Lack of HPV in pterygium with no evidence of autoinoculation and the role of cytokines in pterygium with dry eye.

This study evaluated human papillomavirus's (HPV) role in pterygium pathogenesis, its autoinoculation from genitalia to ocular surface, potential cytokines involved, and crosstalk cytokines between pterygium and dry eye (DE). This cross-sectional study enrolled 25 healthy controls (HCs) and 116 pterygium patients. Four subgroups of pterygium and DE were used in cytokine evaluations. Conjunctival and pterygium swabs and first-void urine samples (i.e., genitalia samples) were collected for HPV DNA detection using real-time polymerase chain reaction. Tear cytokines interleukin (IL)-6, IL-18, and vascular endothelial growth factor (VEGF) in tears were evaluated. No HPV DNA was detected in conjunctival or pterygium swabs. No association was found between HPV DNA in urine samples and that from conjunctival or pterygium swabs. Tear VEGF levels were significantly higher in pterygium patients than in HCs, with no markedly different levels between primary and recurrent pterygia. Tear IL-6, IL-18, and tear VEGF were significantly higher in participants with DE, regardless of pterygium status. In conclusion, HPV infection was not a pathogenic factor of pterygia. The hypothesis of HPV transmitting from the genitals to ocular surfaces was nullified. Tear VEGF was involved in both pterygia and DE, whereas tear IL-6 and IL-18 played roles only in DE.

Pterigión dorsal y onicólisis asociados a un penfigoide ampolloso / Dorsal Pterygium and Onycholysis Associated With Bullous Pemphigoid

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Evaluation of transforming growth factor-beta1 gene expression in pterygium tissue of atopic patients.

BACKGROUND: The exact pathogenesis of pterygium is still not fully understood. Growth factors are considered to play an important role in the formation of pterygium. Transforming growth factor (TGF)-ß1 is considered to be one of the main mediators of fibroblast stimulation and tissue remodeling in allergic conditions. The objective of the present study was to investigate the association between TGF-ß1 gene expression and pterygium in atopic and nonatopic participants. METHODS: We used questionnaires to record demographic and clinical information from patients who underwent pterygium excision surgery. Skin prick examination was done to confirm or rule out atopy in 30 patients with atopy (Case Group) and 30 individuals without atopy (Control Group). Additionally, measurement of serum immunoglobulin E, cytokines, including interleukin-4 and interferon-γ, and peripheral blood eosinophil count was performed to confirm atopy in 30 consecutive patients (Case Group). A semiquantitative reverse transcription polymerase chain reaction was performed to determine TGF-ß1 gene expression in all individuals. RESULTS: TGF-ß1 mRNA gene expression was significantly higher (p = 0.0001) in atopic patients 2.50 ± 1.11 compared to nonatopic individuals 1.40 ± 0.46. Eosinophil count and serum immunoglobulin E were significantly higher (p = 0.031 and p = 0.001, respectively) in atopic patients compared to the Control Group. Serum interleukin-4 was also significantly higher (p = 0.01) in atopic patients compared with nonatopic individuals. CONCLUSION: Excess expression of TGF-ß1 gene in pterygium tissue of atopic individuals suggests that growth factors play a role in the pathogenesis of pterygium.

Fibroblast biology in pterygia.

Activation of fibroblasts is a vital process during wound healing. However, if prolonged and exaggerated, profibrotic pathways lead to tissue fibrosis or scarring and further organ malfunction. Although the pathogenesis of pterygium is known to be multi-factorial, additional studies are needed to better understand the pathways initiated by fibroblast activation for the purpose of therapeutic translation. Regarding pterygium as a possible systemic disorder, we discuss the different cell types that pterygium fibroblasts originate from. These may include bone marrow-derived progenitor cells, cells undergoing epithelial-mesenchymal transition (EMT), and local resident stromal cells. We also describe how pterygium fibroblasts can be activated and perpetuate profibrotic signaling elicited by various proliferative drivers, immune-inflammation, and novel factors such as stromal cell-derived factor-1 (SDF-1) as well as a known key fibrotic factor, transforming growth factor-beta (TGF-ß). Finally, epigenetic modification is discussed to explain inherited susceptibility to pterygium.

