‘Order from disorder sprung’: recognition and regulation in the immune system
Open Access
- 2 May 2003
- journal article
- Published by The Royal Society in Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences
- Vol. 361 (1807) , 1235-1250
- https://doi.org/10.1098/rsta.2003.1196
Abstract
Milton's epic poem Paradise lost supplies a colourful metaphor for the immune system and its responses to pathogens. With the role of Satan played by pathogens seeking to destroy the paradise of human health, GOD intervenes and imposes order out of chaos. In this context, GOD means 'generation of diversity': the capacity of the innate and specific immune responses to recognize and eliminate a universe of pathogens. Thus, the immune system can be thought of as an entity that self-assembles the elements required to combat bodily invasion and injury. In so doing, it brings to bear the power of specific recognition: the ability to distinguish self from non-self, and the threatening from the benign. This ability to define and protect self is evolutionarily very old. Self-recognition and biochemical and barrier defences can be detected in primitive organisms, and elements of these mechanisms are built upon in an orderly way to establish the mammalian immune system. Innate immune responses depend on the use of a limited number of germline-encoded receptors to recognize conserved molecular patterns that occur on the surfaces of a broad range of pathogens. The B and T lymphocytes of the specific immune response use complex gene-rearrangement machinery to generate a diversity of antigen receptors capable of recognizing any pathogen in the universe. Binding to receptors on both innate and specific immune-system cells triggers intricate intracellular signalling pathways that lead to new gene transcription and effector-cell activation. And yet, regulation is imposed on these responses so that Paradise is not lost to the turning of the immune system onto self-tissues, the spectre of autoimmunity. Lymphocyte activation requires multiple signals and intercellular interactions. Mechanisms exist to establish tolerance to self by the selection and elimination of cells recognizing self-antigens. Immune system cell populations are reduced by programmed cell death once the pathogen threat is resolved. Once Paradise has been regained, memory cells remain in the body to sharply reduce the impact of a second exposure to a pathogen. Vaccination programs take advantage of this capacity of the human immune system for immunological memory, sparing millions the suffering associated with disease scourges. Thus does the order of the immune response spring from the disorder of pathogen attacks, and thus is Paradise preserved.Keywords
This publication has 27 references indexed in Scilit:
- IRAK-M Is a Negative Regulator of Toll-like Receptor SignalingCell, 2002
- Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4Nature, 2002
- Fas Ligand-Induced ApoptosisAnnual Review of Genetics, 1999
- Regulation of T Cell Receptor Signaling by Tyrosine Phosphatase SYP Association with CTLA-4Science, 1996
- Update on immunizationCurrent Opinion in Pediatrics, 1996
- Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4Science, 1995
- Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4Immunity, 1995
- The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigensNature, 1987
- Transfer of specificity by murine α and β T-cell receptor genesNature, 1986
- Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic systemNature, 1974