Any opinions, findings, conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of UK Essays.
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)
- Moir, S., Malaspina, A., Li, Y., Chun, T., Lowe, T., Adelsberger, J., Baseler, M., Ehler, L., Liu, S., Davey Jr., R., Mican, J. and Fauci, A. (2000) ‘B Cells of HIV-1–infected Patients Bind Virions through CD21–Complement Interactions and Transmit Infectious Virus to Activated T Cells’, The Journal of Experimental Medicine, 192 (5), pp.637-645.
- Jakubik, J., Saifuddin, M., Takefman, D. and Spear, G. (2000) ‘Immune Complexes Containing Human Immunodeficiency Virus Type 1 Primary Isolates Bind to Lymphoid Tissue B Lymphocytes and Are Infectious for T Lymphocytes’, Journal Of Virology, 74(1), pp.552-555.
- Eisen, S., Dzwonek, A. and Klein, NJ. (2008) ‘Mannose-binding lectin in HIV infection’, Future Virol., 3(3), pp.225-233
- Haurum , JS., Thiel, S., Jones, IM., Fischer, PB., Laursen, SB. and Jensenius, JC. (1993) ‘Complement activation upon binding of mannan-binding protein to HIV envelope glycoproteins.’, AIDS, 7(10), pp.1307-1313
- Muraguchi, A., Hirano, T., Tang, B., Matsuda, T., Horii, Y, Nakajima, K. and Kishimoto, T. (1998) ‘ The Essential Role Of B Cell Stimulatory Factor 2 (Bsf-2/Il-6) For The Terminal Differentiation Of B Cells’, J Exp Med, 167, pp.332-344.
- Jego, G., Palucka, A., Blanck, J., Chalouni, C., Pascual, V. and Banchereau, J. (2003) ‘Plasmacytoid Dendritic Cells Induce Plasma Cell Differentiation through Type I Interferon and Interleukin 6’, Immunity, 19, pp.225-234.
- Chung, N., Matthews, K., Klasse, P., Sanders, R. and Moore, J. (2012) ‘HIV-1 gp120 impairs the induction of B cell responses by TLR9-activated plasmacytoid dendritic cells’, J Immunol, 189(11), pp. 5257- 5265.
- Shaw, J., Wang, Y., Ito, T., Arima, K. and Liu, Y. (2010) ‘Plasmacytoid dendritic cells regulate B-cell growth and differentiation via CD70.’, Blood, 115, pp.3051–3057.
- He, B., Qiao, X., Klasse, P., Chiu, A., Chadburn, A., Knowles, D., Moore, J. and Cerutti, A. (2006) ‘HIV-1 envelope triggers polyclonal Ig class switch recombination through a CD40-independent mechanism involving BAFF and C-type lectin receptors.’ J. Immunol, 176, pp.3931–3941.
- Martinelli, E., Cicala, C., Van Ryk, D., Goode, D., Macleod, K., Arthos, J. and Fauci, A. (2007) ‘HIV-1 gp120 inhibits TLR9-mediated activation and IFN-α secretion in plasmacytoid dendritic cells.’ Proc Natl Acad Sci USA, 104, pp.3396–3401.
- Kadowaki, N., Ho, S., Antonenko, S., Malefyt, RW., Kastelein, RA., Bazan, F. and Liu, YJ. (2001) ‘Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens.’, J Exp Med, 194 (6), pp.863-870
- Lund, J., Sato, A., Akira, S., Medzhitov, R. and Iwasaki, A. (2003) ‘Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells.’, J Exp Med., 198 (3), pp. 513-520
- Lund, JM., Alexopoulou, L., Sato, A., Karow, M., Adams, NC., Gale, NW., Iwasaki, A. and Flavell, RA. (2004) ‘Recognition of single-stranded RNA viruses by Toll-like receptor 7.’, Proc Natl Acad Sci USA, 101 (15), pp 5598-5603
- Lambert, AA., Gilbert, C., Richard, M., Beaulieu, AD. and Tremblay, MJ. (2008) ‘The C-type lectin surface receptor DCIR acts as a new attachment factor for HIV-1 in dendritic cells and contributes to trans- and cis- infection pathways.’, Blood, 112(4), pp.1299-1307
- Jego, G., Palucka, AK., Blanck, JP., Chalouni, C., Pascual, V. and Banchereau, J. (2003) ‘Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6.’, Immunity, 19(2), pp.225-234
- Litinskiy, MB., Nardelli, B., Hilbert, DM., He, B., Schaffer, A., Casali, P. and Cerutti, A.(2002) ‘DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL.’, Nat Immunol., 3(9), pp. 822-829
- Tezuka, H., Abe, Y., Asano, J., Sato, T., Liu, J., Iwata, M. and Ohteki T. (2011) ‘Prominent role for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction.’, Immunity, 34(2), pp.247-257
- Dai, J., Megjugorac, NJ., Amrute, SB. and Fitzgerald-Bocarsly, P. (2004) ‘Regulation of IFN regulatory factor-7 and IFN-alpha production by enveloped virus and lipopolysaccharide in human plasmacytoid dendritic cells.’, J Immunol., 173(3), pp.1535-48
- Cerutti A., Qiao, X. and H, B. (2005) ‘Plasmacytoid dendritic cells and the regulation of immunoglobulin heavy chain class switching.’, Immunol Cell Biol., 83(5), pp.554-562
- Swingler, S., Zhou, J., Swingler, C., Dauphin,A., Greenough, T., Jolicoeur, P. and Stevenson, M. (2008) ‘Evidence for a pathogenic determinant in HIV-1 Nef involved in B cell dysfunction in HIV/AIDS’, Cell Host Microbe, 4(1), pp. 63-76.
- Geijtenbeek, TB., Kwon, DS., Torensma, R., van Vliet, SJ., van Duijnhoven, GC., Middel, J., Cornelissen, IL., Nottet, HS., KewalRamani, VN., Littman, DR., Figdor, CG. and van Kooyk ,Y. (2000) ‘DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells.’, Cell, 100 (5), pp.587-597.
- Dedeoglu, F., Horwitz, B., Chaudhuri, J., Alt, FW. and S. Geha, RS. (2004) ‘Induction of activation-induced cytidine deaminase gene expression by IL-4 and CD40 ligation is dependent on STAT6 and NFkB.’, International Immunology, 16(3), pp.395-404
- Qiao, X., He, B., Chiu, A., Knowles, DM., Chadburn, A. and Cerutti, A. (2006) ‘Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells.’, Nature Immunology, 7, pp.302-310
- JESSIE FLORENCE GHANSAH
Cite This Work
To export a reference to this article please select a referencing stye below:
Related ServicesView all
DMCA / Removal Request
If you are the original writer of this essay and no longer wish to have the essay published on the UK Essays website then please.