S100A proteins as molecular targets in the ocular surface inflammatory diseases.

The S100 proteins are calcium-binding proteins that are exclusively expressed in vertebrates, where they interact with enzymes, cytoskeletal proteins, receptors, transcription factors, and nucleic acids to regulate proliferation, differentiation, apoptosis, inflammation, cell migration, energy metabolism, and Ca(2+) homeostasis. In this review, we focus on the S100A8 and S100A9 members of the family that are involved in the regulation of neutrophil chemotaxis and inflammation related to ocular surface diseases such as dry eye, meibomian gland dysfunction, pterygium, and corneal neovascularization. In our previous studies, we have found that the levels of S100A8 and S100A9 were elevated in these inflammatory ocular diseases. For instance, S100A8 and A9 were found to be upregulated in pterygium tissues at both transcript and protein levels. These findings are consistent with the role of S100A8 and S100A9 proteins in activating the innate immune system in the eye via Toll-like receptors (TLRs) and altering the immune tolerance of the eye-associated lymphoid system. Recently, use of S100A8-targeting antibody has shown promising results in targeting corneal neovascularization. Injection of S100A8 has been shown to inhibit eosinophilic infiltration and thus may have potential therapeutic implications in allergic diseases.

Chronic inflammatory cells and damaged limbal cells in pterygium.

BACKGROUND: Chronic inflammation in pterygium occurrence has not been explained. Whether damaged limbal basal epithelial cells are associated with pterygium occurrence in black Africans is not clear. OBJECTIVE: To explain chronic inflammation in pterygium, and to clarify whether damaged limbal basal epithelial cells were associated with pterygium occurrence in black Africans. METHODS: Chronic inflammatory changes and damaged limbal basal epithelial cells were assessed in 59 samples. RESULTS: Chronic inflammatory cells were present in 59 pterygia. Inflammatory cell count in 5 (27.8%) of 18 small pterygia was >200 (high) while in 22 (53.7%) of 41 large growths was <200 (low); p = 0.25. The proportion of pterygia with high counts tended to increase with pterygium extent. Twenty (33.9%) of 59 pterygia recurred after surgery. Ten (50%) of 20 samples had high cell counts and 10 (50%), low counts; p = 0.40. P53 expression was detected in 11 (18.6%) of 59 pterygium samples and 5 (71.4%) of 7 controls; p = 0.007. MMP 1 staining was present in 14 (23.7%) of 59 sections and 5 (71.4%) of 7 controls; p = 0.02. MMP2 in 16 (27.1%) cases and 5 (71.4%) controls; p = 0.03. MMP3 was overexpressed in 16 (27.1%) of 59 cases and 5 (71.4%) controls; p = 0.03. CONCLUSIONS: Mild chronic inflammation has a tendency to be more frequent than severe inflammation in pterygia. It is clear that damaged limbal basal epithelial cells are unlikely to be related to pterygium occurrence.

The change of cytokines in tear and blood after different pterygium operation.

Pterygium is an invasion of altered ocular tissue into the cornea. Bone marrow-derived stem cells have been reported to be involved in wound healing under chemotactic factors after pterygium removal and pain may act as a trigger signal. We evaluated the change of systemic and local chemotactic factors that could affect the mobilization and migration of BMSCs to the wound bed after conventional bare sclera pterygium excision. We also applied temporary amniotic membrane patch after pterygium removal, and compared the changes of cytokines with those of conventional bare sclera excision group. Substance-P (SP), vascular endothelial growth factor (VEGF), and stem cell factor (SCF) were measured in plasma and tear using ELISA and migrating CD34(+) cells by flow cytometry. The results showed that post-operative pain was much reduced (p<0.05), and SP, VEGF and SCF kept consistently lower levels in plasma after temporary amniotic membrane application. Circulating CD34(+) cells increased slightly in the temporary amniotic membrane patch group compared with marked increase in the bare sclera group. Thus, the application of a temporary amniotic membrane after pterygium removal might be an effective therapeutic means by controlling pain and excessive infiltration of bone marrow-derived stem cells.

