The Cellular Bases of Antibody Responses during Dengue Virus Infection

Abstract

Dengue virus (DENV) is one of the most significant human viral pathogens transmitted by mosquitoes and can cause from an asymptomatic disease to mild undifferentiated fever, classical dengue, and severe dengue. Neutralizing memory antibody (Ab) responses are one of the most important mechanisms that counteract reinfections and are therefore the main aim of vaccination. However, it has also been proposed that in dengue, some of these class-switched (IgG) memory Abs might worsen the disease. Although these memory Abs derive from B cells by T-cell-dependent processes, we know rather little about the (acute, chronic, or memory) B cell responses and the complex cellular mechanisms generating these Abs during DENV infections. This review aims to provide an updated and comprehensive perspective of the B cell responses during DENV infection, starting since the very early events such as the cutaneous DENV entrance and the arrival into draining lymph nodes, to the putative B cell activation, proliferation, and germinal centers (GCs) formation (the source of affinity-matured class-switched memory Abs), till the outcome of GC reactions such as the generation of plasmablasts, Ab-secreting plasma cells, and memory B cells. We discuss topics very poorly explored such as the possibility of B cell infection by DENV or even activation-induced B cell death. The current information about the nature of the Ab responses to DENV is also illustrated.

Keywords: antibodies; dengue virus; in vivo B cell responses; memory B cells; plasma cells.

Figure 1

The B cell responses during DENV infection. Mosquitoes inoculate DENV mostly intradermally (1); inoculum is a mixture of mature (black circles) and immature (yellow circles) virions. DCs would capture DENV or DENV Ags and enter lymphatics (2) ferrying these Ags to regional DLNs (3). On the other hand, DENV could also reach the DLN via the lymph flow in a putative cell-free manner. Upon arrival into DLNs, viruses can encounter DENV-specific naive B cells and could generate short-lived PCs producing IgMs by a T-cell-independent extrafollicular B cell response (4) or could enter to a T-cell-dependent GC reaction (5). GCs will generate long-lived PCs and MBCs (6), which can produce a mixture of both neutralizing and cross-reactive DENV-specific Abs. These Abs would either neutralize the virus, containing the spread of infection (7) or enhance the infection of other targets cells, according to ADE (8). Cross-reactive non-neutralizing Abs seem to predominate in the memory response by MBCs (9). On the other hand, DENV may infect B cells “directly” either in circulation or in tissues such as in secondary lymphoid organs (10).