Innate and adaptive immunity through autophagy

The two main proteolytic machineries of eukaryotic cells, lysosomes and proteasomes, receive substrates by different routes. Polyubiquitination targets proteins for proteasomal degradation, whereas autophagy delivers intracellular material for lysosomal hydrolysis. The importance of autophagy for cell survival has long been appreciated, but more recently, its essential role in both innate and adaptive immunity has been characterized. Autophagy is now recognized to restrict viral infections and replication of intracellular bacteria and parasites. Additionally, this pathway delivers cytoplasmic antigens for MHC class II presentation to the adaptive immune system, which then in turn is able to regulate autophagy. At the same time, autophagy plays a role in the survival and the cell death of T cells. Thus, the immune system utilizes autophagic degradation of cytoplasmic material, to both restrict intracellular pathogens and regulate adaptive immunity.     

Autophagy and adaptive immunity

Autophagy plays an important role in maintaining intracellular homeostasis by promoting the transit of cytoplasmic material, such as proteins, organelles and pathogens, for degradation within acidic organelles. Yet, in immune cells, autophagy pathways serve an additional role in facilitating intracellular surveillance for pathogens and changes in self. Autophagy pathways can modulate key steps in the development of innate and adaptive immunity. In terms of adaptive immunity, autophagy regulates the development and survival of lymphocytes as well as the modulation of antigen processing and presentation. Specialized forms of autophagy may be induced by some viral pathogens, providing a novel route for major histocompatibility complex (MHC) class I antigen presentation and enhanced CD8⁺ T-cell responses. Autophagy induction in target cells also increases their potential to serve as immunogens for dendritic cell cross-presentation to CD8⁺ T cells. The requirement for autophagy in MHC class II presentation of cytoplasmic and nuclear antigens is well established, yet recent studies also point to a critical role for autophagy in modulating CD4⁺ T-cell responses to phagocytosed pathogens. Autophagy pathways can also modulate the selection and survival of some CD4⁺ T cells in the thymus. However, much still remains to be learned mechanistically with respect to how autophagy and autophagy-linked genes regulate pathogen recognition and antigen presentation, as well as the development and survival of immune cells.     

Autophagy and immunological aberrations in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease, in which immune defects can occur at multiple points of the cascading auto‐aggressive immune reactions, resulting in a striking heterogeneity of clinical presentations. The clinical manifestations of such autoimmune response can be severe: common manifestations symptoms include rash and renal inflammation progressing to kidney failure. Autophagy, the cellular “self‐digestion” process, is a key factor in the interplay between innate and adaptive immunity. Dysregulation of autophagy has been implicated in numerous autoimmune diseases. Several lines of evidence from genomic studies, cell culture systems, animal models, and human patients are emerging to support the role of autophagy in progression and pathogenesis of SLE. In this review, we summarize recent key findings on the aberrations of autophagy in SLE, with a special focus on how deregulated autophagy promotes autoimmunity and renal damage. We will also discuss how the observed findings may be translated into therapeutic settings.     

Viral interactions with macroautophagy: A double-edged sword

Autophagy is a conserved eukaryotic mechanism that mediates the removal of long-lived cytoplasmic macromolecules and damaged organelles via a lysosomal degradative pathway. Recently, a multitude of studies have reported that viral infections may have complex interconnections with the autophagic process. These observations strongly imply that autophagy has virus-specific roles relating to viral replication, host innate and adaptive immune responses, virus-induced cell death programs, and viral pathogenesis. Autophagy can supply internal membrane structures necessary for viral replication or may prolong cell survival during viral infections and postpone cell death. It can influence the survival of both infected and bystander cells. This process has also been linked to the recognition of viral signature molecules during innate immunity and has been suggested to help rid the cell of infection. This review discusses interactions between different viruses and the autophagy pathway, and surveys the current state of knowledge and emerging themes within this field.     

