Basic and clinical immunology in uveitis

Understanding the basic immune mechanisms and how they relate to the eye are becoming obtainable goals with far reaching implications. Attempts are made to classically divide the immune responses noted into Type I-IgE mediated, Type II-Antibody mediated killing, Type III-Immune complex mediation, and Type IV-Cell mediated. Though several mechanisms are surely working simultaneously, it remains an helpful method of analysis. Until recently, Type III hypersensitivity reactions were thought to be the basic underlying cause of most ocular inflammatory disease, but recent evidence would suggest that cell mediated mechanisms are more important for sight threatening ocular disease (uveitis). The S-antigen and IRBP induced experimental models for uveitis have provided us with invaluable information concerning the potential mechanisms underpinning uveitis, while the diseases themselves manifest many aspects of that seen in human disease. Additionally, it has permitted us to investigate the way in which immune cells may "home" to a target organ, this in part due to the expression of HLA antigens on non-immune tissues in the eye. The observation that T-cell mechanisms appear of major import in uveitis permitted a new approach to therapy, the use of the anti-T-cell drug cyclosporine. Its use in severe sight threatening disease has shown it to be effective, thereby confirming the notion of the importance of T-cell mediation of these diseases. Perhaps most notable is this agent's efficacy in the treatment of Beh?et uveitis. The problem of renal toxicity has been addressed by using cyclosporine in combination with other agents, including those not directly affecting the immune system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Association of human histocompatibility antigens with ophthalmological disorders

Many studies have been trying to identify genetic markers for ophthalmological diseases, including, among others, the HLA (Human Leukocyte Antigens). Localized on the short arm of chromosome 6, the human leukocyte antigen system is well known for its capacity to confer susceptibility or resistance to different diseases. In view of its accentuated polymorphism, the strength and type of association differs with the disease and sometimes, with the studied ethnic-racial group. The development of molecular methods to typify HLA alleles and recent updates of their nomenclature has contributed to a better understanding of this system. In this review, some aspects of the human leukocyte antigen system are discussed, such as the methods of detection, nomenclature and association with acute anterior uveitis, ocular cicatricial pemphigoid, young-onset keratoconus and birdshot retinochoroidopathy.     

Studies on exogenous and endogenous factors associated with various ocular diseases

The exact cause and nature of various ocular diseases are still unknown. In accordance with the progress of modern medical science, technology for research investigations has greatly developed and a variety of new results have recently been produced. However, they were mostly about exogenous factors such as bacteria or parasites. On the other hand, molecular biology has markedly progressed in the second half of the 20th century and has been applied to medical science. As for the exogenous factors, molecular techniques have been introduced to the diagnosis of infectious diseases, and their diagnosis has become much easier and much more exact than before. Similarly, in the field of immunogenetics, molecular genetics has greatly developed, and disease susceptibility or disease resistance has been investigated at the DNA or molecular level. Regarding the exogenous disease mechanisms, most infectious diseases occur when the microorganisms are transmitted to some individuals. In this case, endogenous factors play almost no or very little role. Adenovirus keratoconjunctivitis is one example. Human adenovirus (HAdV) is a DNA virus. Although HAdVs are classified into 51 different serotypes, only 7 of them such as HAdV-3, -4, -7, -8, -11, -19, and -37 usually develop acute keratoconjunctivitis. The genome of HAdV develops constant mutation, and new genome types often cause epidemics of nosocomial infections. Recent studies showed that most of the keratoconjunctivitis cases are caused by HAdV-37 in Japan. With regard to the endogenous disease mechanisms, only 30 years have passed since the recent molecular genetic studies on disease susceptibility started. Before that, genetic disease mechanisms were studied only in hereditary diseases such as color vision defects, which follow the modes of Mendelian inheritance. Therefore, the presence of disease susceptibility was not clearly understood in the so-called nonhereditary diseases. However, after our initial findings of the close association between Beh?et's disease and HL-A 5 (later HLA-B 5 or HLA-B 51) in 1973, there were many reports on the presence of genetic predisposition to certain non-hereditary diseases. One example is Vogt-Koyanagi-Harada's (VKH) disease which has a close association with HLA-DRB 1*0405 in Japanese patients, as also was the case with sympathetic ophthalmia. These studies indicate that Beh?et's disease may be called "a disease of the Yayoi people" and Vogt-Koyanagi-Harada's disease as "a disease of the Jomon people" when analyze the associated genetic factors. On the other hand, the human genome project has been successfully completed and it is now possible for us to investigate any genetic factor associated with certain diseases either on 22 pairs of autosomal chromosomes or on one pair of sex chromosomes. Our collaborative team has adopted the microsatellite methods utilizing the pooled DNA PCR method, and started investigation of any genetic association with ocular diseases, in addition to the HLA system on the short arm of autosomal chromosome 6. In the first screening of 100 DNA samples of Beh?et's disease patients, for example, 9 % of microsatellite markers on the autosomal chromosomes 1, 6, 17, and 19 showed significant positive association. The same studies are now in progress by our collaborative team on inflammatory diseases such as sarcoidosis, and on noninflammatory conditions like hypertension or high myopia. These results suggest that exogenous environmental factors such as infections which may trigger the occurrence of the disease or conditions, and endogenous genetic factors which may predispose someone to contracting a disease, are both significantly associated with various ocular diseases, and construct intricate disease mechanisms. Therefore, in future studies of diagnosis, treatment, and prevention of various ocular diseases, both exogenous factors and endogenous factors have to be carefully analyzed and investigated.     

