Approaching the Asymptote? Evolution and Revolution in Immunology

Ca, Janeway

doi:10.1101/sqb.1989.054.01.003

Cited by 2,767 publications

(1,806 citation statements)

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“…In Janeway's "stranger" model 3 antigen presenting cells (later appreciated to be DC) were endowed with pattern recognition receptors that recognized the unique features of microbial molecules (pathogen-associated molecular patterns or PAMPs). When PAMPs were present, for example, from an infection or adjuvant, then DCs were stimulated to migrate to lymphoid tissues and present both antigen and costimulatory molecules to T cells.…”

Section: Fig 1 Stranger and Danger Modelsmentioning

confidence: 99%

How dying cells alert the immune system to danger

2008

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When a cell dies in vivo the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes, that is, it is part of normal physiological processes, then there is little threat to the organism. In this situation, little else is done other than removing the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized. The importance of this process to host defence and disease pathogenesis has only been appreciated relatively recently. This article will review our current knowledge of these processes.The immune system was recognized in ancient times and rediscovered by Jenner and Pasteur based on its ability to confer protection upon repeat exposure to a pathogen. Through subsequent studies by Von Behring and others it rapidly became apparent that the immune system had the potential to respond not only to whole microorganisms, but to virtually any molecule that was "foreign" to the host. However, whereas injection of such molecules would often provoke a robust immune response, this did not invariably occur. Immunization protocols improved in the 1920s with the discovery by Ramon and Glenny of immunostimulatory molecules (adjuvants [G]) that could boost immune responses to co-administered antigens. Adjuvants were typically of microbial origin and became widely used to promote the effectiveness of immunizations. In the 1960s, Dresser showed that a foreign protein when highly purified would only elicit an immune response if it was admixed with a microbial adjuvant 1 . Injected by itself, the antigen not only failed to elicit immunity but actually induced a state of tolerance 2 . However, the significance of these observations was not well appreciated and adjuvants remained one of those things that everyone used because they were part of standard operating procedures.In 1989 Janeway put these empirical observations into a conceptual framework 3 (Fig. 1). He proposed that the immune system did not respond to all foreign antigens but only to those that are potentially associated with infection. The underlying idea here was that the immune system evolved to protect organisms against microorganisms and this discrimination between infectious versus noninfectious antigens focused defences on real threats rather than innocuous situations.At this time, it was already recognized that in order to stimulate T cell responses, antigens had to first be acquired and presented on MHC molecules of an antigen presenting cell (APC). Moreover, it was further known that APCs also provided additional costimulatory signals necessary to activate T cells. Janeway incorporated these principles into his model (Fig. 1). He postulated that the discrimination between infectious and noninfectious non-self molecules was made by the APCs of the innate immune system through receptors that would recognize pathogen-associated molecular patterns (PAMP...

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Section: Fig 1 Stranger and Danger Modelsmentioning

confidence: 99%

How dying cells alert the immune system to danger

2008

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“…Even after its re-discovery, costimulation was often dismissed [9] or ignored [17] until, in 1989, Charlie Janeway found an ingenious way to meld costimulation with self-nonself discrimination. He expanded the SNSD model to include a set of genetically encoded able to recognise evolutionarily distant nonself [18,19].…”

Section: Historical Foundationsmentioning

confidence: 99%

Essay 1: The Danger Model in Its Historical Context

2001

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“…Providing a rapid but incomplete antimicrobial defense, innate immunity has been considered a separate entity from the adaptive immune response and is regarded as secondarily important in the hierarchy of immune functions 3. Nevertheless, Janeway4 reported that the adaptive immune response is induced by the exposure of pure antigens combined with adjuvants. This suggests that the innate immune system communicates its biological evaluation of an antigen to the adaptive immune system in some manner.…”

Section: Introductionmentioning

confidence: 99%

Tolerance-like innate immunity and spleen injury: a novel discovery via the weekly administrations and consecutive injections of PEGylated emulsions

Wang¹,

Jiao²,

Su³

et al. 2014

IJN

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There has been an increasing interest in the study of the innate immune system in recent years. However, few studies have focused on whether innate immunity can acquire tolerance. Therefore, in this study, we investigated tolerance in the innate immune system via the consecutive weekly and daily injections of emulsions modified with polyethylene glycol (PEG), referred to as PEGylated emulsions (PE). The effects of these injections of PE on pharmacokinetics and biodistribution were studied in normal and macrophage-depleted rats. Additionally, we evaluated the antigenic specificity of immunologic tolerance. Immunologic tolerance against PE developed after 21 days of consecutive daily injections or the fourth week of PE administration. Compared with a single administration, it was observed that the tolerant rats had a lower rate of PE clearance from the blood, which was independent of the stress response. In addition, weekly PE injections caused injury to the spleen. Furthermore, the rats tolerant to PEs with the methoxy group (–OCH3) of PEG, failed to respond to the PEs with a different terminal group of PEG or to non-PEG emulsions. Innate immunity tolerance was induced by PE, regardless of the mode of administration. Further study of this mechanism suggested that monocytes play an essential role in the suppression of innate immunity. These findings provide novel insights into the understanding of the innate immune system.

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Approaching the Asymptote? Evolution and Revolution in Immunology

Cited by 2,767 publications

References 0 publications

How dying cells alert the immune system to danger

How dying cells alert the immune system to danger

Essay 1: The Danger Model in Its Historical Context

Tolerance-like innate immunity and spleen injury: a novel discovery via the weekly administrations and consecutive injections of PEGylated emulsions

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