During inflammation, leukocytes undergo a series of consecutive adhesive interactions orchestrated by leukocyte adhesion molecules expressed on the cell surface of leukocytes and the vascular endothelium and migrate to the inflamed tissues. Also, inflammatory cytokines secreted by recruited leukocytes and resident cells regulate the inflammatory response in inflamed tissues. Under proper conditions, inflammation contributes to clear away invading agents, degrade necrotized tissue components and promote tissue regeneration. However, if inflammation becomes chronic, it can turn out to be detrimental by prolonged and excessive tissue damages.
One of the major microvascular complications of diabetes is diabetic retinopathy (DR), a leading cause of blindness in developed countries. The mechanisms underlying the development of DR are not fully understood; however, recent studies have implicated chronic inflammation in the pathophysiology of DR. In this review, we focus on the role of leukocyte adhesion molecules and inflammatory cytokines in the pathophysiology of DR.

抄録全体を表示

Dry eye disease is a devastating and multifactorial disorder of the tear-film layer and ocular surface. Multiple symptoms include eye irritation, and visual disturbances, and sign have tear-film instability, along with the potential for injuring the ocular surface. Accumulating evidence indicates that dry eye disease is accompanied by hyperosmolarity of the tear film and inflammation of the ocular surface microenvironment. Most cases of dry eye disease are secondary to any of a vast array of inflammatory conditions and disorders, including auto- and allo-immune diseases, infection, aging, neuroinflammation, and sterile Inflammation. Sterile inflammation is induced by several different kinds of non-infectious triggers, including altered cellular and tissue states. New results have implicated damage-associated molecular patterns, microorganisms, and neurotransmitters in primary dry eye disease. Furthermore, in conjunction with inflammatory and fibrotic changes, the renin angiotensin system and epithelial mesenchymal transition may be involved in disease-associated and immune-mediated dry eye disease, such as chronic GVHD-related dry eye. Collectively, studies show that at least some and possibly many factors influence the condition of the ocular surface, leading to chronic inflammation that exacerbates dry eye symptoms in a vicious cycle. Since the pathway for each type of dry eye disease may differ, and specific pathways may be responsible for the disease in individual patients, patient-tailored therapies should be developed in the future. In this review article, we focus on emerging concepts on the role of the inflammatory process in dry eye disease.

抄録全体を表示

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute inflammatory vesiculobullous reactions of the skin and mucous membranes including oral cavity and ocular surface.
Single nucleotide polymorphism (SNP) association analysis of SJS/TEN patients with severe mucosal involvements (MI) revealed that TLR3 SNPs and IL4R SNP Gln551Arg were significantly associated with SJS/TEN with MI. We also found that PTGER3 SNPs were associated with the SJS/TEN using genome-wide association study (GWAS). The expression of EP3 (protein of PTGER3 gene) was greatly reduced in the conjunctival epithelium of the SJS/TEN patients compared to the controls. About 80% of our SJS/TEN patients with MI had used cold medications before the onset of their disease, and cold medicines including non-steroid anti-inflammatory drugs (NSAIDs) could inhibit the production of the EP3 ligand PGE₂. Thus, EP3 may contribute to the development of SJS/TEN with MI.
We also found that a combination of TLR3 and PTGER3 SNPs could raise the genetic susceptibility of SJS/TEN with MI, and that there were functional interactions between TLR3 and EP3, the protein of PTGER3. This suggests that a lack of balance between TLR3 and EP3 may trigger mucosal inflammation at sites such as the ocular surface.
Elsewhere we documented that in Japanese patients HLA-A^*0206 is strongly associated with the SJS/TEN. We also reported multiplicative interaction(s) between HLA-A^*0206 and TLR3 SNPs in patients with the SJS/TEN.
Together, our observations suggest that not only environmental- but also genetic factors, including epistatic interactions, play a role in an integrated etiology of SJS/TEN with MI.

