Microbial TLR Agonists and Humoral Immunopathogenesis in HIV Disease
Received Date: Dec 20, 2012 / Accepted Date: Jan 29, 2013 / Published Date: Feb 02, 2013
Although T cells are the primary and most-studied targets of the Human Immunodeficiency Virus (HIV), B cells, especially memory B lymphocytes, are also chronically depleted in the course of HIV disease. Although the lack of CD4+ T cell help may explain these deficiencies, intrinsic defects in B lymphocytes appear to contribute to B cell depletion and reduced antibody (Ab) production in the setting of HIV, especially of some antigens eliciting T cell-independent responses. The gut mucosal barrier is disrupted in HIV disease, resulting in increased systemic exposure to microbial products such as Toll-Like Receptor (TLR) agonists. The association of enhanced systemic levels of TLR agonists and B cell dysfunction in HIV disease is not understood. This review discusses the potential role of microbial TLR agonists in the B cell depletion, enhanced autoantibody production and impaired responses to vaccination observed in HIV-infected hosts. Increased microbial translocation in HIV infection may drive B cells to produce autoantibodies and increase susceptibilities of B cells to apoptosis through activation-induced cell death. Determining the mechanisms of B cell perturbations in HIV disease will inform the design of novel strategies of improve immune responses to vaccines, reduce opportunistic infections and slow disease progression.
Keywords: Antibody; Toll-like receptor; Human Immunodeficiency Virus (HIV)
Toll-like Receptor and its Ligands
TLRs represent a class of pattern recognition receptors that play a key role in the innate immune system. They recognize Pathogen- Associated Molecular Patterns (PAMPs) expressed by pathogens and distinctly distinguishable from any host molecules. TLR ligands are found in a variety of microbes (bacteria, fungi and also viruses) and provide, via TLR binding, a mechanism for early recognition of microbial invasion [1,2]. Thus PAMP activation is a component of the innate immune system, triggering production of proinflammatory cytokines and enabling initial antimicrobial immune responses [1,2]. Activation of PAMPs also plays a key role in shaping subsequent adaptive immune responses. There are 10 TLRs in human (Table 1). TLR1, TLR2 and TLR6 are triggered by peptidoglycan and other microbial products, TLR3 by double-stranded RNA, TLR4 by Lipopolysaccharide (LPS), TLR5 by flagellin, TLR7 and TLR8 by imidazoquinolines and TLR9 by unmethylated CpG DNA . In addition to imidazoquinoline, TLR7 and TLR8 have been reported to recognize single-stranded RNAs, and possibly play a role in IFN-α induction in response to viral infections, such as HIV and influenza virus infection [4-6]. All TLRs, except TLR3, activate pathways dependent on the adaptor molecule (MyD88) which culminate in the activation of nuclear factor-kB (NF-kB) transcription factors. Mitogen-Activated Protein Kinases (MAPKs), Extracellular signal- Regulated Kinase (ERK), p38 and c-Jun N-terminal Kinase (JNK) [3,7]. These transcription factors function in concert to promote inflammatory responses (e.g., IL-6, IL-10 and TNF-a) [8-10]. HIV itself may also function as TLR ligands since RNA sequences derived from the retroviral genome are capable of signaling through TLR 7 and TLR 8 .
|TLR1||[11-13]||Cell surface||Bacterial lipoproteins||MyD88||Monocytes|
|TLR3||[11,12,18]||Intracellular||Double-stranded RNA||TRIF||NK cells|
|TLR4||[11,12,16]||Cell surface||Lipopolysaccharide (LPS)||MyD88||Monocytes|
|Soluble tuberculosis factor (STF)|
|Phenol-soluble modulin (PSM)|
|TLR9||[1,11,25]||Intracellular||Unmethylated CpG ODNs||MyD88||pDCs|
|||Membrane microparticles||B cells|
|TLR10||[11,30]||Intracellular||Pam(3) CSK(4)||MyD88||B cells|
Table 1: 10 TLRs in human.
B cells and TLRs
Different research groups have reached conflicting conclusions regarding TLR expression on human B cells. For example, Hanten et al. reports that human peripheral B cells express high levels of mRNA for TLR9, TLR10, TLR7 and TLR6, intermediate levels of TLR2 and TLR4, and low levels of TLR3, TLR5 and TLR8 . Hornung et al. reports that human peripheral B cells express high mRNA levels of TLR1, TLR6, TLR9 and TLR10, intermediate levels of TLR7 and low levels of TLR2 and TLR4 . Nevertheless, there is a clear consensus that human B cells express TLR9, TLR10, TLR7 and TLR6. Upon TLR ligand stimulation, B cells are activated, leading to production of cytokines and chemokines, proliferationand secretion of antibodies. Different TLR ligands have distinct capabilities to regulate human B cell function. For example, hematopoietic growth factors (e.g., G-CSF, GM-CSF) are induced predominantly by TLR1/TLR2 ligands,  whereas proliferation is predominantly induced by TLR9 ligand .
