Uveitis and Multiple Sclerosis: Potential Common Causal Mutations

Abstract

Uveitis, defined as inflammation of the uveal tract of the eye, is a leading cause of blindness and visual impairment throughout the world. The etiology of uveitis is complex, and autoimmunity plays a major role in its pathogenesis. Intermediate uveitis (IU), a subtype of ocular inflammation, has been associated with systemic autoimmune disorders, specifically with multiple sclerosis (MS). This article reports a rare three-generation family with several members affected by IU (four siblings) and comorbid MS (two siblings fulfilling MS diagnostic criteria and a third sibling presenting some neurological symptoms). Based on the clinical findings, we captured and sequenced whole exomes of seven pedigree members (affected and unaffected). Using a recessive model of transmission with full penetrance, we applied genetic linkage analysis to define minimal critical regions (MCRs) in suggestive or nominal regions of linkage. In these MCRs, we defined functional (some pathogenic), novel, and rare mutations that segregated as homozygous in affected and heterozygous in unaffected family members. The genes harboring these mutations, including DGKI, TNFRSF10A, GNGT1, CPAMD8, and BAFF, which are expressed in both eye and brain tissues and/or are related to autoimmune diseases, provide new avenues to evaluate the inherited causes of these devastating autoimmune conditions.

Intermediate Uveitis

“…Familial intermediate uveitis has been reported [29][30][31]. HLA typing in patients with intermediate uveitis confirms the presence of the HLA-DR2 (now HLA-DR15) allele in many patients; when compared to controls, the association has been statistically significant in several series [32][33][34][35], but did not correlate with other important variables such as age at onset or outcome [36].…”

“…The prevalence of the HLA-DR2 or HLA-DR15 alleles is also increased in multiple sclerosis (MS); this is of interest because MS and intermediate uveitis will occasionally occur in the same patient [33,35]. Genetic linkage analysis in an informative family with multiple members affected by intermediate uveitis and multiple sclerosis detected homozygous mutations in affected members in several genes including those related to autoimmune disease [31]. The association between polymorphisms in HLA-DR15 haplotype and non-infectious, non-anterior uveitis was reinforced by an immunochip approach [38].…”

“…Long-term surveillance of infliximab in noninfectious uveitis reported good efficacy with no unexpected safety issues [254]. Homozygous mutations in a TNF receptor superfamily gene segregated with pars planitis in one kindred suggesting that variants in the TNF pathway may be important in susceptibility to pars planitis [31].…”

Intermediate uveitis associated with MS

“…4 Other shared genetic risk loci provide clues to immunologic effector pathways common to both disorders: tumor necrosis factor ( TNF , rs361525, rs1800629), lymphotoxin alpha (rs909253), interleukin 6 ( IL-6 , rs1800795), IL-2/IL-21 (rs6822844), IL-2 receptor alpha (rs2104286, rs12722489), interferon regulatory factor 5 (rs10954213), 7 , 9 , 10 and through one genetic linkage study, functional variants affecting TNF receptor superfamily members 10a and 13b (B cell–activating factor), G-protein subunit gamma transducing-1, alpha-2-macroglobulin domain containing-8, diacylglycerol kinase iota and reelin. 11 Further support for their role in MS and uveitis pathogenesis comes from animal models (section Common immunologic effector mechanisms in MS and IU, figures 1 and 2 ).…”

“…IU accounts for 10%–20% of uveitis cases overall, but 61%–80% of MS-associated uveitis. 3 , 11 At present, MS-associated uveitis is not defined separately from undifferentiated (formerly idiopathic) IU, a term normally reserved for anatomically defined IU that is not associated with infection or systemic diseases, like sarcoidosis or Behçet disease. 2 This is because a sizable proportion of people first diagnosed with IU might develop MS several years later.…”