Description of the Behçet’s Disease and Its Treatment Methods

Published: 2021-09-13 22:00:08
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Behçet’s disease (BD) affects multiple organs. It is mainly characterized by recurrent oral, skin, genital aphthous ulcers, and eye involvement. Successful management of BD is increasing, although its etiology remains unclear. A number of etiologies have been proposed, including environmental, genetic, viral, and immunological factors. To understand its complex etiology and improve its management, animal models of BD have been used to enable more effective therapeutic applications with increased clinical significance. Herpes simplex virus (HSV) type 1 induced BD mouse model has shown disease characteristics most similar to those seen in BD patients. It is the only animal model that has been used to test various therapeutic modalities. It is continuously being used for such purpose.
Behçet’s disease (BD) is a chronic, relapsing, multi-systemic, and vascular inflammatory disorder that affects many organ systems, including mucocutaneous, ocular, vascular, arthritic, gastrointestinal, and central nervous systems. Several factors, including environmental pollutants, infections, genetic polymorphism, and immune dysregulation have been suggested as factors affecting the pathogenesis of BD. Herpes simplex virus (HSV) infection is still strongly believed to be the triggering factor of BD. Using HSV-induced inflammatory animal models, therapeutic effects of natural products and new biological agents on BD have been determined in recent years. They are reviewed and discussed here. In 1937, Hulusi Behçet proposed that the syndrome might be caused by viral infection in his first description of BD. However, he could not demonstrate that the virus was HSV in his publication. In 1953, Sezer et al. isolated the virus from ocular fluid of patients. Later, Lee et al. detected HSV DNA in the saliva of patients with BD and hypothesized that HSV infection might be the trigger of BD. Based on such hypothesis, Sohn et al. developed an animal model of BD by inoculating 1×106 p.f.u. HSV type 1 (KOS strain) to needle scratched earlobe of ICR mice and found that mice developed BD-like symptoms, including genital ulcer, oral ulcer, skin lesions, eye lesions, arthritis, and intestinal ulcers. These induced BD-like symptoms were similar to clinical manifestations in BD patients.
Genetic susceptibility of BD has been widely studied. It is well-known that human leukocyte antigen (HLA)-B gene, particularly HLA-B51, is associated with BD patients. However, the relative risk of BD associated with HLA-B51 varies widely among different ethnic populations. HLA-B51 allele is more frequent in some populations where BD is virtually unknown. It has been recognized that the association of HLA-B51 with BD is stronger in Turkish and Japanese populations than that in Western population. Transgenic mice with HLA-B51 generated by Takeno et al. have shown neutrophil hyperfunction without showing any clinical manifestations that mimic BD. This indicates the HLA-B51 molecule alone is insufficient to induce clinical BD. This result suggests that other factors are involved in BD susceptibility.
HLA-G gene variants have also been studied in BD. HLA-G was first identified in placenta. It is involved in maintaining tolerance of maternal immune system to semi-allogeneic fetus. HLA-G has an inhibitory effect on cytotoxicity of NK and T-cell, and T-cell proliferation. HLA-G can inhibit trans endothelial migration of natural killer (NK) cells, shift cytokine balance toward Th2 dominance, and suppress the proliferation of allogeneic CD4+ T lymphocytes. These results suggest that HLA-G has specific inhibitory effects on immune cells. Qa-2 is the functional homolog of HLA-G in mice. HSV-induced BD mice show decreased Qa-2 levels. Down-regulation of Qa-2 is known to bring deterioration of BD-like symptoms.
HSV induced BD-like symptoms have been reported in mice. However, virus infection alone is insufficient to explain the pathogenesis of BD. In BD patients, dysregulations of immune functions have been reported. There are plenty of evidence of aberrant T-cell responses in BD. Type 1 helper T cells (Th1) are known to secrete interleukin (IL)-2 and interferon gamma (IFN activate macrophages, and elicit delayed hypersensitivity reactions while type 2 helper T cells (Th2) can produce IL-4, IL-5, and IL-10 to suppress cell-mediated immunity. In BD, these cytokines perform a cross-regulatory function between Th1 and Th2 subsets. Th1/Th2 imbalance is thought to be an important factor in BD. Induction of macrophages promotes Th1 dependent cellular immune responses and suppresses Th2 cell activity. Sohn et al. have demonstrated that deletion of macrophages decreases the incidence of BD in mice.
