Introduction 

Eales disease is a rare disorder that affects the eye, specifically the retina, which is a light-sensitive tissue at the back of the eye.¹ It mainly affects young adults, predominantly people assigned male at birth (AMAB), and it is seen in greater numbers in India.¹ People who suffer from Eales disease start by having vitreous haemorrhage, a condition where there is blood in the transparent and gel-like part of the eye that is responsible for preserving the eye’s structure and integrity.^1,2 Eales disease does not have a clearly defined cause; it involves the inflammation and blocking of the blood vessels of the retina, where an unusual immune response from the body triggers this event.¹ It is therefore characterised as an idiopathic obliterative vasculopathy.¹ The progression of Eales disease can be divided into different stages, where the underlying disease mechanisms, symptoms and therapeutic management options show variability.¹ This article will describe the underlying causes behind Eales disease and the role of cytokines and vascular endothelial growth factor (VEGF) in the progression of the disease. This field is important to identify the factors that determine the severity of disease and for characterising therapeutic targets for Eales disease. 

Pathophysiology and clinical symptoms of Eales disease

Even though the underlying causes of Eales disease are not completely understood, it is generally considered a multi-factorial disease where several assumptions of its origin have been proposed.¹ Importantly, it is proposed that Eales disease occurs due to a response of the immune system to external stimuli that enter the body, namely the unusual immune reaction against the tuberculosis-causing bacteria Mycobacterium tuberculosis in people who are genetically susceptible.¹ Studies have reported the finding of DNA belonging to this tuberculosis-causing agent in the eyes of many Eales disease patients.¹ The disease mechanisms which are responsible for this condition also include autoimmune mechanisms, oxidative stress, problems with coagulation factors, along with infections and systemic conditions.¹ Importantly, cytokines that elucidate the inflammatory responses and growth factors like Vascular Endothelial Growth Factor (VEGF) involved in irregular driving vessel formation are significant to understand Eales disease.¹  

Eales disease can be classified into different stages based on the underlying disease mechanisms and the degree of changes to the retina.³ The progression of the disease can follow certain steps starting from the inflammation of the veins in the retina (retinal periphlebitis), blockage of these vessels due to inflammation, causing decreased blood flow to the retina, which causes oxygen deficiency and ischemia. This then triggers the release of VEGF, assisting the formation of new vessels (neovascularisation), where these fragile new vessels can easily fracture and lead to bleeding in the vitreous part of the eye, causing many different impediments.^1,3 Different patients can progress through these stages differently and the degree of disease severity can vary, with clinical symptoms also showing variability across patients.³

The symptoms of Eales disease include bleeding in the vitreous part of the eye, blurred vision/vision loss, headache, constipation, nosebleeds, along with possible neurological problems, stroke and ischemic attacks.¹ These clinical causes can be traced to the inflammation of the veins in the retina, along with blocked blood flow to the eye and the formation of new blood vessels within the eye that have an increased risk of rupturing and contributing to the bleeding in the retina and vitreous area.¹ 

Inflammatory cytokines in Eales disease 

The immune system operates through the expression of pro- and anti-inflammatory cytokines released from immune cells.⁴ These cytokines can increase or decrease the production of each other and communicate to regulate the immune response and inflammation.⁴ Studies have identified a correlation between the stage of inflammation and the severity of Eales disease and the level of pro-inflammatory cytokines in the serum obtained from patients.⁵ C-reactive protein and interleukin-6 (IL-6) have been characterised as markers of disease stage.⁵ The activation of toll-like receptors (TLR) and increased numbers of CD16+ monocytes, both causing the release of pro-inflammatory cytokines, have been reported to play an important role in the development of the disease.⁵ 

Furthermore, a study has collected samples from the vitreous area of the eye from various Eales disease patients and analysed these samples for cytokines involved in promoting inflammation and the formation of new blood vessels.⁶ It has been demonstrated that in the vitreous samples obtained from patients, there is an increased level of pro-inflammatory cytokines, including IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and VEGF.⁶ Moreover, it has been shown that the administration of antibodies that block the effect of IL-6 and VEGF reduced the formation of blood vessels and decreased inflammation in the retinal area.⁶ 

Eales disease has similar disease mechanisms and clinical signs to the retinopathy that occurs due to diabetes.³ The increase in the release of cytokines and growth factors is seen in both cases, leading to problems in the vascular endothelium and increased permeability of blood vessels, promoting inflammation.³ These changes can cause swelling of blood vessels, along with fatty deposits and bleeding in the retina.³ As these blood vessels become blocked, the blood flow and oxygen supply to the tissues in the retina decrease, leading to the production of new vessels in an attempt to regain blood supply.³ As mentioned previously, the rupture of these new fragile vessels contributes further to inflammation and bleeding in the retina.³ 

