Abstract
BackgroundConflicting results regarding changes in mucosal IgA production or in the proportions of IgA plasma cells in the small and large intestines during HIV-infection have been previously reported. Except in individuals repeatedly exposed to HIV-1 but yet remaining uninfected, HIV-specific IgAs are frequently absent in mucosal secretions from HIV-infected patients. However, little is known about the organization and functionality of mucosal B-cell follicles in acute HIV/SIV infection during which a T-dependent IgA response should have been initiated. In the present study, we evaluated changes in B-cell and T-cell subsets as well as the extent of apoptosis and class-specific plasma cells in Peyer’s Patches, isolated lymphoid follicles, and lamina propria. Plasma levels of IgA, BAFF and APRIL were also determined.ResultsPlasma IgA level was reduced by 46% by 28 days post infection (dpi), and no IgA plasma cells were found within germinal centers of Peyer’s Patches and isolated lymphoid follicles. This lack of a T-dependent IgA response occurs although germinal centers remained functional with no sign of follicular damage, while a prolonged survival of follicular CD4+ T-cells and normal generation of IgG plasma cells is observed. Whereas the average plasma BAFF level was increased by 4.5-fold and total plasma cells were 1.7 to 1.9-fold more numerous in the lamina propria, the relative proportion of IgA plasma cells in this effector site was reduced by 19% (duodemun) to 35% (ileum) at 28 dpi.ConclusionOur data provide evidence that SIV is unable to initiate a T-dependent IgA response during the acute phase of infection and favors the production of IgG (ileum) or IgM (duodenum) plasma cells at the expense of IgA plasma cells. Therefore, an early and generalized default in IgA production takes place during the acute of phase of HIV/SIV infection, which might impair not only the virus-specific antibody response but also IgA responses to other pathogens and vaccines as well. Understanding the mechanisms that impair IgA production during acute HIV/SIV infection is crucial to improve virus-specific response in mucosa and control microbial translocation.
Highlights
Conflicting results regarding changes in mucosal IgA production or in the proportions of IgA plasma cells in the small and large intestines during human Immunodeficiency Virus (HIV)-infection have been previously reported
Conflicting results exist concerning the presence of HIV-specific IgA in genital secretions of women repeatedly exposed to HIV-1 but yet remaining uninfected [16,17,18,19], HIV-specific IgA are generally absent or present at very low levels in plasma and mucosal secretions of chronically HIV-infected patients [20,21,22,23,24]
Distinct kinetics of apoptosis in germinal centers (GC), follicular T-cell zones and lamina propria (LP) Because increased apoptosis might contribute to the paucity of IgA plasma cells, we examined the expression of the cleaved caspase-3, a key mediator of apoptosis shared by membrane- and mitochondrial-mediated pathways
Summary
Conflicting results regarding changes in mucosal IgA production or in the proportions of IgA plasma cells in the small and large intestines during HIV-infection have been previously reported. TNF Family (BAFF) and A Proliferation-Inducing Ligand (APRIL) are key factors involved in both T-dependent and T-independent immunoglobulin class switching [9,11] These latter cytokines most likely account for IgA production in children with defective CD40L [12,13]. Decreased levels of IgA in intestinal fluids associates with reduced proportions of IgA plasma cells within the lamina propria (LP) of the duodenum and colon of chronically HIV-infected patients [25]. The lack of IgA in intestinal fluids of chronically HIV-infected patients or SIV-infected macaques can be explained by a default in shedding, impaired homing of IgA plasmablasts to LP or their impaired terminal differentiation into plasma cells. Recent data of Xu et al suggested that an impaired isotype switching towards IgA occurs in inductive sites [31], preventing the generation of IgA plasmablasts
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