Role of DAMPs and cell death in autoimmune diseases: the example of multiple sclerosis.

Multiple sclerosis is a chronic neuroinflammatory demyelinating disease of the central nervous system (CNS) of unknown etiology and still incompletely clarified pathogenesis. The disease is generally considered a disorder resulting from a complex interplay between environmental risk factors and predisposing causal genetic variants. To examine the etiopathogenesis of the disease, two complementary pre-clinical models are currently discussed: the "outside-in" model proposing a peripherally elicited inflammatory/autoimmune attack against degraded myelin as the cause of the disease, and the "inside-out" paradigm implying a primary cytodegenerative process of cells in the CNS that triggers secondary reactive inflammatory/autoimmune responses against myelin debris. In this review, the integrating pathogenetic role of damage-associated molecular patterns (DAMPs) in these two scenario models is examined by focusing on the origin and sources of these molecules, which are known to promote neuroinflammation and, via activation of pattern recognition receptor-bearing antigen-presenting cells, drive and shape autoimmune responses. In particular, environmental factors are discussed that are conceptually defined as agents which produce endogenous DAMPs via induction of regulated cell death (RCD) or act themselves as exogenous DAMPs. Indeed, in the field of autoimmune diseases, including multiple sclerosis, recent research has focused on environmental triggers that cause secondary events in terms of subroutines of RCD, which have been identified as prolific sources of DAMPs. Finally, a model of a DAMP-driven positive feed-forward loop of chronic inflammatory demyelinating processes is proposed, aimed at reconciling the competing "inside-out" and "outside-in" paradigms.

Role of DAMPs in respiratory virus-induced acute respiratory distress syndrome-with a preliminary reference to SARS-CoV-2 pneumonia.

When surveying the current literature on COVID-19, the "cytokine storm" is considered to be pathogenetically involved in its severe outcomes such as acute respiratory distress syndrome, systemic inflammatory response syndrome, and eventually multiple organ failure. In this review, the similar role of DAMPs is addressed, that is, of those molecules, which operate upstream of the inflammatory pathway by activating those cells, which ultimately release the cytokines. Given the still limited reports on their role in COVID-19, the emerging topic is extended to respiratory viral infections with focus on influenza. At first, a brief introduction is given on the function of various classes of activating DAMPs and counterbalancing suppressing DAMPs (SAMPs) in initiating controlled inflammation-promoting and inflammation-resolving defense responses upon infectious and sterile insults. It is stressed that the excessive emission of DAMPs upon severe injury uncovers their fateful property in triggering dysregulated life-threatening hyperinflammatory responses. Such a scenario may happen when the viral load is too high, for example, in the respiratory tract, "forcing" many virus-infected host cells to decide to commit "suicidal" regulated cell death (e.g., necroptosis, pyroptosis) associated with release of large amounts of DAMPs: an important topic of this review. Ironically, although the aim of this "suicidal" cell death is to save and restore organismal homeostasis, the intrinsic release of excessive amounts of DAMPs leads to those dysregulated hyperinflammatory responses-as typically involved in the pathogenesis of acute respiratory distress syndrome and systemic inflammatory response syndrome in respiratory viral infections. Consequently, as briefly outlined in this review, these molecules can be considered valuable diagnostic and prognostic biomarkers to monitor and evaluate the course of the viral disorder, in particular, to grasp the eventual transition precociously from a controlled defense response as observed in mild/moderate cases to a dysregulated life-threatening hyperinflammatory response as seen, for example, in severe/fatal COVID-19. Moreover, the pathogenetic involvement of these molecules qualifies them as relevant future therapeutic targets to prevent severe/ fatal outcomes. Finally, a theory is presented proposing that the superimposition of coronavirus-induced DAMPs with non-virus-induced DAMPs from other origins such as air pollution or high age may contribute to severe and fatal courses of coronavirus pneumonia.

Role of Damage-Associated Molecular Patterns in Light of Modern Environmental Research: A Tautological Approach.

