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Enterovirus 71 (EV71) is one of the most important causes of herpangina and hand, foot, and mouth disease. It can also cause severe complications of the central nervous system (CNS). Brain stem encephalitis with pulmonary edema is the severe complication that can lead to death. EV71 replicates in leukocytes, endothelial cells, and dendritic cells resulting in the production of immune and inflammatory mediators that shape innate and acquired immune responses and the complications of disease. Cytokines, as a part of innate immunity, favor the development of antiviral and Th1 immune responses. Cytokines and chemokines play an important role in the pathogenesis EV71 brain stem encephalitis. Both the CNS and the systemic inflammatory responses to infection play important, but distinctly different, roles in the pathogenesis of EV71 pulmonary edema. Administration of intravenous immunoglobulin and milrinone, a phosphodiesterase inhibitor, has been shown to modulate inflammation, to reduce sympathetic overactivity, and to improve survival in patients with EV71 autonomic nervous system dysregulation and pulmonary edema.

Background: Several epidemics of enterovirus 71 (EV71) infections occurred in Taiwan since 1998., Objectives: We performed the study to determine the changes in cytokine profiles associated with administration of intravenous immunoglobulin (IVIG) in patients with EV71-associated brainstem encephalitis complicated by autonomic nervous system (ANS) dysfunction and pulmonary edema., Study Design: Plasma cytokine concentrations (IL-1beta, IL-6, IL-8, IFN-gamma, TNF-alpha, IL-2, IL-4, IL-5, IL-10, and IL-13) were monitored on admission and within 12-24h after administration of IVIG in a cohort of children (n=22) with virologically confirmed EV71 infection, from March 2000 through April 2004., Result: Plasma levels of IFN-gamma, IL-6, IL-8, IL-10, and IL-13 levels significantly decreased in patients with pulmonary edema after administration of IVIG, P<0.05. Plasma levels of IL-6 and IL-8 were significantly decreased in patients with ANS dysregulation after administration of IVIG, P<0.05. Administration of IVIG was not associated with significant changes in plasma concentration of IL-1beta, IL-2, IL-4, IL-5 IL-10, IL-13 and TNF-alpha in patients with ANS dysregulation., Conclusions: These findings suggest that IVIG might be considered to have a therapeutic role in EV71-associated brainstem encephalitis. A clinical trial is needed to support this hypothesis.

Fourteen cytokines or chemokines were analyzed on 88 RT-PCR-confirmed severe acute respiratory syndrome (SARS) patients. IFN-gamma, IL-18, TGF-beta, IL-6, IP-10, MCP-1, MIG, and IL-8, but not of TNF-alpha, IL-2, IL-4, IL-10, IL-13, or TNFRI, were highly elevated in the acute phase sera of Taiwan SARS patients. IFN-gamma was significantly higher in the Ab(+) group than in the Ab(-) group. IFN-gamma, IL-18, MCP-1, MIG, and IP-10 were already elevated at early days post fever onset. Furthermore, levels of IL-18, IP-10, MIG, and MCP-1 were significantly higher in the death group than in the survival group. For the survival group, IFN-gamma and MCP-1 were inversely associated with circulating lymphocytes count and monocytes count, but positively associated with circulating neutrophils count. It is concluded that an interferon-gamma-related cytokine storm was induced post SARS coronavirus infection, and this cytokine storm might be involved in the immunopathological damage in SARS patients.

Vascular dysfunction is a hallmark associated with disease onset in dengue hemorrhagic fever and dengue shock syndrome. In addition to direct viral damage, immune responses to dengue virus (DV) infection may also underlie the pathogenesis of disease. We have proposed a mechanism of molecular mimicry in which Abs directed against DV nonstructural protein 1 (NS1) cross-react with endothelial cells and induce damage. In this study, we demonstrated the inflammatory endothelial cell activation induced by anti-DV NS1 via the transcription factor NF-kappaB-regulated pathway. Protein phosphorylation and NF-kappaB activation were observed after anti-DV NS1 stimulation in a human microvascular endothelial cell line-1. The cytokine and chemokine production, including IL-6, IL-8, and MCP-1, but not RANTES, in endothelial cells increased after treatment with anti-DV NS1 Abs. The expression of IL-6, IL-8, and MCP-1 was blocked by the preabsorption of anti-DV NS1 with DV NS1 or by the inhibition of NF-kappaB activation. Furthermore, the increases in both ICAM-1 expression and the ability of human PBMC to adhere to endothelial cells were also observed, and these effects were inhibited by pretreatment with anti-ICAM-1 or anti-MCP-1 Abs. Therefore, in addition to endothelial cell apoptosis, as previously reported, inflammatory activation occurs in endothelial cells after stimulation by anti-DV NS1 Abs. These results suggest the involvement of anti-DV NS1 Abs in the vasculopathy of DV infection.