Autophagy in immunity and cell-autonomous defense against intracellular microbes

Autophagy was viewed until very recently primarily as a metabolic and intracellular biomass and organelle quality and quantity control pathway. It has now been recognized that autophagy represents a bona fide immunologic process with a wide array of roles in immunity. The immunologic functions of autophagy, as we understand them now, span both innate and adaptive immunity. They range from unique and sometimes highly specialized immunologic effectors and regulatory functions (referred to here as type I immunophagy) to generic homeostatic influence on immune cells (type II immunophagy), akin to the effects on survival and homeostasis of other cell types in the body. As a concept-building tool for understanding why and how autophagy is intertwined with immunity, it is useful to consider that the presently complex picture has emerged in increments, starting in part from the realization that autophagy acts as an evolutionarily ancient microbial clearance mechanism defending eukaryotic cells against intracellular pathogens. In this review, we build a stepwise model of how the core axis of autophagy as a cell-autonomous immune defense against microbes evolved into a complex but orderly web of intersections with innate and adaptive immunity processes. The connections between autophagy and conventional immunity systems include Toll-like receptors, Nod-like receptors, RIG-I-like receptors, damage-associated molecular patterns such as HMGB1, other known innate and adaptive immunity receptors and cytokines, sequestasome (p62)-like receptors that act as autophagy adapters, immunity-related GTPase IRGM, innate and adaptive functions of macrophages and dendritic cells, and differential effects on development and homeostasis of T- and B-lymphocyte subsets. The disease contexts covered here include tuberculosis, infections with human immunodeficiency virus and other viruses, Salmonella, Listeria, Shigella, Toxoplasma, and inflammatory disorders such as Crohn's disease and multiple sclerosis.     

Autophagy in innate recognition of pathogens and adaptive immunity

Autophagy is a specialized cellular pathway involved in maintaining homeostasis by degrading long-lived cellular proteins and organelles. Recent studies have demonstrated that autophagy is utilized by immune systems to protect host cells from invading pathogens and regulate uncontrolled immune responses. During pathogen recognition, induction of autophagy by pattern recognition receptors leads to the promotion or inhibition of consequent signaling pathways. Furthermore, autophagy plays a role in the delivery of pathogen signatures in order to promote the recognition thereof by pattern recognition receptors. In addition to innate recognition, autophagy has been shown to facilitate MHC class II presentation of intracellular antigens to activate CD4 T cells. In this review, we describe the roles of autophagy in innate recognition of pathogens and adaptive immunity, such as antigen presentation, as well as the clinical relevance of autophagy in the treatment of human diseases.     

自噬的免疫调节作用和机制

自噬是细胞内降解细胞成分的主要通道,对生物体的生存、分化、发育和维持其动态平衡具有关键作用。自噬机制既可作为免疫系统清除细胞内病原物质的效应器,也可作为模式识别受体或细胞因子的效应器,帮助免疫系统确认病原侵入和细胞转化。更为重要的是,自噬过程还可通过将细胞内物质转移到溶酶体降解并呈递给Ⅱ型MHC分子,与细胞应激和炎症反应耦联,参与调节固有免疫和适应性免疫反应。对自噬参与免疫反应分子机制的研究将加深对免疫反应分子机制的全面了解,为自噬相关疾病防治提供新的机会和途径。     

