ABSTRACT
Toll-like receptors (TLR) are transmembrane pattern recognition receptors that recognize microbial ligands and signal for production of inflammatory cytokines and type I interferon in macrophages and dendritic cells (DC). Whereas TLR-induced inflammatory mediators are required for pathogen clearance, many are toxic to the host and can cause pathological inflammation when over-produced. This is demonstrated by the role of TLR-induced cytokines in autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. Because of the potent effects of TLR-induced cytokines, we have diverse mechanisms to dampen TLR signaling. Here, we highlight three pathways that participate in inhibition of TLR responses in macrophages and DC, and their implications in autoimmunity; A20, encoded by the TNFAIP3 gene, Lyp encoded by the PTPN22 gene, and the BCAP/PI3K pathway. We present new findings that Lyp promotes TLR responses in primary human monocytes and that the autoimmunity risk Lyp620W variant is more effective at promoting TLR-induced interleukin-6 than the non-risk Lyp620R protein. This suggests that Lyp serves to downregulate a TLR inhibitory pathway in monocytes, and we propose that Lyp inhibits the TREM2/DAP12 inhibitory pathway. Overall, these pathways demonstrate distinct mechanisms of negative regulation of TLR responses, and all impact autoimmune disease pathogenesis and treatment.
Subject(s)
Autoimmune Diseases/immunology , Dendritic Cells/immunology , Macrophages/immunology , Myeloid Cells/immunology , Toll-Like Receptors/metabolism , Animals , Carrier Proteins/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Humans , Immunomodulation , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 22/metabolism , Signal Transduction , Tumor Necrosis Factor alpha-Induced Protein 3ABSTRACT
This article discusses the role of nurses and nurse leaders in the prevention and resolution of patient stigmatisation. The multiple nurse, patient and environmental factors that contribute to difficulties in nurse-patient interactions are outlined. The antecedents and consequences of patient stigmatisation are discussed and leadership strategies for counteracting and preventing patient stigmatisation are explored. The reader is encouraged to reflect on the role of patient stigmatisation in nursing practice and consider ways to promote better care of stigmatised patients.
