Elsevier

The Lancet

Volume 382, Issue 9894, 31 August–6 September 2013, Pages 819-831
The Lancet

Series
Immunopathogenic mechanisms of systemic autoimmune disease

https://doi.org/10.1016/S0140-6736(13)60954-XGet rights and content

Summary

Systemic lupus erythematosus, Sjögren's syndrome, and dermatomyositis are systemic autoimmune diseases that develop after environmental triggering of genetically susceptible individuals. The precise cellular and molecular mechanisms leading to autoimmune disease, and what factors determine which organs are involved, remain poorly understood. Recent insights into genetic susceptibility now make obvious that environmental triggers often act via cellular pathways containing disease-associated polymorphisms. In the breaking of tolerance, the initiating tissue—including dendritic cells—provides a decisive microenvironment that affects immune-cell differentiation, leading to activation of adaptive immunity. Type 1 interferon produced by innate immune cells has a central role in systemic autoimmunity and activates B cells and T cells. In turn, B-cell-derived autoantibodies stimulate dendritic cells to produce type 1 interferon; thus, a positive feedforward loop is formed that includes both the innate and adaptive systems. New treatments could simultaneously and specifically target several such vital pathways in autoimmunity.

Introduction

Our immune system developed to protect us against invading pathogens and to aid tissue healing after injury. In systemic autoimmune diseases, mechanisms that regulate the balance between recognition of pathogens and avoidance of self-attack are impaired. Furthermore, control of inflammation is lost, resulting in continuous immune activation without any overt infection, with different amplitudes during flares and quiescent disease. Adaptive immunity providing immune memory remains of central interest, but the role of the innate immune system in the pathogenesis of systemic autoimmunity is also currently under intense investigation. Study findings suggest genetic risk loci are shared in systemic autoimmune diseases and, therefore, that pathogenic mechanisms may be similar.1 However, distinct loci have also been identified that are specific to individual diseases, indicating that various immunopathogenic pathways are present.2 Concordance rates of 20–30% in monozygotic twins emphasise that environmental components that interact with the host genetic factors are important to our understanding of autoimmunity.

Two hypotheses for systemic autoimmune inflammation have been suggested. First, barrier control between innate and adaptive immunity could be disturbed, fuelling continuous inflammation by a positive feedforward loop, consistent with interferon effects. Second, impaired reactivity of adaptive immunity with reactivated (auto)reactive memory by lymphocytes could result in persistent inflammation and include defects of tolerance checkpoints. These two ideas are not mutually exclusive, and both innate and adaptive mechanisms seem operational in systemic autoimmunity.

Systemic lupus erythematosus, Sjögren's syndrome, and dermatomyositis are systemic autoimmune diseases that share clinical, immunological, and genetic features but have disease-specific traits. In people with systemic lupus erythematosus, almost any organ of the body could be a target for autoimmune inflammation, whereas Sjögren's syndrome is restricted mostly to exocrine glands; in dermatomyositis, proximal muscles and skin are affected predominantly. In this Review, we describe our current understanding of the immunopathogenic mechanisms underlying systemic autoimmunity, with particular reference to systemic lupus erythematosus, Sjögren's syndrome, and dermatomyositis.

Section snippets

Induction of autoimmunity

The idea that we are predisposed genetically to either an increased or diminished risk of developing systemic autoimmunity stems from observations of disease prevalence within families and in the general population. Most autoimmune disorders have a frequency in the general population of 0·1–1·0%, whereas prevalence in first-degree relatives is around five times higher, with a further five times increase in monozygotic twins of affected individuals. Although risk is obviously raised with

The innate system in systemic autoimmunity

The innate immune system—consisting of physical mucosal barriers, proteins, and cells such as granulocytes, natural killer cells, macrophages, and dendritic cells—serves as the front line against infectious agents and other environmental challenges. Dendritic cell homoeostasis is implicated directly in systemic autoimmunity, and dendritic cells contribute to disease both as antigen presenters and as major producers of type 1 interferon.21 Different subsets of dendritic cells regulate humoral

Directing role of cytokines in T-cell differentiation

T-cell abnormalities have been detected in autoimmunity, but whether these aberrations represent primary deviations or reflect a response to exogenous effects by cytokines produced by an impaired immune system is uncertain. Naive CD4+ T cells differentiate into subsets of effector T-helper cells after activation and costimulation, a process controlled by specific cytokines (figure 3). T-helper-1 cell differentiation is promoted by interleukin 12 and interferon γ, T-helper-2 cells depend on

Role of target tissue in autoimmune disease development

Interactions between organ tissue and the immune system are important to establish the degree of autoreactivity (panel 1). Organs serve as direct autoimmune targets and provide the microenvironment for induction and maintenance of ectopic immune responses, which further propagate tissue damage and dysfunction.

Considerations for therapeutic development and future directions

Targeting central molecules in upstream regulatory checkpoints in initiation of the inflammatory cascade, before all downstream pathways have been activated, has been suggested as a potentially effective strategy for treatment of systemic autoimmune diseases. However, the effectiveness of targeted treatments is hard to predict. Although not the primary factor in regulation of inflammation, tumour necrosis factor α has proved a target for amelioration of joint-related autoimmune diseases. When

Search strategy and selection criteria

We searched the Cochrane Library, Medline, and Embase (date last accessed March 15, 2013) with the terms: “autoimmunity”, “T cell”, “B cell”, “regulatory”, “Th1”, “Th2”, “Th17”, “autoantibodies”, “dendritic cell”, “lymphoid organs”, “germinal centers”, “follicles”, “cytokines”, “organ damage”, “lupus”, “autoimmune myositis”, “dermatomyositis”, “Sjögren”, and “co-stimulation” in different combinations. Because of the comprehensive topic, we selected the most relevant publications from the

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