Profiling of human leukocyte antigens in Eales‘ disease

Eales' disease is a primary retinal perivasculitis of an undetermined etiology seen predominantly in the Indian sub-continent and rarely in the West. Strong HLA association has been proven in retinal vasculitis of Behcet's disease. HLA association of Eales' disease is unknown and therefore the present study was undertaken to determine the same. The frequency of 30 HLA antigens (9 HLA-A antigens, 10 HLA-B antigens, 3 HLA-C antigens, 7 HLA-DR antigens and 1 HLA-DQ antigen) was studied by standard micro-lymphocytotoxicity test in 57 patients with Eales' disease and 50 age and sex-matched normal persons as controls. Both the patients and controls underwent complete ocular and clinical examinations and laboratory investigations. Inflammatory diseases similar to Eales' disease were ruled out in the patients before they were enrolled. Statistically significant higher phenotype frequencies of HLA B5 (B51), DR1 and DR4 were observed among patients with Eales‘ disease as compared to controls. The gene frequency of HLA B5 (B51) in our group of patients and controls was comparable with other earlier studies in the Indian population. The finding of significant association of Eales' patients with positive disequilibrium (Δ)haplotypes A3-B44 and A11-B12 may be related to the development of this disease. The presence of the above HLA antigens may be indicative of predisposition to Eales' disease. This revised version was published online in July 2006 with corrections to the Cover Date.     

Role of HLA and T lymphocytes in the immune response

Human leukocyte antigens (HLA) play a role in the pathogenesis of diseases involving an immune response. Because HLA are strongly associated with ophthalmologic diseases such as Behcet's disease, VogtKoyanagi-Harada's disease and birdshot retinochoroidopathy, an understanding of HLA is essential in analyzing the immunogenetic mechanisms underlying many diseases. Recent advances in molecular biology have made it possible to characterize the HLA gene region at the DNA level. This paper provides a comprehensive overview of the etiology of various immunologic disorders with emphasis on the role of HLA, a self/not-self discrimination mechanism, and of T lymphocytes.     

Role of HLA and T lymphocytes in the immune response

Human leukocyte antigens (HLA) play a role in the pathogenesis of diseases involving an immune response. Because HLA are strongly associated with ophthalmologic diseases such as Behcet's disease, VogtKoyanagi-Harada's disease and birdshot retinochoroidopathy, an understanding of HLA is essential in analyzing the immunogenetic mechanisms underlying many diseases. Recent advances in molecular biology have made it possible to characterize the HLA gene region at the DNA level. This paper provides a comprehensive overview of the etiology of various immunologic disorders with emphasis on the role of HLA, a self/not-self discrimination mechanism, and of T lymphocytes.     