抄録全体を表示

Noninfectious uveitis is one of the sight-threatening disorders that are associated with systemic autoimmune diseases, such as Behçet's disease. Uveitis is often recurrent and causes subsequent tissue destruction and scarring, especially in the retina and uvea, leading to permanent loss of vision. Early studies have shown that T-helper (Th) 1 cells are the major effector cells and are critical for the development of uveitis. Recently, Th17 cells, a newly defined effector T-helper lineage that is distinct from Th1 and Th2 cell lineages, were also shown to play a pivotal role in the pathogenesis of uveitis. Furthermore, several clinical studies have reported that biological agents targeting Th17-related cytokines, such as IL-6, IL-23, and TNF-α, induced and maintained remission in human autoimmune diseases, including rheumatoid arthritis, Crohn's disease, psoriasis, and noninfectious uveitis. In this mini-review, we focus on the roles of proinflammatory cytokines in the regulation of Th1 and Th17 cell responses in uveitis, both experimentally and clinically. A deeper understanding of the underlying mechanisms will provide new insights into the development of new therapies for refractory human noninfectious uveitis.

抄録全体を表示

Immune responses against uveitis are broadly divided into innate immune response and adaptive immune response. The group of inflammatory cells that induce innate immunity against uveitis comprises the “non-lymphocytes” such as neutrophils, macrophages and dendritic cells. Among the uveitis in which innate immunity plays a central role, infectious uveitis is the most important. Particularly in endophthalmitis and acute retinal necrosis that have poor visual prognosis, delay in diagnosis directly impacts visual function; therefore early diagnosis and treatment are important to obtain good visual outcome. Neutrophils are the inflammatory cells involved in the earliest pathology of infectious uveitis, causing ocular tissue damage which may result in irreversible visual function impairment. In representative infectious uveitis such as endogenous bacterial or fungal endophthalmitis, a characteristic cytokine profile has been identified; apart from cytokines promoting neutrophil migration, production and activation, other cytokines that enhance neuropathy and intraocular proliferation have also been detected. Although Behçet's disease has been considered to be a uveitis involving adaptive immunity, since the hypopyon observed in this disease is composed of neutrophils, inflammatory cells of the innate immune system are also involved in its pathology. However, considering also the fact that T cell infiltration features prominently in retinal vasculitis of Behçet's disease, innate immunity and adaptive immunity do not act individually, but function simultaneously and form an innate immunity-adaptive immune cycle, contributing to the persistence and chronicity of uveitis.

抄録全体を表示

Inflammation is self-regulated to preserve the functions in the eye, because the eye has immune privilege. At present, three major mechanisms prevail regarding the molecular mechanisms of immune privilege in the eye: there are (a) anatomical, cellular, and molecular barriers in the eye; (b) eye-derived immunological tolerance, the so-called anterior chamber-associated immune deviation; and (c) immune suppressive intraocular microenvironment. In this mini-review, the mechanisms of immune privilege that have been learned from ocular inflammation animal models, especially corneal transplantation, are described. The functions of new molecules on local immune regulation within the cornea are reviewed. Therapeutic strategies for restoring immune privilege are also introduced.

抄録全体を表示

Intracranial aneurysm (IA) is a cerebrovascular disease usually affected the bifurcation sites of intracranial arteries. IA is socially important because IA can develop a lethal subarachnoid hemorrhage after rupture. However, today, there is no medical treatment for IAs because of the lack of knowledge regarding the mechanisms regulating IA formation. Experimental analyses using human IA specimen have revealed the presence of long-lasting inflammation in IA lesions. In other point of view, from studies of flow dynamics, IA formation is presumed to be triggered under high wall shear stress loaded on arterial bifurcations. Nonetheless, the mechanisms regarding how IA formation is regulated under high wall shear stress and how the inflammation lasts for a long period remain to be elucidated. Recently, experimental studies using rodent IA models have revealed a critical role of prostaglandin (PG) E₂ signaling to IA formation. In brief, COX-2, a PGE₂-producing enzyme, is induced under high wall shear stress in endothelial cells. COX-2-producing PGE₂, then, activates NF-κB, a critical transcription factor for IA formation, via EP2. Because NF-κB transcriptionally induces COX-2, a positive feedback loop consisting of COX-2-PGE₂-EP2-NF-κB signaling is formed and high wall shear stress induced inflammation becomes chronic. Here, as a result of NF-κB-mediated MCP-1 induction, macrophages infiltrate in IA walls and expand inflammation into whole arterial walls beyond endothelial cells via secreting a large amount of pro-inflammatory molecules. In summary, the presence of positive feedback loop and macrophage infiltration are two key events regulating the chronicity of inflammation contributing to IA formation.

抄録全体を表示