Primary Development and Participation in a Foreign Antigen-Driven Immune Response of a Chromatin-Reactive B Cell Clonotype Are Not Influenced by TLR9 or Other MyD88-Dependent TLRs

Abstract

Recent findings support a central role for TLRs in both foreign Ag-driven immune responses and systemic autoimmune diseases mediated by B lymphocytes. In vitro studies have shown that the Ag receptors (BCRs) on B cells specific for nuclear autoantigens can facilitate the delivery of these autoantigens to the endocytic compartment, resulting in activation of the nucleic acid-specific TLRs present in this subcellular locale. If this pathway is operative in vivo it might promote the development, survival, or activation of such autoreactive B cells. To test this idea, we evaluated the influence of a deficiency in the CpG DNA-specific TLR, TLR9, or all MyD88-dependent TLRs on the primary development and foreign Ag-driven immune response of B cells in a line of VH knockin mice that contains a high frequency of “dual reactive” B cells specific for DNA-based autoantigens such as chromatin, as well as the hapten arsonate. We found that although development and activation of these B cells in vitro are clearly influenced by DNA-based autoantigens, TLR9 or MyD88 deficiencies had no apparent effect on the primary development and participation in the anti-arsonate response of these B cells in vivo. We discuss these results in the context of previous models for the role of TLR9 and other TLRs in the regulation of antinuclear Ag B cell development and activity.

Influence of B Cell Antigen Receptor Expression Level on Pathways of B Cell Tolerance Induction

“…However, we observed no differences in B cell development and BCR down-regulation in TLR9 or MyD88-deficient and sufficient versions of HKIR +/− and HKIR +/− /V κ 10 mice (Ref. 33 and F. Coffey and T. Manser, unpublished results).…”

Megakaryocyte Progenitors Are the Main APCs Inducing Th17 Response to Lupus Autoantigens and Foreign Antigens

“…Hence, to generate the activating IC, IgG-switched autoantibodies have to be made first by T cell help. Moreover, B cells become efficient APC to Th cells pre-primed by other APC (19), and B cells can be stimulated by nuclear antigens synergistically via BCR and TLR after developing high affinity somatically hypermutated receptors with T cell help (20, 21), otherwise anti-DNA B cells are inactivated (22, 23). Thus, conventional APCs are essential for disease progression, but it is unknown who initially primes autoimmune Th cells.…”

Autoinmunidad y receptores tipo Toll

“…Así, los LB pueden reconocer estos autoantígenos al ser ligandos para RTT y, en consecuencia, diferenciarse a células productoras de autoanticuerpos. Varios trabajos apoyan esta hipótesis al encontrar que las células B tienen la capacidad de reconocer cromatina por medio de RTT9 y activarse produciendo anticuerpos contra ella (46)(47)(48).…”