人眼表微生物群与眼表疾病研究进展

眼表微生物群是人体眼表微环境的一部分,在维持其稳定中占据重要作用。许多研究对于健康与疾病状态下眼表微生物群的组成进行探究,但研究结果基于内外因素的不同而存在差异,且微生物失调与疾病之间的关系也尚未明确。近年来,随着肠道微生物与全身性疾病的研究不断深入,眼科研究者们也从中获得了一些启发,对眼表微生物群与眼表非感染性疾病的关系有了更进一步的探讨。本文将对正常眼表核心微生物群、眼部及全身性疾病眼表微生物群的变化进行综述,并讨论微生物失调引起疾病的可能机制,希望对未来眼表微生物群的进一步研究提供参考依据。     

HLA DR and DQ expression on human retinal pigment epithelial cells in vitro

In a previous immunohistopathological study, we demonstrated a deviant expression of class II antigens on the uveal pigment epithelial cells of patients with proliferative diabetic retinopathy. The mechanisms triggering this abnormal expression by epithelial cells are not well known, and we tried to induce this phenomenon on primary cultures of human retinal pigment epithelial (RPE) cells. Confluent RPE-cell monolayers were supplemented with several biological or chemical reagents [recombinant interferon gamma, phytohemaglutinin A-P (PHA-P), phorbolmyristate acetate (PMA), recombinant interleukin-2, fibroblast growth factor (FGF), Insulin], to investigate their ability to induce HLA DR and DQ expression. On days 1, 3 and 5 after stimulation, the cells were incubated with monoclonal antibodies directed against human class II antigens: all reagents used failed to induce class II antigen expression. However, on day 7, we demonstrated the presence of numerous positive HLA DR and HLA DQ cells stimulated by gamma interferon, the percentages being closely related to the dose of this lymphokine. These findings, together with those of other investigators and our previous work on uveal pigmented epithelial cells in diabetic patients, may shed light on the exact implication of RPE in many poorly documented ocular diseases.     

Immunogenetic and molecular genetic studies on ocular diseases]

The immunogenetic mechanisms of various ocular diseases were investigated utilizing recently developed molecular biological and molecular genetic techniques. It was revealed that HLA-B 51 was closely associated with Beh?et's disease. Investigation of genetic polymorphism of TNF-beta (tumor necrosis factor-beta) showed that 95% of Beh?et's disease patients had the 10.5 kbp Nco I fragment. It was therefore concluded that the gene of susceptibility to Beh?et's disease is located between HLA-B and TNF-beta loci on the short arm of chromosome 6. Similar studies of HLA-DNA typing in Harada's disease frequently seen in Japan showed that frequencies of HLA-DRB1 * 0405, HLA-DQA1 * 0301 and HLA-DQB1 * 0401 were significantly increased in patients compared with normal controls. These data suggested that those who have serine at position 57 of HLA-DR, glutamic acid at position 70 and aspertic acid at position 71 of HLA-DQ respond to certain unknown agents significantly more than those without them, thus leading to the development of Harada's disease. The same HLA association was observed between Harada's disease and sympathetic ophthalmia, and the immunogenetic mechanism was thought to be similar in both diseases. Recent immunogenetic and molecular genetic investigations on various ocular diseases have shed new light not only on the genetic individual susceptibility and biased racial differences, but also on the diagnosis of the ocular diseases, reclassification of disease entities according to HLA associations, and judgement of disease prognosis. Further progress of molecular medicine may make it possible to treat various intractable ocular diseases by gene therapy in the near future.     

HLA and eye disease.

This review article discusses the evolution and function of the histocompatibility system, the nature of the HLA antigens and their classification, the phenomenon of linkage disequilibrium, and the mechanisms of HLA and disease susceptibility. The reported associations between HLA antigens and various eye diseases are analysed and their significance is discussed. Problems in designing studies on HLA and disease associations are highlighted and suitable statistical procedures for the analysis of the results are outlined.     

Histocompatibility (HLA) antigens and eye diseases other than uveitis

In recent years, numerous studies on the possible associations of histocompatibility (HLA) antigens with various eye diseases other than uveitis have been carried out. This paper presents, discusses and evaluates the results of these studies. Undoubtedly, apart from acute anterior uveitis, HLA-typing has very limited usefulness in the practice of clinical ophthalmology. Many reported HLA associations with other eye diseases have not been confirmed by subsequent studies. However, a sizable residuum of highly significant and reproducible associations between HLA antigens and several eye diseases remains, suggesting that HLA-typing in patients with these diseases may contribute to the understanding of pathogenesis and etiology and may prove a valuable prognostic indicator for some diseases.     

