B Cell Activation in HIV Infection

B cadreular telephone Activation in human immunodeficiency virus InfectionDuring HIV infection, B cells preempt be activated by HIV virions, plasmcytoid dendritic cells, infected macrophages and CD40 ligands.Mannose screening lectin (MBL), a C-type lectin, is in a complex with the MASP (MBL-associated serine proteases) enzyme and is relate in recognising and salad dressing 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 energizing of the complement system by cleaving C2 and C4 complements resulting in the organisation of C3 convertase. This activating and formation of C3 convertase is cognise 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 complex es) interact with CD21 (complement sense organ) on B cells and C3 fragments acts as a mediator in the IC-CD21 fundamental interaction. CD21 is tough in the activation of B cells and a constant IC-CD21 activation could cancel the polyclonal activation of B cells in HIV viremia. (1-4)Plasma dendritic cells (pDCs) chat 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 cistron transcription of Type I IFN, leading to Type I IFN payoff by pDCs. NF-kB is withal activated by MyD88 and causes the employment of pro-inflammatory cytokines much(prenominal) as TNF- and IL-6 by upregulating their gene transcri ption in pDCs.IFN- (a Type l IFN) induces the activation and differentiation of B cells into plasmblasts. The presence of IL-6 causes differentiation of plasmblasts into antibody secreting plasma cells. TNF- is involved in the polyclonal activation of B cells. The production of Type I IFN upregulates the template RNA face 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 mortification 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 by 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 done the NF-B 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 locution of B cell gene. This activation of B cells can lead to hypergammaglobulinemia the sum up 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 immunoglobulin A, immunoglobulin G and immunoglobulin M in the HIV infected individuals studied. As plasma ferritin levels increased, plasma IgA, immunoglobulin G 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 by and through the upregulation in the expression of the activation-induce cytidine deaminase, an enzyme involved in class-switch DNA recombination. The HIV gp120 has also been found to inhibit the production of IFN- 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- by the TLR9 pathway. This prevents the activation of B cells by the TLR9 pathway through the release of IFN-. (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). 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