B Cell Activation in HIV Infection
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Published: Wed, 11 Apr 2018
During HIV infection, B cells can be activated by HIV virions, plasmacytoid dendritic cells, infected macrophages and CD40 ligands.
Mannose binding lectin (MBL), a C-type lectin, is in a complex with the MASP (MBL-associated serine proteases) enzyme and is involved in recognising and binding carbohydrates on pathogens (e.g. HIV envelope protein gp120 is highly glycosylated). When the carbohydrates are recognised, MBL activates the enzyme activity of MASP which causes the activation of the complement system by cleaving C2 and C4 complements resulting in the formation of C3 convertase. This activation and formation of C3 convertase is known as the alternative pathway of the complement system. C3 complement is cleaved by the C3 convertase enzyme and C3 fragments (C3d/C3dg, iC3b) are formed from this breakdown. These fragments are deposited onto the HIV virion surface. HIV IC (immune complexes) interact with CD21 (complement receptor) on B cells and C3 fragments acts as a mediator in the IC-CD21 interaction. CD21 is involved in the activation of B cells and a constant IC-CD21 activation could trigger the polyclonal activation of B cells in HIV viremia. (1-4)
Plasma dendritic cells (pDCs) express TLR9, TLR7, CD4, CCR5, CXCR4 and MCLR receptors. TLR7 receptor is stimulated by its interaction with viral ssRNA and TLR9 by its interaction with unmethylated DNA motifs of the viral genome. Stimulation of these receptors leads to the activation of intracellular pathways both of which involves the activation of the adaptor protein, MyD88. The MyD88-IRF7 pathway involves the activation of IRF7 by MyD88 which goes on to regulate the gene transcription of Type I IFN, leading to Type I IFN production by pDCs. NF-kB is also activated by MyD88 and causes the production of pro-inflammatory cytokines such as TNF-α and IL-6 by upregulating their gene transcription in pDCs.
IFN-α (a Type l IFN) induces the activation and differentiation of B cells into plasmablasts. The presence of IL-6 causes differentiation of plasmablasts into antibody secreting plasma cells. TNF-α is involved in the polyclonal activation of B cells. The production of Type I IFN upregulates the mRNA expression of two cytokines involved in stimulating B cells in pDCs. These cytokines cause the activation, proliferation and survival of B cells, immunoglobulin class- switching and are known as BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand). Both cytokines belong to the tumour necrosis factor (TNF) ligand family. BAFF interacts with B cells by binding to the BAFF receptor (BAFFR) located on the surface of B cells.
Plasmacytoid dendritic cells also activate B cells through the interaction of their CD70 ligand with the CD27 receptor on B cells, causing proliferation and differentiation of memory cells into plasma cells.
HIV infected macrophages, activate B cells by Nef protein indirectly when it is taken up and expressed de novo by infected macrophages. HIV Nef induces the production of ferritin through the NF-κB pathway causing gene transcription and releasing ferritin from the infected macrophages. Adequate production of ferritin induces proliferation of resting B cells into antibody secreting plasma cells by upregulating the expression of B cell gene. This activation of B cells can lead to hypergammaglobulinemia – the increase in the level of gamma globulins (immunoglobulins) in the blood. (1,20)
Figure 1 shows adequate levels of ferritin can lead to increase in immunoglobulin (Ig) levels in the plasma (hypergammaglobulinemia).
To determine whether there is a correlation between hypergammaglobulinemia (B cell dysfunction) and plasma ferritin level in HIV infection. Plasma Ig levels were compare to plasma ferritin levels of 83 infected HIV infected people. The results obtained show that there is a positive correlation between plasma ferritin levels and plasma levels of IgA, IgG and IgM in the HIV infected individuals studied. As plasma ferritin levels increased, plasma IgA, IgG and IgM levels also increased generally. (20)
The outer layer (envelope) of HIV virions contains viral protein, gp120, which can directly bind to receptors on B cells. Activation of B cells by gp120 causes polyclonal immunoglobulin class switching. This occurs in the presence of BAFF which binds to its receptor on B cells, BAFFR and gp120 binds to MCLRs (mannose-binding C-type lectin receptors) on B cells. The interaction causes IgM to switch to IgG and IgA through the upregulation in the expression of the activation-induced cytidine deaminase, an enzyme involved in class-switch DNA recombination. The HIV gp120 has also been found to inhibit the production of IFN-α by pDCs by affecting the activation of the TL9 pathway involved in its production. The protein, gp120 binds to CD4, CCR5, CRCR4 and MCLR receptors on pDCs and its binding to CD4 and MCLR has been found to not produce IFN-α by the TLR9 pathway. This prevents the activation of B cells by the TLR9 pathway through the release of IFN-α. (7,9,10,21)
B cells can also be activated by the interaction between CD40 receptors on B cells and CD40 ligands on T cells in the presence of cytokines (e.g. IL-10). This interaction activates the B cells to differentiate and undergo immunoglobulin class switching by causing class-switch recombination. Class-switch recombination is induced by the activation of NF-kB transcription factor which induces the gene expression of activation-induced cytidine deaminase (AID). However, during HIV infection CD4+ T cells are targets for the HIV virus so number of CD4+ T cells are depleted suppressing this activation of B cells. (22,23)
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- JESSIE FLORENCE GHANSAH
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