Most B cell studies have focused on TLR9, the main TLR on human B cells, which binds to bacterial DNA [33-35]. It has been suggested that the repeated stimulation through unmethylated CpG may function to continuously stimulate B cells and maintain serologic memory in the absence of traditional protein antigens . However, whether bystander nonspecific polyclonal stimulation of memory B cells contributes to the homeostatic maintenance of cellular and humoral memory remains controversial. Studies from Lee et al.  and Slifka and Amanna  show that vaccine induced antibody-secreting cells are vaccine antigen-specific, not bystander nonspecific B cell responses.
It has been demonstrated recently that switched and IgM positive memory B cells constitutively express TLR9 . In this model, serum IgG antibodies constitute the specific memory with B Cell Receptor (BCR) signals, accrued through previous experience and vaccinations, whereas IgM antibodies may represent first-line memory . There is a consensus that TLR ligands enhance antigen-specific B cell responses,  making them potentially effective vaccine adjuvants.
TLR Ligands and B cell Autoantibodies
We have shown that naïve B cells could also proliferate and produce IgM (not IgG) in response to CpG ODN (TLR9 ligand) independent of other cellular help [33,40]. Others show that IgG class which is induced among human naïve B cells in response to CpG ODN and IL-10 . TLRs have been proven to induce autoantibodies and play a role in autoimmune diseases, [42-51] but in some setting have been implicated to prevent autoantibody production and autoimmune diseases. Increasing evidences suggests that immune complexes associated with self-DNA and -RNA can directly activate plasmacytoid DCs (pDCs) to produce high levels of IFN-α through TLR7 or TLR9, resulting in autoantibody-producing B cell activation [52,53]. Such TLR7/TLR9-mediated disorders play an important role in the pathogenesis of autoimmune diseases [47,54-57]. Moieties of HIV itself are also functional as TLR7 and TLR8 ligands, [6,27,58] and thus could potentially activate pDCs to produce IFN-α, and activate autoantibody-producing B cells. This argument might explain at least partially the high levels of IFN-α and autoantibody reported in HIV disease [27,44,45,47,59,60].
Microbial TLR Agonists and Chronic Immune Activation in HIV Disease
Persistent immune activation and immune perturbation is the hallmark in HIV disease, resulting in dysfunction and loss of CD4+ T cells and B cells . In HIV infection, there is increasing consensus that immune activation is central to disease pathogenesis . Recent studies suggest that increased microbial products from the damaged gut in chronic HIV infection are at least partially responsible for this chronic immune activation [63,64]. High levels of the TLR4 ligand, Lipopolysaccharide (LPS) and bacterial ribosomal 16S RNA are found in the plasma of individuals with chronic HIV infection. Levels of LPS and 16S rDNAcorrelate with indices of immune activation and predict the magnitude of immune restoration after 48 weeks of antiretroviral treatment [63,64].
B cell Perturbations in HIV Disease
B cell dysfunction in HIV disease includesdepletion of B cells especially memory B cells, impaired vaccine or antigen responsiveness, [65-68] and enhanced levels of autoantibodies. Several mechanisms account for memory B cell depletion and dysfunction in HIV disease, including less CD4 T cell help, binding to CD21 and direct activation of B cells by HIV, [69-72] polyclonal activation of B cells, [73,74] indirect induction of B cell apoptosis by IL-7, [73,75,76] impaired trafficking and differentiation of B cells,  and dysfunction of T follicular helper cells [78,79]. As a consequence of impaired antigen-specific B cell antibody production, the integrity of the gut mucosa is further impaired .
B cells may also be activated and functionally impaired by HIV itself. It has been shown that B cells from HIV-infected viremic patients carry replication-competent virus on their surface through CD21, a complement receptor . There are also reports that virus bound to B cells can efficiently infect activated CD4 T cells and cause B cell dysfunction [71,81]. A study from Feng et al.  showed that HIV interacts with CXCR4 on the B cell surface and induces B cell apoptosis. HIV-1 nef protein can activate and stimulate B cells to differentiate [83,84] and may contribute to B cellpolyclonal activation resulting in hyperimmunoglobulinmia in HIV infection [65,85]. In contrast, a study by Qiao et al.  showedthat HIV nef protein directly inhibits B cell functional class switches. However, the mechanisms of HIVassociated B cell defects need to be further elucidated.
TLR Agonists and B cell Pertubations in HIV Disease
Loss of memory B cells and reduced production of antigen (Ag)- specific antibodies are typically seen in chronic HIV infection even though the humoral system is subjected to repeated and long-term stimulation through TLR agonists released from the gut [63,65,66,87,88]. This loss is not fully explained by desensitization because at the same time there is B cell polyclonal activation as reflected by increased total IgM and IgG levels [65,85]. Short-term exposure to TLR ligands (e.g., CpG ODNs) enhances immune responses and has adjuvant effects in healthy and HIV-infected individuals [29,65,1,85,89-92]. Humoral immune dysfunction in HIV disease is reflected by enhanced ex vivo B cell apoptosis with reduced Ag-specific Antibody (Ab) production and polyclonal activation, which differs from other diseases associated with microbial translocation (e.g., inflammatory bowel disease) where an autoimmune response appears to play an important role in immunopathogenesis and gut damage [93,94]. As neither T/B cell lymphopenia nor cell-mediated immune deficiencies are recognized concomitants of untreated inflammatory bowel disease,  it would appear that the virus maintains a central role in cellular and humoral immunodeficiency in HIV infection.