VEGF and angiogenesis in Eales disease 

The biochemical analysis of samples from various Eales disease patients has shown an increase in VEGF levels and oxidative stress.⁸ The levels of VEGF have been reported to be higher in the serum of Eales disease patients, as VEGF is involved in promoting the formation of new blood vessels in the retina.⁵ VEGF plays a crucial role in directing the formation of new blood vessels, defined as angiogenesis, in response to conditions of low oxygen and oxidative stress.⁶ Angiogenesis is important during many conditions, such as the healing of wounds; however, uncontrolled or abnormal angiogenesis can be present in pathogenic cases, such as that seen in the retina in Eales disease.⁴ Angiogenesis and inflammation are closely related since components of the immune system such as cytokines are involved in regulating angiogenesis.⁴ Since the blood vessels are responsible for delivering oxygen to the tissues within the eye, their occlusion due to increased inflammation results in low oxygen supply, stimulating the production of new vessels in the retina in Eales disease.⁶ 

Along with VEGF, pro-inflammatory cytokines like IL-6, IL-8 and MCP-1 are involved in angiogenesis in the retina.⁶ For example, IL-6 has been proposed to facilitate angiogenesis by increasing the expression of VEGF and upregulating the permeability of blood vessels.⁶ The activation of pro-inflammatory transcription factors like NF-Kappa B was shown to increase the expression of IL-6, which then causes an increase in the expression of VEGF through the STAT-3 pathway.⁶ This means that multiple cytokines, such as IL-6 and MCP-1, alongside VEGF, can indirectly promote angiogenesis in the vitreous area of the eye.⁶ 

Furthermore, interferon gamma (IFN-γ) is a cytokine released from T lymphocyte cells that has a key function in the immune system, as it increases the production of pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF-α), alongside activating macrophages.⁴ It has been found that TNF-α can increase angiogenesis (the production of new blood vessels), and its production can be downregulated by the anti-inflammatory cytokine IL-10, which has a role in decreasing inflammation.⁴ It has been demonstrated that there is an increase in the levels of TNF-α in the inflammatory stage of Eales disease. Aside from this, IFN-γ and IL-10 control the production of factors that regulate angiogenesis and the extent of inflammation.⁴ 

Therapeutic approaches in Eales disease and the significance of cytokines 

The aim of treatment for Eales disease is to decrease inflammation around the blood vessels in the retina and in the vitreous part of the eye.³ Corticosteroids have shown to be effective, along with cyclosporine and azathioprine as alternatives for patients who do not respond well to corticosteroids.³ Along with this, laser treatment of lesions within the eye and anti-VEGF therapy have demonstrated to be safe and effective treatments for repairing vision loss and other symptoms.³ Surgery has also been recommended in the cases of retinal detachment.⁷ However, future work is needed to address the gap in developing standardised diagnostic tools and technologies that enable the establishment of personalised treatment plans for different individuals.⁷ 

Importantly, the differences in the levels and types of different cytokines present in the vitreous area of the eye in Eales disease patients impact the type and severity of the immune response, which then dictates the course of the disease.⁴ Since these cytokines modulate the immune response, the genes which determine their synthesis can also impact the course of disease in people.⁴ It has been reported that due to the role of IL-10 in decreasing inflammation and downregulating angiogenesis-promoting factors, the genotypes which give rise to low levels of IL-10 can be associated with severe forms of Eales disease.⁴ On the other hand, genotypes that result in the production of low levels of TNF-α were reported to offer protection against Eales disease.⁴ These findings are important because gene polymorphisms that are related to cytokine production can significantly impact the course of Eales disease, thus being useful to identify accurate and personalised treatments for different individuals.⁴ This highlights the significance of cytokine expression in regulating the immune response and determining the progression and severity of Eales disease. 

Summary 

Eales disease is a rare condition that affects young people. It is predominantly seen in people assigned male at birth. It affects the retina of the eye, causing impairments to vision and other complications. The underlying mechanisms of Eales disease can be summarised as an unusual immune response to external factors like the tuberculosis bacteria, which causes increased inflammation in the veins of the retina, causing blockage, oxygen deficiency and upregulated release of cytokines and growth factors, which contribute to inflammation and cause increased eye bleeding and vision loss. Therefore, studying the levels and effects of different cytokines and growth factors can be useful to develop accurate diagnostic tools and personalised treatment strategies for people with Eales disease.