Humanes Leukozytenantigensystem in der Augenheilkunde

Various inflammatory and non-inflammatory eye diseases are associated with specific HLA isotypes. Therefore, HLA isotyping can be a useful diagnostic tool for these diseases and has already been shown to reduce the rejection rate of corneal allografts. Unfortunately, the volume of published data and the varying quality of these publications complicate obtaining good overview in this field. This review briefly summarizes the genetic structure of the HLA system and elucidates differences between HLA classes I and II in the context of antigen presentation. Possible mechanisms of HLA associations in the field of ophthalmology are discussed, and finally different tools (e.g. genome wide association studies) for assessing associations of HLA isotypes with different ocular diseases are examined.     

HLA associations and ancestry in Vogt-Koyanagi-Harada disease and sympathetic ophthalmia

A strong association with HLA antigens DR4, DRw53, and Bw54 has previously been reported among Japanese patients with Vogt-Koyanagi-Harada disease (VKH) and sympathetic ophthalmia (SO). In the United States, no firm association between HLA-A or -B loci and VKH has been found previously; testing for HLA-DR loci has not been performed to date. The authors performed HLA typing of 23 American patients with VKH and 8 patients with SO. When VKH patients were compared with racially matched controls without disease and patients with other types of uveitis, strong associations with HLA-DR4 and HLA-DRw53 were found. The strongest associations observed in this sample were with HLA-DQw3, an antigen which is in positive linkage disequilibrium with DR4, and with the HLA-DR4/DQw3 haplotype. The small number of patients with SO precluded statistical analysis; however, similar HLA associations were noted. The patients also were questioned regarding their ancestry. The anecdotal association of VKH with American Indian ancestry was confirmed. It appears that the ethnoracial association may be explained by HLA type. One possible explanation for identical HLA associations in two diseases with different precipitating events yet similar ocular manifestations is development of an altered immune response to exogenous microbial antigen with subsequent autoimmunity. Further definition of the genetic susceptibility to VKH and SO may help define the pathophysiology of both diseases and allow the prediction of which patients are at increased risk for SO.     

人类白细胞抗原分型检测及其与眼部疾病相关性的研究进展

人类白细胞抗原(HLA),又称人类主要组织相容性复合体。其分型检测方法历经了血清学分型、细胞学分型及脱氧核糖核酸(DNA)分型的发展过程。目前,DNA分型检测方法为主要的HLA分型检测方法,且有逐渐取代其他两种分型检测方法的趋势。此外,经国内外的诸多学者研究发现,HLA与多种疾病具有相关性。其中,关于眼部疾病与HLA相关性的报道更是层出不穷,尤其是在葡萄膜炎的相关研究中。故本文拟对HLA分型检测及其与眼部疾病的相关性进行综述。     

Human leukocyte antigen serologic and DNA typing of Beh?et's disease and its primary association with B51.

Ninety Japanese patients with Beh?et's disease (BD) were typed for human leukocyte antigen (HLA)-DRB1, -DQA1-, -DQB1, and -DPB1 alleles by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and for HLA-A, -B, -C, -DR, and -DQ antigens by conventional serologic typing. Serologic HLA typing showed a remarkably significant increase of HLA-B51 and a significant decrease of HLA-DQw1 in the patients with BD, especially those with ocular lesions including complete type, as compared with the control group (for B51, chi-squared = 46.75, P corrected < 0.001, relative risk [RR] = 7.9; for DQw1, chi-squared = 12.10, P corrected < 0.01, RR = 0.4). By PCR-RFLP genotyping, no significant difference was revealed in any class II alleles between the patient and the control groups in the corrected P value test, but P value analysis showed the significantly high frequency of DRB1*0802 and the significantly low frequencies of DQA1*0103, DQB1*0601, and DQB1*0501. No significant difference was observed in any DPB1 alleles by either P value analysis. These results indicated that the primary and primordial gene(s) responsible for the susceptibility to BD, especially related to ocular lesions, were not located in the HLA class II gene region but were in or very close to the HLA-B locus in the class I region. They also suggested the possibility that BD was a symptom complex associated with some independent diseases.     

