Innate immune mechanisms contributing to environmentally induced autoimmunity. The toxic response to environmental agents results in self nucleic acid/protein complexes that may become ligands for endosomal TLRs via scavenger receptors, particularly in macrophages. UNC93B1-mediated trafficking of endosomal TLRs leads first to VAMP3+ early endosomes, where signaling results in NF-κB activation and proinflammatory cytokine production. TLRs, again in concert with Unc93b1, also traffic to LAMP2+ LROs where IRF7 is activated to stimulate type I IFN expression. Lipid bodies, which contain components of the TLR signaling complex, may contribute to type I IFN particularly in pDCs. Activation of IRF5 in complex with TRAF6 can lead to proinflammatory cytokine production. NF-κB-mediated proinflammatory cytokine production may be augmented by release of constitutively expressed IL-1α from dead and dying cells. IL-1α may also contribute to adaptive immunity via differentiation and expansion of CD4+ T cells and enhanced expression of IFN-γ-stimulated genes such as IRF1. The large box signifies signaling events in innate immune responses that may occur in one or more cell types. Steps required for mHgIA are shown in rectangles with a thick black line while those not required are shown by ovals with a broken line. Steps required for pristane-induced autoimmunity include those leading to type I IFN and proinflammatory cytokine production and may also include pathways involving IL-1α, particularly IL-1α-driven NF-κB activation. AP-3, adaptor protein complex 3; Hg, mercury; IFN, interferon; IFNAR, type I IFN receptor; IL, interleukin; IRF, interferon regulatory factors; LAMP2, lysosome-associated membrane protein 2; LRO, lysosome-related organelle; NF, nuclear factor; Si, silica; Th1, T helper type 1; TLR, Toll-like receptor; TNF, tumor necrosis factor; TRAF6, TNF receptor associated factor 6; UNC93B1, Unc-93 homolog B1; VAMP3, vesicle-associated membrane protein 3.
Pollard and Kono BMC Medicine 2013 11:100 doi:10.1186/1741-7015-11-100