Autophagy in lupus nephritis: A delicate balance between regulation and disease

Autophagy is a highly regulated process wherein an unwanted cargo of damaged and dysfunctional cytoplasmic components is removed, delivered to lysosomes for degradation, and released back into the cytoplasm.Accumulating evidence suggests an important role of autophagy in the pathophysiology of systemic lupus erythematosus, with profound effects on both innate and adaptive immunity. Autophagy downregulation results in the inhibition of antigen presenting cells, reduced release of neutrophil extracellular traps and decreased activation of effector T and B cells, leading to reduced autoantibody production and attenuated type 1 interferon signaling. However, defective autophagy may accelerate the production of other inflammatory cytokines and reduce the clearance of apoptotic cells, promoting lupus development.In addition, autophagy dysfunction can concur to the pathogenesis of kidney injury in lupus nephritis. Autophagy is a pivotal mechanism to maintain podocyte integrity and endothelial cell survival. Several animal models have demonstrated that defective autophagy leads to podocyte injury and can promote an endothelial pro-inflammatory and atherogenic phenotype. Moreover, autophagy is a key homeostatic regulator of renal tubular cells, and recent evidence has pointed out that chronic autophagy deficiency may accelerate kidney fibrosis.Targeting autophagy may theoretically improve lupus nephritis outcomes, but novel, non-invasive methods to measure and monitor autophagic activity are urgently needed. In addition, the extent and timing of autophagy inhibition still require additional studies before clinical translation may be attempted. In this review, we will also discuss the effect of several clinically available drugs that can regulate the autophagic flux and their effect in lupus nephritis patients.     

Autophagy in the immune system

Autophagy is an intracellular homeostatic mechanism important for the degradation of waste components from the cytoplasm in acidic lysosomal compartments. Originally, surplus parts of the cytoplasm that acted as targets for autophagy were thought to comprise cellular organelles and proteins, but this has now extended to include a range of pathogens with particular emphasis on intracellular bacteria. The finding that autophagy can sequester intracellular bacteria and mediate their destruction has opened the door to a wider role for autophagy as an effector arm of the immune system. In innate immunity, autophagy works downstream of pattern recognition receptors where it facilitates a number of effector responses, including cytokine production and phagocytosis. Autophagy is also able to intersect pathways of innate and adaptive immunity through its potential to deliver antigens for antigen presentation. Autophagy provides a substantial source of antigens for loading onto MHC class II molecules and it may be important in dendritic cells for cross‐priming to CD8⁺ T cells. In lymphocytes, autophagy is essential for cell survival and homeostasis, particularly in T cells. In the thymus, autophagy can modulate the selection of certain CD4⁺ T‐cell clones while in the bone marrow autophagy is needed for B‐cell development at specific stages. However, large holes exist in our knowledge as to how autophagy regulates, and is regulated by, the immune system and it is important to now apply what we have gleaned from in vitro studies to how autophagy operates in vivo in the setting of natural infection.     

自噬相关蛋白对固有免疫调控的研究进展

模式识别受体（PPRs）识别病原微生物成分,诱导机体产生固有免疫应答。固有免疫应答异常,可导致超强的炎症反应,并可引起自身免疫性疾病。因此,必须对固有免疫应答进行严格的调控,才能维持机体生理平衡稳定。近年来,研究发现细胞自噬（autophagy）对固有免疫应答有着重要的调控作用。     

自噬与固有免疫应答相互调节研究进展

自噬在细胞分化、肿瘤、炎症、免疫等多方面发挥关键作用.近年来,随着分子生物学、细胞生物学、免疫学等学科的发展,研究发现细胞自噬与固有免疫应答有着重要的相互调控作用.自噬是固有免疫的重要组成成分,可以通过溶酶体直接降解被自噬体包裹的病原体.自噬参与众多固有免疫信号的调控.固有免疫信号也诱导或抑制自噬.自噬在抗胞内病原体感染中发挥重要作用.     

Innate immunity and graft rejection

Summary: Although innate immunity evolved to combat pathogens, increasing awareness of a pivotal role in driving and shaping adaptive immunity has prompted this review on the role of innate immunity in graft rejection. We present evidence that grafts, especially xenografts, elicit innate responses, required for adaptive immunity. Particular attention is paid to studies by ourselves and others demonstrating the important role of innate immunity in T‐cell trafficking. The mechanisms by which grafts elicit innate immunity are a fertile subject for further investigation and an important target for therapeutic intervention.     

