Sarcoidosis is a chronic systemic disease characterized by marked macrophage and CD4+ T-cell activity, and the accumulation of noncaseating granulomas in a wide range of organs, such as lungs, lymph nodes, eye, skin, and heart.
1 In the current survey of uveitis in Japan, the most frequent inflammatory disease was sarcoidosis (10.6%), followed by Vogt-Koyanagi-Harada disease (7.0%), acute anterior uveitis (6.5%), scleritis (6.1%), herpetic iridocyclitis (4.2%), Behçet's disease (3.9%), bacterial endophthalmitis (2.5%), masquerade syndrome (2.5%), Posner-Schlossman syndrome (1.8%), and retinal vasculitis (1.6%).
2 The etiology of sarcoidosis still is uncertain, but the disease currently is thought to be triggered by various genetic as well as environmental factors. It is well established that sarcoidosis is associated with the human leukocyte antigen (HLA) class II genes, especially
HLA-DRB1 and
HLA-DQB1 genes, in several ethnic groups.
3–7 However, to our knowledge it has not yet been clarified whether HLA genes themselves are the pathogenic gene related directly to sarcoidosis or are associated with the disease only because of linkage disequilibrium with some other genes. Recently, a single nucleotide polymorphism within
butyrophilin-like 2 (
BTNL2), rs2076530, has been implicated as a risk factor for sarcoidosis.
8 The
BTNL2 gene, located only 170 kilobases (kb) from the
HLA-DRB1 gene telomerically on chromosome 6, is a member of the immunoglobulin superfamily with likely costimulatory activities in T-cell activation on the basis of amino acid homology to B7 molecules.
9 The G/A transition of rs2076530 causes a premature truncation of protein, disrupting the membrane localization of the protein and a necessary process for down-regulating activated T-cells (Th1).
8,10 The truncated protein increases the risk of developing sarcoidosis independent of
HLA-DRB1 risk alleles.
8,11 However, subsequent studies have showed inconsistent results on a sarcoidosis risk factor of
BTNL2 rs2076530_A and its independent effect of
HLA-DRB1.
12,13 In other diseases, such as type 1 diabetes (T1D),
14 rheumatoid arthritis (RA),
15 systemic lupus erythematosus (SLE),
14 multiple sclerosis (MS),
15 Graves' disease (GD),
16 chronic beryllium disease (CBD),
17 and ulcerative colitis (UC),
18 a significant association with
BTNL2 polymorphisms appeared to be secondary to the primary
HLA-DRB1 association because of its strong linkage disequilibrium (LD) with
DRB1 alleles.