Autoimmune Diseases
The immune system is made up of organs and cells meant to protect the human body from bacteria, parasites, viruses and cancer cells. In autoimmune diseases this defensive system erroneously targets the body's tissues, leading to chronic inflammation and tissue damage. There are over 100 known autoimmune diseases, including but not limited to diabetes, multiple sclerosis (MS), rheumatoid arthritis (RA), and myasthenia gravis (MG). Many autoimmune diseases are still poorly understood and often persist for life without a cure; however, they can be treated with anti-inflammatory or immunosuppressive drugs to alleviate the symptoms or delay or stop the destruction of the affected organs. Despite their diverse clinical manifestations, autoimmune Diseases share common underlying biochemical principles involving genetic predisposition, environmental triggers, and immune dysregulation. This abstract examines these shared principles and explores potential therapeutic targets.
Autoinflammatory Diseases
Autoimmune diseases are distinct from autoinflammatory diseases. While both involve immune system malfunctions and can produce similar symptoms like rash, swelling, or fatigue, their underlying causes and mechanisms differ. Autoinflammatory diseases primarily result from defects in the innate immune system, whereas autoimmune diseases arise from dysfunctions in the adaptive immune system.
Pathogenesis of Autoimmune Diseases - Key Player
The pathogenesis of autoimmune diseases involves the breakdown of immune tolerance, where central and peripheral mechanisms fail to eliminate autoreactive lymphocytes. Key to this process is the presentation of autoantigens by antigen-presenting cells (APCs) to autoreactive T and B cells. Genetic factors, such as polymorphisms in the human leukocyte antigen (HLA) complex and genes encoding cytokines and their receptors, significantly contribute to susceptibility.
Central to many autoimmune diseases is the dysregulation of cytokine networks, particularly the overproduction of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, and IL-17. These cytokines orchestrate a cascade of inflammatory responses, including the activation of macrophages, dendritic cells, and fibroblasts, leading to tissue destruction.
T cell-mediated responses play a pivotal role, where CD4+ T helper cells (Th1, Th17) produce cytokines that further stimulate inflammation. Regulatory T cells (Tregs), which normally maintain tolerance, are often dysfunctional in autoimmune diseases, exacerbating the immune response. B cells also contribute through the production of autoantibodies, forming immune complexes that deposit in tissues and activate the complement system.
Therapeutic Approaches to Combat Autoimmune Diseases
Therapeutic strategies focus on modulating these immune responses. Biologic agents targeting cytokines, such as TNF inhibitors (adalimumab, infliximab), IL-6 receptor antagonists (tocilizumab), and IL-17 inhibitors (secukinumab), have shown efficacy in reducing inflammation and tissue damage. Small molecule inhibitors, such as Janus kinase (JAK) inhibitors (tofacitinib), disrupt intracellular signaling pathways involved in cytokine production.
Immunomodulatory approaches aim to restore tolerance by selectively targeting autoreactive lymphocytes while sparing normal immune function. This includes therapies like anti-CD20 monoclonal antibodies (rituximab) that deplete B cells, and selective inhibition of costimulatory signals required for T cell activation.
Importance of FcRn in Development of Therapeutics
The neonatal Fc receptor (FcRn) plays a crucial role in the development of therapeutics for autoimmune diseases due to its ability to regulate the half-life of immunoglobulin G (IgG) antibodies. FcRn protects IgG from lysosomal degradation, extending its circulation time in the bloodstream. This property is leveraged in designing therapies that either enhance the half-life of therapeutic antibodies, ensuring sustained efficacy, or in developing FcRn inhibitors to decrease the levels of pathogenic IgG autoantibodies. By modulating FcRn function, it is possible to improve the effectiveness and reduce the dosing frequency of antibody-based treatments for autoimmune diseases.
In conclusion, the biochemical principles underlying autoimmune disease involve complex interactions between genetic predisposition, cytokine dysregulation, and defective immune tolerance. Understanding these mechanisms has led to the development of targeted therapies that aim to modulate specific immune pathways, offering new hope for effective management of these chronic diseases.
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References
- : "Antigen-Presenting Cells in Psoriasis." in: Life (Basel, Switzerland), Vol. 12, Issue 2, (2022) (PubMed).
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