Although the lack of CD4+ T cell help may explain some of these deficiencies, there also appear to be intrinsic defects in B lymphocytes that can be demonstrated in functional assays not requiring T helper cells . The functional defects that have been described in B cells from HIV- infected persons include impaired proliferation responses to B cell antigen receptor stimulation, CD40L and CpG ODNs, reduced antibody production following vaccination, B cell hyperactivation and hypergammaglobulinemia and increased susceptibility to spontaneous apoptosis [90,97,98].
Therefore, TLRs and TLR agonists likely play a role in HIVassociated B cell perturbations.
The loss of memory B cells may be related to increased susceptibility of these cells to apoptosis. Spontaneous B cell apoptosis ex vivo as measured by binding of annexin V is increased in acute and chronic HIV infection [99,100]. Several cell death signaling pathways have been implicated in HIV infection, such as TNFα/TNFR, TRAIL/DR5, Fas/ FasL, and Foxo3a [101-107]. Moreover, studies by Moir et al. indicate that increased CD95/Fas expression on B cells in treatment-naïve HIV+ donors is related to B cell apoptosis by exogenous FasL in vitro,  suggesting that HIV infection is associated with increased susceptibility of memory B cells to death in response to FasL. Fas is expressed at low levels on the surface of naïve B cells and at enhanced levels on memory B cells [108,109]. In contrast with Fas expression, the expression of FasL is reported to be much more restricted and often requires cell activation. Monocytes or macrophages may be capable of producing FasL after activation by opsonized zymosan, CD4 cross-linking, or HIV infection in vitro [110-112]. Importantly, in vivo treatment of SIVinfected macaques with anti-FasLAb (RNOK203) reduces cell death in circulating B cells and increases Ab responses to viral proteins .
The effects of B cell depletion and impaired HIV-specific antibodies on SIV/HIV pathogenesis and disease progression are not clear and the results are contradictory [114-118]. However, B cells are depleted and functionally impaired in pathogenic SIV-infected rhesus macaques, but not in non-pathogenic African green monkeys [100,119,120]. Nonpathogenic SIV-infected animal models also do not demonstrate gut damage or increased systemic levels of microbial products [63,121]. B cell apoptosis is rare in non-pathogenic SIV-infected monkeys in the absence of gut enteropathy, but is present in pathogenic SIV-infected monkeys coexisting with microbial translocation, suggesting that B cell death may be induced by HIV infection and microbial translocation. However, it is also possible that microbial translocation and B cell death demonstratesome kind of complex reciprocal causal relationship.
A remaining gap in knowledge is the effect of antiretroviral therapy on microbial translocation and B cell restoration. Data from previous studies have shown that the levels of LPS and the 16s rDNA in plasma are significantly reduced after initiation of antiretroviral therapy, but they do not decrease to normal even among patients with restored normal CD4 counts . Consistent with this finding, B cell recovery was slower than CD4 T cell recovery after antiretroviral therapy and ultimately failed to reconstitute to normal levels [67,122]. Although the data relating to HIV-specific IgA are conflicting, it is clear that the majority of chronically HIV-infected individuals do not mount vigorous HIV-specific IgA antibody responses either locally at mucosal sites or systemically [117,123-125]. Although short-term administration of antiretroviral therapy may improve antibody responses,  long-term administration often fails to maintain protective levels of antibodies against vaccination antigens like measles, tetanus, influenza and pneumococcus, even in the context of normalized CD4 counts [66,127]. This suggests that factors other than absolute T cell numberssome toxicity of antiretroviral treatment to B cells, sustained virusmediated responses, or the impairment of B pregenitor cells- contribute to the incomplete recovery of antibody responses. Thusfurther studies are necessary tounderstand the mechanisms of B cell dysfuction and improvement in treated HIV-infected subjects. This knowledge would be valuable to improve vaccine responsiveness, decrease opportunistic infections and slow down disease progression in HIV-infected hosts.
This work is supported by the NIH grant NIAID R01AI091526 (to J.W.).
- Krieg AM, Vollmer J (2007) Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity. Immunol Rev 220: 251-269.
- Krug A (2008) Nucleic acid recognition receptors in autoimmunity. Handb Exp Pharmacol: 129-151.
- Barton GM, Medzhitov R (2003) Toll-like receptor signaling pathways. Science 300: 1524-1525.
- Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303: 1529-1531.
- Forsbach A, Nemorin JG, Völp K, Samulowitz U, Montino C, et al. (2007) Characterization of conserved viral leader RNA sequences that stimulate innate immunity through TLRs. Oligonucleotides 17: 405-417.
- Meier A, Alter G, Frahm N, Sidhu H, Li B, et al. (2007) MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands. J Virol 81: 8180-8191.
- O'Neill L (2000) The Toll/interleukin-1 receptor domain: a molecular switch for inflammation and host defence. Biochem Soc Trans 28: 557-563.
- Lamping N, Dettmer R, Schröder NW, Pfeil D, Hallatschek W, et al. (1998) LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria. J Clin Invest 101: 2065-2071.
