Introduction
Many of the rheumatological chronic diseases and degenerative diseases have complex genetic etiology. Advancements in the past decades have improved the technologies that have discovered genetic etiology. The causes of rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis are changes in genes. Autoimmunity arises when the immune system responds to an antigen within the host's body. Autoimmune diseases occur when this specific immune response leads to a pathological condition. Typically, these diseases involve the activation of both the adaptive immune system (including T and B cells recognizing self-antigens) and the innate immune system (consisting of macrophages and dendritic cells). Autoimmunity is genetically driven through antigen recognition and cellular interactions, and environmental factors can also induce autoimmune responses. Infections like the Coxsackie virus can serve as a primary natural source of antigens that mimic self-antigens, triggering organ-specific autoimmune diseases like myocarditis. Alternatively, the Epstein–Barr virus can act as both an initiating agent and a polyclonal activator of B cells, contributing to organ-specific and systemic autoimmune diseases such as multiple sclerosis, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Therefore, autoimmune diseases can be classified into two major categories: organ-specific and systemic. This article explains the role of genes in rheumatic disease.
What Are Rheumatic Diseases?
Rheumatic disease serves as a broad term encompassing arthritis and various other conditions impacting joints, tendons, muscles, ligaments, bones, and connective tissues (with arthritis specifically focusing on joint-related disorders). Conditions like osteoarthritis, within the realm of rheumatic diseases, can result in significant joint pain due to the deterioration of cartilage – the resilient yet pliable tissue safeguarding joints – when not effectively managed. Among the prevalent rheumatic diseases are osteoarthritis, recognized as the most widespread type of arthritis, and rheumatoid arthritis, often abbreviated as RA. In rheumatoid arthritis, the immune system mistakenly targets and attacks normal cells, resulting in inflammation, swelling, and pain that affect several joints simultaneously, leading to inflammation, swelling, and pain across multiple joints simultaneously. Fibromyalgia, gout, and juvenile arthritis are types of rheumatic diseases.
What Is the Role of Genetics in Rheumatic Diseases?
Rheumatic disease is heritable and has complex genetic causes. The contribution of genes involved in the clinical representation as well as the pathogenesis of rheumatological disease. The genome-wide association (GWA) gained popularity in technical advances for common diseases that have genetic risks. In simpler terms, evidence supporting a genetic link to systemic lupus erythematosus (SLE) is found in twin studies. The likelihood of lupus in identical twins is higher (24 %) compared to non-identical twins (2 %). Approximately 100 genes are thought to contribute to autoimmune rheumatic diseases.
The following are the genes responsible for rheumatic disease:
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HLA Gene - The human leukocyte antigen (HLA) locus, including major histocompatibility complex (MHC) and complement genes, strongly influences genetics, leading to personalized recognition and processing of antigens, a key pathway in autoimmunity.
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C1q Deficiency - C1q deficiency in 90 % of patients results in lupus-like symptoms, while C4 deficiency causes SLE with over 75 % penetrance. Genes like PTPN22 and STAT4 play a role in signal regulation and confer a lesser risk. Polymorphisms in these genes are linked to both rheumatoid arthritis (RA) and SLE, suggesting a common genetic pathway. Autoimmunity-related polymorphisms in PTPN22 lead to sustained signaling in T and B cells.
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Interferon Regulatory Factors - The activation of the innate immune system is controlled by various factors, including interferon regulatory factors (IRFs). Polymorphisms associated with SLE involve genes like ITGAM and IRAK1, which impact macrophage function. Cytosolic DNA detection triggers an immune response, and mutations in the Trex1 gene affect this response, leading to autoimmunity. Monogenic lupus, though rare, provides insights into SLE pathogenesis.
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Mutations - Mutations in genes like Trex1 and SAMHD1 are associated with specific lupus-like syndromes, revealing the relation between genetic and environmental factors in SLE development.
What Is the Role Of Epigenetics in Rheumatic Diseases?
The change in genetic activity in individuals with a genetic predisposition, known as epigenetic modifications, is the key factor initiating diseases in response to environmental factors. In systemic lupus erythematosus (SLE), patients with active disease typically have DNA with reduced methylation levels.
The following are the factors for epigenetics responsible for rheumatic diseases:
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Methylation In Gene - A recent study found 41 differently methylated sites between SLE patients and healthy individuals, with about 85 % of these sites showing reduced methylation. This hypomethylation is particularly common in genes regulated by interferon. Lymphocytes in lupus patients, which are cells involved in the immune system, lack sufficient glutathione, indicating oxidative stress that supports DNA hypomethylation.
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Histone Acetylation - Histone acetylation is another epigenetic modification that influences the activation of genes in specific ways depending on the disease and cell type. For instance, in SLE, monocytes (a type of white blood cell) exhibit increased acetylation of H4 histones, leading to higher production of TNFa. On the other hand, CD4+ T cells in lupus patients show reduced acetylation of histone H3, which is linked to disease activity.
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Hypomethylation - Similar epigenetic changes, such as hypomethylation, have been observed in fibroblasts and T cells of individuals with scleroderma, affecting genes regulated by interferon. The promoter region of the ITGAL gene, which encodes a cell-surface molecule involved in T-cell function, is found to be hypomethylated in CD4+ T cells of both systemic sclerosis (SSc) and SLE patients, correlating with disease activity.
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MicroRNAs - MicroRNAs (miRNAs) are molecules that also play a role in regulating gene expression. For example, miR-618 inhibits the differentiation of plasmacytoid dendritic cells, a significant source of interferon-alpha in SLE. MiR-29a has properties that counteract fibrosis by reducing the expression of certain proteins involved in tissue scarring. MiR-21 increases the death of fibroblasts and could potentially be used as a treatment for patients with scleroderma.
Conclusion
Autoimmune diseases exhibit a multifaceted nature, involving complexity in terms of their scope, pathogenesis, severity, prognosis, and responsiveness to existing treatment methods. The development of autoimmunity arises from the interplay of genetic and environmental factors, influencing cell development and cytokine production that contribute to either organ-specific or systemic inflammation. Metabolic pathways play a crucial role, encompassing processes such as fatty acid oxidation in mitochondria, glycolysis in the cytosol, nucleotide synthesis, antioxidant NADPH production via the pentose phosphate pathway (PPP), support for cell growth through increased protein, lipid, and carbohydrate synthesis during ample fuel availability, and autophagy for cell survival during metabolic stress.
However, many aspects of these mechanisms still require further clarification. The clinical diversity observed within a single diagnostic category, such as systemic lupus erythematosus (SLE), poses challenges in selecting personalized therapies but is inherently necessary. A more comprehensive understanding of the immunopathogenesis of autoimmunity can aid clinicians in choosing more effective interventions from an expanding array of mechanistically driven therapeutic approaches.
