Immunopathogenic Background of Pars Planitis.

Pars planitis is defined as an intermediate uveitis of unknown background of systemic disease with characteristic formations such as vitreous snowballs, snowbanks and changes in peripheral retina. The incidence of pars planitis varies 2.4-15.4 % of the uveitis patients. The pathogenesis of the disease is to be determined in future. Clinical and histopathological findings suggest an autoimmune etiology, most likely as a reaction to endogenous antigen of unknown source, with T cells predominant in both vitreous and pars plana infiltrations. T cells subsets play an important role as a memory-effector peripheral cell. Snowbanks are formed as an effect of post inflammatory glial proliferation of fibrous astrocytes. There is also a genetic predisposition for pars planitis by human leukocyte antigen and several other genes. A coexistence of multiple sclerosis and optic neuritis has been described in numerous studies. Epiretinal membrane, cataract, cystoid macular edema, retinal detachment, retinal vasculitis, neovascularization, vitreous peripheral traction, peripheral hole formation, vitreous hemorrhage, disc edema are common complications observed in pars planitis. There is a need to expand the knowledge of the pathogenic and immunologic background of the pars planitis to create an accurate pharmacological treatment.

[Clinical and epidemiological features and HLA association in patients with pars planitis]. / Características clínicas, epidemiológicas y asociación con el sistema HLA en pacientes con pars planitis.

BACKGROUND AND OBJECTIVES: Epidemiological studies on North American patients reported an association between HLA DR15 and pars planitis. This association has not been studied in the Spanish population. The objectives of the present study were to describe the clinical and epidemiological features of patients with pars planitis diagnosed in our hospital as well as the prevalence of multiple sclerosis and HLA class I and II. PATIENTS AND METHODS: Twenty four patients with pars planitis were identified among 226 patients with uveitis diagnosed in the Ophtahlmology Department of our center from January 1992 to October 2006. Twenty four patients and 194 healthy controls underwent HLA A, B and DR genotyping. RESULTS: The most frequent complication was cystic macular edema. Most patients needed many medical treatments. No statistical association was found between pars planitis and HLA. CONCLUSIONS: Epidemiological data were consistent with previously reported studies. There appears to be no association between the occurrence of pars planitis and HLA DR 15 or other known HLA genotypes in Spanish patients. However, the small sample size could have limited the power of this study.

Peptidic sequence "HSEAETGPP" is recognized by the sera of pars planitis patients.

PURPOSE: HLA class II, p-36 protein, heat shock protein and retinal antigens have been associated with pars planitis (PP), but their participation in the development of the disease are unknown. A search for new molecules related to PP is necessary. This work focused on the identification of peptides recognized by PP patient sera using the phage display method. METHODS: Sera of PP patients were used to isolate peptides fused to M13-phage pIII protein. The response of PP and healthy sera to peptides was determined by ELISA. PCR amplification and sequencing of peptide-encoding fragments from clones with high recognition by PP sera were used to characterize displayed peptides. RESULTS: One hundred clones were randomly selected from a phage display library after three panning rounds using serum proteins from a PP patient. The immunologic response level of 100 clones selected were determined with a major number of patients, it was found that one clone was recognized stronger in PP patients sera than in healthy sera (PP vs. healthy; P < 0.05). The peptide-encoding region of this clone was sequenced and translated. The peptide sequence corresponded to HSEAETGPP. An identical amino acid sequence to HSEAETGPP is found in the human proline-rich transmembrane protein 2 which has not been related with eye diseases. CONCLUSION: These results suggest that the peptide HSEAETGPP is associated with PP.

Pars planitis is associated with an increased frequency of effector-memory CD57+ T cells.

AIM: To evaluate the frequency, phenotype and the potential function of CD57+ T cell subsets in patients with pars planitis. METHODS: CD4+CD57+ and CD8+CD57+ T cells were quantitated in peripheral blood from 15 patients with pars planitis and 15 healthy controls. To evaluate the phenotype and potential function of CD57+ T cell subsets CCR7, CD27, CD28, CD45RA, CD45RO, intracellular IFN-gamma, IL-4, perforin and granzyme-A expression were assessed by flow cytometry. RESULTS: CD57+ T cells subsets were increased in patients with pars planitis (p = 0.002). The majority of CD4+CD57+ T cells were CCR7-CD27-CD28-CD45RO+, while the most CD8+CD57+ T cells were CCR7-CD27-CD28-CD45RA+. The number of cells positive for intracellular IFN-gamma and IL-4 was higher in the CD57+ T cell populations. A greater number of CD8+CD57+ T cells than CD8+CD57- T cells were positive to perforin (p = 0.006) and granzyme-A (p = 0.01). CONCLUSIONS: CD57+ T cells had a phenotype associated with peripheral memory (CCR7-CD27-CD28-). Cytokine production by CD57+ T cells suggests that these cells may play a role in helper cell regulation. High expression of intracellular proteins involved in cytotoxicity suggests that CD8+CD57+ T cells may play an effector role. Taken together, this study proposes that CD57+ T cells function as memory-effector T cell subsets during pars planitis pathogenesis.