Conjunctival autograft transplantation for unilateral ocular surface diseases

Rehabilitation of the diseased ocular surface by autologous conjunctival transplantation as first described by Thoft has expanded the possibilities for eventual visual restoration of patients with severe ocular surface disease. This paper will introduce a new surgical technique for diseased ocular surface preparation and for the acquisition, transfer, and placement of a 360 degrees ring of autologous conjunctiva in patients with unilateral surface pathology. Patients representing different unilateral surface diseases with up to 2 years follow-up are presented and discussed.     

The human leukocyte antigen complex and chronic ocular inflammatory disorders

PURPOSE: To review the role of gene products from the human leukocyte antigen (HLA) complex in the normal functioning of the immune system, ocular inflammation, and models of autoimmunity. METHOD: A review of recently published reports. RESULTS: Many chronic ocular inflammatory diseases are associated with specific alleles of the HLA complex. Understanding how HLA gene products function normally provides clues to the mechanism of disease associations. In the thymus, these molecules control the shape of the developing T-cell repertoire, leading to self-tolerance. In the periphery, HLA molecules bind and present peptide fragments to T cells, leading to a variety of effector functions. Although effector functions are for the most part beneficial, models are reviewed in which peptide-HLA interactions lead to T-cell responses with pathologic consequences. Herpes stromal keratitis is an informative animal model highlighting the role of self-tolerance, infection, and molecular mimicry in the development of autoimmunity. CONCLUSIONS: Human leukocyte antigen gene products may be associated with chronic inflammatory disorders through the unique presentation of "disease-inducing" peptides or the development of a T-cell repertoire prone to autoreactivity and molecular mimicry.     

Oberfl?chenrekonstruktion bei Limbusstammzellinsuffizienz

Various ocular surface diseases are caused by loss of corneal epithelial stem cells or dysfunction of the limbal stem cell niche. Besides conventional transplantation of autologous or allogenic limbal tissue, recent advances in tissue engineering have led to the development of new culture and expansion techniques of human limbal stem and progenitor cells (LSPC) as a new strategy to successfully treat limbal stem cell deficiency (LSCD). From a small autologous limbal biopsy with a limited amount of LSPC an epithelium ready for transplantation is achieved. Autologous grafting of cultured limbal epithelium led in most of the treated cases to a successful reconstruction of the corneal surface. Alternative methods which have recently been introduced to treat LSCD use other stem cell sources including the transplantation of oral mucosal epithelium. In this article the challenges and controversies associated with these stem cell culture techniques for ocular surface reconstruction are reviewed.     

Experimental models of autoimmune inflammatory ocular diseases

Ocular inflammation is one of the leading causes of blindness and loss of vision. Human uveitis is a complex and heterogeneous group of diseases characterized by inflammation of intraocular tissues. The eye may be the only organ involved, or uveitis may be part of a systemic disease. A significant number of cases are of unknown etiology and are labeled idiopathic. Animal models have been developed to the study of the physiopathogenesis of autoimmune uveitis due to the difficulty in obtaining human eye inflamed tissues for experiments. Most of those models are induced by injection of specific photoreceptors proteins (e.g., S-antigen, interphotoreceptor retinoid-binding protein, rhodopsin, recoverin, phosducin). Non-retinal antigens, including melanin-associated proteins and myelin basic protein, are also good inducers of uveitis in animals. Understanding the basic mechanisms and pathogenesis of autoimmune ocular diseases are essential for the development of new treatment approaches and therapeutic agents. The present review describes the main experimental models of autoimmune ocular inflammatory diseases.     

汉族人群Behcet病和Vogt-小柳原田综合征遗传易感性研究进展

葡萄膜炎是一类发生于葡萄膜、视网膜、视网膜血管及玻璃体的炎症。Behcet病和Vogt-小柳原田综合征是我国常见且致盲率较高的2种葡萄膜炎类型,其发病机制复杂,涉及遗传和环境因素的相互作用。长期以来,与人类白细胞抗原（HLA）的显著相关性是遗传背景参与多种葡萄膜炎类型发生的最重要证据。近年来,随着新技术的发展和研究的深入,利用候选基因法发现多种免疫相关基因的多态性与Behcet病和Vogt-小柳原田综合征的发生相关,如IL-23R、IL-17、miR-146a等;利用全基因相关分析的方法全面分析了遗传因素在这2种疾病发生中的作用。现就发现的汉族人群Behcet病和Vogt-小柳原田综合征相关遗传易感因素的研究进展做一综述。