*3.5.4. High-mobility group box-1*

High-mobility group box-1 (HMGB1) is a nonhistone DNA-binding protein that facilitates transcription. HMGB1 can be released into the extracellular space by active secretion from certain cells such as activated monocytes and macrophages, mature dendritic cells, natural killer cells, and endothelial cells. Necrotic cell death can also cause passive leakage of HMGB1 from the nucleus as the protein is no longer bound to DNA. HMGB1 can bind to the receptor for advanced glycation end products (RAGE) and toll-like receptor 2 (TLR-2), where it acts as a pro-inflammatory cytokine, activating NF-κβ resulting in the overexpression of other proinflammatory molecules such as TNF-α, MCP-1, and ICAM-1 [41, 102, 103]. El-Asrar et al. demonstrated a significant correlation between neovascularization levels in epiretinal membranes of patients with PDR and the expression of HMGB1 and RAGE [41]. Yao Yu et al. also found an increase of HMGB1 concentration in the vitreous of PDR patients. This increase in vitreous happens in the later phases of DR, and differs from other inflammatory cytokines. They also found increases of RAGE protein and decreases of TLR-2 protein in DR rats, suggesting that the involvement of HMGB-1 is mainly through its binding with RAGE [102].

## **3.6. Cell adhesion molecules**

Adhesion molecules have many roles in our body, including embryology, immunology, and malignancy [21]. Several studies show increases of these molecules in PDR patients, suggesting that cell to cell interaction plays a major role in the development of PDR [79, 104–106]. These molecules regulate lymphocyte recruitment to vascular endothelium. Well-known adhesion molecules found in PDR patients are intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecules-1 (VCAM-1), which are required for initiation of adhesion-dependent immune response [21, 106].

#### *3.6.1. Intercellular adhesion molecule-1*

Intercellular adhesion molecule-1 (ICAM-1), also known as CD54, is a cell surface glycoprotein encoded by the ICAM1 gene. ICAM-1 is usually expressed on the surface of endothelial cells and cells of the immune system. It works as a cell adhesion molecule that recruits nearby circulating leukocytes to the inflamed location. In PDR patients, ICAM-1 is suspected as one of the deteriorating factors, promoting leukostasis and inflammation on nearby retinal tissue. Several experiments show leukostasis as a possible mechanism in diabetic retinal vasculature injury. Cells which are attached, mainly granulocytes and monocytes cause microvascular occlusion and capillary injury [106]. Leukostasis in DR is mainly caused by endothelial activation and increased surface expression of intercellular adhesion molecules (ICAM-1) [107]. Hillier et al. stated that increases in ICAM-1 correlate with the severity of DR in patients [108]. Our study on ICAM-1 showed an increase of ICAM-1 expression in PDR patients with more than 10 years of diabetes history [103]. Yan et al. in their study about the effects of intravitreal ranibizumab injection on ICAM-1 levels in PDR patients, demonstrated a decrease of ICAM-1 levels a week after intravitreal injection [109].

**Acknowledgements**

**Conflict of interest**

**Author details**

**References**

1600004, Sub Grant #IIE-00000078-UI-1.

Andi Arus Victor\* and Ratna Sitompul

DOI: 10.1155/2012/872978

DOI: 10.5772/28635

**53**:7567. DOI: 10.1167/iovs.12-9446

There are no conflicts of interest in this chapter.

\*Address all correspondence to: arvimadao@yahoo.com

Mangunkusumo National General Hospital, Jakarta, Indonesia

Department of Ophthalmology, Faculty of Medicine, Universitas Indonesia, Cipto

[1] Simó-Servat O, Hernández C, Simó R.Usefulness of the vitreous fluid analysis in the translational research of diabetic retinopathy. Mediators of Inflammation. 2012;**2012**:872978.

[2] Dong N et al. Upregulation of retinal neuronal MCP-1 in the rodent model of diabetic retinopathy and its function in vitro. Investigative Ophthalmology & Visual Science. 2012;

[3] Paine SK et al. Association of tumor necrosis factor α, interleukin 6, and interleukin 10 promoter polymorphism with proliferative diabetic retinopathy in type 2 diabetic sub-

[4] Lü H. Inflammation and diabetic retinopathy. Diabetic Retinopathy. 2012;**1**:125-136.

[5] Abcouwer SF. Angiogenic factors and cytokines in diabetic retinopathy. Journal of

[6] Xu H, Chen M. Diabetic retinopathy and dysregulated innate immunity. Vision Research.

jects. Retina. 2012;**32**:1197-1203. DOI: 10.1097/IAE.0b013e31822f55f3

Clinical & Cellular Immunology. 2013;**11**:1. DOI: 10.4172/2155-9899

2017;**139**:39-46. DOI: 10.1016/j.visres.2017.04.013

This article's publication is partially supported by the United States Agency for International Development (USAID) through the Sustainable Higher Education Research Alliance (SHERA) Program for Universitas Indonesia's Scientific Modeling, Application, Research and Training for City-centered Innovation and Technology (SMART CITY) Project, Grant #AID-497-A-

Proliferative Diabetic Retinopathy: An Overview of Vitreous Immune and Biomarkers

http://dx.doi.org/10.5772/intechopen.74366

83

#### *3.6.2. Vascular cell adhesion molecule-1*

Vascular cell adhesion molecule-1 (VCAM-1) is an immunoglobulin supergene family of cellular adhesion molecules that are involved in the transmigration of monocytes, eosinophils, and lymphocytes [105, 110–112]. Oxidative stress, VEGF, and hypercholesterolemia increase the expression of VCAM-1 in the brain and retina [111, 113, 114]. It is released by endothelial cells and is present as an early feature of inflammatory disease [111, 113]. Several studies state that VCAM-1 promotes angiogenesis in PDR patients [105, 112–114]. Burgos et al. demonstrated increases in vitreous concentration of VCAM-1 in PDR patients (26 ng/mL) compared to non-diabetic patients in whom a vitrectomy was performed (22 ng/mL) [104]. These results are also consistent with Mroczek et al. in their study about the influence of glucose control on the activation of the intraocular molecular system [114]. There are also reports of increase VCAM-1 concentration in the retinal vessels and serum of PDR patients [111, 112].

### **3.7. Soluble CD200**

CD200 is a novel immunosuppressive molecule found in neuronal cells. CD200 exists in a cell membrane-bound form and a soluble form. It exerts inhibitory effects on microglia/ macrophages via interaction with the CD200 receptor (CD200R) [115]. DR-related neuronal degeneration also reduces CD200 concentration and further induces microglial activation [6]. Recent study on CD200 revealed that levels of sCD200 in vitreous of patients with PDR are significantly higher compared to that in the vitreous of patients without PDR. Xu et al. showed increases in mean sCD200 levels in the PDR group (182 ± 17.63 pg/mL) compared to non-diabetic patients with other conditions who requires pars plana vitrectomy (56.86 ± 6.573 pg/mL). This study also showed that vitreous levels of sCD200 are higher in PDR patients with DME (266.9 ± 28.82 pg/mL) or traction retinal detachment (TRD) (256.9 ± 34.50 pg/mL) compared to PDR patients without DME (136.9 ± 15.13 pg/mL) or TRD (146.9 ± 15.97 pg/mL). sCD200 level increases also have significant statistical correlations with the increase of several angiogenic and inflammatory molecules such as VEGF, IL-6, IL-8 and IL-10 [115].
