, Munoz-Saá I, et al. Phenotype markers and cytokine intracellular production by CD8+ gammadelta T lymphocytes do not support a regulatory T profile in Behçet’s disease patients and healthy controls Immunol Lett 2010; 129(2): 57-63.
[http://dx.doi.org/10.1016/j.imlet.2010.02.005] [PMID: 20167234]
]. In another study, HLA-B51-restricted cytotoxic T lymphocytes autoreactive to MICA transmembrane peptides were detected in active DB patients [69Yasuoka H, Okazaki Y, Kawakami Y, et al. Autoreactive CD8+ cytotoxic T lymphocytes to major histocompatibility complex class I chain-related gene A in patients with Behçet’s disease Arthritis Rheum 2004; 50(11): 3658-62.
[http://dx.doi.org/10.1002/art.20597] [PMID: 15529349]
].

MICA IN RHEUMATIC DISEASE ASSOCIATED INFLAMMATORY BOWEL DISEASE (IBD) INCLU-DING ULCERATIVE COLITIS (UC) AND CROHN'S DISEASE (CD)

Although IBD is not categorized as rheumatic disease, strong association between IBD and spondyloarthropathy (SpA) is well documented [70Bargen JA, Jackman RJ, Kerr JG. Complications and sequelae of chronic ulcerative colitis Ann Intern Med 1929; 3: 335-52.
[http://dx.doi.org/10.7326/0003-4819-3-4-335]
-73Wright V. Seronegative polyarthritis: a unified concept Arthritis Rheum 1978; 21(6): 619-33.
[http://dx.doi.org/10.1002/art.1780210603] [PMID: 83870]
]. About 10% SpA patients develop IBD in the follow-up studies [74Mielants H, Veys EM, De Vos M, et al. The evolution of spondyloarthropathies in relation to gut histology. I. Clinical aspects J Rheumatol 1995; 22(12): 2266-72.
[PMID: 8835560]
-76Leirisalo-Repo M, Turunen U, Stenman S, Helenius P, Seppälä K. High frequency of silent inflammatory bowel disease in spondylarthropathy Arthritis Rheum 1994; 37(1): 23-31.
[http://dx.doi.org/10.1002/art.1780370105] [PMID: 8129761]
], and 20-30% patients with IBD have rheumatic abnormality [77Repiso A, Alcántara M, Muñoz-Rosas C, et al. Extraintestinal manifestations of Crohn’s disease: prevalence and related factors Rev Esp Enferm Dig 2006; 98(7): 510-7.
[http://dx.doi.org/10.4321/S1130-01082006000700004] [PMID: 17022700]
, 78Paredes JM, Barrachina MM, Román J, Moreno-Osset E. [Joint disease in inflammatory bowel disease] Gastroenterol Hepatol 2005; 28(4): 240-9.
[http://dx.doi.org/10.1157/13073095] [PMID: 15811268]
]. Moreover, studies indicated that 20%-40% of patients with IBD fulfill the criteria for SpA [79Podswiadek M, Punzi L, Stramare R, et al. [The prevalence of radiographic sacroiliitis in patients affected by inflammatory bowel disease with inflammatory low back pain] Reumatismo 2004; 56(2): 110-3.
[PMID: 15309219]
, 80Salvarani C, Vlachonikolis IG, van der Heijde DM, et al. Musculoskeletal manifestations in a population-based cohort of inflammatory bowel disease patients Scand J Gastroenterol 2001; 36(12): 1307-13.
[http://dx.doi.org/10.1080/003655201317097173] [PMID: 11761022]
].

