RESUMO
Beside its key diagnostic value, the humoral immune response is thought to play a protective role in hantavirus pulmonary syndrome. However, little is known about the cell source of these antibodies during ongoing human infection. Herein we characterized B-cell subsets circulating in Andes-virus-infected patients. A notable potent plasmablast (PB) response that increased 100-fold over the baseline levels was observed around 1 week after the onset of symptoms. These PB present a CD3neg CD19low CD20neg CD38hi CD27hi CD138+/- IgA+/- surface phenotype together with the presence of cytoplasmic functional immunoglobulins. They are large lymphocytes (lymphoblasts) morphologically coincident with the 'immunoblast-like' cells that have been previously described during blood cytology examinations of hantavirus-infected patients. Immunoreactivity analysis of white blood cell lysates suggests that some circulating PB are virus-specific but we also observed a significant increase of reactivity against virus-unrelated antigens, which suggests a possible bystander effect by polyclonal B-cell activation. The presence of this large and transient PB response raises the question as to whether these cells might have a protective or pathological role during the ongoing hantavirus pulmonary syndrome and suggest their practical application as a diagnostic/prognostic biomarker.
Assuntos
Subpopulações de Linfócitos B/imunologia , Síndrome Pulmonar por Hantavirus/imunologia , Orthohantavírus/imunologia , Plasmócitos/imunologia , Células Precursoras de Linfócitos B/imunologia , Doença Aguda , Adulto , Anticorpos Antivirais/sangue , Antígenos CD/metabolismo , Autoantígenos/imunologia , Subpopulações de Linfócitos B/virologia , Biomarcadores/metabolismo , Proliferação de Células , Feminino , Síndrome Pulmonar por Hantavirus/diagnóstico , Humanos , Imunoglobulina A/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Plasmócitos/virologia , Células Precursoras de Linfócitos B/virologia , Adulto JovemRESUMO
The response of antibody-secreting cells (ASC) induced by dengue has only recently started to be characterized. We propose that young age and previous infections could be simple factors that affect this response. Here, we evaluated the primary and secondary responses of circulating ASC in infants (6-12 months old) and children (1-14 years old) infected with dengue showing different degrees of clinical severity. The ASC response was delayed and of lower magnitude in infants, compared with older children. In primary infection (PI), the total and envelope (E) protein-specific IgM ASC were dominant in infants but not in children, and a negative correlation was found between age and the number of IgM ASC (rho = -0.59, P = 0.03). However, infants with plasma dengue-specific IgG detectable in the acute phase developed an intense ASC response largely dominated by IgG and comparable to that of children with secondary infection (SI). IgM and IgG produced by ASC circulating in PI or SI were highly cross-reactive among the four serotypes. Dengue infection caused the disturbance of B cell subsets, particularly a decrease in the relative frequency of naïve B cells. Higher frequencies of total and E protein-specific IgM ASC in the infants and IgG in the children were associated with clinically severe forms of infection. Therefore, the ASC response induced by dengue is highly influenced by the age at which infection occurs and previous immune status, and its magnitude is a relevant element in the clinical outcome. These results are important in the search for correlates of protection and for determining the ideal age for vaccinating against dengue.
Assuntos
Anticorpos Antivirais/imunologia , Células Produtoras de Anticorpos/imunologia , Vírus da Dengue/imunologia , Dengue/imunologia , Proteínas do Envelope Viral/imunologia , Adolescente , Fatores Etários , Anticorpos Antivirais/sangue , Células Produtoras de Anticorpos/virologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/virologia , Criança , Pré-Escolar , Reações Cruzadas/imunologia , Dengue/sangue , Dengue/virologia , Vírus da Dengue/genética , Vírus da Dengue/fisiologia , ELISPOT , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Lactente , Masculino , SorogrupoRESUMO
Dengue is a globally expanding disease caused by infection with dengue virus (DENV) that ranges from febrile illness to acute disease with serious complications. Secondary infection predisposes individuals to more severe disease, and B lymphocytes may play a role in this phenomenon through production of Ab that enhance infection. To better define the acute B cell response during dengue, we analyzed peripheral B cells from an adult Brazilian hospital cohort with primary and secondary DENV infections of varying clinical severity. Circulating B cells in dengue patients were proliferating, activated, and apoptotic relative to individuals with other febrile illnesses. Severe secondary DENV infection was associated with extraordinary peak plasmablast frequencies between 4 and 7 d of illness, averaging 46% and reaching 87% of B cells, significantly greater than those seen in mild illness or primary infections. On average >70% of IgG-secreting cells in individuals with severe secondary DENV infection were DENV specific. Plasmablasts produced Ab that cross-reacted with heterotypic DENV serotypes, but with a 3-fold greater reactivity to DENV-3, the infecting serotype. Plasmablast frequency did not correlate with acute serum-neutralizing Ab titers to any DENV serotype regardless of severity of disease. These findings indicate that massive expansion of DENV-specific and serotype cross-reactive plasmablasts occurs in acute secondary DENV infection of adults in Brazil, which is associated with increasing disease severity.