T Cell-Independent and Toll-like Receptor-Dependent Antigen-Driven Activation of Autoreactive B Cells

Herlands, Robin; Christensen, Sean R.; Sweet, Rebecca A.; Hershberg, Uri; Shlomchik, Mark J.

doi:10.1016/j.immuni.2008.06.009

Cited by 192 publications

(221 citation statements)

References 53 publications

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“…Thus, eTLRs are largely dispensable for humoral responses to foreign protein antigens (Ags), but are, for all practical purposes, necessary for the generation of autoAbs to nucleic acid and nucleic acid-containing material and IgM RF in systemic autoimmunity. These results definitively demonstrate that the eTLRs play a key and essential role in the pathogenesis of lupus in 2 susceptible strains and, in conjunction with previous studies (6,7,12,18,20,33), provide an explanation for the frequent and dominant presence of ANAs in SLE.…”

Section: Discussionsupporting

confidence: 86%

Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus

Kono¹,

Haraldsson²,

Lawson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

140

119

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Using the Unc93b1 3d mutation that selectively abolishes nucleic acid-binding Toll-like receptor (TLR) (TLR3, -7, -9) signaling, we show these endosomal TLRs are required for optimal production of IgG autoAbs, IgM rheumatoid factor, and other clinical parameters of disease in 2 lupus strains, B6-Fas lpr and BXSB. Strikingly, treatment with lipid A, an autoAb-inducing TLR4 agonist, could not overcome this requirement. The 3d mutation slightly reduced complete Freund's adjuvant (CFA)-mediated antigen presentation, but did not affect T-independent type 1 or alum-mediated T-dependent humoral responses or TLR-independent IFN production induced by cytoplasmic nucleic acids. These findings suggest that nucleic acid-sensing TLRs might act as an Achilles' heel in susceptible individuals by providing a critical pathway by which relative tolerance for nucleic acid-containing antigens is breached and systemic autoimmunity ensues. Importantly, this helps provide an explanation for the high frequency of anti-nucleic acid Abs in lupus-like systemic autoimmunity.autoimmunity ͉ SLE ͉ Unc93b1 ͉ innate immunity

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Section: Discussionsupporting

confidence: 86%

Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus

Kono¹,

Haraldsson²,

Lawson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

140

119

View full text Add to dashboard Cite

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“…5). Preventing receptor endocytic transit uncouples the sequential linkage between BCR and TLR engagement necessary to induce B cells to secrete anti-DNA antibodies (12,13,15,19). Thus, our results identify an important functional consequence of the alterations in signaling observed in anergic B cells.…”

Section: Discussionmentioning

confidence: 73%

“…Given the frequency of DNA-binding B cells in the peripheral repertoire, it might be expected that polyclonal anti-DNA antibody secretion would be a usual feature of the immune system (18,19). However, in nonautoimmune prone strains, TLR ligands fail to overcome anergy.…”

mentioning

confidence: 99%

Endocytic sequestration of the B cell antigen receptor and toll-like receptor 9 in anergic cells

O'Neill

Veselits

Zhang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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In autoimmune prone murine strains, sequential engagement of the B cell antigen receptor (BCR) on the cell surface and toll-like receptors (TLRs) in late endosomes is necessary and sufficient for secretion of autoantibodies. However, ubiquitous nucleoprotein self-antigens fail to elicit productive TLR activation, and break self-tolerance in anergic DNA-reactive B cells. Immunogenicity is associated with the coordinated activation of a network of signaling pathways, including those leading to rapid intracellular calcium elevation, ERK, and JNK activation. Most anergic B cells manifest aberrant BCR-induced calcium responses and attenuated JNK activation (4, 5).Little is known about how immunogenic and tolerogenic ligands induce opposing cell fates. Initial investigations focused on differences in transcriptional programs (6). However, only a few transcription factors are consistently differentially regulated in anergic B cells (7). The apparent lack of correlation between transcriptional events and B cell anergy is not surprising, given the rapidity with which anergy can be reversed (5,(8)(9)(10).BCR signaling is not the only determinant of peripheral B cell activation. The recognition of pathogen-associated molecular patterns by toll-like receptors (TLRs) is important in the loss of B cell tolerance. Deficiency of myeloid differentiation primary response gene-88 (MyD88) in MRL/lpr mice abrogates autoantibody production (11), whereas deficiencies in TLR7 or TLR9 inhibit the production of antibodies against RNP and dsDNA, respectively (12). B cell activation through TLR7 and TLR9 is coupled to BCR recognition of ligand containing antigenic complexes (13-15). Presumably, this is because the BCR is the primary conduit into the late endosomes where these TLRs reside (16,17).Given the frequency of DNA-binding B cells in the peripheral repertoire, it might be expected that polyclonal anti-DNA antibody secretion would be a usual feature of the immune system (18, 19). However, in nonautoimmune prone strains, TLR ligands fail to overcome anergy. In anergic HEL-specific B cells, chronic activation of ERK inhibits CpG DNA-induced plasma cell differentiation in vitro (20). However, ERK activation is not a universal feature of B cell anergy (5). Therefore, other mechanism(s) must attenuate TLR activation in anergic B cells. Results Aberrant Endocytic Antigen Receptor Trafficking in Anergic 3H9/V 8Splenic B Cells. We first examined whether BCR endocytic trafficking was attenuated in peripheral anergic B cells from genetargeted mice expressing 3H9/V 8, a BCR specific for ssDNA and cardiolipin (21,22). Splenic B cells expressing either V 8, 3H9/V 8, or nontransgenic C57BL/6 WT B cells were stimulated with FITC-conjugated F(abЈ) 2 goat anti-mouse IgG/M (heavy and light chain) antibodies for 30 min at 37°C then fixed, counterstained with anti-Lamp-1 antibodies (ID4B), and visualized by confocal microscopy (23). As we show in Fig. 1A, BCR aggregation on WT splenic B cells induced internalization and endocytic targeting of aggregate...

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“…4). Granted that this seems counterintuitive, recent publications have unequivocally demonstrated that affinity maturation and class-switching can occur without T cells, albeit the process is more cumbersome (33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

Fiskesund

Stéen

Amara

et al. 2014

The Journal of Immunology

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Phosphorylcholine (PC) is a classic T-independent Ag that is exposed on apoptotic cells, oxidized phospholipids, and bacterial polysaccharides. Experimental as well as epidemiological studies have over the past decade implicated Abs against PC (anti-PC) as anti-inflammatory and a strong protective factor in cardiovascular disease. Although clinically important, little is known about the development of anti-PC in humans. This study was conceived to dissect the human anti-PC repertoire and generate human mAbs. We designed a PC-specific probe to identify, isolate, and characterize PC-reactive B cells from 10 healthy individuals. The donors had all mounted somatically mutated Abs toward PC using a broad variety of Ig genes. PC-reactive B cells were primarily found in the IgM+ memory subset, although significant numbers also were detected among naive, IgG+, and CD27+CD43+ B cells. Abs from these subsets were clonally related, suggesting a common origin. mAbs derived from the same donors exhibited equivalent or higher affinity for PC than the well-characterized murine T-15 clone. These results provide novel insights into the cellular and molecular ontogeny of atheroprotective PC Abs, thereby offering new opportunities for Ab-based therapeutic interventions.

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T Cell-Independent and Toll-like Receptor-Dependent Antigen-Driven Activation of Autoreactive B Cells

Cited by 192 publications

References 53 publications

Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus

Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus

Endocytic sequestration of the B cell antigen receptor and toll-like receptor 9 in anergic cells

Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

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