MICA has been extensively studied in IBD. MICA-A5.1 was identified as a protective allele to CD and extensive form of UC in two independent case-control studies including Tunisian (36 cases/123 controls) and Spanish (121/116) cohorts, respectively [81Kamoun A, Bouzid D, Mahfoudh N, et al. Association study of MICA-TM polymorphism with inflammatory bowel disease in the South Tunisian population Genet Test Mol Biomarkers 2013; 17(8): 615-9.
[http://dx.doi.org/10.1089/gtmb.2012.0423] [PMID: 23822824]
, 82Fdez-Morera JL, Rodrigo L, López-Vázquez A, et al. MHC class I chain-related gene A transmembrane polymorphism modulates the extension of ulcerative colitis Hum Immunol 2003; 64(8): 816-22.
[http://dx.doi.org/10.1016/S0198-8859(03)00121-6] [PMID: 12878361]
]. On the other hand, MICA-A5 was correlated with worse progression of UC [82Fdez-Morera JL, Rodrigo L, López-Vázquez A, et al. MHC class I chain-related gene A transmembrane polymorphism modulates the extension of ulcerative colitis Hum Immunol 2003; 64(8): 816-22.
[http://dx.doi.org/10.1016/S0198-8859(03)00121-6] [PMID: 12878361]
], and was associated with late age of onset of CD [81Kamoun A, Bouzid D, Mahfoudh N, et al. Association study of MICA-TM polymorphism with inflammatory bowel disease in the South Tunisian population Genet Test Mol Biomarkers 2013; 17(8): 615-9.
[http://dx.doi.org/10.1089/gtmb.2012.0423] [PMID: 23822824]
]. MICA-A6 also was associated with UC in Tunish and Japanese (case/control: 36/12 and 83/132, respectively) studies [81Kamoun A, Bouzid D, Mahfoudh N, et al. Association study of MICA-TM polymorphism with inflammatory bowel disease in the South Tunisian population Genet Test Mol Biomarkers 2013; 17(8): 615-9.
[http://dx.doi.org/10.1089/gtmb.2012.0423] [PMID: 23822824]
, 83Sugimura K, Ota M, Matsuzawa J, et al. A close relationship of triplet repeat polymorphism in MHC class I chain-related gene A (MICA) to the disease susceptibility and behavior in ulcerative colitis Tissue Antigens 2001; 57(1): 9-14.
[http://dx.doi.org/10.1034/j.1399-0039.2001.057001009.x] [PMID: 11169253]
]. A higher frequency of MICA-129met/met was reported in IBD patients of Murcians (case/control: 88/154) [84López-Hernández R, Valdés M, Lucas D, et al. Association analysis of MICA gene polymorphism and MICA-129 dimorphism with inflammatory bowel disease susceptibility in a Spanish population Hum Immunol 2010; 71(5): 512-4.
[http://dx.doi.org/10.1016/j.humimm.2010.02.003] [PMID: 20152875]
]. A haplotype study showed that allele MICA*007 was associated with UC of North European Caucasian (141 cases vs 118 controls) [85Orchard TR, Dhar A, Simmons JD, Vaughan R, Welsh KI, Jewell DP. MHC class I chain-like gene A (MICA) and its associations with inflammatory bowel disease and peripheral arthropathy Clin Exp Immunol 2001; 126(3): 437-40.
[http://dx.doi.org/10.1046/j.1365-2249.2001.01662.x] [PMID: 11737059]
]. However, these associations were not in agreement with several other reports. Two Chinese studies presented contradictory results by showing an increase of MICA-A5.1 in UC patients [86Ding Y, Xia B, Lü M, et al. MHC class I chain-related gene A-A5.1 allele is associated with ulcerative colitis in Chinese population Clin Exp Immunol 2005; 142(1): 193-8.
[http://dx.doi.org/10.1111/j.1365-2249.2005.02907.x] [PMID: 16178876]
, 87Lü M, Xia B, Ge L, et al. Role of major histocompatibility complex class I-related molecules A*A5.1 allele in ulcerative colitis in Chinese patients Immunology 2009; 128(1)(Suppl.): e230-6.
[http://dx.doi.org/10.1111/j.1365-2567.2008.02953.x] [PMID: 19016911]
]. The frequencies of MICA-129-val was significantly higher in UC patients of a Chinese cohort (case/control: 272/560) [88Zhao J, Jiang Y, Lei Y, et al. Functional MICA-129 polymorphism and serum levels of soluble MICA are correlated with ulcerative colitis in Chinese patients J Gastroenterol Hepatol 2011; 26(3): 593-8.
[http://dx.doi.org/10.1111/j.1440-1746.2010.06524.x] [PMID: 21155878]
]. A later report of Japanese case-control (64/236) cohort of UC patients indicated that MICA-A6 association attributed to LD with HLA-B52 [89Seki SS, Sugimura K, Ota M, et al. Stratification analysis of MICA triplet repeat polymorphisms and HLA antigens associated with ulcerative colitis in Japanese Tissue Antigens 2001; 58(2): 71-6.
[http://dx.doi.org/10.1034/j.1399-0039.2001.580201.x] [PMID: 11696218]
]. Two study of Caucasoid origin with CD (n=94 and 248), UC (n=94 and 329) and controls (n=154 and 354) could not find any associations of particular alleles of the MICA gene [90Glas J, Martin K, Brünnler G, et al. MICA, MICB and C1_4_1 polymorphism in Crohn’s disease and ulcerative colitis Tissue Antigens 2001; 58(4): 243-9.
[http://dx.doi.org/10.1034/j.1399-0039.2001.580404.x] [PMID: 11782275]
, 91Ahmad T, Marshall SE, Mulcahy-Hawes K, et al. High resolution MIC genotyping: design and application to the investigation of inflammatory bowel disease susceptibility Tissue Antigens 2002; 60(2): 164-79.
[http://dx.doi.org/10.1034/j.1399-0039.2002.600207.x] [PMID: 12392511]
]. Taking together, like other genetic association studies, in addition to sample size as an important factor, the incidence of MICA variants in patients with IBD may vary between different racial and ethnic populations.