Monocyte and Macrophage Abnormalities in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with profound effects on multiple organ systems. In patients with SLE, the immune system is subverted to target numerous self antigens and the ensuing inflammatory response elicits a vicious cycle of immune-cell activation and tissue damage. Both genetic and environmental factors are essential for the development of this debilitating condition, although the exact cause remains unclear. Early studies on the pathogenesis of lupus centered on the adaptive immune system as lymphocyte abnormalities were thought to be the primary cause of autoimmunity. In the past decade, however, this paradigm has shifted with rapid advances in the field of innate immunity. These developments have yielded important insights into how the autoimmune response in SLE is initiated and maintained. Monocytes and macrophages are an essential arm of the innate immune system with a multitude of immunological functions, including antigen presentation, phagocytosis, and cytokine production. Aberrations of monocyte/macrophage phenotype and function are increasingly recognized in SLE and animal models of the disease. In this review we summarize the current knowledge of monocyte/macrophage abnormalities in human SLE and discuss their implications for understanding the pathogenesis of lupus.     

Autophagy as an emerging dimension to adaptive and innate immunity

Autophagy is an evolutionary conserved cellular process during which cytoplasmic material is engulfed in double membrane vacuoles that then fuse with lysosomes, ultimately degrading their cargo. Emerging evidence, however, now suggests that autophagy can form part of our innate and adaptive immune defense programs. Recent studies have identified pattern recognition molecules as mediators of this process and shown that intracellular pathogens can interact with and even manipulate autophagy. Recent translational evidence has also implicated autophagy in the pathogenesis of several immune-mediated diseases, including Crohn disease. In this review, we present autophagy in the context of its role as an immune system component and effector and speculate on imminent and future research directions in this field.     

Autophagy and antiviral immunity

Autophagy is an ancient pathway designed to maintain cellular homeostasis by degrading long-lived proteins and organelles in the cytosol. Recent studies demonstrate that autophagy is utilized by the cells of the innate and adaptive immune systems to combat viral infections. Autophagy plays a key role in recognizing signatures of viral infection, and represents a critical effector mechanism to restrict viral replication. On the other hand, autophagosomes have been exploited by certain viruses as a niche for viral replication. Furthermore, autophagy can be used to deliver endogenous viral antigens to the MHC class II loading compartment, allowing activation of CD4 T cells. In this review, we describe recent advances in the field of autophagy as it relates to innate and adaptive antiviral immune responses.     

Association study of Toll-like receptor 9 gene polymorphism in Korean patients with systemic lupus erythematosus

Mammalian Toll-like receptors (TLR) play an important role in both adaptive immunity and innate immunity. Genetic variations within TLR genes are known to be associated with a variety of inflammatory and infectious diseases. TLR9 is potentially associated with autoimmune diseases, because it participates in the production of pro-inflammatory cytokines and the maturation of dendritic cells. We investigated the association of four TLR9 gene polymorphisms (-1486 T>C, -1237 C>T, +1174 A>G and +2848 G>A) with the susceptibility to systemic lupus erythematosus (SLE) and related phenotypes in 680 Korean people (350 SLE patients and 330 controls). TLR9 gene polymorphisms were not significantly associated with the susceptibility to SLE and related phenotypes.     

Endosomal Toll-like receptors in clinically overt and silent autoimmunity

Toll-like receptors (TLRs), first identified as pattern recognition receptors, are now recognized to serve as a key interface between innate and adaptive immunity. Systemic lupus erythematosus (SLE) is characterized by both continuous and cyclic stimulation of the innate and adaptive immune system by endogenous nucleic acids released from apoptotic or necrotic cells. TLR7 and TLR9 function as innate sensors of viral infection as their ligands are ssRNA and dsDNA, respectively. Recognition of self nucleic acids by endosomal TLRs in B cells and pDCs is thought to be an important step in the pathogenesis of SLE, generating anti-nuclear antibodies and producing type I IFN. In this review, we take a specific look at how TLR7, non-coding RNA, and SSA/Ro60 can contribute to clinical autoimmunity and organ damage in the context of neonatal lupus (NL). Although 15 times less common than SLE, NL provides a unique opportunity to study two different aspects of autoimmunity: passively acquired tissue injury in a developing fetus and clinical progression of disease in an asymptomatic mother found to have anti-Ro60 autoantibodies only after identification of heart block/rash in a child. Finally, we discuss hydroxychloroquine (HCQ) use by asymptomatic subjects which may forestall the clinical expression of autoimmunity.     

