The contribution of Asian researchers to the field of rheumatology

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emain unknown. The putative etiological agents associated with Behçet syndrome may have spread along the ancient Silk Routes, which extend from Eastern Europe to Japan. 16 The geographical distribution of several predisposing genetic factors, such as the HLA‑B*51 allele, 16 might also be associated with this regional variation in incidence. The pathogenesis of this syndrome also remains unclear, and several studies have focused on a potential infectious etiology. The acne lesions associated with Behçet syndrome are frequently colonized by Staphylococcus aureus, and to a lesser extent by Prevotella spp., 17 suggesting that at least some patients with this syndrome develop a reactive inflammatory response to infective agents. Thus, the characteristics of Behçet syndrome are different from the classic features of autoimmune disease, and there is an ongoing debate about whether Behçet syndrome belongs to a newly designated group of autoinflammatory diseases. 18 Takayasu arteritis Takayasu arteritis, first described in 1908 by Mikoto Takayasu, is an idiopathic chronic inflammatory disease that results in granulomatous panarteritis involving the large vessels, such as the aorta and its major branches. This disease has a worldwide distribution, with a high prevalence in people of Latin American and Asian ancestry. 19 The annual incidence of Takayasu arteritis in Japan is estimated to be 150 new cases per million people, 20 compared with 1–3 new cases per million people in the uSA and Europe. 21 Several reports indicate an increased frequency of the antigens HLA-Bw52 and HLA-B39.2 among patients in Japan, suggesting an immunogenetic association. 22 Although the pathogenesis of Takayasu arteritis remains unclear, evidence strongly indicates the involvement of T cells. Interestingly, immuno histopathologic examination has shown that the cells infiltrating aortic tissue mainly consist of cytotoxic lymphocytes, particularly γδ T lymphocytes, 23 which might cause vascular injury by releasing large amounts of cytolytic compounds, such as perforin. Kawasaki disease Kawasaki disease, initially described by Tomisaku Kawasaki in 1967, is one of the most common forms of childhood vasculitides that predominantly affects the medium and small arteries. The incidence of Kawasaki disease is highest in children residing in East Asia (annual incidence 140 per 100,000 in Japan, 69 per 100,000 in Taiwan, and 51 per 100,000 in Beijing) 24 and those of Asian ancestry residing in other parts of the world. In the uSA, the annual incidence of Kawasaki disease was highest among Asians and Pacific Islanders (33 per 100,000), and lowest among white people (9 per 100,000). 25 Thus, genetic susceptibility factors seem to contribute to the pathogenesis of this disorder. Although the precise cause of Kawasaki disease remains elusive, evidence suggests an infectious etiology. For example, incidence varies seasonally, with increases seen during the winter month of January and summer months of June and July, 26 outbreaks have been linked to clusters of cases Key points ■ Varied ethnicity, microbial endemicity and heterogeneity among Asian patients in presentation and outcomes provide opportunities for some unique studies reviews ■ Several diseases, such as Behçet syndrome, Takayasu arteritis, Kawasaki disease, and immunological disorders associated with human T‑lymphotropic virus type 1 were first defined in Asia ■ Asian research has been at the forefront of several avenues in rheumatology, such as establishment of the field of osteoimmunology, and the discoveries of regulatory T cells and synoviolin ■ Asian scientists have achieved considerable success in the translation of laboratory findings to clinical practice, exemplified by the therapeutic application of tocilizumab and agonistic antibodies to Fasr occurring in association with heavy rainfall, and the clinical features of Kawasaki disease are similar to those of other infectious diseases, such as adenovirus infection and scarlet fever. However, no single infectious agent has yet been identified. Several genetic polymorphisms have been linked to Kawasaki disease. Notably, a 2008 study by Onouchi et al. 27 reported an association between a singlenucleotide polymorphism in ITPKC and an increased risk of Kawasaki disease in children. 27 ITPKC acts as a negative regulator of T-cell activation, and may contribute to immune hyper-reactivity in this disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease, and emphasizes the role of activated T cells in its pathogenesis. hTlv‑1‑associated immunological disorders HTLV-1 is a retrovirus associated with chronic, persistent infection of human T cells. This virus is endemic in southern Japan, the Caribbean, and parts of South America, Africa, the Middle East and Melanesia. 28 Studies conducted in these areas have demonstrated that HTLV-1 infection is associated with several human diseases, including adult T-cell leukemia, an aggressive mature T-cell malignancy. 29 HTLV-1 is also associated with nonneoplastic immunological disorders charac terized by multiorgan lymphocytic infiltrates, such as myelopathy/ tropical spastic paraparesis, 4 HTLV-1-associated arthropathy (HAAP), 5 uveitis, 6 bronchoalveolitis, 7 Sjögren syndrome, and polymyositis. 8 Some patients present with multiple HTLV-1-associated immuno logical disorders. A progressive course and persistent inflammation affecting various organs are frequently seen in patients with idiopathic autoimmune disorders. These HTLV-1associated multiorgan immunological disorders are, therefore, extremely important models for understanding the pathogenic mechanisms of other organ-specific immune disorders. 30,31 HAAP is characterized by chronic inflammatory and proliferative synovitis with lymphoid follicles and pannus formation in the affected joints. Although the predominant viral reservoirs in peripheral blood of HTLV-1infected individuals are CD4 + CD25 + T cells, HTLV-1 has been reported to infect in vitro and in vivo a number of cell types, including synovial cells. In synoviocytes, NATuRE REVIEWS | rheumATologY VOLuME 6 | FEBRuARY 2010 | 107 © 20 10 Macmillan Publishers Limited. All rights reserved