The intestinal epithelial cell (IEC) is a major MICA expression cell type. Increased MICA expression was found on IECs in CD. Correspondingly, an increased subset of CD4(+) T cells expressing NKG2D was also found in the lamina propria from patients with CD, along with an increased Th1 cytokine profile and perforin in the periphery and in the mucosa in CD [92Allez M, Tieng V, Nakazawa A, et al. CD4+NKG2D+ T cells in Crohn’s disease mediate inflammatory and cytotoxic responses through MICA interactions Gastroenterology 2007; 132(7): 2346-58.
[http://dx.doi.org/10.1053/j.gastro.2007.03.025] [PMID: 17570210]
, 93Ge LQ, Jiang T, Zhao J, Chen ZT, Zhou F, Xia B. Upregulated mRNA expression of major histocompatibility complex class I chain-related gene A in colon and activated natural killer cells of Chinese patients with ulcerative colitis J Dig Dis 2011; 12(2): 82-9.
[http://dx.doi.org/10.1111/j.1751-2980.2010.00464.x] [PMID: 21091928]
]. These findings highlight the role of MICA-NKG2D in the activation of a unique subset of CD4(+) T cells with inflammatory and cytotoxic properties in CD [92Allez M, Tieng V, Nakazawa A, et al. CD4+NKG2D+ T cells in Crohn’s disease mediate inflammatory and cytotoxic responses through MICA interactions Gastroenterology 2007; 132(7): 2346-58.
[http://dx.doi.org/10.1053/j.gastro.2007.03.025] [PMID: 17570210]
].

SUMMARY AND PERSPECTIVE

Multiple polymorphisms of the MICA gene have been extensively examined in rheumatic diseases. Although some results are inconsistent, which are mainly conflicted in primary susceptibility verses secondary effect from the HLA class I or II genes. There seems to be an agreement that significantly increased frequencies of specific MICA alleles occur in various rheumatic diseases. The discrepancies of the genetic association of the MICA gene with the diseases may be largely caused by sample size and heterogeneity of study populations (Table 1). It is particularly concerned that the numbers of study subjects in most of the reports were relatively small with low statistical power.

Table 1

Summary of associations between inflammatory rheumatic diseases and MICA




In addition, genotyping methods and disease subtypes may also be important factors. Therefore, much research remains to be done on the genetics of MICA in rheumatic diseases.