Two prominent models emerged as a result of intense interdisciplinary discussions on the environmental health paradigm, called the "exposome" concept and the "adverse outcome pathway" (AOP) concept that links a molecular initiating event to the adverse outcome via key events. Here, evidence is discussed, suggesting that environmental stress/injury-induced damage-associated molecular patterns (DAMPs) may operate as an essential integrating element of both environmental health research paradigms. DAMP-promoted controlled/uncontrolled innate/adaptive immune responses reflect the key events of the AOP concept. The whole process starting from exposure to a distinct environmental stress/injury-associated with the presence/emission of DAMPs-up to the manifestation of a disease may be regarded as an exposome. Clinical examples of such a scenario are briefly sketched, in particular, a model in relation to the emerging COVID-19 pandemic, where the interaction of noninfectious environmental factors (e.g., particulate matter) and infectious factors (SARS CoV-2) may promote SARS case fatality via superimposition of both exogenous and endogenous DAMPs.

Use of DAMPs and SAMPs as Therapeutic Targets or Therapeutics: A Note of Caution.

This opinion article discusses the increasing attention paid to the role of activating damage-associated molecular patterns (DAMPs) in initiation of inflammatory diseases and suppressing/inhibiting DAMPs (SAMPs) in resolution of inflammatory diseases and, consequently, to the future roles of these novel biomarkers as therapeutic targets and therapeutics. Since controlled production of DAMPs and SAMPs is needed to achieve full homeostatic restoration and repair from tissue injury, only their pathological, not their homeostatic, concentrations should be therapeutically tackled. Therefore, distinct caveats are proposed regarding choosing DAMPs and SAMPs for therapeutic purposes. For example, we discuss the need to a priori identify and define a context-dependent "homeostatic DAMP:SAMP ratio" in each case and a "homeostatic window" of DAMP and SAMP concentrations to guarantee a safe treatment modality to patients. Finally, a few clinical examples of how DAMPs and SAMPs might be used as therapeutic targets or therapeutics in the future are discussed, including inhibition of DAMPs in hyperinflammatory processes (e.g., systemic inflammatory response syndrome, as currently observed in Covid-19), administration of SAMPs in chronic inflammatory diseases, inhibition of SAMPs in hyperresolving processes (e.g., compensatory anti-inflammatory response syndrome), and administration/induction of DAMPs in vaccination procedures and anti-cancer therapy.

Damage-associated molecular patterns in trauma.

In 1994, the "danger model" argued that adaptive immune responses are driven rather by molecules released upon tissue damage than by the recognition of "strange" molecules. Thus, an alternative to the "self versus non-self recognition model" has been provided. The model, which suggests that the immune system discriminates dangerous from safe molecules, has established the basis for the future designation of damage-associated molecular patterns (DAMPs), a term that was coined by Walter G. Land, Seong, and Matzinger. The pathological importance of DAMPs is barely somewhere else evident as in the posttraumatic or post-surgical inflammation and regeneration. Since DAMPs have been identified to trigger specific immune responses and inflammation, which is not necessarily detrimental but also regenerative, it still remains difficult to describe their "friend or foe" role in the posttraumatic immunogenicity and healing process. DAMPs can be used as biomarkers to indicate and/or to monitor a disease or injury severity, but they also may serve as clinically applicable parameters for optimized indication of the timing for, i.e., secondary surgeries. While experimental studies allow the detection of these biomarkers on different levels including cellular, tissue, and circulatory milieu, this is not always easily transferable to the human situation. Thus, in this review, we focus on the recent literature dealing with the pathophysiological importance of DAMPs after traumatic injury. Since dysregulated inflammation in traumatized patients always implies disturbed resolution of inflammation, so-called model of suppressing/inhibiting inducible DAMPs (SAMPs) will be very briefly introduced. Thus, an update on this topic in the field of trauma will be provided.

How evolution tells us to induce allotolerance.

