Figures & data
Figure 1 Consequences of protein misfolding. Proper folding of newly synthesized proteins is critical for normal function. Protein misfolding has been linked to a number of diseases that can be broadly categorized as loss-of-function or gain-of-function. Loss-of-function phenotypes result from destruction of partially folded or misfolded proteins by elaborate quality control processes. Gain-of-function phenotypes can result from toxicity if the gene product accumulates and/or activation of cellular stress response pathways such as the UPR. HLA-B27 misfolding is hypothesized to result in gain-of-function abnormalities through sensitization of immune response cells such as macrophages to other exogenous stimuli as reviewed in this chapter.
Figure 2 Proposed paradigm linking HLA-B27 misfolding to innate immune activation. The tendency of HLA-B27 to misfold and activate the UPR when upregulated sensitizes cells to certain pathogen-associated molecular patterns and possibly damage-associated molecular patterns, many of which signal through pattern recognition receptors such as the Toll-like receptors (TLR Agonists). Enhanced upregulation of IL-23 promotes IL-17 production from CD4 T-cells of the Th17 lineage. Th17 cells can produce TNFα and IL-6 and IL-17 is also a potent pro-inflammatory cytokine that acts on many tissue cell types and further induces TNFα, IL-6 and IL-1 as well as chemokines and metalloproteinases. IL-17 is hypothesized to be a key pro-inflammatory cytokine in the immunopathology that develops in the colon of HLA-B27 transgenic rats.