MICA has been attributed to play important roles in immune surveillance. However, the evidence of functional MICA variants contributing to pathogenesis of many rheumatic diseases is still unconvincing. MICA polymorphism and/or haplotype alleles encode unique protein structures, and/or exhibit specific functions. For instance, MICA-A5.1 contains an insertion of guanine at codon 295 that results in a premature stop codon at position 304, which in turn encodes a truncated MICA protein lacking part of the transmembrane domain and the whole cytoplasmic tail [2Choy MK, Phipps ME. MICA polymorphism: biology and importance in immunity and disease Trends Mol Med 2010; 16(3): 97-106.
[http://dx.doi.org/10.1016/j.molmed.2010.01.002] [PMID: 20153697]
]; The proteins encoded by MICA-129-met possess stronger binding affinity to NKG2D than MICA-129-val [3Steinle A, Li P, Morris DL, et al. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family Immunogenetics 2001; 53(4): 279-87.
[http://dx.doi.org/10.1007/s002510100325] [PMID: 11491531]
]; Among MICA*008, *007 and *019, MICA*008 expresses less on the surface of human fibroblasts, but can be excreted in exosomes that down-regulate NKG2D activity [27Ashiru O, Boutet P, Fernández-Messina L, et al. Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes Cancer Res 2010; 70(2): 481-9.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1688] [PMID: 20068167]
, 94Shi C, Li H, Couturier JP, et al. Allele specific expression of MICA variants in human fibroblasts suggests a pathogenic mechanism Open Rheumatol J 2015; 9: 60-4.
[http://dx.doi.org/10.2174/1874312901409010060] [PMID: 26322142]
], MICA*019 highly expressed on the surface of the fibroblasts whereas expression of MICA*007 was the lowest in the soluble form, which may suggest a predominant up-regulation on NKG2D by both alleles. From its functional point of view, no matter contributing to primary or secondary disease susceptibility, changes of frequencies of MICA variants may impact cellular functions and subsequent immune responses or inflammatory process in the diseases. Therefore, a possible change of NKG2D signaling caused by high affinity of MICA to NKG2D may present in AS, PsA, SLE and IBD that were reported in association with MICA-129met [35Amroun H, Djoudi H, Busson M, et al. Early-onset ankylosing spondylitis is associated with a functional MICA polymorphism Hum Immunol 2005; 66(10): 1057-61.
[http://dx.doi.org/10.1016/j.humimm.2005.09.004] [PMID: 16386647]
, 36Zhou X, Wang J, Zou H, et al. MICA, a gene contributing strong susceptibility to ankylosing spondylitis Ann Rheum Dis 2014; 73(8): 1552-7.
[http://dx.doi.org/10.1136/annrheumdis-2013-203352] [PMID: 23727634]
, 44Pollock RA, Chandran V, Pellett FJ, et al. The functional MICA-129 polymorphism is associated with skin but not joint manifestations of psoriatic disease independently of HLA-B and HLA-C Tissue Antigens 2013; 82(1): 43-7.
[http://dx.doi.org/10.1111/tan.12126] [PMID: 23611695]
, 50Yoshida K, Komai K, Shiozawa K, et al. Role of the MICA polymorphism in systemic lupus erythematosus Arthritis Rheum 2011; 63(10): 3058-66.
[http://dx.doi.org/10.1002/art.30501] [PMID: 21702010]
, 84López-Hernández R, Valdés M, Lucas D, et al. Association analysis of MICA gene polymorphism and MICA-129 dimorphism with inflammatory bowel disease susceptibility in a Spanish population Hum Immunol 2010; 71(5): 512-4.
[http://dx.doi.org/10.1016/j.humimm.2010.02.003] [PMID: 20152875]
], and a potentially predominant up-regulation of NKG2D may occur in AS, BD and UC that were associated with MICA*007 and/or *019 [36Zhou X, Wang J, Zou H, et al. MICA, a gene contributing strong susceptibility to ankylosing spondylitis Ann Rheum Dis 2014; 73(8): 1552-7.
[http://dx.doi.org/10.1136/annrheumdis-2013-203352] [PMID: 23727634]
, 67Muñoz-Saá I, Cambra A, Pallarés L, et al. Allelic diversity and affinity variants of MICA are imbalanced in Spanish patients with Behçet’s disease Scand J Immunol 2006; 64(1): 77-82.
[http://dx.doi.org/10.1111/j.1365-3083.2006.01780.x] [PMID: 16784494]
, 85Orchard TR, Dhar A, Simmons JD, Vaughan R, Welsh KI, Jewell DP. MHC class I chain-like gene A (MICA) and its associations with inflammatory bowel disease and peripheral arthropathy Clin Exp Immunol 2001; 126(3): 437-40.
[http://dx.doi.org/10.1046/j.1365-2249.2001.01662.x] [PMID: 11737059]
].

In fact, altered expression of MICA and activity of NKG2G, and/or its downstream signals have been reported in RA, SLE, BD and IBD [31Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis Proc Natl Acad Sci USA 2003; 100(16): 9452-7.
[http://dx.doi.org/10.1073/pnas.1632807100] [PMID: 12878725]
, 52Spada R, Rojas JM, Pérez-Yagüe S, et al. NKG2D ligand overexpression in lupus nephritis correlates with increased NK cell activity and differentiation in kidneys but not in the periphery J Leukoc Biol 2015; 97(3): 583-98.
[http://dx.doi.org/10.1189/jlb.4A0714-326R] [PMID: 25583577]
, 53Dai Z, Turtle CJ, Booth GC, et al. Normally occurring NKG2D+CD4+ T cells are immunosuppressive and inversely correlated with disease activity in juvenile-onset lupus J Exp Med 2009; 206(4): 793-805.
[http://dx.doi.org/10.1084/jem.20081648] [PMID: 19289577]
, 69Yasuoka H, Okazaki Y, Kawakami Y, et al. Autoreactive CD8+ cytotoxic T lymphocytes to major histocompatibility complex class I chain-related gene A in patients with Behçet’s disease Arthritis Rheum 2004; 50(11): 3658-62.
[http://dx.doi.org/10.1002/art.20597] [PMID: 15529349]
, 92Allez M, Tieng V, Nakazawa A, et al. CD4+NKG2D+ T cells in Crohn’s disease mediate inflammatory and cytotoxic responses through MICA interactions Gastroenterology 2007; 132(7): 2346-58.
[http://dx.doi.org/10.1053/j.gastro.2007.03.025] [PMID: 17570210]
, 93Ge LQ, Jiang T, Zhao J, Chen ZT, Zhou F, Xia B. Upregulated mRNA expression of major histocompatibility complex class I chain-related gene A in colon and activated natural killer cells of Chinese patients with ulcerative colitis J Dig Dis 2011; 12(2): 82-9.
[http://dx.doi.org/10.1111/j.1751-2980.2010.00464.x] [PMID: 21091928]
]. Further research may be focused on how MICA variants are associated with MICA/NKG2D signaling that contributes to pathogenesis in rheumatic diseases.

CONFLICT INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

This study was supported by the NIH NIAID 1U01AI09090-01.

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"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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