Modern immunology, in many ways, is based on 3 major paradigms: the clonal selection theory (Medawar, Burnet; 1953/1959), the pattern recognition theory (Janeway; 1989), and the danger/injury theory (Matzinger, Land; 1994). The last theory holds that any cell stress and tissue injury including allograft injury, via induction of damage-associated molecular patterns, induces immunity including alloimmunity leading to allograft rejection. On the other hand, the concept precludes that "non-self " per se induces immunity as proposed by the two former theories. Today, the danger/injury model has been largely accepted by immunologists, as documented by a steadily increasing number of publications. In particular, overwhelming evidence in support of the correctness of the model has come from recent studies on the gut microbiota representing a huge assemblage of "non-self. " Here, harmless noninjurious commensal microbes are protected by innate immunity-based immune tolerance whereas intestinal injury-causing pathogenic microbes are immunology attacked. The ability of the immune system to discriminate between harmless beneficial "non-self " to induce tolerance and harmful life-threatening "non-self " to induce immunity has apparently emerged during evolution: Protection of innate immunity-controlled beneficial "non-self " (eg, as reflected by microbiotas but also by the fetus of placental mammals) as well as immune defense responses to injuring/injured "non-self " (eg, as reflected by plant resistance to biotic and abiotic stress and allograft rejection in mammals) evolved under pressure across the tree of life, that is, in plants, lower and higher invertebrates as well as lower and higher vertebrates. And evolution tells us why the overall existence of protected microbiotas really makes sense: It is the formation of the "holobiont, " - a metaorganism - that is, the host plus all of its associated microorganisms that - in terms of a strong unit of selection in evolution - provides that kind of fitness to all species on earth to successfully live, survive and reproduce. In other words: "We all evolve, develop, grow, and reproduce as multigenomic ecosystems! Regarding reproduction, another impressive example of active immunologic protection of "nonself " refers to pregnancy in placental mammals that emerged about 400 millions of years ago. Similar to "non-self " microbiotas, pregnancy in placental mammals reflects an evolution-driven phenomenon on the basis of innate immunity-controlled tolerance induction to semiallogeneic non-injuring/non-injured "non-self " aiming to ensure reproduction! Altogether, the lesson learned from evolution of how to avoid allograft rejection is clear: prevent allograft injury to induce allotolerance, in other words: create a "transplant holobiont. ".

Chronic allograft dysfunction: a model disorder of innate immunity.

The innate immune system is a highly sensitive organ of perception sensing any cell stress and tissue injury. Its major type of response to all potential inciting and dangerous challenges is inflammation and tissue repair and, if needed, induction of a supportive adaptive immune response, the aim always being to maintain homeostasis. However, although initially beneficial, innate immunity-mediated, protection-intended repair processes become pathogenic when they are exaggerated and uncontrolled, resulting in permanent fibrosis which replaces atrophic or dying tissue and may lead to organ dysfunction or even failure. In this sense, atherosclerosis and organ fibrosis reflect classical disorders caused by an overreacting innate immune system. Strikingly, these two pathologies dominate the development of chronic allograft dysfunction as the main clinical problem still left in transplantation medicine. Growing evidence suggests that acute and chronic allograft injuries, including alloimmune-, isoimmune-, nonimmune-, and infection-mediated insults, not only lead to cell death-associated graft atrophy but also activate the innate immune system which, over time, leads to uncontrolled intragraft fibrogenesis, thereby compromising allograft function. Acute and chronic allograft injuries lead to induction of damage-associated molecular patterns (DAMPs) which, after recognition by pattern recognition receptors, activate cells of the innate immune system such as donor-derived intragraft fibroblasts and vascular cells as well as recipient-derived graft-invading macrophages and leukocytes. It is mainly the orchestrated action and function of these cells that slowly but steadily metamorphose the originally life-saving allograft into a poorly functioning organ of marginal viability.

Calcineurin-inhibitor avoidance in elderly renal allograft recipients using ATG and basiliximab combined with mycophenolate mofetil.