[Etiopathogenic aspects in development and evolution of pterigyum]. / Aspecte etiopatogenice ale dezvoltarii si evolutiei pterigionului.

Pterygium is an epithelial hyperplasia accompanied by a fibrovascular growth originating at the corneo-conjunctival junction, from where the modified limbic cells migrate and surpass the cornea. The studies reviewed show that it is an active process associated with cell growth, remodelling of the connective tissue, angiogenesis and inflammation. Despite the lack of knowledge regarding the pathogenesis of pterygia, epidemiologic evidence suggests that exposure to UV-irradiation may be an initial trigger in the development of this lesion. Other theories include changes of the apoptotic pathway the presence of some active angiogenetic factors or involvement of the MMPs, cytokines and growths factors. UV light could be the initial trigger that activates epithelial cells at or near the limbus to produce cytokines such as IL-6 and IL-8 and growth factors. These multifactorial proteins set up a cascade of events that include inflammation, proliferation, angiogenesis and antiapoptosis. Cytokines are able to induce the expression of MMPs and their tissue inhibitors (TIMPs) making it likely that they would also affect the rate of tissue remodeling, such as destruction of Bowman's membrane and the invasion of pterygium. In the etiology of pterygium abnormalities in tear functions have also been emphasized.

The presence of T-lymphocyte subpopulations (CD4 and CD8) in pterygia: evaluation of the inflammatory response.

INTRODUCTION: The aim of our study was to confirm the presence of inflammatory T-lymphocyte subpopulations (CD4 and CD8) in pterygium specimens with regards to clinical severity. Additionally, we examined the effect of topical anti-inflammatory agents on the presence of T-lymphocyte subpopulations. METHODS: Pterygia from nineteen eyes of nineteen patients who underwent surgical excision at Duke University, North Carolina, were included in this study. Normal conjunctiva from one patient was included as a control. Pterygia were pre-operatively graded as mild, moderate or severe based on objective signs of inflammation. Immunohistochemical staining for both CD4 and CD8 subpopulations of T lymphocytes was performed. Distribution of lymphocytes within the epithelium and substantia propria was graded by a masked observer on the following scale: 0 (none/rare), 1+ (mild), 2+ (moderate), or 3+ severe. Statistical analysis was performed using the Fisher exact test and Chi-square test. RESULTS: A total of 16 (84%) pterygia specimens stained for T lymphocytes displayed approximately equal CD4 and CD8 infiltration of both the epithelium and the substantia propria. The majority of CD4 and CD8 lymphocytes were located in aggregates in the epithelium and upper substantia propria. The control specimen contained scant evidence of lymphocytic infiltration. There was no significant difference in the amount of lymphocytic infiltration between mild, moderate or severe pterygia. There was also no significant difference in lymphocytic infiltration between patients with (n=8) or without (n=11) a history of topical anti-inflammatory use. CONCLUSION: The presence of CD4 and CD8 lymphocytes was confirmed in pterygia. There was no significant difference in lymphocytic infiltrate in patients with or without prior topical anti-inflammatory use. Based on these findings, topical immunomodulators may have an adjunctive role in the treatment of pterygia.

Flow cytometrical analysis of adhesion molecules, T-lymphocyte subpopulations and inflammatory markers in pterygium.

