ReviewUnderstanding the immunopathogenesis of autoimmune diseases by animal studies using gene modulation: A comprehensive review
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.
References (105)
- et al.
CTLA4-Ig modifies dendritic cells from mice with collagen-induced arthritis to increase the CD4+CD25+Foxp3+ regulatory T cell population
J Autoimmun
(2010) - et al.
Tissue inhibitors of metalloproteinases: evolution, structure and function
Biochim Biophys Acta
(2000) - et al.
Collagenase-3 (MMP-13) and its activators in rheumatoid arthritis: localization in the pannus-hard tissue junction and inhibition by alendronate
Matrix Biol
(1999) - et al.
Expression of stromelysin 3 and tissue inhibitors of matrix metallo-proteinases, TIMP-1 and TIMP-2, in rheumatoid arthritis
Pathol Res Pract
(1994) - et al.
CTLA4IgG gene delivery prevents autoantibody production and lupus nephritis in MRL/lpr mice
Life Sci
(2000) - et al.
Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus
Immunity
(2006) - et al.
Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis
Gastroenterology
(2011) - et al.
A novel PPAR gamma gene therapy to control inflammation associated with inflammatory bowel disease in a murine model
Gastroenterology
(2003) - et al.
CNS-specific therapy for ongoing EAE by silencing IL-17 pathway in astrocytes
Mol Ther
(2012) - et al.
Brain-derived neurotrophic factor gene delivery in an animal model of multiple sclerosis using bone marrow stem cells as a vehicle
J Neuroimmunol
(2009)
Tolerance induction in experimental autoimmune encephalomyelitis using non-myeloablative hematopoietic gene therapy with autoantigen
Mol Ther
Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) inhibits experimental autoimmune encephalomyelitis in Dark Agouti (DA) rats
Life Sci
Autoimmune diseases
N Engl J Med
Somatic mutation in autoantibody-associated VH genes of circulating IgM+IgD+ B cells
Eur J Immunol
Pathogenesis and spectrum of autoimmunity
Methods Mol Biol
Current and future immunomodulation strategies to restore tolerance in autoimmune diseases
Cold Spring Harb Perspect Biol
Pathogenesis of autoimmune diseases: a short review
Oral Maxillofac Pathol J
Restoring the balance: immunotherapeutic combinations for autoimmune disease
Dis Model Mech
Autoimmune diseases: early diagnosis and new treatment strategies
Clin Chem
The treatment strategies of autoimmune disease may need a different approach from conventional protocol: a review
Indian J Pharm
Optimization of current and future therapy for autoimmune diseases
Nat Med
Recent advances in the genetics of autoimmune disease
Annu Rev Immunol
The emerging role of resident memory T cells in protective immunity and inflammatory disease
Nat Med
Genetic and epigenetic fine mapping of causal autoimmune disease variants
Nature
Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers
Nat Genet
Monogenic autoimmunity
Annu Rev Immunol
Efficient suppression of murine arthritis by combined anticytokine small interfering RNA lipoplexes
Arthritis Rheum
Protection against collagen-induced arthritis by intramuscular gene therapy with an expression plasmid for the interleukin-1 receptor antagonist
Gene Ther
Adenoviral delivery of IL-18 binding protein C ameliorates collagen-induced arthritis in mice
Gene Ther
Soluble interleukin-1 receptor accessory protein ameliorates collagen-induced arthritis by a different mode of action from that of interleukin-1 receptor antagonist
Arthritis Rheum
Cytosolic phospholipase A2alpha gene silencing in the myeloid lineage alters development of Th1 responses and reduces disease severity in collagen-induced arthritis
Arthritis Rheum
Protective effect of Pinitol against inflammatory mediators of rheumatoid arthritis via inhibition of protein tyrosine phosphatase non-receptor type 22 (PTPN22)
Med Sci Monit
Arthritic joint-targeting small interfering RNA-encapsulated liposome: implication for treatment strategy for rheumatoid arthritis
J Pharmacol Exp Ther
Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis
J Immunol
Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis
Arthritis Rheum
Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis
Arthritis Rheum
Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) abrogates disease activity in murine collagen-induced arthritis
Gene Ther
Angiostatin gene transfer as an effective treatment strategy in murine collagen-induced arthritis
Arthritis Rheum
Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth
J Cell Mol Med
Thrombospondin 1 as an effective gene therapeutic strategy in collagen-induced arthritis
Arthritis Rheum
Primer on the rheumatic diseases
Kinetics of aggrecanase- and metalloproteinase-induced neoepitopes in various stages of cartilage destruction in murine arthritis
Arthritis Rheum
Cleavage of aggrecan at the Asn341-Phe342 site coincides with the initiation of collagen damage in murine antigen-induced arthritis: a pivotal role for stromelysin 1 in matrix metalloproteinase activity
Arthritis Rheum
Activation mechanisms of matrix metalloproteinases
Biol Chem
Inhibitory effect of cyclo-oxygenase-2 inhibitor on the production of matrix metalloproteinases in rheumatoid fibroblast-like synoviocytes
Rheumatol Int
Matrix metalloproteinases in immunity
J Immunol
Transin/stromelysin expression in rheumatoid synovium. A transformation-associated metalloproteinase secreted by phenotypically invasive synoviocytes
Am J Pathol
Immunolocalisation studies on six matrix metalloproteinases and their inhibitors, TIMP-1 and TIMP-2, in synovia from patients with osteo- and rheumatoid arthritis
Ann Rheum Dis
Analysis of 16 different matrix metalloproteinases (MMP-1 to MMP-20) in the synovial membrane: different profiles in trauma and rheumatoid arthritis
Ann Rheum Dis
Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis
Arthritis Rheum
Cited by (40)
Roles of interferon induced protein with tetratricopeptide repeats (IFIT) family in autoimmune disease
2023, Autoimmunity ReviewsA review on pharmacokinetics of sinomenine and its anti-inflammatory and immunomodulatory effects
2023, International ImmunopharmacologyInvolvement of trained immunity during autoimmune responses
2023, Journal of AutoimmunityCitation Excerpt :As was previously mentioned, autoimmune diseases are caused by self-antigens, loss of immune tolerance, and the induction of autoreactive T and B cells [15,18,56]. These diseases are an essential focus of study based on the prevalence and constant presence of the disease throughout the patient's life [57]. Even though the mechanisms of autoimmune diseases are still unknown, there is a dysfunction in innate and adaptative immunity [18].
Photoacoustic/ultrasound-guided gene silencing: Multifunctional microbubbles for treating adjuvant-induced arthritis
2023, International ImmunopharmacologyThe role of iron in chronic inflammatory diseases: from mechanisms to treatment options in anemia of inflammation
2022, BloodCitation Excerpt :Both genetic and environmental factors contribute to autoimmunity. Although the exact disease mechanisms differ between various autoimmune disorders, increased levels of inflammatory mediators (eg, TNF family members and interleukins) or JAK/STAT pathway activation are commonly observed.98,99 AI has been reported in 30% to 60% of patients with rheumatoid arthritis (RA), whereas IDA only occurs in a minority of patients, mainly because of therapy-induced, gastrointestinal, or urogenital blood losses.