In old recipients of renal allografts from old donors, benefits of calcineurin-inhibitors (CNI) are curtailed by nephrotoxicity. Intending to improve the outcome of these recipients, we analyzed a CNI-free immunosuppressive regimen consisting of anti-thymocyte globulin (ATG), basiliximab, mycophenolate mofetil (MMF) and steroids. Kidney allograft recipients with low immunological risk (panel reactive antibodies <30%) were eligible for this study. Immunosuppression induction included ATG (4 mg/kg, day 0), basiliximab (20 mg, day 0 + 4) and steroids, followed by MMF (TL 2-6 microg/ml) and steroid maintenance treatment. Patient and graft survival rates respectively were 89.3% and 85.4% (12 months), and 86.6% and 76.8% (24 months). Delayed graft function occurred in 44.6%. S-creatinine at 12 months was 1.85 +/- 0.94 mg/dl. Thirty patients (53.6%) showed biopsy-proven rejections (6x Banff 3, 13x Banff 4I and 16x Banff 4II), 77% of which were steroid-sensitive, 23% required antibody treatment. After 12 months, 83% of the patients had an MMF-based immunosuppression, 43% were CNI-free. Cytomegalovirus (CMV) infections occurred in 28, tissue-invasive disease in three patients. Despite acceptable renal graft survival and function in some of patients with marginal organs, high incidences of rejections and CMV infections suggest the feasibility of CNI-avoidance using an MMF-based protocol only in carefully selected patients.

Immunosuppressive strategies in organ transplantation in the light of innate immunity.

Evidence has accumulated to support the notion that injury-induced activation of the donor's and the recipient's innate immune system largely determines the outcome of organ transplantation. Future potential therapeutic strategies to suppress events of both innate immune systems, as well as approaches to mitigate allograft injury, are discussed with regard to inhibiting both complement activation and dendritic cell maturation, and to blocking innate effector functions. Applications of pharmacological drug therapy as well as gene-specific manipulations are theoretical tools to reach these goals. A variety of encouraging experimental data in this research field are already available and promise further discoveries that ultimately will lead to the design of appropriate clinical trials.

Ageing and immunosuppression in kidney transplantation.

Modern approaches to tailor-made, individualized immunosuppressive therapy for patients receiving organ transplantation require a rethinking of therapeutic strategies when it comes to older persons receiving kidney transplants, especially from deceased older donors. This review article makes the case for the use of calcineurin-inhibitor-free immunosuppressive induction/maintenance protocols in this "worst-case scenario" and discusses the theoretical and clinical data that support this recommendation. We will discuss modern theories of ageing, emphasizing the free-radical theory in relation to new insights into the mechanisms of innate immunity. In this context, a new, modified theory of ageing is presented. Increased generation of reactive oxygen species during ageing, via increased leakage of these oxidizing molecules from mitochondria, may contribute to senescence and age-related diseases by direct damage to intracellular DNA, proteins, and lipids. In addition, free-radical-mediated tissue injury, accompanied by induction of damage-associated molecular patterns, may result in activation of both inflammatory and vascular cells of the innate immune system, contributing (via inflammatory processes) to ageing and age-related diseases such as atherosclerosis. Calcineurin-inhibiting agents have been shown to induce oxidative stress and are thus defined as "proageing" drugs. Their use in older patients may aggravate the preexisting oxidized intracellular state and therefore should be avoided. In contrast, inosine-monophosphate dehydrogenase-inhibiting agents such as mycophenolate mofetil have been shown to even ameliorate oxidative stress and are thus defined as "antiageing" drugs. Therefore, their use for immunosuppression in older patients receiving kidney transplantation is suggested. This recommendation is supported by data from a prospective trial on the application of a calcineurin inhibitor-free, mycophenolate-mofetil--based induction/ maintenance immunosuppressive protocol in older recipients of kidneys from deceased older donors: the 5-year patient and 5-year allograft survival rates are currently 87% and 70%, respectively.