Common innate pathways to autoimmune disease

Abstract

Until recently, autoimmune disease research has primarily been focused on elucidating the role of the adaptive immune system. In the past decade or so, the role of the innate immune system in the pathogenesis of autoimmunity has increasingly been realized. Recent findings have elucidated paradigm-shifting concepts, for example, the implications of "trained immunity" and a dysbiotic microbiome in the susceptibility of predisposed individuals to clinical autoimmunity. In addition, the application of modern technologies such as the quantum dot (Qdot) system and 'Omics' (e.g., genomics, proteomics, and metabolomics) data-processing tools has proven fruitful in revisiting mechanisms underlying autoimmune pathogenesis and in identifying novel therapeutic targets. This review highlights recent findings discussed at the American Autoimmune Related Disease Association (AARDA) 2019 colloquium. The findings covering autoimmune diseases and autoinflammatory diseases illustrate how new developments in common innate immune pathways can contribute to the better understanding and management of these immune-mediated disorders.

Keywords: Autoimmune disease; Autoimmunity; Autoinflammatory disease; Inflammation; Innate immunity; Trained immunity.

Fig. 1.

Contribution of innate immunity to disease pathogenesis. Besides the well-known contribution of adaptive immune system, the innate immune system also plays a vital role in autoimmunity. Initiation of the innate immune response involves pattern-recognition receptors (PRRs) that recognize stress and danger signals. The origin of these signals might be endogenous (e.g., danger- associated molecular patterns (DAMPs) released from stressed and damaged cells) or exogenous (e.g., pathogen-associated molecules patterns (PAMPs) from pathogens; and xenobiotic agents (e.g., mercury and cigarette smoke)). The hos’s microbiota and metabolic pathways can also influence innate responses, which can influence gender bias in autoimmune susceptibility and certain metabolic disorders. Similarly, altered cellular trafficking and recruitment, as well as excessive cell death and impaired clearance of cellular debris can also lead to immune pathology. (Abbreviations: BP, Bullous pemphigoid; CHB, congenital heart block; CVD, cardiovascular disease; RA, rheumatoid arthritis; SLE (or Lupus) systemic lupus erythematosus; T1D, type 1 diabetes; T2D, type 2 diabetes; and autoinflammatory syndromes such as CANDLE, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome, and SAVI, stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy.

Fig. 2.

A schematic view of “trained immunity”. A myeloid cell undergoes a ‘trained’ immune response to a primary stimulus, danger-associated molecule pattern (DAMP) or pathogen-associated molecular pattern (PAMP), which binds and signals through the Toll-like receptor (TLR)2 or TLR4 pathway. This stimulus alters the epigenetic and metabolic state of the cell in a manner that is conserved so as to position it for a hyper-inflammatory response to a secondary stimulus. Secondary stimuli can be immunologically unrelated but, as a result, the elevated expression of pro-inflammatory cytokines to this secondary stimulus can propagate or exacerbate an autoimmune response.

Fig. 3.

Cellular processes involved in the pathogenesis of autoimmunity. Tissue damage during autoimmunity contributes to, and can result from, a chronic forward-feeding pathophysiological network involving the innate immune system. The perturbed clearance of dead cells or improper regulation of apoptosis can be an underlying factor in autoimmune disease. The intracellular/nuclear debris released from dead cells may form immune complexes with autoantibodies. Free intracellular debris, including DAMPS (e.g., nucleic acids) is recognized by TLR-family receptors, whereas the Fc portion of autoantibodies in immune-complexes are recognized by Fc receptors (FcRs) on myeloid cells. This in turn induces the expression of pro-inflammatory cytokines (e.g., IFNs, IL-6, TNFα), which contribute to other pathophysiological processes, including enhanced tissue remodeling/damage, autoreactive adaptive immune response, and inflammatory response of other innate immune cells in the affected tissues.