B Lymphocyte Activation by Human Papillomavirus-Like Particles Directly Induces Ig Class Switch Recombination via TLR4-MyD88

Yang, Rongcun; Murillo, Francisco Martinez; Delannoy, Michaël; Blosser, Richard L.; Yutzy, William H.; Uematsu, Satoshi; Takeda, Kiyoshi; Akira, Shizuo; Viscidi, Raphael P.; Roden, Richard B.S.

doi:10.4049/jimmunol.174.12.7912

Cited by 77 publications

(62 citation statements)

References 70 publications

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“…HPV16 VLPs, for example, can directly activate B cells in a TLR4-dependent manner to induce CD4 ϩ T cell-independent class switching (16). In contrast, our data show that T help is strictly required for the induction of both anti-self and anti-foreign Abs by VLP-HEL.…”

Section: Discussioncontrasting

confidence: 51%

“…However, some multivalent Ags, including papillomavirus VLPs, are able to activate B cells and induce class switching in the absence of T help (16). In this regard, T-independent responses to pathogens and autoantibody responses to conjugated VLPs are promoted by similar repetitive antigenic structures and are perhaps dependent on similar stringent requirements for Ag-induced crosslinking of BCRs (15,17,18).…”

mentioning

confidence: 99%

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Virus-Like Display of a Neo-Self Antigen Reverses B Cell Anergy in a B Cell Receptor Transgenic Mouse Model

Chackerian

Durfee

Schiller

2008

The Journal of Immunology

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The ability to distinguish between self and foreign Ags is a central feature of immune recognition. For B cells, however, immune tolerance is not absolute, and factors that include Ag valency, the availability of T help, and polyclonal B cell stimuli can influence the induction of autoantibody responses. Here, we evaluated whether multivalent virus-like particle (VLP)-based immunogens could induce autoantibody responses in well-characterized transgenic (Tg) mice that express a soluble form of hen egg lysozyme (HEL) and in which B cell tolerance to HEL is maintained by anergy. Immunization with multivalent VLP-arrayed HEL, but not a trivalent form of HEL, induced high-titer Ab responses against HEL in both soluble HEL Tg mice and double Tg mice that also express a monoclonal HEL-specific BCR. Induction of autoantibodies against HEL was not dependent on coadministration of strong adjuvants, such as CFA. In contrast to previous data showing the T-independent induction of Abs to foreign epitopes on VLPs, the ability of HEL-conjugated VLPs to induce anti-HEL Abs in tolerant mice was dependent on the presence of CD4+ Th cells, and could be enhanced by the presence of pre-existing cognate T cells. In in vitro studies, VLP-conjugated HEL was more potent than trivalent HEL in up-regulating surface activation markers on purified anergic B cells. Moreover, immunization with VLP-HEL reversed B cell anergy in vivo in an adoptive transfer model. Thus, Ag multivalency and T help cooperate to reverse B cell anergy, a major mechanism of B cell tolerance.

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Section: Discussioncontrasting

confidence: 51%

mentioning

confidence: 99%

Virus-Like Display of a Neo-Self Antigen Reverses B Cell Anergy in a B Cell Receptor Transgenic Mouse Model

Chackerian

Durfee

Schiller

2008

The Journal of Immunology

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“…QARVLAVERY elicits significantly higher IgA than does ELDKWA independent of the vector-delivery regimen Recent evidence has suggested that factors such as mucosal delivery of antigens, 58 use of adjuvants, 59,60 certain viral antigens, 61,62 or VLP administration 63,64 may influence IgA induction and can directly or indirectly modulate Ab class-switch recombination. Here, we determined whether the significantly higher IgA generated against QARVLAVERY was a property of the epitope alone, independent of such factors in our immunization model.…”

Section: Articlesmentioning

confidence: 99%

The gp41 epitope, QARVLAVERY, is highly conserved and a potent inducer of IgA that neutralizes HIV-1 and inhibits viral transcytosis

