Toll-like receptors and NOD/CARD proteins: pattern recognition receptors are key elements in the regulation of immune response.
The magnitude of the response to a specific immunogen such as an infectious agent is the result of a complex interaction between genetic and environmental factors. For example, in intestinal inflammation, the inflammatory response appears to be regulated by the indigenous microflora of the gut, by receptors in epithelial cells and antigen-presenting cells in the intestinal mucosa, and by immunologic factors. Recent evidence suggests that genetic variants of human immunomodulating genes influence the susceptibility to and severity of infectious diseases and the subsequent clinical outcome of disease. This review will focus on recently identified pattern recognition receptors which are located on innate immune and epithelial cells, and recognize pathogen-associated molecular patterns. The binding of specific pathogen-associated molecular patterns to these receptors results in the activation of a signal transduction pathway through nuclear factor (NF)-kappaB which leads to either enhanced or inhibited immune responses that modify the production of inflammatory effectors, such as cytokines. This article reports on the identification and functional characterization including the discovery of mutants which completely abolish NF-kappaB signal transduction of pattern recognition receptors, such as the extracellular Toll-like receptors and the intracellular nucleotide oligomerization domain/caspase recruitment domain (NOD/CARD) receptors, as well as their role in clinical disease. Knowledge of pattern recognition receptors such as Toll-like receptors and NOD/CARD intracytoplasmic proteins, including their functions and their downstream signaling pathways, may provide a new molecular basis for preventing or blocking inflammation associated with pathogenic microorganisms. This could direct a new focus for better and more specific therapeutic treatments based on immuno-intervention that can promise a better quality of life for those suffering from chronic disturbances of the immune response.
Murillo
Laura S
LS
Laboratory of Immunogenetics and Department of Gastroenterology, VU University Medical Centre, Amsterdam, The Netherlands.
Morré
Servaas A
SA
Peña
A Salvador
AS
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001424:Bacterial Infections / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D009154:Mutation; D016328:NF-kappa B / Q000502:physiology; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors