**2. The immune system in proliferative diabetic retinopathy**

The immune system protects the body from both exogenous pathogens called pathogenassociated molecular patterns (PAMPs) and endogenous harmful molecules known as damage-associated molecular patterns (DAMPs). DAMPs include oxidized or glycated proteins, mislocated proteins/antigens, and intracellular contents released by necrotic cells. In normal conditions, the immune system regulates the inflammatory process and prevents uncontrolled inflammation that damages cells. In hyperglycemic conditions, the accumulation of DAMPs induces chronic inflammation in various tissues, which in turn manifests into the various complications of diabetes, including diabetic retinopathy [6].

The retina is one of few tissues in the human body that has immune privilege. It is protected from the attack of the systemic immune system by a series of complex defense mechanisms. This protection is afforded by a physical barrier formed between endothelial cells of retinal vasculature as the inner blood-retinal barrier (BRB) and retinal pigmented epithelial cells as the outer BRB. This barrier limits the movement of cells and molecules from the systemic circulation into the retinal parenchyma. The BRB also separates retinal antigens within the intraocular compartment, avoiding activation of T cells. This phenomenon is known as immunological ignorance. In addition, there is no lymphatic system in the retina. This inhibits systemic immune cells from detecting damage-associated molecular patterns in the retina thus preventing an overt systemic inflammatory response. Retinal cells (retinal neurons and RPE cells) express immune modulators that can suppress immune cells and complement system activation. The retina is protected by the local innate immune system (microglia, perivascular macrophages, and the complement system) whose activation is tightly controlled [6].

The immune system plays an important role in the progression of DR. Under hyperglycemic conditions, over activation of the innate immune system takes place, resulting in chronic inflammation of the retina. A study by Urbančič et al. showed the presence of T lymphocytes in the vitreous of patients with PDR. They found that the CD4/CD8 lymphocyte ratio in vitreous is higher compared to the blood ratio in these PDR patients, demonstrating the presence of a local inflammatory process [7]. Prolonged local inflammation in hyperglycemic conditions in the retina may develop into a chronic inflammatory response that is detrimental to the integrity of BRB [6, 8–10]. The destruction of the barrier shifts the retina from its "privileged state" when the BRB functions normally to "compromised state" when the BRB has broken down. Complement system activation also increases in diabetic conditions and this dysregulated activation is known to be involved in the degeneration of retinal vessels. Dysfunctional barriers permit inflammatory molecules and immune cells from systemic circulation to enter the retina and cause further deterioration of the tissue [6, 11]. Cytological examination of the vitreous samples from PDR patients were found to contain significant amounts of macrophages suggesting the infiltration of systemic immune cells into the retina [12, 13]. In addition, there was an increase in adhesion molecule expression and pro-inflammatory cytokine production, suggesting the role of defective neutrophil activity in the development of chronic inflammation in diabetic retinopathy [14, 15] (**Figure 1**).
