Review articleShaping the spectrum — From autoinflammation to autoimmunity
Introduction
Under physiological conditions, immune responses are induced by pathogens or other danger signals and conducted by immune and/or sometimes epithelial cells. The immune system can be subdivided into two parts, the developmentally more ancient innate immune system, and the evolutionarily younger adaptive or acquired immune system [1], [2], [3], [4], [5].
The innate immune system comprises a number of non-specific defense mechanism, constituting the “first line of defense” against pathogens. Innate mechanisms include both cellular and humoral components, which are involved in the detection and elimination of danger signals. Targets of the innate immune system can be of microbial origin (pathogen-associated molecular patterns, PAMPs) but also host molecules (danger-associated molecular patterns, DAMPs) [1], [2], [6]. Innate immune mechanisms are manifold and our understanding of their molecular composition and function is continuously expanding. Central molecules of innate immune mechanisms include Toll-like receptors (TLRs), Nod-like receptors (NLRs), scaffolding proteins, such as the caspase recruitment domain (CARD) family of proteins, and cytosolic DNA-sensing molecules, inflammatory multi-protein complexes, referred to as inflammasomes, the complement system, and others. Cellular components of the innate immune system comprise monocytes and macrophages, neutrophilic granulocytes, natural killer (NK) cells, and dendritic cells (DC). However, also non-immune cells, e.g. epithelial cells, express molecules that are considered part of the innate system, including TLR4/5, CARD family proteins, and inflammasome components [1], [2], [3], [4], [5], [6], [7].
The adaptive immune system is evolutionary younger and exclusive to vertebrates. Adaptive immune mechanisms create the immunological memory to pathogens in response to an initial contact. This results in a rapid and enhanced response to subsequent exposures. In contrast to inflammation mediated by the innate immune system, acquired immune responses are highly specific and can provide long-lasting protection from pathogens. Specificity to pathogens, spatiotemporal or regional control, and the limitation of inflammatory responses is necessary to prevent tissue damage, and is mediated by cells of the adaptive immune system (B and T cells), which provide humoral and cellular immune responses to “intruders” [8], [9], [10], [11].
Following the definition suggested by Kastner et al., autoinflammatory disorders are characterized by seemingly unprovoked systemic inflammation in the absence of high-titer autoantibodies and autoreactive T lymphocytes [12], [13]. More recently, however, the definition was expanded by the observation that external factors, including the environment, infections, temperature, etc., may promote flares, alter the phenotypes, and/or directly contribute to pathogenesis [1], [3], [4], [14]. Thus, historically autoinflammatory disorders used to be strictly separated from autoimmune disorders, in which adaptive immune cells (B and/or T lymphocytes) largely contribute to the pathophysiology. About a decade ago, McDermott and McGonagle proposed a classification of immunological diseases with prototypical, mostly monogenic autoinflammatory disorders at the one end, and classical autoimmune disorders at the other end of an immunological spectrum [13]. Over the recent years, a number of monogenic and polygenic common and rare disorders have been identified, providing advanced insight into the pathophysiology of autoinflammatory and autoimmune disorders, further establishing the interplay between the two “parts” of the immune system in complex systems (such as the human body) [4], [14], [15]. Furthermore, genome-wide association studies, molecular imaging techniques, gene function studies, and the identification of tissue-specific factors in some disorders provided insights into the relative contribution of innate and adaptive immune mechanisms to some non-infectious immunological disorders, aided in gaining a better understanding of autoimmune/inflammatory conditions, and scientifically verified the hypotheses of McGonagle et al. Here, we provide an update on molecular pathomechanisms contributing to the immunological continuum, focusing on three exemplary disorders: i) the “classical” autoinflammatory disease systemic juvenile idiopathic arthritis (sJIA), ii) the mixed-pattern disorder psoriasis, and iii) the prototypical autoimmune disease systemic lupus erythematosus [16] and what we learned from rare monogenic disorders. The goal of this manuscript is not to deliver an all-embracing review of molecular pathomechanisms of single disorders, however, to provide an overview of recent developments in three “model disorders”, focusing on proposed or established interconnections between innate and adaptive immune mechanisms in autoimmune-inflammatory disorders.
Section snippets
Classical autoinflammatory disorders: sJIA
The systemic form of juvenile idiopathic arthritis (sJIA) is a prototypical autoinflammatory disorder [17], [18]. During its early and highly acute phase it is characterized by clinical signs of inflammation including fevers, skin rash, lymphadenopathy, hepatosplenomegaly, and/or serositis [17], [19], [20], [21]. Particularly in this early inflammatory stage, sJIA is characterized by the absence of autoreactive T cells and high-titer autoantibodies, thus following the “traditional” definition
Mixed pattern disorders: psoriasis
Psoriasis is an immunologically mediated disease that covers a range of subtypes or disease-stages representing mixed patterns of dysregulated innate and/or adaptive immune responses (Fig. 1) [38], [39], [40]. Early psoriasis but also highly active disease during flares sometimes presents with pustulous lesions, which entail dermal infiltrates with innate immune cells, including neutrophilic granulocytes, monocytes/macrophages, activated mast cells, as well as classical dendritic and
“Classical” autoimmune disorders: systemic lupus erythematosus
Systemic lupus erythematosus [16] is a prototypical autoimmune disorder, characterized by the presence of autoantibodies, the formation of immune complexes, and self-reactive B- and T lymphocytes [52], [53]. As a result of severe immune dysregulation, affected individuals present with systemic inflammation and variable organ damage. The molecular pathology of SLE is highly complex and only incompletely understood. It is known to involve both genetic and environmental factors. While most genetic
Conclusions
Over the past decade, the identification of disease-causing mutations in single genes and the association of polymorphisms in disease-associated gene loci contributed to a deeper understanding of the pathophysiology of various autoimmune-inflammatory disorders. Recent observations underscore the significance and relevance of a previously proposed immunological continuum, ranging from monogenetic autoinflammatory disorders at the one end to autoimmune diseases at the other end [13]. Scientific
Acknowledgments
C.M.H. actively participated in advisory boards of Novartis pharmaceuticals. The author declares no conflict of interest concerning this manuscript. C.M.H.'s research is supported by the Fritz-Thyssen-Foundation (10.15.1.019MN) and the MeDDrive intramural program of the University of Technology Dresden (60.364). C.M.H. wishes to thank Susanne Abraham for helpful discussion and clinical images, Sigrun Hofmann and Angela-Rösen-Wolff for helpful discussion.
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