Elevated levels of interleukin 6 in the vitreous fluid of patients with pars planitis and posterior uveitis: the Massachusetts eye & ear experience and review of previous studies.

INTRODUCTION: Although the exact mechanisms that lead to uveitis are not entirely known, the role of cytokines in the pathogenesis of this disease has been shown to be important. Prior studies described the presence of an array of cytokines in the intraocular fluid of patients with uveitis. Review of these studies indicate that Interleukin-6 (IL-6) is present, and animal data suggest the important role of IL-6 in the regulation of ophthalmologic immune responses. PURPOSE: We investigated whether IL-6, TNF-alpha, IL-1 alpha, beta, IL-2 are present in the vitreous of patients with active intermediate and posterior uveitis. METHODS: Vitreous specimens were collected from 23 eyes of patients with active intermediate and posterior uveitis who underwent diagnostic or therapeutic vitrectomies. TNF-alpha, IL-1 alpha and beta, IL-2 and IL-6 were measured by enzyme-linked immunosorbent assay. Eight vitreous fluid samples from eye bank eyes were used as control. RESULTS: IL-6 was higher in the vitreous of patients with uveitis compared to control samples (p = 0.0119). No TNF-alpha, IL-2, IL1-alpha or beta was detected. The levels of IL-6 did not correlate with a specific clinical diagnosis, but patients with pars planitis and panuveitis had the highest levels (p = 0.58) CONCLUSIONS: IL-6 is elevated in the vitreous of patients with active intermediate and posterior uveitis.

High levels of IgG class antibodies to recombinant HSP60 kDa of Yersinia enterocolitica in sera of patients with uveitis.

AIMS: To determine the levels of IgG class antibodies to recombinant heat shock protein 60 kDa of Yersinia enterocolitica (rHSP60Ye), Klebsiella pneumoniae (rHSP60Kp), Escherichia coli (rHSP60Ec), Shigella flexneri (rHSP60Sf), and Streptococcus pyogenes (rHSP60Sp) in the serum of patients with HLA-B27 associated acute anterior uveitis (HLA-B27 associated AAU), idiopathic acute anterior uveitis (idiopathic AAU), pars planitis, Vogt-Koyanagi-Harada (VKH), and healthy subjects. METHODS: The genes that code for HSP60Ye, HSP60Kp, HSP60Ec, HSP60Sf, and HSP60Sp were cloned by PCR from genomic DNA. The rHSPs were purified by affinity using a Ni-NTA resin. The serum levels of IgG class antibodies to rHSP60s were determined by ELISA in patients with uveitis (n = 42) and in healthy subjects (n = 25). RESULTS: The majority of patients with uveitis had higher levels of IgG class antibodies to rHSP60Ye compared with levels of healthy subjects (p = 0.01), although these differences were only observed in the HLA-B27 associated AAU (p = 0.005) and in pars planitis patients (p = 0.001). The levels of IgG antibodies to the rHSP60Kp, rHSP60Sf, rHSP60Ec, and rHSP60Sp were similar in patients with uveitis and in healthy subjects (p>0.05). CONCLUSION: The results suggest that HSP60Ye could be involved in the aetiology of HLA-B27 associated AAU and pars planitis.

Circulating antibodies to inducible heat shock protein 70 in patients with uveitis.

Heat shock proteins with molecular weight 70 kDa (hsp70) are highly conserved immunogenic intracellular molecules. There are two main subtypes: one is expressed constitutively (hsc70), while the other is induced under stressful conditions (ihsp70). Using an ELISA directed against recombinant human ihsp70, antibody titers were determined in patients with defined ocular inflammatory conditions (Behçet's disease, Vogt-Koyanagi-Harada (VKH), pars planitis, and sarcoidosis) as well as in a group of age-matched normal volunteers. In comparison to healthy controls (n = 14, absorbance 0.269), levels were significantly elevated in Behçet's disease (n = 18; 0.412), sarcoidosis (n = 15; 0.432), and pars planitis (n = 13; 0.346), but not in VKH (n = 10; 0.263). A correlation was also noted for treatment versus no treatment in pars planitis (p = 0.028), but not in other inflammatory conditions. There was no correlation with the level of intraocular disease activity as defined by vitreous haze and vision drop. Since pars planitis is a purely ocular condition, circulating levels of ihsp antibodies likely reflect the extent of disease involvement within the eye.

Characterization of phenotype and cytokine profiles of T cell lines derived from vitreous humour in ocular inflammation in man.

Intermediate uveitis (IU) and Fuchs' heterochromic cyclitis (FHC) are two chronic ocular inflammatory disorders. They differ considerably in ocular morbidity, which is higher in IU. T cell lines were derived from the vitreous humour (VH) and peripheral blood (PB) of 10 patients with IU and four patients with FHC. There was a predominance of CD8+ in all the lines. However, there was a significantly higher percentage of CD4+ T cells in the T cell lines derived from VH of IU (32.0 +/- 8.6%) compared with FHC patients (19. 2 +/- 8.9%) (P = 0.04). The VH-derived T cell lines (VDTC) produced significantly higher levels of IL-2, interferon-gamma (IFN-gamma) and IL-10, but not IL-4, compared with PB-derived T cell lines (PBDTC) in both entities. There was significantly higher IL-2 production by VDTC from IU when compared with FHC patients (1810 +/- 220 pg/ml versus 518 +/- 94 pg/ml; P = 0.009), which could account for the more aggressive clinical features of this condition. In contrast IL-10 production was significantly higher by the VDTC from FHC compared with IU patients. The high IL-10 production by T cells infiltrating VH of FHC patients could down-regulate the inflammatory responses, thereby contributing to the benign clinical course seen in these patients. The accumulation of T cells with differing cytokine profiles in the VH suggests an important role for these cytokines in the pathogenesis of these chronic uveitides.

The association of HLA-B8, B51, DR2, and multiple sclerosis in pars planitis.

PURPOSE: To establish a human leukocyte antigen (HLA) association in a homogeneous population of patients with pars planitis. METHODS: A strict set of inclusion parameters was established for the diagnosis of pars planitis. Forty patients with pars planitis who met these criteria underwent HLA analysis of class I and II phenotypes. RESULTS: HLA-B8 was present in 15 (37.5%) of 40 patients versus 85 (19.7%) of 431 controls (relative risk, 2.44; P = 0.011). HLA-B51 was present in 9 (22.5%) of 40 patients versus 51 (11.8%) of 431 controls (relative risk, 2.16; P = 0.049). HLA-DR2 was present in 27 (67.5%) of 40 patients versus 121 (28.0%) of 431 controls (relative risk, 5.32; P < 0.0001). HLA-DR2 has been associated with multiple sclerosis (MS). Exclusion of five patients with pars planitis in whom MS subsequently developed did not change the significance of these findings. CONCLUSIONS: The strongest association of pars planitis with HLA-DR2 and the temporal development of MS in some patients with pars planitis further supports an association between pars planitis and MS.

[Lyme disease in Switzerland: ocular involvement]. / Maladie de Lyme en Suisse: atteintes oculaires.

Lyme disease is a multisystem disorder caused by the spirochete Borrelia burgdorferi, which is transmitted by a tick (Ixodes Ricinus). Lyme disease is divided into three stages (infection, dissemination and immunological reactions). Ocular manifestations are rare except for conjunctivitis and facial nerve palsy. Switzerland is an endemic zone for Lyme disease; the presence of an atypical pars planitis should prompt a search for Lyme disease.

Immune mechanisms in choroido-retinal inflammation in man.

The immunohistopathological findings of enucleated eyes and immunological abnormalities in several clinical disorders which result in intraocular inflammation are presented. With current immunological techniques, it is possible to define the type and activation status of the cells infiltrating the tissues. In all eyes examined, the predominant cell type was of activated CD4+ T-cells suggesting that the mechanisms involved in the perpetuation of the inflammatory response are similar and it is the initiating events which are likely to determine the site of pathology. The effects of activated CD4+ T-cells and the lymphokines they secrete in the chronic inflammatory process in the ocular tissues are discussed.