Frequency of circulating T lymphocytes expressing complement receptors in Dengue-infected patients
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1
FIOCRUZ/IOC, Laboratório de Imunologia Viral, Brazil
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2
Hospital Plantadores de Cana, Centro de Referência para Dengue, Brazil
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3
Universidade Federal de Mato Grosso do Sul, Faculdade de Medicina /UFMS,, Departamento de Clínica Médica, Brazil
Background: Dengue virus (DENV) is a member of the Flaviviridae family, which circulates as four closely-related but antigenically distinct serotypes, numbered 1 to 4. The human infection by DENV leads to an extensive morbidity and mortality. All DENV serotypes can cause similar clinical symptoms that vary from a mild disease, known as dengue fever (DF) to a life-threatening syndrome the dengue hemorrhagic fever/ dengue shock syndrome (DHF/DSS), characterised by spontaneous bleeding and vascular leakage that can progress to hypovolemic shock and death. Given the difficulty of classifying serious cases in Central American countries and Latin America, the Special Program for Research and Training in Tropical Diseases World Health Organization (TDR/WHO) proposed a new classification, where the illness is understood as a systemic and dynamic event, facilitating the approach to cases and subsequent clinical management of patients. According to this criterion, the new classification addresses three sets of clinical signs and symptoms: (1) dengue without warning signs (DF), (2) dengue with warning signs (DF/WS), and (3) severe dengue (S). The mechanisms by which pathophysiologic changes occur in dengue fever are still not fully understood and the interaction of several factors seems to be responsible for the development of the severe disease, including: the virulence of the circulating strain, the presence of efficient or high density vector, the wide circulation of the virus, and characteristics of the host, as genetic factors, ethnicity, presence of chronic diseases, and subsequent DENV infections. Natural infection by one of the four DENV serotypes produces lasting immunity against reinfection for the same serotype, but heterotypic protection is temporary and partial, thus allowing sequential infections. These observations indicate that a previous infection with dengue is a risk factor for development of severe illness. The phenomenon known as the Original Antigenic Sin was described more recently, in humans infected with DENV. According to that T cells, generated during primary infection for a viral serotype, showed a low affinity for the different serotype of the secondary infection, which in turn leads to development of altered immune responses, including decreased viral clearance. In addition, the extensive activation of cross-reactive memory cells promotes the aberrant release of cytokines (cytokine storm) that contribute to disease severity. Recent studies have shown that the complement system (CS) is a key factor in coordinating important events during the immune response, facilitating antigen identification and localisation; cell activation, proliferation and apoptosis; B-cell triggering; and immunological memory as a bridge between innate and adaptive immunity. Various aspects related to the activation and regulation of the CS during dengue infection remains unknown. The complement system consists of a tightly regulated network of more than 30 circulating and membrane-bound proteins, whose activation leads to the coating of foreign antigens with the key complement fragments, C3b and, to a lesser degree, C4b. It is well understood that the CS plays a role in protection against pathogens by activation of its proteolytic cascade, which results in the adherence of opsonins (C1q, C3b, iC3b and C3d[g]) to the surface of microbes; the release of pro-inflammatory peptides (the anaphylatoxins, C3a and C5a); and the assembly of the membrane attack complex (terminal complement complex, or C5b-9). These activation products are the ligands of various complement receptors (CRs), namely C3aR, C5aR, CR1 (CD35), CR2 (CD21), CR3 (CD11b), CR4 (CD11c) and, CRIg, which are expressed by a wide variety of immune cells. Complement system is in a constant state of low-level activation, allowing a rapid response to danger signals. However, its role goes beyond the participation in front line against pathogens. As a potent pro-inflammatory system disturbances in its balance can result in self damage, to avoid this CS is tightly controlled by regulatory proteins. In Dengue infection, it has been demonstrated increased catabolic amounts of complement components as C3, C5 and C1q and decreased amounts of complement regulators as the serum amounts of factor H and, the CD59 expression among monocytes in severe patients compared with those with mild dengue fever disease. Additionally, was observed that C5a and SC5b9 were increased in serum from dengue patients even before the occurrence of plasma leakage. These results suggest that an unbalanced CS activation could contribute to unfavorable outcome of Dengue disease. Objective: Once was demonstrated that CR would affect not only the cell susceptibility to complement mediated lysis, but also the activation status of T cells we aimed to investigate the profile of CR expression of T cells in dengue infected patients and also the CS activation. Methodology: The Dengue patients, from 2010 and 2013 outbreak in Brazil, were classified according to the parameters established for the WHO in 2009. The frequency of CD4 and CD8 T cells expressing of complement receptors (CR1, CR2, CR3 and CR4) or regulators (CD46, CD55 and CD59) and cell activation markers (CCR5 and CD107a) were evaluated by flow cytometry. The circulating levels of SC5b-9 was quantified in the serum samples from a cohort of 70 patients in the acute phase of DENV infection and 10 healthy individuals as controls by ELISA. The Mann Whitney test was used for the statistical analysis. Principal Findings: Our results show that T cells from DENV-patients presented an activation profile by increased expression of CCR5 and CD107a compared to healthy controls. Among the complement receptors (CR), we did not observe any alteration on frequency of T cells expressing CR4 or CR3 in DENV-patients compared to healthy individuals. However, the frequency of T cells expressing CR2 was decreased in CD4 T cells from DF compared to controls and S patients. Interestingly, data from the literature shows decreased expression of CR2 on activated T cells. For CR1, which is involved in both T cells activation and complement regulation, its frequency among CD4 T cells was decreased in all DENV-patients, regardless of clinical severity, as compared to healthy controls. While among CD8 T cells, frequency of CR2 cells trends to decrease, being significantly lower in DF compared to healthy controls. Besides of the increased levels of the serum amounts of SC5b-9 the frequencies of regulators expression among T cells CD46, CD55 and CD59 was not altered in DENV infected patients compared to healthy subjects. However, the expression of CCR5 and CD107a between T cells expressing CD46, CD55 and CD59 was significantly increased in DENV-patients compared to controls. Conclusions/Significance: Taken together these results suggest that in acute DENV infection, the decreased expression of CR1 and CR2 among T cells could be related to activation profile. Interestingly, T cells expressing complement regulators present an activation phenotype with ability to migrate to sites of infection and perform effector function, such as cytotoxicity, at same time these cells seems to be protected of complement attack by the presence of regulators.
Keywords:
Complement receptors,
Dengue Virus,
sC5b-9,
Complement regulators,
T lymphocytes
Conference:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015.
Presentation Type:
Poster Presentation
Topic:
Infectious and parasitic diseases
Citation:
Marinho
CF,
Da Silva
JB,
Azeredo
EL,
Kubelka
CF,
De Souza
LJ,
Da Cunha
RV and
De-Oliveira-Pinto
LM
(2015). Frequency of circulating T lymphocytes expressing complement receptors in Dengue-infected patients.
Front. Immunol.
Conference Abstract:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología.
doi: 10.3389/conf.fimmu.2015.05.00181
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Received:
15 Apr 2015;
Published Online:
14 Sep 2015.
*
Correspondence:
Mrs. Cintia F Marinho, FIOCRUZ/IOC, Laboratório de Imunologia Viral, Rio de Janeiro, RJ, 21040-360, Brazil, cintiafm11@gmail.com