BACKGROUND/AIM: Pterygium is a relatively frequent ocular surface disease with an unexplained etiopathogenesis. Our study was carried out with the aim to identify the presence of inflammatory cells and mediators such as T-lymphocyte subgroups (CD4 and CD8), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and human leukocyte antigen-DR (HLA-DR) in pterygium tissue. METHODS: Pterygium tissue, obtained from 24 patients, and normal conjunctival tissue, from the nasal bulbar conjunctiva obtained from 14 patients operated for ocular perforations or vitrectomy, were separated into epithelial and stromal components under the microscope and suspended with phosphate-buffered saline solution to form a suspension. Cell suspensions were treated with specific antibodies for ICAM-1, VCAM-1, and HLA-DR and T-lymphocyte subgroups and evaluated with flow cytometry. The obtained data were compared statistically. RESULTS: When compared to the control tissue samples, higher rates of ICAM-1-positive cells, VCAM-1-positive cells and HLA-DR-positive cells were recorded in pterygium tissue samples. CD4 and CD8 lymphocytes were also found to be at higher levels when compared to the control group. There was a statistically significant difference between the two groups. CONCLUSION: When compared with normal conjunctival tissue, pterygium tissue had increased levels of T-lymphocyte infiltration and inflammatory markers demonstrating the possible contribution of cellular immunity to the pathogenesis.

[Pterygium: allergic etiology?]. / Skrzydlik--etiologia alergiczna?

Pterygium is a wedge-shaped fibrovascular growth of conjunctiva that extends onto the cornea. The etiopathogenesis of pterygium is still not fully elucidated. Exposure to ultraviolet light is suggested as one of the most important factors contributing to pterygium development. However, other factors including allergens, harmful chemical substances, wind, dust and pollens also may contribute to its development. The aim of the study was to evaluate the influence of immune reactions on the pathogenesis of pterygium.

Immunohistochemical HLA-DR antigen expression with lymphocyte subsets and proliferative activity in pterygium.

The immunohistochemical expression of HLA-DR antigen, CD8, CD4, CD68, S1OO, PCNA and Ki-67 was performed in order to investigate the role of immune mechanisms in pterygium, in correlation with proliferative activity. A series of 98 surgically-excised pterygia, 18 pingueculae and 20 normal conjunctivae, was studied by the avidin-biotin method, on formalin-fixed, paraffin-embedded tissue. HLA-DR antigen was abundantly expressed in pterygium epithelial cells, whereas almost no expression was found in pinguecula and normal conjunctiva. A high value of Ki-67 and PCNA expression coexisted in the same areas with HLA-DR antigen expression in pterygium and a statistically significant positive correlation resulted between them (p = 0.002). Aberrant infiltration of inflammatory cells (CD4, CD8, CD68, S100) was detected in pterygium, while lower densities were found in pinguecula and conjunctiva. The data suggest that immunopathological mechanisms may contribute in the pathogenesis of pterygium. In addition, the aberrant HLA-DR antigen expression seems to be correlated with the growth fraction of the lesion.

Presence and possible significance of immunohistochemically demonstrable metallothionein expression in pterygium versus pinguecula and normal conjunctiva.

PURPOSE: To investigate metallothionein (MT) expression in pterygium, pinguecula and normal conjunctiva and define its possible significance in this area of the eye. In order to further elucidate the mechanism of MT expression we correlated it with lymphocyte subpopulations (T4, T8), macrophages (CD68), Langerhans' cells (S100) and the proliferation-associated indices (PCNA, Ki67). METHODS: Eighty-five surgically excised pterygia, 15 pingueculae and 20 normal conjunctivae were immunohistochemically studied by the avidin-biotin (ABC) method. A monoclonal antibody (E9) against a conserved epitope of I and II isoforms of MT was used on formalin-fixed, paraffin-embedded tissues. Statistical analysis was performed using the SPSS statistical package. RESULTS: Epithelial MT expression was detected in all 120 cases examined and in most of them both nuclear and cytoplasmic immunoreactivity was present. Nevertheless no statistically significant difference of MT expression was found between the three types of tissue. A statistically significant positive correlation between MT expression and lymphocyte subsets, macrophages and Langerhans' cells was found in pterygium. On the contrary, we did not find any statistical correlation in pinguecula and normal conjunctiva. In all three types of tissues MT expression was also positively correlated with the proliferation-associated indices. CONCLUSION: The data suggest that there is immunohistochemically demonstrable MT expression in the epithelium of pterygium, but also of normal conjunctiva and pinguecula. MT may serve a photoprotective role in this region. In pterygium in particular, the biochemical pathway of MT synthesis seems interestingly to cross the pathways of cell proliferation, inflammation and immune activation.