- Shen W, Stone K, Jales A, Leitenberg D, Ladisch S (2008) Inhibition of TLR activation and up-regulation of IL-1R-associated kinase-M expression by exogenous gangliosides. J Immunol 180: 4425-4432.
- Soboll G, Shen L, Wira CR (2006) Expression of Toll-like receptors (TLR) and responsiveness to TLR agonists by polarized mouse uterine epithelial cells in culture. Biol Reprod 75: 131-139.
- Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdörfer B, et al. (2002) Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 168: 4531-4537.
- Hennessy EJ, Parker AE, O'Neill LA (2010) Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov 9: 293-307.
- Funderburg NT, Jadlowsky JK, Lederman MM, Feng Z, Weinberg A, et al. (2011) The Toll-like receptor 1/2 agonists Pam(3) CSK(4) and human ß-defensin-3 differentially induce interleukin-10 and nuclear factor-?B signalling patterns in human monocytes. Immunology 134: 151-160.
- Cook DN, Pisetsky DS, Schwartz DA (2004) Toll-like receptors in the pathogenesis of human disease. Nat Immunol 5: 975-979.
- Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, et al. (2001) Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194: 863-869.
- O'Mahony DS, Pham U, Iyer R, Hawn TR, Liles WC (2008) Differential constitutive and cytokine-modulated expression of human Toll-like receptors in primary neutrophils, monocytes, and macrophages. Int J Med Sci 5: 1-8.
- Sandor F, Latz E, Re F, Mandell L, Repik G, et al. (2003) Importance of extra- and intracellular domains of TLR1 and TLR2 in NFkappa B signaling. J Cell Biol 162: 1099-1110.
- Stahl-Hennig C, Eisenblätter M, Jasny E, Rzehak T, Tenner-Racz K, et al. (2009) Synthetic double-stranded RNAs are adjuvants for the induction of T helper 1 and humoral immune responses to human papillomavirus in rhesus macaques. PLoS Pathog 5: e1000373.
- Rossato M, Curtale G, Tamassia N, Castellucci M, Mori L, et al. (2012) IL-10-induced microRNA-187 negatively regulates TNF-a, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. Proc Natl Acad Sci U S A 109: E3101-3110.
- Yew KH, Carpenter C, Duncan RS, Harrison CJ (2012) Human cytomegalovirus induces TLR4 signaling components in monocytes altering TIRAP, TRAM and downstream interferon-beta and TNF-alpha expression. PLoS One 7: e44500.
- Nakao Y, Funami K, Kikkawa S, Taniguchi M, Nishiguchi M, et al. (2005) Surface-expressed TLR6 participates in the recognition of diacylated lipopeptide and peptidoglycan in human cells. J Immunol 174: 1566-1573.
- Poovassery JS, Bishop GA (2012) Type I IFN receptor and the B cell antigen receptor regulate TLR7 responses via distinct molecular mechanisms. J Immunol 189: 1757-1764.
- Xu N, Yao HP, Lv GC, Chen Z (2012) Downregulation of TLR7/9 leads to deficient production of IFN-a from plasmacytoid dendritic cells in chronic hepatitis B. Inflamm Res 61: 997-1004.
- Wermuth PJ, Jimenez SA (2012) Gadolinium compounds signaling through TLR4 and TLR7 in normal human macrophages: establishment of a proinflammatory phenotype and implications for the pathogenesis of nephrogenic systemic fibrosis. J Immunol 189: 318-327.
- Kücüksezer UC, Palomares O, Rückert B, Jartti T, Puhakka T, et al. (2012) Triggering of specific Toll-like receptors and proinflammatory cytokines breaks allergen-specific T-cell tolerance in human tonsils and peripheral blood. J Allergy Clin Immunol .
- Cervantes JL, Dunham-Ems SM, La Vake CJ, Petzke MM, Sahay B, et al. (2011) Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-beta. Proc Natl Acad Sci U S A 108: 3683-3688.
- Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, et al. (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303: 1526-1529.
- Gorden KB, Gorski KS, Gibson SJ, Kedl RM, Kieper WC, et al. (2005) Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol 174: 1259-1268.
- Krug A, Towarowski A, Britsch S, Rothenfusser S, Hornung V, et al. (2001) Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur J Immunol 31: 3026-3037.
- Govindaraj RG, Manavalan B, Lee G, Choi S (2010) Molecular modeling-based evaluation of hTLR10 and identification of potential ligands in Toll-like receptor signaling. PLoS One 5: e12713.
- Hanten JA, Vasilakos JP, Riter CL, Neys L, Lipson KE, et al. (2008) Comparison of human B cell activation by TLR7 and TLR9 agonists. BMC Immunol 9: 39.
- Agrawal S, Gupta S (2011) TLR1/2, TLR7, and TLR9 signals directly activate human peripheral blood naive and memory B cell subsets to produce cytokines, chemokines, and hematopoietic growth factors. J Clin Immunol 31: 89-98.
- Jiang W, Lederman MM, Harding CV, Rodriguez B, Mohner RJ, et al. (2007) TLR9 stimulation drives naïve B cells to proliferate and to attain enhanced antigen presenting function. Eur J Immunol 37: 2205-2213.
