Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses

Seong, Seung Yong; Matzinger, Polly

doi:10.1038/nri1372

Cited by 1,064 publications

(929 citation statements)

References 120 publications

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“…This could explain how adaptive immune responses were stimulated by both infectious and noninfectious agents, such as tumours and transplanted tissues, all situations in which necrotic cell death would be occurring. In the danger model, dying cells were postulated to release endogenous adjuvants that, using similar nomenclature to PAMPs, have been called damage-associated molecular patterns (DAMPs); for simplicity we will use this terminology even though it is not clear whether endogenous danger signals really have distinctive molecular patterns as do PAMPs, although some have been proposed 8 . Although the term DAMP was originally introduced to cover damage-associated-molecular patterns in all living organisms 8 , we will use it here primarily to refer to danger signals of non-microbial origin.…”

Section: The Danger Hypothesismentioning

confidence: 99%

“…In the danger model, dying cells were postulated to release endogenous adjuvants that, using similar nomenclature to PAMPs, have been called damage-associated molecular patterns (DAMPs); for simplicity we will use this terminology even though it is not clear whether endogenous danger signals really have distinctive molecular patterns as do PAMPs, although some have been proposed 8 . Although the term DAMP was originally introduced to cover damage-associated-molecular patterns in all living organisms 8 , we will use it here primarily to refer to danger signals of non-microbial origin. Like PAMPs, DAMPs have been proposed to activate local APCs to become stimulatory to the adaptive immune system.…”

Section: The Danger Hypothesismentioning

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: 99%

Section: The Danger Hypothesismentioning

confidence: 99%

How dying cells alert the immune system to danger

2008

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“…We envisage that a set of charged residues from these apo and holo planes within the gC1q heterotrimer form different ionic and hydrogen bonds with complementary residues similar to polyspecific antibodies (41), a concept that can be extended to other versatile pattern-recognition proteins in innate immunity. Because hydrophobic patches are present on the gC1q domain, the recognition of the danger-alerting hydrophobic portions (acting as damage-associated molecular patterns) is also an interesting proposition (42). Interaction of C1q, ghA, ghB, or ghC with IgG1, CRP, or PTX3 at various NaCl concentrations: (a) C1q, (b) ghA, (c) ghB, and (d) ghC.…”

Section: Cluster Analysis Reveals the Differential Contributions Of Tmentioning

confidence: 99%

Interaction of C1q with IgG1, C-reactive Protein and Pentraxin 3: Mutational Studies Using Recombinant Globular Head Modules of Human C1q A, B, and C Chains

et al. 2006

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C1q is the first subcomponent of the classical complement pathway that can interact with a range of biochemically and structurally diverse self and nonself ligands. The globular domain of C1q (gC1q), which is the ligand-recognition domain, is a heterotrimeric structure composed of the Cterminal regions of A (ghA), B (ghB), and C (ghC) chains. The expression and functional characterization of ghA, ghB, and ghC modules have revealed that each chain has specific and differential binding properties toward C1q ligands. It is largely considered that C1q-ligand interactions are ionic in nature; however, the complementary ligand-binding sites on C1q and the mechanisms of interactions are still unclear. To identify the residues on the gC1q domain that are likely to be involved in ligand recognition, we have generated a number of substitution mutants of ghA, ghB, and ghC modules and examined their interactions with three selected ligands: IgG1, Creactive protein (CRP), and pentraxin 3 (PTX3). Our results suggest that charged residues belonging to the apex of the gC1q heterotrimer (with participation of all three chains) as well as the side of the ghB are crucial for C1q binding to these ligands, and their contribution to each interaction is different. It is likely that a set of charged residues from the gC1q surface participate † This study was supported by the National Science Foundation of Bulgaria, Grant MY-K-1303 to L.T.R. and L-1000 to M.S.K. R.G.is sponsored by the Deutsche Forschungsgemeinschaft through the Graduiertenkolleg GK370. U.K. is funded by the European Commission, University of Oxford, and the Alexander von Humboldt Foundation. A.M. and B.B. are funded by TELETHON, MIUR (FIRB Fund), the European Commission, and AIRC.© 2006 American Chemical Society * Corresponding author. Phone: +44-1865+44- -222325. Fax: +44-1865 +49-641-9941259. ukishore@hotmail.comu.kishore@rediffmail.com. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2013 December 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript via different ionic and hydrogen bonds with corresponding residues from the ligand, instead of forming separate binding sites. Thus, a recently proposed model suggesting the rotation of the gC1q domain upon ligand recognition may be extended to C1q interaction with CRP and PTX3 in addition to IgG1.C1q is the first subcomponent of the classical complement pathway and its binding to IgGor IgM-containing immune complexes leads to the autoactivation of C1r, which in turn, activates C1s. C1r and C1s, the two serine protease proenzymes, together with C1q constitute C1, the first component of the classical pathway. The activation of the C1 complex (C1q + C1r2 + C1s2) subsequently leads to the activation of the C2−C9 components of the classical pathway and the formation of the terminal-membrane-attack complex (MAC) (1, 2). C1q is a versatile innate immune molecule that can bind a diverse range of self and nonself ligands, ranging from proteins to lipids ...