A prospective study of clinical and cytokine profiles of 107 infants with dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) was conducted. Fever, petechiae on the skin, and hepatomegaly were the most common clinical findings associated with DHF/DSS in infants. DSS occurred in 20.5% of the patients. Hemoconcentration and thrombocytopenia were observed in 91.5% and 92.5% of the patients, respectively. Serologic testing revealed that almost all of the patients (95.3%) had primary dengue virus infections. These data demonstrate that clinical and laboratory findings of DHF/DSS in infants are compatible with the World Health Organization's clinical diagnostic criteria for pediatric DHF. The present study is the first to report evidence of production of cytokines in infants with DHF/DSS and to describe the difference between the cytokine profile of infants with primary dengue virus infections and children with secondary infections. Overproduction of both proinflammatory cytokines (interferon-gamma and tumor necrosis factor-alpha) and anti-inflammatory cytokines (interleukin-10 and -6) may play a role in the pathogenesis of DHF/DSS in infants.

Taiwan experienced several epidemics of enterovirus 71 (EV71) infections, which were associated with brainstem encephalitis (BE) and pulmonary edema (PE). To elucidate the role of immune mechanisms in the pathogenesis of BE caused by EV71 and its fatal complication, PE, we analyzed the laboratory findings, cytokine, and immunophenotypes of 73 EV71-infected patients with BE. Patients were stratified by disease: PE (n=14), autonomic nervous system (ANS) dysregulation (n=25), and isolated BE (n=34). The mortality rate for PE was 64.3%. Leukocytosis and thrombocytosis were significantly more frequent among patients with PE. A significant elevation of plasma interleukin (IL)-10, IL-13, and interferon (IFN)-gamma levels observed in patients with PE. Patients with PE also had lower circulating CD4(+) T cells, CD8(+) T cells, and natural killer (NK) cells. An extensive peripheral and central nervous system inflammatory response with abnormal IL-10, IL-13, and IFN-gamma cytokine production and lymphocyte depletion appears to be responsible for the pathogenesis of EV71-associated PE.

Dengue virus (DV) replication, antibody-enhanced viral infection, and cytokine responses of human primary B lymphocytes (cells) were characterized and compared with those of monocytes. The presence of a replication template (negative-strand RNA intermediate), viral antigens including core and nonstructural proteins, and increasing amounts of virus with time postinfection indicated that DV actively replicated in B cells. Virus infection also induced B cells to produce interleukin-6 and tumor necrosis factor alpha, which have been previously implicated in virus pathogenesis. In addition, a heterologous antibody was able to enhance both virus and cytokine production in B cells. Furthermore, the levels of virus replication, antibody-enhanced virus replication, and cytokine responses observed in B cells were not statistically different from those in monocytes. These results suggest that B cells may play an important role in DV pathogenesis.

The effect of a water-soluble trimalonic acid derivative of fullerene, carboxyfullerene (C63(COOH)6), on the opening of blood-brain barrier (BBB) in Escherichia coli (E. coli)-induced meningitis was tested. In E. coli-induced meningitis model, the increase of BBB permeability was manifested in two distinct phases based on cytokine expression pattern and neutrophilic infiltration in B6 mice. An early increase in BBB permeability was occurred at 1–5 h post injection that could be blocked by either anti-TNF-αor anti-IL-1β antibodies. A late one (neutrophil-associated BBB opening) was manifested at 6–12 h that was inhibited by vinblastine pretreatment. Inhibition of the early E. coli-induced BBB opening blocked the development of the late one. Furthermore, the neutrophil-associated BBB opening (the late phase), but not cytokine- induced one (the early phase), was inhibited by a water-soluble carboxyfullerene. [ABSTRACT FROM AUTHOR]

The CD3+/TCRαβ+ T-cell-mediated hepatic inflammation induced by Propionibacterium acnes could be divided into an acute and a chronic phase. The acute phase occurred within 72 h after injection and displayed hepatic apoptosis. Anti-TNFα antibody inhibited both the P. acnes-induced hepatic apoptosis and lymphocyte infiltration seen in this phase, indicating the involvement of this cytokine. Thereafter, a chronic phase was manifested from days 7 to 14 after injection. It was characterized as granulomatous inflammation admixed with apoptosis of infiltrating lymphocytes and some hepatocytes. Immunohistochemical staining showed that the infiltrating lymphocytes displayed TNFα, TNF type I receptor and a variety of cytokines including IL-1β, IL-4, IL-6, IL-10, IFNγ or IL-12. Interestingly, in naive mice, the arteries in the liver constitutively expressed IFNγ. Its expression appeared to be substantially increased at 48 h, decreased at 72 h, and increased again on day 14 after P. acnes injection. Furthermore, Fas or FasL was only detected on the lymphocytes within the granuloma. We conclude that P. acnes can induce a TNFα-mediated acute hepatic apoptosis which subsequently progress to a T-cell-mediated granulomatous hepatitis with increased expression of multiple cytokines and Fas/FasL. [ABSTRACT FROM AUTHOR]