- Månsson A, Adner M, Höckerfelt U, Cardell LO (2006) A distinct Toll-like receptor repertoire in human tonsillar B cells, directly activated by PamCSK, R-837 and CpG-2006 stimulation. Immunology 118: 539-548.
- Schetter C, Vollmer J (2004) Toll-like receptors involved in the response to microbial pathogens: development of agonists for toll-like receptor 9. Curr Opin Drug Discov Devel 7: 204-210.
- Bernasconi NL, Onai N, Lanzavecchia A (2003) A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood 101: 4500-4504.
- Lee FE, Halliley JL, Walsh EE, Moscatiello AP, Kmush BL, et al. (2011) Circulating human antibody-secreting cells during vaccinations and respiratory viral infections are characterized by high specificity and lack of bystander effect. J Immunol 186: 5514-5521.
- Amanna IJ, Slifka MK (2010) Mechanisms that determine plasma cell lifespan and the duration of humoral immunity. Immunol Rev 236: 125-138.
- Poeck H, Wagner M, Battiany J, Rothenfusser S, Wellisch D, et al. (2004) Plasmacytoid dendritic cells, antigen, and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T-cell help. Blood 103: 3058-3064.
- Bekeredjian-Ding IB, Wagner M, Hornung V, Giese T, Schnurr M, et al. (2005) Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN. J Immunol 174: 4043-4050.
- He B, Qiao X, Cerutti A (2004) CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J Immunol 173: 4479-4491.
- Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, et al. (2006) Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25: 417-428.
- Ehlers M, Fukuyama H, McGaha TL, Aderem A, Ravetch JV (2006) TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE. J Exp Med 203: 553-561.
- Fields ML, Metzgar MH, Hondowicz BD, Kang SA, Alexander ST, et al. (2006) Exogenous and endogenous TLR ligands activate anti-chromatin and polyreactive B cells. J Immunol 176: 6491-6502.
- Herlands RA, Christensen SR, Sweet RA, Hershberg U, Shlomchik MJ (2008) T cell-independent and toll-like receptor-dependent antigen-driven activation of autoreactive B cells. Immunity 29: 249-260.
- Lau CM, Broughton C, Tabor AS, Akira S, Flavell RA, et al. (2005) RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med 202: 1171-1177.
- Lee PY, Kumagai Y, Li Y, Takeuchi O, Yoshida H, et al. (2008) TLR7-dependent and FcgammaR-independent production of type I interferon in experimental mouse lupus. J Exp Med 205: 2995-3006.
- Nickerson KM, Christensen SR, Shupe J, Kashgarian M, Kim D, et al. (2010) TLR9 regulates TLR7- and MyD88-dependent autoantibody production and disease in a murine model of lupus. J Immunol 184: 1840-1848.
- Prinz N, Clemens N, Strand D, Pütz I, Lorenz M, et al. (2011) Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells. Blood 118: 2322-2332.
- Silver KL, Crockford TL, Bouriez-Jones T, Milling S, Lambe T, et al. (2007) MyD88-dependent autoimmune disease in Lyn-deficient mice. Eur J Immunol 37: 2734-2743.
- Sweet RA, Ols ML, Cullen JL, Milam AV, Yagita H, et al. (2011) Facultative role for T cells in extrafollicular Toll-like receptor-dependent autoreactive B-cell responses in vivo. Proc Natl Acad Sci U S A 108: 7932-7937.
- Lech M, Kulkarni OP, Pfeiffer S, Savarese E, Krug A, et al. (2008) Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens. J Exp Med 205: 1879-1888.
- Wu X, Peng SL (2006) Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum 54: 336-342.
- Hooks JJ, Moutsopoulos HM, Geis SA, Stahl NI, Decker JL, et al. (1979) Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med 301: 5-8.
- Ytterberg SR, Schnitzer TJ (1982) Serum interferon levels in patients with systemic lupus erythematosus. Arthritis Rheum 25: 401-406.
- Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J (2001) Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science 294: 1540-1543.
- Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, et al. (2007) Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449: 564-569.
- Gringhuis SI, van der Vlist M, van den Berg LM, den Dunnen J, Litjens M, et al. (2010) HIV-1 exploits innate signaling by TLR8 and DC-SIGN for productive infection of dendritic cells. Nat Immunol 11: 419-426.
- Prohászka Z, Daha MR, Süsal C, Daniel V, Szlávik J, et al. (1999) C1q autoantibodies in HIV infection: correlation to elevated levels of autoantibodies against 60-kDa heat-shock proteins. Clin Immunol 90: 247-255.
- Stahl D, Lacroix-Desmazes S, Misra N, Karmochkine M, Kaveri SV, et al. (2005) Alterations of self-reactive antibody repertoires in HIV disease: an insight into the role of T cells in the selection of autoreactive B cells. Immunol Lett 99: 198-208.
- Grossman Z, Meier-Schellersheim M, Sousa AE, Victorino RM, Paul WE (2002) CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat Med 8: 319-323.
- Giorgi JV, Liu Z, Hultin LE, Cumberland WG, Hennessey K, et al. (1993) Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr 6: 904-912.
- Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, et al. (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12: 1365-1371.
- Jiang W, Lederman MM, Hunt P, Sieg SF, Haley K, et al. (2009) Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 199: 1177-1185.
- De Milito A, Nilsson A, Titanji K, Thorstensson R, Reizenstein E, et al. (2004) Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection. Blood 103: 2180-2186.
- Titanji K, De Milito A, Cagigi A, Thorstensson R, Grützmeier S, et al. (2006) Loss of memory B cells impairs maintenance of long-term serologic memory during HIV-1 infection. Blood 108: 1580-1587.
- De Milito A (2004) B lymphocyte dysfunctions in HIV infection. Curr HIV Res 2: 11-21.
- Guan Y, Sajadi MM, Kamin-Lewis R, Fouts TR, Dimitrov A, et al. (2009) Discordant memory B cell and circulating anti-Env antibody responses in HIV-1 infection. Proc Natl Acad Sci U S A 106: 3952-3957.
- Perisé-Barrios AJ, Muñoz-Fernandez MÁ, Pion M (2012) Direct phenotypical and functional dysregulation of primary human B cells by human immunodeficiency virus (HIV) type 1 in vitro. PLoS One 7: e39472.
- Melchers M, Bontjer I, Tong T, Chung NP, Klasse PJ, et al. (2012) Targeting HIV-1 envelope glycoprotein trimers to B cells by using APRIL improves antibody responses. J Virol 86: 2488-2500.
- Moir S, Malaspina A, Li Y, Chun TW, Lowe T, et al. (2000) B cells of HIV-1-infected patients bind virions through CD21-complement interactions and transmit infectious virus to activated T cells. J Exp Med 192: 637-646.
- Doepper S, Stoiber H, Kacani L, Sprinzl G, Steindl F, et al. (2000) B cell-mediated infection of stimulated and unstimulated autologous T lymphocytes with HIV-1: role of complement. Immunobiology 202: 293-305.
- Ruffin N, Lantto R, Pensieroso S, Sammicheli S, Hejdeman B, et al. (2012) Immune activation and increased IL-21R expression are associated with the loss of memory B cells during HIV-1 infection. J Intern Med 272: 492-503.
- Haas A, Zimmermann K, Graw F, Slack E, Rusert P, et al. (2011) Systemic antibody responses to gut commensal bacteria during chronic HIV-1 infection. Gut 60: 1506-1519.
- Sammicheli S, Dang VP, Ruffin N, Pham HT, Lantto R, et al. (2011) IL-7 promotes CD95-induced apoptosis in B cells via the IFN-?/STAT1 pathway. PLoS One 6: e28629.
- Rethi B, Sammicheli S, Amu S, Pensieroso S, Hejdeman B, et al. (2012) Concerted effect of lymphopenia, viremia and T cell activation on Fas expression of peripheral B cells in HIV-1 infected patients. AIDS.
- Peruchon S, Chaoul N, Burelout C, Delache B, Brochard P, et al. (2009) Tissue-specific B-cell dysfunction and generalized memory B-cell loss during acute SIV infection. PLoS One 4: e5966.
- Lindqvist M, van Lunzen J, Soghoian DZ, Kuhl BD, Ranasinghe S, et al. (2012) Expansion of HIV-specific T follicular helper cells in chronic HIV infection. J Clin Invest 122: 3271-3280.
- Pallikkuth S, Parmigiani A, Silva SY, George VK, Fischl M, et al. (2012) Impaired peripheral blood T-follicular helper cell function in HIV-infected nonresponders to the 2009 H1N1/09 vaccine. Blood 120: 985-993.
- Lim A, Amini A, D'Orsogna LJ, Rajasuriar R, Kramski M, et al. (2011) Antibody and B-cell responses may control circulating lipopolysaccharide in patients with HIV infection. AIDS 25: 1379-1383.
- Moir S, Malaspina A, Ogwaro KM, Donoghue ET, Hallahan CW, et al. (2001) HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals. Proc Natl Acad Sci U S A 98: 10362-10367.
- Feng Z, Dubyak GR, Lederman MM, Weinberg A (2006) Cutting edge: human beta defensin 3--a novel antagonist of the HIV-1 coreceptor CXCR4. J Immunol 177: 782-786.
- Chirmule N, Wang XP, Hu R, Oyaizu N, Roifman C, et al. (1994) Envelope glycoproteins of HIV-1 interfere with T-cell-dependent B cell differentiation: role of CD4-MHC class II interaction in the effector phase of T cell help. Cell Immunol 155: 169-182.
- Swingler S, Brichacek B, Jacque JM, Ulich C, Zhou J, et al. (2003) HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection. Nature 424: 213-219.
- Nagase H, Agematsu K, Kitano K, Takamoto M, Okubo Y, et al. (2001) Mechanism of hypergammaglobulinemia by HIV infection: circulating memory B-cell reduction with plasmacytosis. Clin Immunol 100: 250-259.
- Qiao X, He B, Chiu A, Knowles DM, Chadburn A, et al. (2006) Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells. Nat Immunol 7: 302-310.
