The understanding of the pathogenesis of uveitis has progressed through studies using animal models, and the findings have been applied to novel therapeutic agents such as tumor necrosis factor (TNF) inhibitors, but there are still many unclear issues. Here we report our studies aimed at elucidating the pathogenesis and developing new treatments for Behçet's disease, an ocular inflammatory disease, retinal vasculitis, and intraocular malignant lymphoma as follows:
1. Clinical features of Behçet's disease and analysis of human leukocyte antigen (HLA)-related antigens that activate lymphocytes
Uveitis in Behçet's disease is one of the most severe manifestations of endogenous uveitis. We developed Behçet's disease ocular attack score 24 (BOS24) as a new method for assessing the activity of uveitis in Behçet's disease and showed that the scores significantly correlated with changes in visual acuity. In contrast, HLA is a key molecule required for antigen presentation to lymphocytes, and in Behcet's disease, approximately 80% of patients with uveitis are HLA-B^*5101- or HLA-A^*2601-positive. We report ed that patients with HLA-A^*2601 resulted in poor visual prognosis. In addition, we performed 3D molecular dynamic simulations to estimate the amino acid sequences with high affinity to the pocket structure of HLA-B^*51 from the antigens that had been reported to react with lymphocytes of patients with Behçet's disease. These peptides significantly promoted the proliferation of peripheral blood lymphocytes in patients with Behçet's uveitis. These findings suggested the direct involvement of the affinity between HLA and antigenic peptide in lymphocyte activation.
2. A new understanding of retinal vasculitis in uveitis
Retinal vasculitis occurs in uveitis and various retinal diseases and is classified into retinal arteritis, phlebitis, and capillaritis based on fluorescein angiography (FA) image. We examined FA images of various uveitis diseases and found that infectious uveitis was associated with a higher incidence of retinal arteritis and arteriovenous occlusions compared with non-infectious uveitis. To determine the mechanism, inflammatory cytokines in the vitreous humor of patients with various uveitis diseases during the active period were extensively examined. TNF-α and chemokine levels were commonly elevated in all cases of uveitis. Interleukin (IL) -10 was specifically elevated in intraocular lymphoma. Interferon (IFN) -α2 was specifically increased in acute retinal necrosis. In bacterial endophthalmitis, IL-6, IL-17A, and granulocyte colony stimulating factor (G-CSF) were specifically increased. These findings indicated that expression patterns of inflammatory cytokines in the vitreous humor were characterized by primary diseases of uveitis.
3. Diagnosis and treatment of intraocular lymphoma
Recently, the percentage of intraocular lymphoma among patients with uveitis has been increasing. It is easily misdiagnosed as other uveitis diseases and is a disease with poor prognosis owing to the central nervous system (CNS) lesions that are easily induced. No clear diagnostic criteria and standard treatments for this disease have been established yet. We conducted a prospective clinical trial to investigate the effect of combination therapy of intravitreal injection of methotrexate, systemic chemotherapy, and prophylactic low-dose whole-brain radiotherapy in patients with primary intraocular lymphoma, showing the improvement of prognosis of the disease and the reduction of CNS relapse. In contrast, secondary intraocular lymphoma develops in organs other than the eye and the CNS and metastasizes into the eye. We retrospectively analyzed clinical features and treatment outcomes of secondary intraocular lymphoma and discovered that the extremely poor prognosis was due to repeated relapses despite various treatments. The development of new treatments for intraocular lymphoma, particularly for secondary intraocular lymphoma, is required.
Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc) 124: 220-246, 2020.