Deletion of macrophages also up-regulates Th2 cytokines that are closely related to improvement of BD symptoms. Regulatory T (Treg) cells play an important role in the pathogenesis of autoimmune disorders, including BD. Frequencies of Treg cells are reduced in the peripheral blood of BD patients with eye lesions. Therefore, low levels of CD4+CD25+ regulatory T cells can be a factor in the pathogenesis of BD. According to Shim et al., when CD4+CD25+ T cells isolated from healthy mice are transferred to BD mice, the disease severity is significantly down-regulated by Treg cells transferred in a dose-dependent manner. Increased Treg cells up-regulated IL-10 and TGF- levels but down-regulated IFNg, tumor necrosis factor alpha (TNF, IL-6, and IL-17 levels.
TNF is a potent paracrine and endocrine mediator of inflammatory and immune functions. There is growing evidence showing that TNF plays an important role in the management of inflammatory diseases, including BD. In BD patients, TNF production is high. Infliximab (anti-TNF antibody) and Etanercept (soluble TNF receptor) have been used to treat BD patients. Inhibition of TNFexpression by administration of TNFsiRNA can ameliorate HSV induced BD mice. The severity score of BD was significantly decreased compared to that in the control group. SK126 and SK94 are synthesized pyridine derivatives based on gentianine, a major component of Gentiana Macrophylla Radix. When SK126 and SK94 were used to treat TNF stimulated human umbilical vein endothelial cells, they down-regulated adhesion molecules such as ICAM-1, VCAM-1, and E-selectin. In addition, oral administration of SK126 and SK94 effectively down-regulated serum levels of TNFin HSV induced BD mice accompanied by symptom improvement.
Herba Taraxaci (Taraxacum mongolicum Hand.-Mazz.) is frequently used for bacterial and viral infections. It has anti-inflammtory, anti-carcinogenic, anti-allergic, anti-hyperglycemic, and analgesic activities. Its known effects include reducing heat, decreasing edema, and clearing toxic substances in inflamed areas. In addition, it has antibiotic effects against Staphylococcus aureus, Streptococcus agalactiae, and Streptococcus dysgalactiae. Herba Taraxaci contains taraxasterol, choline, inulin, and pectin. Treatment of BD mice with Herba Taraxaci can induce IL-4 and improve symptoms. Herba Taraxaci can alter Th1/Th2 balance by increasing IL-4 and Th2 immune responses.
In addition, Herba Taraxaci can induce Fas-mediated apoptosis of abnormal proliferated leukocytes involved in induction of BD symptoms. Nakamura et al. have suggested that activated CD4+ T cells may cause severe chronic inflammation due to insufficient expressions of Fas in BD patients. Combination therapy of Herba Taraxaci and colchicine can reduce symptoms in 80% of BD mice, much higher than colchicine (30%) or Famciclovir (40%) treatment alone. Herba Taraxaci alone or in combination with colchicine can up-regulate frequencies of IL-10 secreting splenocytes. Increased IL-10 by Herba Taraxaci might have acted as an improving factor. Thus, combination therapy with natural products can be an another strategy for BD treatment.
Chitosan is a biocompatible, biodegradable, and nontoxic natural polymer with high cationic potential. Chitosan is a safe and effective adjuvant with many biological effects on drug delivery. A mixture of chitosan and pCIN-mIL-4 can significantly increase IL-4 mRNA and IL-4 protein levels after in vivo mouse administration. Oral administration of pCIN-mIL-4 DNA vector in combination with chitosan has effectively delivered DNA vector to intestinal tissues of mice. Our recent study has shown that chitosan itself can be a potential immune modulator. Oral administration of chitosan significantly up-regulated frequencies of DX5+ natural killer cell populations in peripheral blood leukocytes (PBL). In HSV infected mice, chitosan increased frequencies of CD4+ T cells, CD8+ T cells, and CD11c+ dendritic cells in PBL. In addition, chitosan treatment down-regulated levels of anti-HSV antibody in the serum of HSV infected mice compared to the control group. Thus, chitosan can be used as an adjuvant for gene delivery and an immune modulator by oral administration.

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