作者：Mahtab Alam Khanzada Siddiqa Gul Syed Asher Dabir Shafi Muhammad Jatoi Ashok Kumar Narsan
作者单位：巴基斯坦海德拉巴，Liaquat大学眼科医院
【摘要】 目的：评价植入聚甲基丙烯酸甲酯（PMMA）人工晶状体和软性人工晶状体(AcroSof)致后发性白内障的严重程度。
方法：总共100人（110眼）进行了人工晶状体植入术，随机分为两组植入不同类型的晶状体。组I: AcrySof（SA60AT）人工晶状体，组II:PMMA（LX10BD）人工晶状体。分别在术后3，6，12和18mo,通过测定最佳矫正视力和数码照片拍摄评价后囊膜浑浊的密度。
结果：术后3mo, PMMA组后囊膜浑浊的密度明显增加（3.6%），而Acrylic组并未发现增加。术后18mo，显著后囊膜浑浊两组的发生率相比较，Acrylic组（14.5%）较PMMA组（34.5%）低。由于PMMA人工晶状体比AcrySof人工晶状体所致后囊膜浑浊的范围广，故其导致更严重的视力降低。
结论：与PMMA人工晶状体相比较，植入AcrySof人工晶状体在一定程度上有助于降低后发性白内障的发生率。
【关键词】 后囊膜浑浊 晶状体上皮细胞 人工晶状体
INTRODUCTION
Uveitis is an inflammation of the uveal tract and anatomically categorized as anterior, intermediate, posterior and panuveitis. The inflammatory form of uveitis can occur either as an isolated disease or as part of a systemic syndrome such as Behcets disease (BD), VKH syndrome and spondyloarthritis. It often affects those aged between 20 and 50. Despite current advances in diagnosis and management, visual loss occurs in 35% 40% of patients with uveitis.
The pathogenesis of uveitis is not well understood. The inheritance pattern of uveitis is complex and influenced by multiple genetic factors[1]. Susceptibility to uveitis has been associated with the MHC genes[2]. Since HLAB27 itself plays only a minor role in the overall genetic background of uveitis[3], other genetic variants like TNFα, CCL2 and CCL5 have been recently suggested to play roles in uveitis. This review introduced the advances in the studies on cytokine and chemokine gene polymorphisms associated with uveitis.
CYTOKINE GENES
Cytokines are regulatory proteins produced by cells in response to a variety of stimuli. They act as mediators of inflammation and can cause tissue damage in chronic inflammatory diseases. Cytokines have been associated with the pathogenesis of uveitis[4].
IL1 Gene IL1 gene contains three related genes that encode the proinflammatory cytokines IL1α, IL1β and their endogenous receptor antagonist IL1ra. Several IL1 gene polymorphisms have been described and associations with uveitis have also been reported. Karasneh et al[5] found that IL1α 899C allele was associated with BD and IL1α 889C/IL1β +5887T haplotype was a risk factor for BD. The IL1α 889 and IL1β+5887 CC/TT combined genotype was significantly more observed in BD patients than in controls. Similarly, Alayli et al[6] also found a significantly increased frequency of IL1α 899C allele in BD patients, IL1β511C allele and CC genotype frequencies were significantly higher in BD patients compared to controls, IL1β +3962 CC genotype was associated with BD susceptibility. In contrast, Coskun et al[7] reported no significant difference in genotype and allele frequencies of IL1β 511 between BD patients and controls, but they identified an increased frequencies of both IL1β +3953 T allele and TT genotype in patients with BD.
Intraocular injection of IL1ra decreases the inflammatory response in anterior uveitis caused by intravitreal injection of IL1 in animal models[8]. Interestingly, patients with chronic uveitis has an increased frequency of the IL1ra T allele than those with recurrent uveitis[9].
IL18 Gene IL18 gene is regarded as a pivotal mediator of Th1 cytokine responses and can enhance the production of TNF α, GMCSF and IFNγ, which were elevated in BD[10]. It has been reported that BD patients have higher serum levels of IL18 than controls, and its concentration is related to disease activity[11]. Giedraitis et al[12] demonstrated that IL18 607A/C and 137C/G polymorphisms in the 5UTR binding affected promoter activity. Though these two polymorphisms have been studied in many inflammatory diseases, only two studies in Korean have been reported on uveitis. Jang et al[13] identified a significant higher frequency of 137GG genotype in BD patients with ocular lesions than patients without ocular lesions, although they didnt find any significantly different distributions of 137 and 607 polymorphisms between patients and controls. Another similar study[14] identified significantly higher frequencies of both 607C allele and CC genotype, and a lower frequency of 607A/137G haplotype in BD patients than controls. These results suggested that IL18 gene may be a susceptibility gene of uveitis.