Jain

Rosenthal

2011

Mucosal Immunology

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Mucosal surfaces are the predominant site of human immunodeficiency virus (HIV)-1 transmission. For prophylactic approaches to effectively prevent HIV infection and subsequent dissemination, the induction of mucosally relevant protective immunity will be critical. Here, we have characterized the antibody (Ab) response generated by a highly conserved gp41epitope, QARVLAVERY, in an optimized immunization model that elicits potent epitope-specific Abs in the serum, vaginal washes, and fecal secretions of immunized mice. Our results show that QARVLAVERY is indeed a potent inducer of IgA and importantly, QARVLAVERY-specific IgA was effective in neutralizing HIV and inhibiting viral transcytosis. Intriguingly, QARVLAVERY also generated an approximate 1:1 ratio of IgG:IgA in the serum of immunized mice, independent of the delivery regimen and produced early systemic IgA, even before IgG. In light of the significantly high IgA induction by QARVLAVERY and the functionality of epitope-specific Abs in the inhibition of HIV infection and transcytosis, QARVLAVERY is an attractive epitope to be considered in mucosal vaccination strategies against HIV.

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“…HPV L1 VLPs have been reported elsewhere to induce cytokine response in DCs, monocytes, and macrophages (41)(42)(43), possibly in a TLR-dependent fashion (44,45). Abs against HPV L1 VLPs were found to be reduced in TLR4-deficient mice by Yang et al (44) but not by others (46).…”

Section: Crucial Role Of Mpl In As04 For the Stimulation Of An Innatementioning

confidence: 95%

AS04, an Aluminum Salt- and TLR4 Agonist-Based Adjuvant System, Induces a Transient Localized Innate Immune Response Leading to Enhanced Adaptive Immunity

Didierlaurent

Morel

Lockman

et al. 2009

The Journal of Immunology

624

471

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Adjuvant System 04 (AS04) combines the TLR4 agonist MPL (3-O-desacyl-4′-monophosphoryl lipid A) and aluminum salt. It is a new generation TLR-based adjuvant licensed for use in human vaccines. One of these vaccines, the human papillomavirus (HPV) vaccine Cervarix, is used in this study to elucidate the mechanism of action of AS04 in human cells and in mice. The adjuvant activity of AS04 was found to be strictly dependent on AS04 and the HPV Ags being injected at the same i.m. site within 24 h of each other. During this period, AS04 transiently induced local NF-κB activity and cytokine production. This led to an increased number of activated Ag-loaded dendritic cells and monocytes in the lymph node draining the injection site, which further increased the activation of Ag-specific T cells. AS04 was also found to directly stimulate those APCs in vitro but not directly stimulate CD4+ T or B lymphocytes. These AS04-induced innate responses were primarily due to MPL. Aluminum salt appeared not to synergize with or inhibit MPL, but rather it prolonged the cytokine responses to MPL at the injection site. Altogether these results support a model in which the addition of MPL to aluminum salt enhances the vaccine response by rapidly triggering a local cytokine response leading to an optimal activation of APCs. The transient and confined nature of these responses provides further supporting evidence for the favorable safety profile of AS04 adjuvanted vaccines.

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B Lymphocyte Activation by Human Papillomavirus-Like Particles Directly Induces Ig Class Switch Recombination via TLR4-MyD88

Cited by 77 publications

References 70 publications

Virus-Like Display of a Neo-Self Antigen Reverses B Cell Anergy in a B Cell Receptor Transgenic Mouse Model

Virus-Like Display of a Neo-Self Antigen Reverses B Cell Anergy in a B Cell Receptor Transgenic Mouse Model

The gp41 epitope, QARVLAVERY, is highly conserved and a potent inducer of IgA that neutralizes HIV-1 and inhibits viral transcytosis

AS04, an Aluminum Salt- and TLR4 Agonist-Based Adjuvant System, Induces a Transient Localized Innate Immune Response Leading to Enhanced Adaptive Immunity

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