Remembering Pathogen Dose: Long-Term Adaptation in Innate Immunity

Bauer, Michael; Weis, Sebastian; Netea, Mihai G.; Wetzker, Reinhard

doi:10.1016/j.it.2018.04.001

Cited by 65 publications

(85 citation statements)

References 36 publications

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“…Experimentation with one may sometimes be more tractable than with the other and may ultimately yield insights into both processes, including their interrelationships. The convergence of studies with lectins and specific antigens has recently become clearer with the affirmation that both innate and acquired immune responses can, within an individual lifetime, display memory …”

Section: Discussionmentioning

confidence: 99%

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Two signal half‐century: From negative selection of self‐reactivity to positive selection of near‐self‐reactivity

Forsdyke

2019

Scand J Immunol

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With the emergence of clonal selection ideas in the 1950s, the development of immune cell repertoires was seen to require the negative selection of self‐reacting cells, with surviving cells exhibiting a broad range of specificities. Thus, confronting a universe of not‐self‐antigens, a potential host organism spread its resources widely. In the 1960s, the two signal hypothesis showed how this might work. However, in the 1970s an affinity/avidity model further proposed that anticipating a pathogen strategy of exploiting “holes” in the repertoire created by negative selection, hosts should also positively select near‐self‐reacting cells. A microbe mutating an antigen from a form foreign to its host to a form resembling that host should prevail over host defences with respect to that antigen. By mutating a step towards host self, along the path from non‐self to self, it should come to dominate the microbe population. By progressive stepwise mutations, such microbes would become better adapted, to the detriment of their hosts. But they would lose this advantage if, as they mutated closer to host self, they encountered progressively stiffer host defences. Thus, as described in the affinity/avidity model, positive selection of lymphocytes for specificities that were very close to, but not quite, anti‐self (ie, “anti‐near‐self”) should be an important host adaptation. While positive selection affects both B and T cells, mechanisms are uncertain. Converging evidence from studies of lymphocyte activation, either polyclonally (with lectins as “antigen‐analogs”) or monoclonally (by specific antigen), supports the original generic affinity/avidity model for countering mutations towards host self.

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Section: Discussionmentioning

confidence: 99%

“…The convergence of studies with lectins and specific antigens has recently become clearer with the affirmation that both innate and acquired immune responses can, within an individual lifetime, display memory. 59,60 ACKNOWLEDGMENT Queen's University hosts my theoretical immunology web pages.…”

Section: Discussionmentioning

confidence: 99%

Two signal half‐century: From negative selection of self‐reactivity to positive selection of near‐self‐reactivity

Forsdyke

2019

Scand J Immunol

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“…B. Komorbidität, bereits durchgemachte Infektionen, Alter und aktuelle Erkrankung oder Verletzungsmuster moduliert werden und kann sowohl Hyperinflammation als auch Immuntoleranz beinhalten. Dabei mehren sich die Hinweise, dass die Stressantwort nicht nur von der Art der Noxe, sondern stark von der Dosis des Stressors beeinflusst wird, wobei moderate Stressantworten adaptive Prozesse und eine hohe Stressdosis maladaptive Zellantworten auslöst [18].…”

Section: Die Neue Definition -Sepsis-3unclassified

“…Des Weiteren erfordern sie z. B. die Bildung und Freisetzung zytotoxischer Faktoren, wie Sauerstoffradikale [18]. Obwohl diese Reaktionen wichtig sind, um Débris zu eliminieren und den Wirt vor einer Infektion zu schützen, kann diese Verteidigungsstrategie selbst zu Schäden vor Ort oder systemisch in Organen, wie der Lunge (ARDS), führenein Phänomen, das als "Immunpathologie" (▶ Abb.…”

Section: Die Neue Definition -Sepsis-3unclassified

Sepsis 2019 – New Trends and Their Implications for Multiple Trauma Patients

Dickmann

Bauer

2019

Z Orthop Unfall

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In spring 2016, an updated sepsis definition (Sepsis-3) introduced a new explanation for the clinical picture of sepsis. Until then, sepsis had been understood as a “systemic inflammatory response syndrome (SIRS)” resulting from infection. An improved understanding of the molecular mechanisms and broad epidemiological studies of the clinical appearance shifted the focus from the inflammatory response to the multicausal tissue damage resulting in organ dysfunction. This paradigm shift highlights organ failure as a result of a dysregulated response of an organism to infection. Central to the new definition is the understanding that sepsis patients form a heterogeneous group and that the clinical picture requires alternative explanation patterns: e.g. sepsis is insufficiently explained by an overwhelming inflammatory response, it also comprises “immune paralysis” as another important pattern. Furthermore, severity of sepsis reflects the capacity of an organism to adapt and to mitigate the tissue damage through metabolic changes and repair mechanisms. Consistent with the paradigm of the new sepsis definition, adaptation in the presence of infections is crucial for the organism. Seriously injured or multiple trauma patients represent a patient group at particular risk, as sepsis often complicates the courses of these patients due to nosocomial infections. Along with comorbidities, past infections and age, leakage of skin and intestinal barriers as well as impaired defence and repair mechanism predispose trauma patients for a septic course. New pathophysiological insights suggest that the control of extracellular haem is of paramount significance. Haemolysis, transfusion and the consecutive expression of haem binding (such as haemopexin) or haem catabolic pathways (such as haem oxygenase) impair the ability of an organism to adapt, correlate with the prognosis and/or are strongly influenced by the surgical treatment concepts. Established treatment concepts of early causal and supportive therapy (damage control, antibiotic and fluid therapy) contribute to the reduction of mortality, depending on stringent implementation as part of Standard Operating Procedures (SOPs) and quality management. The paradigm shift in sepsis research offers an improved understanding of the underlying pathogenic factors within complex and heterogeneous patient groups, such as nosocomial sepsis following trauma. These novel approaches will allow developing new treatment strategies potentially contributing to a significant reduction in morbidity and mortality of trauma patients.Key messages1) According to the new paradigm, the ability to adapt to the pathogenic load associated with trauma and infection is crucial for an organism.2) Seriously injured or multiple trauma patients are predisposed for septic courses due to impaired adaptation mechanisms.3) Established treatment concepts of early causal and supportive therapy (damage control, antibiotic treatment, restrictive transfusion, and volume resuscitation) reduce mortality, in particular as part of SOPs and quality management strategies.4) Newly emerging treatment concepts that focus on the control of extracellular haem are promising, but require more evidence for translation into clinical practice.

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“…Infection-specific cues influence macrophage phenotypes through "trained immunity" (20). The type, dose, and duration of microbial stimuli can guide monocytes and macrophages toward new antiinflammatory, proinflammatory, or other more complex phenotypes (21). Metabolic changes contribute to this training (22), with macrophage metabolism changes guided by diverse types of stimuli (such as different microbes and microbial products), tissue environments (such as different organs and their state of health or disease), and cell types (such as monocytes or macrophages or subsets thereof).…”

Section: Introductionmentioning

confidence: 99%