TNFα Gene TNFα is produced predominantly by macrophages. High serum level of TNFα has been associated with recurrent uveitis, and disease inflammation has been found in TNFreceptordeficient mice in immunecomplexinduced uveitis[15,16]. Kuo et al[17] investigated the associations between TNFα and TNFreceptor gene polymorphisms and idiopathic acute anterior uveitis (IAU) in Caucasians, they found a significant increase in the frequency of TNF857T allele in patients with IAU compared with controls. Menezo et al[9] also found a significant increase in the frequency of TNF308G allele in Caucasian patients with HLAB27 positive anterior uveitis compared to patients negative for HLAB27. In Turkish population, the relation and functional importance of TNFα1031T/C was investigated, the results showed that the frequency of TNF1031C allele was significantly higher in BD patients compared to controls; whereas carrying the T allele render patients were more prone to develop a positive shin pathergy test[18].
CHEMOKINE GENES
Chemokines are a group of low molecular weight (～8 14kDa), mostly basic structurally related proteins that function as potent mediators of inflammation by their ability to recruit and activate leukocytes[19,20]. There are two major subfamilies of chemokines: CXC chemokines like CXCL8/IL8 usually recruit neutrophils, whereas CC chemokines like CCL2 and CCL5 tend to attract monocytes[21].
IL8 and its Receptor Genes IL8 can cause a transient increase in cytosolic calcium concentrations and release of enzymes from granules, thus enhance the production of reactive oxygen species and increase chemotaxis to neutrophils. Cellular activities of IL8 are mediated by its two receptors, CXCR1 and CXCR2. Serum and cerebrospinal fluid levels of IL8 have been found to be elevated in BD patients and correlated with disease activity[22,23]. Concentration of IL8 increase significantly in the aqueous humor of patients with acute anterior uveitis (AAU)[24].
DuymazTozkir et al[25] reported no skewed deviation of IL8 or CXCR2 gene polymorphisms in Turkish patients with BD. Yeo et al[26] reported no association between IL8 or CXCR1 gene polymorphisms and IAU either. On the contrary, Lee et al[27] found that though there were no SNPs associated with BD, the increased frequency of haplotype TAT inferred from SNPs IL8353A/T, 251A/T and +678T/C has strong association with BD. These results suggested that a combined effect of IL8 SNPs is necessary to disease susceptibility, while the individual effect is not strong enough to show it.
CCL2 and its Receptor Genes CCL2, known as monocyte chemoattractant protein1 (MCP1), is a chemoattractive cytokine. In animal models CCL2 was shown to play a role in autoimmune response and was thought to participate in the leukocyte infiltration and protein leakage in AAU and in the induction of uveitis itself[28,29]. MCP1 can be detected easily in the aqueous humor of patients with active AAU[24]. CCL2 2518A>G polymorphism, which correlates with individual difference in production of MCP1, was identified in the MCP1 gene distal regulatory region[30]; monocytes from individuals carrying 2518G allele produce more MCP1 after proper stimulus.
Chen et al[31] found that CCL2 haplotype with GA/AA were more prevalent in females and AA/AA or AA/AT were more prevalent in males. Wegscheider et al[32] showed that carriers of CCL22518G allele were significantly more often in patients with HLAB27 associated AAU than HLAB27 positive controls. Another study[26] demonstrated that the frequency of MCP1 63555T allele was significantly higher in controls compared to patients with IAU, which indicated that T allele may be a protective marker against uveitis.
The associations of SNPs in CCL2 gene and clinical phenotypes of uveitis were identified by the study of idiopathic immunemediated posterior uveitis[33]. The results showed that CCL22518G allele was associated with a younger age onset of disease, the mean age of disease onset in patients with AA genotype was 41 years compared to 33 years in patients with G allele. The study also found that patients with CCR2 64I allele had a higher risk of developing an elevated intraocular pressure compared to patients with wildtype genotype.
CCL5 and its Receptor Genes CCL5, earlier called regulated upon activation, normal Tcell expressed, and secreted (RANTES), is chemotactic for T cells and plays an active role in recruiting leukocytes into inflammatory sites. Two polymorphic sites ( 28 and 403) in the upstream region of the CCL5 gene that contains cisacting element involved with CCL5 promoter activity[34,35]. They were in linkage disequilibrium. The CCL5 403AA genotype was only found in male patients with BD but not in controls[31].
Ahad et al[33] found that CCL5 403GG genotype was associated with disease severity and G allele was associated with worse visual acuity (VA) in the affected eye. CCL5 del32 was found to be associated with visual outcome even after correction for disease phenotype and treatment. CCL559029 polymorphism was associated with the need for persistent corticosteroid therapy of more than 10mg per day to control inflammation. Yang et al[36] and Mojtahedi et al[37] reported no association of CCR5del32 polymorphism with BD but revealed a significant difference in distribution of the CCR5 del32 in female patients compared with female controls.
CONCLUSION
In addition to above gene polymorphisms, other cytokines and their receptor genes, such as IL6, IL10 and IFNγ, have also been studied[9]. Studies of the genetics of uveitis have revealed that cytokine and chemokine gene polymorphisms have strong associations with uveitis. But current studies of these genes concentrated on casecontrol study, small sample size is a frequent problem and can result in insufficient statistical power and provide imprecise estimates of the disease association. In the future, largescale studies and different populations will be necessary to validate the associations of these genes and uveitis development and clinical phenotypes.
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