The eye fights back!

Immune, inflammatory processes play large, but poorly understood, uveitis role

Howard Larkin

Posted: Monday, April 1, 2019

The eye’s immune privilege is not passive, but rather a system that tightly regulates inflammation, actively maintaining tissue clarity and integrity using an inner and outer blood-retinal barrier. However, this control can be knocked out of balance resulting in chronic uveitis and other inflammatory diseases, said Janet L Davis MD in the C Stephen and Frances Foster Lecture on Uveitis and Immunology at the 2018 American Academy of Ophthalmology Annual Meeting in Chicago, USA.

Regaining the null point of no inflammation after uveitis sets in requires understanding of both inciting events, such as active or past infections, and sustaining mechanisms, including persistent autoimmune and autoinflammatory processes. Better understanding of these mechanisms also could improve treatment for other eye diseases that include an inflammatory component, such as inherited retinal degenerations and age-related macular degeneration, said Dr Davis, of the Bascom Palmer Eye Institute, University of Miami, USA.

However, “we are woefully ignorant of that [inflammation null] point”, Dr Davis said. But even without complete knowledge and the specific molecular tests that would be required to precisely diagnose many immune and inflammatory conditions, much can be done to help calm ocular inflammation as the eye fights back against infection and other insults and allergens.

Diverse causes
Dr Davis started with a case of undifferentiated panuveitis involving blurred vision but no pain or associated disease that persisted for 30 years. The patient had received topical corticosteroids, intraocular triamcinolone, bevacizumab and vitrectomy, as well as methotrexate, azithioprine, chlorambucil and anti-IL17. For eight years she had been mostly stable on infliximab.

So why does she still have uveitis 30 years on? Dr Davis considered the possibilities:

Autoimmune uveitis: When the blood-retina barrier is disrupted, T-cells produced to attack self-antigens in response to infection or systemic immunologic disease can enter and may become resident in the eye, where they attack that antigen in ocular tissues, provoking inflammation, Dr Davis said. Inciting causes may be an autoimmune disease such as Vogt-Koyanagi-Harada, which is treatable with corticosteroids and immunosuppressants; or infiltrating lymphocytes from remote tumours leading to conditions such as melanoma-associated retinopathy that is difficult to treat, but may be partially reversed with reduction of primary tumour burden.

Only a handful of true autoimmune antigens have been identified, though patient serum staining of banked retinal tissue often indicates the presence of antibodies to unknown antigens identified only by molecular weight, and some of these may be stimulated by viruses. This makes it difficult to identify and treat true autoimmune disease, which requires agents addressing specific antigens.

Infection: Herpes viruses, tuberculosis and syphilis are among infections that can persist for 30 years or more, and may often be involved in what appears to be non-infectious uveitis, Davis noted. Tuberculosis with actively replicating organisms is not uncommon and is treatable with antibiotics. However, antibiotic treatment sometimes provokes the eye to fight back with an excessive inflammatory response known as immune recovery uveitis, which requires anti-inflammatory treatment.

Retinal vasculitis may result when the inner blood-retinal barrier breaks down and can often be treated with anti-inflammatories. Choroidopathy that can occur when the outer barrier is breached, stimulating inflammation that destroys the retinal pigment epithelium, may require immune suppression.

Autoinflammatory disease: What looks like autoimmune disease may be autoinflammatory, which does not require a specific antigen to stimulate an innate immune response. Autoinflammation can result from a genetic predisposition, and uveitis may be involved in a multi-system inflammatory response. For example, mutation of the NLRP3 inflammasome is associated with several autoinflammatory syndromes, and uveitis involving this mutation is the only type that responds to IL-1 beta inhibitors.

Biologic therapy and control of environmental triggers can be effective in treating these. Some uveitis may involve both autoinflammatory and autoimmune processes. These include Behçet’s disease and HLA-B27-associate uveitis.

Protein persistence in macrophages: Proteins from infective agents engulfed by macrophages may persist after the macrophage dies, leading to engulfment and re-presentation by another macrophage in a repeating cycle, perpetually stimulating an immune response that manifests as persistent uveitis. The mechanism may be similar to that of tattoo pigment granules observed in a recent mouse study (Baranska and Malissen. J Exp Med 2018:215(4), Dr Davis said.

Lacking better diagnostics and insights, sorting through the various causes and treatments for persistent uveitis is challenging, Dr Davis said. However, she offered a treatment strategy.

“We don’t go nuclear with bone marrow transplants. We can cut immune and inflammatory supply chains with cytokine inhibitors, lay siege with corticosteroids with local or systemic treatment. We can broadcast propaganda with immunomodulatory drugs. If macrophages pass antigens from one generation to the next, we can control the myeloid population. For now, we realise that genetic causes cannot be modified.”

She also recommended two articles for insight into eye immunity and implications for better treatment of uveitis (Forrester JV, Kuffova L, Dick AD. Autoimmunity, autoinflammation and infection in uveitis. Am J Ophthalmol 2018;189:77–85; Lee et al. Autoimmune and autoinflammatory mechanisms in uveitis. Semin Immunopathol. 2014; 36(5): 581–594).

“Keep treating with the expectation that with complete control the eye will stop fighting back,” Dr Davis said.