Natural endogenous adjuvants

Rock, Kenneth L.; Hearn, Arron; Chen, Chun‐Jen; Shi, Yan

doi:10.1007/s00281-004-0173-3

Cited by 138 publications

(123 citation statements)

References 103 publications

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“…It was known that cells by themselves, including dead ones, could be immunogenic 9 , but whereas such findings were consistent with the model, there was no direct evidence that cellular immunogens actually contained adjuvant activity. However, it was subsequently shown that when dead cells were admixed with an antigen and injected into animals, they augmented antigen-specific CD4 + and CD8 + T-cell responses 10 11.…”

Section: The Danger Hypothesismentioning

confidence: 75%

“…Thus, injury to one eye can initiate an autoimmune response that destroys the contralateral eye and ischemic necrosis of the heart can lead to an autoimmune pericarditis 16 17. In the case of tumours, injection of dead cancer cells can stimulate T-cell responses 9 . Moreover, killing tumour cells with chemotherapeutic agents in vivo can also lead to increased T-cell immunity 18 .…”

Section: Danger and Diseasementioning

confidence: 99%

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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: The Danger Hypothesismentioning

confidence: 75%

Section: Danger and Diseasementioning

confidence: 99%

How dying cells alert the immune system to danger

2008

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“…Uric acid (UA) is a natural product of the purine metabolic pathway and is a principal endogenous danger signal released from injured cells (Rock, Hearn, Chen, & Shi, 2005; Shi, Evans, & Rock, 2003). The role of UA in the central nervous system (CNS) remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Elevated cerebrospinal fluid uric acid during relapse of neuromyelitis optica spectrum disorders

Shu

Zhang

et al. 2016

Brain and Behavior

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IntroductionPrevious studies have shown that serum uric acid (UA) modulates outcomes of neurological diseases, although little is known about cerebrospinal fluid (CSF) UA levels in neuromyelitis optica spectrum disorders (NMOSDs).MethodsCerebrospinal fluid and serum UA levels were measured in samples from 68 patients, including NMOSDs during relapse (n = 38) and controls with noninflammatory and non‐neurodegenerative diseases (CTLs, n = 30). Correlation analysis was performed between CSF UA and clinical characteristics, serum UA, and blood–brain barrier integrity in NMOSDs.ResultsCerebrospinal fluid UA levels in NMOSDs were significantly higher than in CTLs (p = .002), while serum UA differences between NMOSDs and CTLs were not statistically significant. In NMOSDs, CSF UA levels were significantly higher in patients with an impaired blood–brain barrier than in patients with an intact one (p < .001), and significantly higher in longer disease duration than in shorter disease duration patients (p = .002). CSF UA levels were also significantly higher in active patients upon MRI than in inactive patients (p < .001), and significantly higher in patients with brain lesions than without brain lesions (p = .024). CSF UA was significantly associated with the serum UA levels (r = .454, p = .002), disease duration (r = .383, p = .018), and blood–brain barrier index (r = .805, p < .001), but did not correlate with age, gender, annualized relapse rate, duration, or severity of NMOSD. Multiple regression analysis demonstrated that CSF UA was independent of the blood–brain barrier index (β = .765, p < .001) and serum UA levels (β = .01, p = .019) in NMOSDs.ConclusionsCerebrospinal fluid UA levels were elevated in NMOSD patients during relapse, and were likely modified by serum UA levels and blood–brain barrier integrity.

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“…These endogenous activating molecules are collectively called damage-associated molecular pattern molecules (DAMPs) [27]. They include heat shock proteins (HSPs) [28], high mobility group box 1 protein (HMGB1) [29], β-defensin [30] and uric acid [31].…”

Section: Dendritic Cell Maturationmentioning

confidence: 99%

Dendritic cells and cytokines in human inflammatory and autoimmune diseases

Blanco

Palucka

Pascual

et al. 2008

Cytokine & Growth Factor Reviews

459

362

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Dendritic cells (DCs) produce cytokines and are susceptible to cytokine-mediated activation. Thus, interaction of resting immature DCs with TLR ligands, for example nucleic acids, or with microbes leads to a cascade of pro-inflammatory cytokines and skewing of T cell responses. Conversely, several cytokines are able to trigger DC activation (maturation) via autocrine, for example TNF and plasmacytoid DCs, and paracrine, for example type I IFN and myeloid DCs, pathways. By controlling DC activation, cytokines regulate immune homeostasis and the balance between tolerance and immunity. The increased production and/or bioavailability of cytokines and associated alterations in DC homeostasis have been implicated in various human inflammatory and autoimmune diseases. Targeting these cytokines with biological agents as already is the case with TNF and IL-1 represents a success of immunology and the coming years will expand the range of cytokines as therapeutic targets in autoinflammatory and autoimmune pathology.

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Natural endogenous adjuvants

Cited by 138 publications

References 103 publications

How dying cells alert the immune system to danger

How dying cells alert the immune system to danger

Elevated cerebrospinal fluid uric acid during relapse of neuromyelitis optica spectrum disorders

Dendritic cells and cytokines in human inflammatory and autoimmune diseases

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