- De Milito A, Mörch C, Sönnerborg A, Chiodi F (2001) Loss of memory (CD27) B lymphocytes in HIV-1 infection. AIDS 15: 957-964.
- Malaspina A, Moir S, Orsega SM, Vasquez J, Miller NJ, et al. (2005) Compromised B cell responses to influenza vaccination in HIV-infected individuals. J Infect Dis 191: 1442-1450.
- Malaspina A, Moir S, DiPoto AC, Ho J, Wang W, et al. (2008) CpG oligonucleotides enhance proliferative and effector responses of B Cells in HIV-infected individuals. J Immunol 181: 1199-1206.
- Crompton PD, Mircetic M, Weiss G, Baughman A, Huang CY, et al. (2009) The TLR9 ligand CpG promotes the acquisition of Plasmodium falciparum-specific memory B cells in malaria-naive individuals. J Immunol 182: 3318-3326.
- Kwissa M, Nakaya HI, Oluoch H, Pulendran B (2012) Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates. Blood 119: 2044-2055.
- Jiang W, Lederman MM, Mohner RJ, Rodriguez B, Nedrich TM, et al. (2008) Impaired naive and memory B-cell responsiveness to TLR9 stimulation in human immunodeficiency virus infection. J Virol 82: 7837-7845.
- Kazemi-Shirazi L, Gasche CH, Natter S, Gangl A, Smolen J, et al. (2002) IgA autoreactivity: a feature common to inflammatory bowel and connective tissue diseases. Clin Exp Immunol 128: 102-109.
- Roggenbuck D, Hausdorf G, Martinez-Gamboa L, Reinhold D, Büttner T, et al. (2009) Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn's disease. Gut 58: 1620-1628.
- Melmed GY, Agarwal N, Frenck RW, Ippoliti AF, Ibanez P, et al. (2010) Immunosuppression impairs response to pneumococcal polysaccharide vaccination in patients with inflammatory bowel disease. Am J Gastroenterol 105: 148-154.
- Malaspina A, Moir S, Kottilil S, Hallahan CW, Ehler LA, et al. (2003) Deleterious effect of HIV-1 plasma viremia on B cell costimulatory function. J Immunol 170: 5965-5972.
- Moir S, Malaspina A, Pickeral OK, Donoghue ET, Vasquez J, et al. (2004) Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily. J Exp Med 200: 587-599.
- Conge AM, Tarte K, Reynes J, Segondy M, Gerfaux J, et al. (1998) Impairment of B-lymphocyte differentiation induced by dual triggering of the B-cell antigen receptor and CD40 in advanced HIV-1-disease. AIDS 12: 1437-1449.
- Samuelsson A, Broström C, van Dijk N, Sönnerborg A, Chiodi F (1997) Apoptosis of CD4+ and CD19+ cells during human immunodeficiency virus type 1 infection--correlation with clinical progression, viral load, and loss of humoral immunity. Virology 238: 180-188.
- Titanji K, Chiodi F, Bellocco R, Schepis D, Osorio L, et al. (2005) Primary HIV-1 infection sets the stage for important B lymphocyte dysfunctions. AIDS 19: 1947-1955.
- Gasper-Smith N, Crossman DM, Whitesides JF, Mensali N, Ottinger JS, et al. (2008) Induction of plasma (TRAIL), TNFR-2, Fas ligand, and plasma microparticles after human immunodeficiency virus type 1 (HIV-1) transmission: implications for HIV-1 vaccine design. J Virol 82: 7700-7710.
- Katsikis PD, García-Ojeda ME, Torres-Roca JF, Greenwald DR, Herzenberg LA, et al. (1997) HIV type 1 Tat protein enhances activation-but not Fas (CD95)-induced peripheral blood T cell apoptosis in healthy individuals. Int Immunol 9: 835-841.
- Lichtner M, Marañón C, Vidalain PO, Azocar O, Hanau D, et al. (2004) HIV type 1-infected dendritic cells induce apoptotic death in infected and uninfected primary CD4 T lymphocytes. AIDS Res Hum Retroviruses 20: 175-182.
- Stylianou E, Yndestad A, Sikkeland LI, Bjerkeli V, Damås JK, et al. (2002) Effects of interferon-alpha on gene expression of chemokines and members of the tumour necrosis factor superfamily in HIV-infected patients. Clin Exp Immunol 130: 279-285.
- van Grevenynghe J, Cubas RA, Noto A, DaFonseca S, He Z, et al. (2011) Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis. J Clin Invest 121: 3877-3888.
- Zhang M, Li X, Pang X, Ding L, Wood O, et al. (2001) Identification of a potential HIV-induced source of bystander-mediated apoptosis in T cells: upregulation of trail in primary human macrophages by HIV-1 tat. J Biomed Sci 8: 290-296.
- Mueller YM, De Rosa SC, Hutton JA, Witek J, Roederer M, et al. (2001) Increased CD95/Fas-induced apoptosis of HIV-specific CD8(+) T cells. Immunity 15: 871-882.
- Miyawaki T, Uehara T, Nibu R, Tsuji T, Yachie A, et al. (1992) Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J Immunol 149: 3753-3758.
- Schattner E, Friedman SM (1996) Fas expression and apoptosis in human B cells. Immunol Res 15: 246-257.
