Genome-oriented treatment strategies for autoimmune diseases

Abstract

Autoimmune diseases are defined as conditions in which various organs are damaged by activated autoreactive T cells involved in the failure of immune tolerance or autoantibodies produced by B cells. Organ-specific autoimmune diseases, including ulcerative colitis, Hashimoto’s thyroiditis, multiple sclerosis, and systemic autoimmune diseases that affect and damage multiple organs, such as the skin, joints, heart, kidneys, serosa, nerves, and blood vessels, are also referred to as connective tissue diseases. Rheumatoid arthritis is a typical systemic autoimmune disease affecting most patients, but no specific autoantigens have been identified [1–3]. Various disease-susceptibility genes have been identified, including HLA-DRB1, PTPN22, CTLA4, STAT4, TNFA IP3, CCL21, and PADI4. It has been established that when these genes are combined with environmental factors and epigenetically modified through citrullination of extracellular matrix molecules such as filaggrin and fibrinogen, immune tolerance to antigens fails, thereby inducing autoimmunity. Activated lymphocytes produce inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin (IL)-6, which cause inflammation in multiple organs, including joints, irreversible structural damage to joints due to prolonged inflammation, and multi-organ disorders such as the lung. Joint injury progresses soon after onset, and deformed joints cause irreversible physical dysfunction. Therefore, prompt and appropriate diagnosis and treatment are necessary. In the 20th century, corticosteroids and non-steroidal anti-inflammatory drugs were used to relieve pain and swelling in multiple joints. However, these drugs cannot control the progression of joint destruction. The consequent issue for treatment was to control endocrine and metabolic adverse drug reactions to the long-term use of corticosteroids and infection associated with susceptibility to infection due to immunosuppression. In the 21st century, the advent of drugs targeting important molecules involved in the pathogenesis of rheumatoid arthritis has brought a paradigm shift in treatment. In addition to the conventional synthetic antirheumatic drugs such as methotrexate, several new drugs have been developed. These include biological antirheumatic drugs purified from biological drugs to target TNF, IL-6, T cell co-stimulation molecule CD28, and others, and targeted synthetic antirheumatic drugs such as Janus kinase inhibitors that are involved in signal transduction of cytokines and others. Clinical remission has become a realistic therapeutic goal for most patients. The maintenance of remission has allowed the prevention of structural joint damage and control of the progression of physical dysfunction over a long period [1–3]. These drugs, approved for treating rheumatoid arthritis, are being used to treat many autoimmune diseases. Systemic lupus erythematosus (SLE) is a typical systemic autoimmune disease. It commonly occurs in women of childbearing age, affects systemic organs such as the skin, joints, kidneys, serosa, nerves, heart, and blood vessels, and manifests various clinical symptoms. In the past, nonspecific treatment with corticosteroids, immunosuppressants, and other drugs, has been applied to suppress immune abnormalities and prevent the progression of organ dysfunction. Although these drugs have improved the prognosis of this disease, their longterm use causes various adverse reactions. In particular, severe and opportunistic infections associated with susceptibility to infection due to immunosuppression are the leading causes of death from this disease. The development of molecular target drugs has also been attempted for this disease. Its main pathological characteristics are the activation of B cells and the production of autoantibodies due to autoimmune abnormalities [4– 6]. B cells are stimulated by T follicular helper cells and