HLA-DR antigen expression in pterygium epithelial cells and lymphocyte subpopulations: an immunohistochemistry study.

The purpose of our study was to investigate the role of immune mechanisms in the pathogenesis of pterygium using an immunohistochemical technique. Our material consisted of 35 surgically excised pterygia and 7 samples of normal conjunctiva obtained from an equal number of patients. HLA-DR antigen expression in epithelial cells, B-cells, suppressor and helper lymphocytes, Langerhans' cells, and monocytes/macrophages were studied immunohistochemically in frozen sections using anti-human HLA-DR, anti-CD22, anti-CD8, anti-CD4, anti-CD1a, and anti-LeuM5 monoclonal antibodies. Aberrant HLA-DR antigen expression in epithelial cells was detected in 30 of 35 cases of pterygium. Epithelial cells in samples of normal conjunctiva were found to be negative in HLA-DR antigen expression. HLA-DR antigen expression in pterygium was found to be closely related to the density of T4 cells and, especially, of CD4 lymphocytes. The present findings suggest that an immunopathologic mechanism plays a role in the pathogenesis of pterygium.

Immunological studies on the pathogenesis of pterygium.

Immunohistochemical, electron microscopic and routine pathological studies were conducted to observe the changes in T-cell subsets, B-cells, plasma cells, and mast cells, and the distributions of immunoglobulins (IgE, IgG, IgA, IgM) and C3 in patients with pterygium. The results were as follows. Massive amounts of infiltrating lymphocytes, predominantly T-cells (CD3+), were found in the substantia propria of the pterygial specimens. The helper-suppressor ratio had risen from 1:2.7 in the normal conjunctiva to 1:1.5. Positive cytoplasmic immunoglobulin staining indicated a plasmocytic infiltration in the lesions as well. Abnormal distributions of immunoglobulins were found, and deposition of immunoglobulins in a granular pattern around the basement membrane of the epithelial layer was seen. Mast cell reactions were found, and a linear correlation between the numbers of lymphocytes and mast cells was shown. Basement membrane destruction in the cap area of the pterygium was also confirmed. These results indicate that an immunologic mechanism, possibly of Types 1, 3 and 4 hypersensitivity, may contribute to the pathogenesis of pterygium.

[An immuno-pathological study of pterygium].

Pterygium specimens from 68 patients and normal conjunctiva from 12 controls were examined for the contents of immunoglobulins and C3 by direct immunofluorescence assay. The levels of IgE, IgG and IgA in the epithelial layer, of IgE, IgG and C3 in the basement membrane, and of IgE, IgG in the stroma, were found significantly higher in progressive cases than in the controls. as was the IgG-bearing cell count in the stroma. Also IgG bound to the basement membrane was significantly manifest in the quiescent cases. Routine histologic staining showed an infiltration of lymphocytes and plasma cells in the pterygium. A small amount of immunoglobulins was found in the stroma from the controls, but no C3 was demonstrated. These results suggest that an immunologic mechanism, possibly type I and type III hypersensitivity, may contribute to the pathogenesis of pterygium.

Immunologic basis for the pathogenesis of pterygium.

We examined surgically excised pterygial tissues from 26 patients for the various immunoglobulin classes by direct immunofluorescence. Of the 26 patients, 19 (73.1%) showed positive staining with goat anti-human IgG fluorescein-labeled antibody. Direct immunofluorescence with goat anti-human IgE fluorescein-labeled antibody was found in all 26 samples, varying in fluorescent intensity from 1+ to 4+. Routine histologic staining disclosed an infiltration of small lymphocytes and plasma cells into the pterygium. These results suggest that an immunologic mechanism, possibly Type 1 hypersensitivity, may contribute to the pathogenesis of pterygium.