- Badley AD, McElhinny JA, Leibson PJ, Lynch DH, Alderson MR, et al. (1996) Upregulation of Fas ligand expression by human immunodeficiency virus in human macrophages mediates apoptosis of uninfected T lymphocytes. J Virol 70: 199-206.
- Brown SB, Savill J (1999) Phagocytosis triggers macrophage release of Fas ligand and induces apoptosis of bystander leukocytes. J Immunol 162: 480-485.
- Oyaizu N, Adachi Y, Hashimoto F, McCloskey TW, Hosaka N, et al. (1997) Monocytes express Fas ligand upon CD4 cross-linking and induce CD4+ T cells apoptosis: a possible mechanism of bystander cell death in HIV infection. J Immunol 158: 2456-2463.
- Salvato MS, Yin CC, Yagita H, Maeda T, Okumura K, et al. (2007) Attenuated disease in SIV-infected macaques treated with a monoclonal antibody against FasL. Clin Dev Immunol 2007: 93462.
- Mao H, Lafont BA, Igarashi T, Nishimura Y, Brown C, et al. (2005) CD8+ and CD20+ lymphocytes cooperate to control acute simian immunodeficiency virus/human immunodeficiency virus chimeric virus infections in rhesus monkeys: modulation by major histocompatibility complex genotype. J Virol 79: 14887-14898.
- Miller CJ, Genescà M, Abel K, Montefiori D, Forthal D, et al. (2007) Antiviral antibodies are necessary for control of simian immunodeficiency virus replication. J Virol 81: 5024-5035.
- McKay PF, Barouch DH, Schmitz JE, Veazey RS, Gorgone DA, et al. (2003) Global dysfunction of CD4 T-lymphocyte cytokine expression in simian-human immunodeficiency virus/SIV-infected monkeys is prevented by vaccination. J Virol 77: 4695-4702.
- Mestecky J, Jackson S, Moldoveanu Z, Nesbit LR, Kulhavy R, et al. (2004) Paucity of antigen-specific IgA responses in sera and external secretions of HIV-type 1-infected individuals. AIDS Res Hum Retroviruses 20: 972-988.
- Gaufin T, Pattison M, Gautam R, Stoulig C, Dufour J, et al. (2009) Effect of B-cell depletion on viral replication and clinical outcome of simian immunodeficiency virus infection in a natural host. J Virol 83: 10347-10357.
- Dykhuizen M, Mitchen JL, Montefiori DC, Thomson J, Acker L, et al. (1998) Determinants of disease in the simian immunodeficiency virus-infected rhesus macaque: characterizing animals with low antibody responses and rapid progression. J Gen Virol 79 : 2461-2467.
- Holznagel E, Norley S, Holzammer S, Coulibaly C, Kurth R (2002) Immunological changes in simian immunodeficiency virus (SIV(agm))-infected African green monkeys (AGM): expanded cytotoxic T lymphocyte, natural killer and B cell subsets in the natural host of SIV(agm). J Gen Virol 83: 631-640.
- Pandrea IV, Gautam R, Ribeiro RM, Brenchley JM, Butler IF, et al. (2007) Acute loss of intestinal CD4+ T cells is not predictive of simian immunodeficiency virus virulence. J Immunol 179: 3035-3046.
- Terpstra FG, Al BJ, Roos MT, De Wolf F, Goudsmit J, et al. (1989) Longitudinal study of leukocyte functions in homosexual men seroconverted for HIV: rapid and persistent loss of B cell function after HIV infection. Eur J Immunol 19: 667-673.
- Broliden K, Hinkula J, Devito C, Kiama P, Kimani J, et al. (2001) Functional HIV-1 specific IgA antibodies in HIV-1 exposed, persistently IgG seronegative female sex workers. Immunol Lett 79: 29-36.
- Clerici M, Barassi C, Devito C, Pastori C, Piconi S, et al. (2002) Serum IgA of HIV-exposed uninfected individuals inhibit HIV through recognition of a region within the alpha-helix of gp41. AIDS 16: 1731-1741.
- Devito C, Hinkula J, Kaul R, Lopalco L, Bwayo JJ, et al. (2000) Mucosal and plasma IgA from HIV-exposed seronegative individuals neutralize a primary HIV-1 isolate. AIDS 14: 1917-1920.
- Melvin AJ, Mohan KM (2003) Response to immunization with measles, tetanus, and Haemophilus influenzae type b vaccines in children who have human immunodeficiency virus type 1 infection and are treated with highly active antiretroviral therapy. Pediatrics 111: e641-644.
- Hart M, Steel A, Clark SA, Moyle G, Nelson M, et al. (2007) Loss of discrete memory B cell subsets is associated with impaired immunization responses in HIV-1 infection and may be a risk factor for invasive pneumococcal disease. J Immunol 178: 8212-8220.
Citation: Yu X, Jiang W, Li Z, Kilby JM, Zhou Z (2013) Microbial TLR Agonists and Humoral Immunopathogenesis in HIV Disease. Epidemiol 3:120. Doi: 10.4172/2161-1165.1000120
Copyright: © 2013 Yu X, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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