IL-21 and Sjögren's syndrome

Treatment of Sjögren's syndrome is almost entirely symptomatic. A lack of true understanding of the underlying immunological pathology of the disease prevents directed therapy. Interleukin-21 (IL-21) is elevated in the serum of patients with this disease and is expressed by the lymphocytes infiltrating the salivary glands. The known functions of IL-21 in facilitating differentiation, proliferation, and survival of both B and T cells mesh well with the findings in Sjögren's syndrome. Demonstration of IL-21 as a fundamental aspect of the pathophysiology of Sjögren's syndrome could lead to the development of anti-IL-21 therapy for this disease.

To be perfectly frank, there is no proper therapy for Sjögren's syndrome. Of course, there are therapies to treat the symptoms, but none that treats the underlying patholophysiology. Th ere may be an obvious underlying reason that we cannot target the immunological or biological cause of Sjögren's syndrome. Namely, we as a community (that is, the research and clinical community interested in the disease) do not really understand the (presumed) immunological events leading to, advancing, and perpetuating this disease. Th is predicament begs the question of the basic assumption of biomedical research, especially translational research in which a human condition is under study. Th at is, a fuller understanding of patho physiological mechanisms will naturally lead to therapies based on that understanding.
In the previous issue of Arthritis Research & Th erapy, Kang and colleagues [1] studied interleukin-21 (IL-21) in Sjögren's syndrome. Will determining that this cytokine is involved in Sjögren's syndrome open new therapeutic opportunities? Th is has certainly occurred in other illnesses within the domain of rheuma tology, both in common and in uncommon illnesses. When I was an internal medicine resident, not that long ago, the duties of the rheumatology clinic consisted mostly of checking urine analysis results and complete blood counts to determine whether patients with rheumatoid arthritis could receive a gold shot that day. A lot has changed since then -mostly because research determined that tumor necrosis factor-alpha (TNFα) is involved in the pathogenesis of rheuma toid arthritis. Th is led to the development of specifi c anti-TNF therapies, which basically changed the nature and natural history of the disease [2]. Pascual and colleagues [3] discovered that IL-1 is overexpressed in children with systemic-onset juvenile idiopathic arthritis. Th is know ledge led to a clinical trial of anti-IL-1 therapy in this illness, which was largely unresponsive to other, un directed therapies [4]. Dissecting genetic risk factors has led to therapy. For example, autosomal dominant periodic fever syndromes were determined to be caused by mutations in the TNFα receptor, and anti-TNF therapy works well in this disease [5], which is now known as TNF receptor-associated periodic syndrome (TRAPS). Common population variants of the IL-23 gene are associated with psoriasis, a genetically complex disease [6]. Th ese genetic data, in part, gave rise to a clinical trial of an anti-IL-23 monoclonal antibody, which was found to be eff ective, in psoriasis [7]. Development of anti-interferon therapy is being undertaken with systemic lupus erythematosus as the target illness.
Th e known functions of IL-21 fi t well with the fi ndings in patients with Sjögren's syndrome. Th e disease is characterized by lymphocytic infi ltrates in the salivary and lacrimal glands that contain both B and T cells that in many patients demonstrate ectopic germinal center formation. Kang  IL-21 is involved in the diff erentiation of T helper 17 (Th 17) cells in that IL-21 acts to facilitate IL-23-induced expansion of these cells. As noted above, an IL-23 monoclonal antibody is available clinically, but the involvement of Th 17 cells in the pathogenesis of Sjögren's syndrome is unknown. If Th 17 cells are, in fact, players in Sjögren's syndrome, then perhaps the available anti-IL-23 monoclonal antibodies would be benefi cial in the disease. Th is, of course, remains to be determined.
Certainly, the fi ndings reported by Kang and colleagues [1] as well as others in regard to IL-21 in Sjögren's syndrome [8] and other infl ammatory rheumatic illnesses [9,10] suggest that therapy directed at IL-21 may be useful in human autoimmune disease. Th ese fi ndings need to be confi rmed and advanced but perhaps will underpin the development of therapy directed at the underlying pathophysiology of Sjögren's syndrome.

Competing interests
The author declares that he has no competing interests. 1 Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, 1000 North Lincoln Blvd, Oklahoma City, OK 73104, USA.