Review
Understanding the immunopathogenesis of autoimmune diseases by animal studies using gene modulation: A comprehensive review

https://doi.org/10.1016/j.autrev.2020.102469Get rights and content

Abstract

Autoimmune diseases are clinical syndromes that result from pathogenic inflammatory responses driven by inadequate immune activation by T- and B-cells. Although the exact mechanisms of autoimmune diseases are still elusive, genetic factors also play an important role in the pathogenesis. Recently, with the advancement of understanding of the immunological and molecular basis of autoimmune diseases, gene modulation has become a potential approach for the tailored treatment of autoimmune disorders. Gene modulation can be applied to regulate the levels of interleukins (IL), tumor necrosis factor (TNF), cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), interferon-γ and other inflammatory cytokines by inhibiting these cytokine expressions using short interfering ribonucleic acid (siRNA) or by inhibiting cytokine signaling using small molecules. In addition, gene modulation delivering anti-inflammatory cytokines or cytokine antagonists showed effectiveness in regulating autoimmunity. In this review, we summarize the potential target genes for gene or immunomodulation in autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD) and multiple sclerosis (MS). This article will give a new perspective on understanding immunopathogenesis of autoimmune diseases not only in animals but also in human. Emerging approaches to investigate cytokine regulation through gene modulation may be a potential approach for the tailored immunomodulation of some autoimmune diseases near in the future.

Introduction

Autoimmune diseases are caused by autoantibodies which are generated due to over-activation of the immune system potentiated by inadequate activation of T- and B cells [1,2]. These autoimmune diseases can show autotoxic effects in various organs such as brain, lung, pancreas, endocrine organ, gastrointestinal tract, kidney, bone and skin [3]. Mechanisms leading to autoimmune diseases comprise genetic, epigenetic, molecular, and cellular factors that result in pathogenic inflammatory responses which are driven by self-antigen-specific T-cells [4]. These include genetic or acquired defects of immune regulatory pathways, molecular similarity to viral or bacterial proteins, and impaired clearance of apoptotic cell material [5].

Although several medications such as analgetics, non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, biological agents, and glucocorticoids are effective in some autoimmune diseases [6,7], the proportion of patients achieving long lasting remission by the current management is still low. Reduction of symptoms and improvement of the quality of life are among the unmet needs of the treatment of a majority of autoimmune diseases [8]. Therefore, identification of optimal measures to treat an individual patient is highly desirable [9].

Although the exact mechanisms of autoimmune diseases are still elusive, genetic factors also play an important role in the pathogenesis. Multiple genes have been reported to be associated with autoimmunity and they have a variable implication in one's individual risk [10]. Major regulatory elements of T-cells have been reported to be associated with genetic variants that contribute to the risk of autoimmune disease in human [11]. There is also strong statistical evidence that several genetic variants are associated with 21 autoimmune diseases, indicating that there is a relationship between autoimmune diseases and genes [12]. A number of rare and common variants that contribute to the pathophysiology and the risk of some diseases have been uncovered by large international genomic consortia [13] and there are also familial autoimmune diseases caused by mendelian genetic variant with rare minor allele frequency such as hereditary C1q deficiency, autoimmune lymphoproliferative syndrome (ALPS), and immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome [14].

Recently, with the advancement of our understanding of the immunological and molecular basis of autoimmune diseases, gene modulation has become a promising approach for the tailored treatment of autoimmune diseases. The goal of gene modulation is to regulate the level of interleukins (IL), tumor necrosis factor (TNF), cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), interferon-γ and other inflammatory cytokines, thus leading to reduced infiltration of lymphocytes to the affected sites. In this review, we highlight studies on potential target genes for gene or immunomodulation in animal models of autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD) and multiple sclerosis (MS). This article will give a new perspective on understanding immunopathogenesis of autoimmune diseases not only in animals but also in human.

Section snippets

TNF-α, IL-1 related gene modulation

There are various cytokines that are known to play major roles in the pathogenesis of RA which led to numerous attempts investigating the relationship between cytokine levels and RA activity (Table 1). Khoury et al. showed that targeting major cytokines such as IL-1β, IL-6 and IL-18 at the same time using intravenous injection of short interfering ribonucleic acid (siRNAs) lipoplex (also known as ‘triple therapy’) not only reduced the severity of established collagen-induced arthritis (CIA) but

Anti-inflammatory cytokine targeted modulations

Inflammatory responses are controlled by a balance between stimulatory cytokines and anti-inflammatory factors [51,52]. Injection of cytokine-related genes into mice leads to an increase in the amount of the respective cytokine in circulation [53]. Furthermore, intramuscular injections of plasmid cDNAs generating TGF-β significantly increased survival rates, while injecting plasmid cDNAs inducing IL-2 decreased the survival rate in the murphy roths large (MRL)/lpr/lpr mice with SLE [54].

In

Anti-inflammatory cytokines

In line with other autoimmune disorders, changes in the immune response play a pivotal role in IBD (Table 3). Cytokines play a critical role in IBD and determine T cell differentiation [67]. Several studies proposed that IL-10 can prevent and attenuate IBD. In rats treated with Ad IL-10 one day prior to the induction of colitis, a prevention of colitis was observed [68]. Ad vector encoding murine IL-10 (AdvmuIL-10) injected into 4–week-old IL-10−/− mice induced no signs of colitis throughout

IL-17, IFN-γ related modulations

In MS, several studies suggested potential immunomodulations related to IL-17 and IFN-γ (Table 4). First, Yan et al. blocked IL-17 signaling in astrocytes of experimental autoimmune encephalomyelitis (EAE) mice by knocking down Act1 which is a major and common transcription factor of the IL-17 pathway [87]. As a result, infiltration of inflammatory cells was decreased in the central nervous system (CNS) and disease progression was inhibited [87]. Another study investigated DNA vaccination

Conclusion

Although the pathophysiology of autoimmune diseases has not been elucidated in detail, genetic factors also play an important role in the pathogenesis. There are shared as well as individual genetic traits which are associated with the risk to develop autoimmune diseases [10]. Because disease activity can in part be determined according to activation or suppression of these genes, cytokine gene modulation might be an interesting approach for the treatment.

Biologic measures neutralizing specific

Take home messages

  • With multiple genes associated with its pathogenesis, autoimmune disorders have a complicated genetic basis, leading to difficulties in selecting optimal individual treatment to cure each patient.

  • Gene modulation delivering anti-inflammatory cytokine or cytokine antagonists showed effectiveness in regulating autoimmunity in animal models.

  • Studies suggest that cytokine regulation through gene modulation may be a potential approach for the tailored immunomodulation treatment of autoimmune diseases

Authorship

K.H.L. and J.I.S. designed study, coordinated data acquisition, analyzed and interpreted the data, drafted the manuscript. All authors also participated in the parts of these and read and approved the final manuscript.

Role of funding source

No financial support was provided for research conduct and/or preparation of the article.

Declaration of Competing Interest

The authors disclose no conflicts of interest.

Acknowledgements

This work was partly performed by medical students during the clinical experience course at Yonsei University College of Medicine. We express our most sincere gratitude to the students who assisted in the preparation of the manuscript.

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