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“…How the dendritic cell responds, and therefore the quality of the induced adaptive immunity, is determined by the danger signals to which the dendritic cell is exposed 17 . PRRs largely recognize pathogen-derived biomolecules referred to as pathogen-associated molecular patterns (PAMPs), which are evolutionarily distant non-self molecules such as LPS and viral doublestranded RNA 18 . Many endogenous molecules can also trigger PRR activation; such molecules, known as danger-associated molecular patterns (DAMPs), are typically associated with tissue damage or distress.…”

Section: Materials As Tools To Modulate Immune-cell Functionmentioning

confidence: 99%

“…20), which has been successfully used to enhance dendritic-cell uptake, for example with an antigen or a biomaterial particle conjugated to anti-DEC205 antibodies 21,22 . Recruitment involves chemoattracting other APCs to the delivery site, and strategies include the use, variously, Complement-activating, nucleophile-containing polymeric nanoparticles 28 Induced antigen-specific monoclonal antibody; induced IFN-γ-producing antigenspecific CD8 + T cells 28 Recombinant C3d 72,95 Recombinant, trimeric C3d protein conjugated to protein antigen through an avidin bridge 18 Induced a more robust and protective response to antigen when administered with IFA than when protein antigen administered in IFA or with alum 18 Recombinant, trimeric C3d-antigen fusion DNA vaccine 95 Generated higher-binding, early-appearing and neutralizing antibody responses; increased the number of IFN-γ-producing antigen-specific CD8 + T cells 95 The responses shown are related to engineering approaches to triggering these pathways or types of immunity using biomaterials. The table is not comprehensive but highlights a few recent biomaterialsbased strategies for immunotherapeutic applications.…”

Section: Materials For Enhancing Antigen Uptake By Apcsmentioning

confidence: 99%

Materials engineering for immunomodulation

Hubbell

Thomas

Swartz

2009

Nature

502

428

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The engineering of materials that can modulate the immune system is an emerging field that is developing alongside immunology. For therapeutic ends such as vaccine development, materials are now being engineered to deliver antigens through specific intracellular pathways, allowing better control of the way in which antigens are presented to one of the key types of immune cell, T cells. Materials are also being designed as adjuvants, to mimic specific 'danger' signals in order to manipulate the resultant cytokine environment, which influences how antigens are interpreted by T cells. In addition to offering the potential for medical advances, immunomodulatory materials can form well-defined model systems, helping to provide new insight into basic immunobiology.The term 'immunobioengineering' is used to describe efforts by immunologists and engineers to design materials, delivery vehicles and molecules both to manipulate and to better understand the immune system. Examples are the engineering of material surfaces to induce or prevent complement activation, the engineering of adjuvants to activate the immune system, the engineering of antigen or adjuvant carriers for subunit vaccine delivery, and the engineering of microenvironments to determine the interaction kinetics of mature dendritic cells and naive T cells. These advances not only will contribute to prophylactic vaccine strategies for infectious diseases but also are likely to affect immunotherapeutics, particularly for cancer, and new approaches to prevent or treat allergies and autoimmune diseases. The field is rapidly evolving along with advances in our understanding of immunology and is also contributing to our knowledge of basic immunology.In this Review, we describe the current state of immunobioengineering as it intersects with the field of materials science, and we give a perspective on its current and future directions. We focus on materials for immunomodulation, particularly with respect to dendritic-cell modulation. We begin by providing a brief introduction to the targets for delivery: the types of cell that materials are being designed to target, the tissues in which those cells reside, the intracellular compartments within those cells, and the influence that delivery to those particular compartments has on immunological outcome. We then discuss the biomolecular payloads used to activate immune cells and the design of the materials used to deliver those 'danger' signals along with, in the context of vaccination, antigens. Finally, we highlight materials approaches that are being developed to explore basic immunological function, especially how dendritic cells and T cells interact. Tissue and cellular targetsAs the general goals of immunobioengineering are to probe and manipulate the immune system, we start with a general discussion of tissue, cellular and subcellular targets -what we want to target and why -to guide the design principles discussed below.The immune cells most frequently targeted include B cells, macrophages and dendritic cells, wh...

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Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses

Cited by 1,064 publications

References 120 publications

How dying cells alert the immune system to danger

How dying cells alert the immune system to danger

Interaction of C1q with IgG1, C-reactive Protein and Pentraxin 3: Mutational Studies Using Recombinant Globular Head Modules of Human C1q A, B, and C Chains

Materials engineering for immunomodulation

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