Programmed necrosis and autophagy in immune function

It has long been known that apoptosis is vital to the generation and maintenance of proper adaptive immune function. An example is the essential requirement for apoptotic signaling during the generation of self-tolerant lymphocytes: the apoptotic death of B and T cells with overt autoreactivity is essential to central tolerance. More recently, the contributions of additional processes including cellular autophagy and programmed necrosis have been implicated in controlling both innate and adaptive immune functions. Evidence has been provided to demonstrate that the death of cells following ligation of death receptors (DRs), a subfamily of cell surface molecules related to tumor necrosis factor receptor 1, is not exclusively the domain of caspase-dependent apoptosis. In cells lacking the capacity to activate caspase-8 following DR ligation, cell death instead occurs via programmed necrosis, or as it has been recently termed, 'necroptosis'. This death process depends on RIP1 and RIP3, serine/threonine kinases that are recruited by DRs, and likely by other cellular signals including DNA damage and antigen receptor ligation. The generation of RIP1/RIP3 containing 'necrosomes' activates downstream necroptotic signaling that ultimately targets cellular energetic metabolism. Also related to cellular metabolic regulation, cellular autophagy has also been found to play unique and important roles in immunity. In this review, we describe the roles of necroptosis and autophagy in innate and adaptive immunity and speculate on the intriguing interplay between these two cellular processes.     

Autophagy and pattern recognition receptors in innate immunity

Summary:  Autophagy is a physiologically and immunologically controlled intracellular homeostatic pathway that sequesters and degrades cytoplasmic targets including macromolecular aggregates, cellular organelles such as mitochondria, and whole microbes or their products. Recent advances show that autophagy plays a role in innate immunity in several ways: (i) direct elimination of intracellular microbes by digestion in autolysosomes, (ii) delivery of cytosolic microbial products to pattern recognition receptors (PRRs) in a process referred to as topological inversion, and (iii) as an anti-microbial effector of Toll-like receptors and other PRR signaling. Autophagy eliminates pathogens in vitro and in vivo but, when aberrant due to mutations, contributes to human inflammatory disorders such as Crohn's disease. In this review, we examine these relationships and propose that autophagy is one of the most ancient innate immune defenses that has possibly evolved at the time of α-protobacteria–pre-eukaryote relationships, leading up to modern eukaryotic cell–mitochondrial symbiosis, and that during the metazoan evolution, additional layers of immunological regulation have been superimposed and integrated with this primordial innate immunity mechanism.     

Involvement of autophagy in viral infections: antiviral function and subversion by viruses

Autophagy is a cellular process involved in the degradation and turn-over of long-lived proteins and organelles, which can be subjected to suppression or further induction in response to different stimuli. According to its essential role in cellular homeostasis, autophagy has been implicated in several pathologies including cancer, neurodegeneration and myopathies. More recently, autophagy has been described as a mechanism of both innate and adaptive immunity against intracellular bacteria and viruses. In this context, autophagy has been proposed as a protective mechanism against viral infection by degrading the pathogens into autolysosomes. This is strengthened by the fact that several proteins involved in interferon (IFN) signalling pathways are linked to autophagy regulation. However, several viruses have evolved strategies to divert IFN-mediated pathways and autophagy to their own benefit. This review provides an overview of the autophagic process and its involvement in the infection by different viral pathogens and of the connections existing between autophagy and proteins involved in IFN signalling pathways.