Abstract
Dendritic cells (DCs) initiate and control immune responses, participate in the maintenance of immunological tolerance and are pivotal players in the pathogenesis of autoimmunity. In patients with autoimmune disease and in experimental animal models of autoimmunity, DCs show abnormalities in both numbers and activation state, expressing immunogenic levels of costimulatory molecules and pro-inflammatory cytokines. Exogenous and endogenous danger signals activate DCs to stimulate the immune response. Classic endogenous danger signals are released, activated, or secreted by host cells and tissues experiencing stress, damage, and non-physiologic cell death; and are therefore referred to as damage-associated molecular patterns (DAMPs). Some DAMPs are released from cells, where they are normally sequestered, during necrosis (e.g., heat shock proteins, uric acid, ATP, HMGB1, mitochondria-derived molecules). Others are actively secreted, like Type I Interferons. Here we discuss important DAMPs in the context of autoimmunity. For some, there is a clear pathogenic link (e.g., nucleic acids and lupus). For others, there is less evidence. Additionally, we explore emerging danger signals. These include inorganic materials and man-made technologies (e.g., nanomaterials) developed as novel therapeutic approaches. Some nanomaterials can activate DCs and may trigger unintended inflammatory responses. Finally, we will review “homeostatic danger signals,” danger signals that do not derive directly from pathogens or dying cells but are associated with perturbations of tissue/cell homeostasis and may signal pathological stress. These signals, like acidosis, hypoxia, and changes in osmolarity, also play a role in inflammation and autoimmunity.
Highlights
Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that help maintain peripheral tolerance and orchestrate the adaptive immune response by presenting both endogenous and exogenous antigens and producing immune modulatory factors, such as costimulatory/inhibitory molecules and cytokines (Banchereau et al, 2000; Hammer and Ma, 2013)
Even when generated in culture from bone marrow precursors, depleted of mature T and B cells, macrophages, and DCs, and severed from the in vivo pro-autoimmune environment, DCs from Sle123 mice expressed an IFN Signature (Sriram et al, 2012). These results indicate that DCs are an independent cellular source of the pathogenic danger signals implicated in lupus (Elkon and Stone, 2011; Sriram et al, 2012)
HOMEOSTATIC ENDOGENOUS DANGER SIGNALS So far, we have briefly described the damageassociated molecular patterns (DAMPs) investigated under the classic paradigm – cell stress/death from tissue damage, possibly induced by trauma, infections or foreign materials, provides endogenous danger signals, which propagate the immune response (Figure 1)
Summary
Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that help maintain peripheral tolerance and orchestrate the adaptive immune response by presenting both endogenous and exogenous antigens and producing immune modulatory factors, such as costimulatory/inhibitory molecules and cytokines (Banchereau et al, 2000; Hammer and Ma, 2013). Danger signals activate DCs and stimulate both the innate and adaptive immune response (Box 1). The recognition of tissue and cell damage – which may involve several types of innate immune cells beside DCs and cascades such as the complement – has been proposed to initiate multiple processes (Bianchi, 2007), including: (a) the development of inflammation, (b) the induction of innate effector functions leading to pathogen clearance, (c) the stimulation of adaptive immunity, which generates immunological memory for future encounters with the same antigen, and (d) the stimulation of tissue repair processes, necessary to reconstitute tissue integrity compromised by the infection or, in some cases, by the immune response itself (Stoecklein et al, 2012) (Figure 1). Autoimmune diseases, in which the adaptive immune system mounts an immune response against self-antigens, are an important class of pathologies in which www.frontiersin.org
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