eviews HTLV-1 Tax, a transactivator protein, has been demonstrated to upregulate the expression of proinflammatory cytokines and several oncogenes, such as FOS, JUN and MYC, which might contribute to synovial proliferation. 32 Furthermore, HTLV-1 Tax transgenic mice develop an inflammatory arthropathy resembling human RA. 33 These findings suggest that HTLV‑1 tax is one of the exogenous retrovirus genes responsible for the synovial hyperplasia associated with immune dysregulation in HAAP. Notable advances in rheumatology osteoimmunology Research indicating that the immune and skeletal systems interact and share a number of regulatory molecules, including cytokines, receptors, signaling molecules and transcription factors, has led to the establishment of a new field: osteoimmunology. 34 Although the inter action between skeletal and immune systems occurs both in health and disease, the effects of disruption to this interaction are exemplified in RA. Bone destruction in RA is caused by increased osteoclastic activity. The osteoclasts are derived from the myeloid cells of the immune system, 35 and proinflammatory cytokines, such as TNF, seem to be crucial for the change in the activity levels of both bone cell types. TNF increases the osteoblastic expression of receptor activator or nuclear factor κB ligand (RANKL; also known as TNF ligand super family, member 11), 36 which in turn increases the local differentiation of bone-resorbing osteoclasts. RANKL is expressed both by bone-forming osteoblasts and activated T cells, indicating that osteoclastic bone resorption is influenced by the immune system. 37 Moreover, Takayanagi et al. 38 discovered a crucial counter-regulatory mechanism, by which activated T cells can inhibit the RANKL-induced maturation and activation of osteoclasts. Together these findings indicate the crucial role of skeletal cells in both the hematopoietic and immune systems. Osteoimmunology encompasses the analysis of develop mental, homeostatic and pathologic consequences of the interactions between the immune and skeletal systems. understanding these complex interactions should provide new insights into the functional regulation of both systems, and also uncover new targets for therapeutic intervention. Discovery of T‑regulatory cells The precise mechanisms underlying the induction of uncontrolled immune reactions and the induction of the accelerated immune responses in rheumatic disorders are not fully understood. In the mid-1990s, Sakaguchi et al. 10 reported the concept of T-cell-mediated suppression by showing that a minor population of CD4 + T cells, which coexpress the IL-2 receptor α-chain (CD25), is crucial for the control of autoreactive T cells in vivo. This discovery of a new CD4 + CD25 + T-cell subset, termed T REG cells, has provided new opportunities and generated increased interest in elucidating these mechanisms. 10,11 In healthy individuals, in vitro studies have shown that T REG cells suppress the proliferation of and production of cytokines by pathogenic T cells. 11 Although T REG cells are phenotypically similar to activated T cells, they can be identified by the intracellular expression of the transcriptional regulator forkhead box P3 (FOXP3). 39 This protein is critical for the develop ment and function of T REG cells in both mice and humans. Substantial reductions in FOXP3 expression and/or T REG cell function have been observed in several human autoimmune diseases, 12 suggesting that altered FOXP3 expression and/or T REG function precipitates the loss of immunologic tolerance. A 2009 study by Miyara et al. 40 demonstrated that human FOXP3 + CD4 + T cells were composed of three phenotypically and functionally distinct subpopulations: CD45RA + FOXP3 low resting T REG cells; CD45RA – FOXP3 high activated T REG cells; and cytokine-secreting CD45RA – FOXP3 low T cells. The former two subtypes are suppressive and the latter is non-suppressive. Interestingly, the number of FOXP3 low non-suppressive memory T cells was increased in patients with active systemic lupus erythematosus 40 and in those with HTLV-1-associated neuroimmunological disorders. 41 Further investigations of the mechanism of action of T REG cells in autoimmune diseases will help identify new molecular pathways, which may in turn provide insight into understanding basic pathogenic mechanisms of immunological disorders. Discovery of synoviolin The pathologic features of RA include chronic, systemic inflammation of joints, which is associated with increased proliferation of synovial cells (Figure 1). Studies in Japan focusing on synovial cells led to the discovery of a novel molecule that is overexpressed in these cells: synoviolin. Amano et al. 42 used immunoscreening to identify the role of synoviolin in the process of endoplasmic-reticulumassociated degradation (ERAD)—an ATP-dependent ubiquitin–proteasome degradation process that eliminates defective proteins. The endoplasmic reticulum (ER) has an important role in protein folding. When the level of unfolded proteins in the ER exceeds its folding capacity, the burden on the ER is reduced by ERAD. 43 A mouse study showed that approximately 30% of mice overexpressing synoviolin developed spontaneous arthropathy as a result of reduced apoptosis of synoviocytes. Conversely, synoviolin-heterozygous (Syvn1 +/– ) mice showed resistance to collagen-induced arthritis owing to and increase in apoptosis of synovial cells. Analysis of protein expression in cells from synoviolin knockout mice (Syvn1 –/– ) revealed that synoviolin targets the tumor suppressor p53 for ubiquitination. 44 Thus, synovi olin is thought to function as an antiapoptotic factor through sequestration of tumor suppressor p53, highlighting its important role in rheumatoid synovial cell hyperplasia. A 2006 study suggested that elevated levels of synovio lin in peripheral blood were associated with a lack of response to infliximab treatment, 45 indicating the possible use of synoviolin as a predictive marker for response to anti-TNF therapy in patients with RA. Collectively, these findings indicate the importance of the ubiquitin– proteasome degrada tion process in the pathogenesis of RA. 108 | FEBRUARY 2010 | volUmE 6 www.nature.com/nrrheum © 20 10 Macmillan Publishers Limited. All rights reserved
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