Immunologic Tolerance and Autoimmunity: A Delicate Balance PDF

Immunologic Tolerance and Autoimmunity: A Delicate Balance The immune system's ability to defend against pathogens while avoiding self-destruction is a remarkable feat of biological engineering. This presentation explores the intricate mechanisms of immunologic tolerance, the consequences of its fai...

Immunologic Tolerance and Autoimmunity: A Delicate Balance The immune system's ability to defend against pathogens while avoiding self-destruction is a remarkable feat of biological engineering. This presentation explores the intricate mechanisms of immunologic tolerance, the consequences of its failure leading to autoimmunity, and the clinical implications in organ transplantation and tumor immunology. We will delve into the molecular intricacies of the Major Histocompatibility Complex (MHC), examine the challenges faced in organ transplantation, and investigate the immune system's role in both suppressing and evading cancer. Finally, we'll explore autoimmune disorders and the cutting-edge treatments being developed to manage these complex conditions. by Eva Kamarudin preencoded.png Fundamentals of Immunologic Tolerance 1 Central Tolerance Occurs in primary lymphoid organs like the thymus (for T cells) and bone marrow (for B cells). Developing lymphocytes that st rongly bind to strongly bind to self-antigens are eliminated through a process called negative selection, preventing them from entering circula tion and circulation and potentially causing autoimmune reactions. 2 Peripheral Tolerance Takes place outside primary lymphoid organs and involves mechanisms such as anergy (functional inactivation of self-reactive cells), deletion (apoptosis of autoreactive cells), and regulation by T regulatory (Treg) cells. These processes ensure that any self-reactive cells that escape central tolerance are kept in check. 3 Breakdown of Tolerance When tolerance mechanisms fail, autoimmunity can occur. This leads to the immune system mistakenly attacking the body's own t issues, body's own tissues, resulting in various autoimmune disorders with potentially severe consequences for affected individuals. individuals. preencoded.png The Major Histocompatibility Complex (MHC): A Crucial Player MHC Class I MHC Class II Polymorphism Found on all nucleated cells, MHC Class Expressed primarily on antigen- MHC genes are highly polymorphic, Class I molecules present endogenous presenting cells (APCs) like dendritic polymorphic, with numerous alleles in endogenous antigens derived from cells, macrophages, and B cells. MHC alleles in the population. This diversity from within the cell. These molecules Class II molecules present exogenous diversity ensures that the immune molecules are recognized by CD8+ antigens from outside the cell to CD4+ system can respond to a wide variety of CD8+ cytotoxic T cells, which can helper T cells, initiating and regulating variety of pathogens. However, it also eliminate cells displaying foreign or adaptive immune responses. also complicates organ transplantation or abnormal peptides, such as those transplantation and influences those infected by viruses or cancerous susceptibility to certain diseases. cancerous cells. preencoded.png Clinical Relevance of MHC Transplantation Disease Susceptibility Pharmacogenomics Matching MHC molecules, known as Certain MHC genes are associated MHC genotypes can influence drug known as Human Leukocyte associated with increased risk of drug responses and side effects. For Antigens (HLA) in humans, is crucial autoimmune diseases. For example, For instance, certain HLA types are crucial for successful organ example, HLA-B27 is strongly linked are associated with adverse transplants. HLA typing is performed linked to ankylosing spondylitis, reactions to specific medications, performed to ensure compatibility while HLA-DR4 is associated with medications, such as abacavir compatibility between donor and with rheumatoid arthritis. hypersensitivity in HIV treatment. and recipient, minimizing the risk of Understanding these associations treatment. Genetic screening for risk of rejection. Mismatched HLA associations helps in disease risk these HLA types can guide safer drug HLA can lead to strong immune risk assessment and personalized drug prescriptions. responses against the transplanted personalized medicine approaches. transplanted organ. approaches. preencoded.png Organ Transplantation: Overcoming Immunological Barriers Barriers Donor Selection Transplantation Procedure Immunosuppression Long-term Monitoring Careful matching of donor and Procedure Post-transplant management Continuous surveillance for signs of recipient HLA types is performed to The surgical process of replacing a involves the use of signs of rejection and adjustment of performed to minimize the risk of replacing a failing organ with a immunosuppressive drugs to adjustment of immunosuppressive of rejection. This process involves healthy donor organ. This delicate prevent rejection. This requires a immunosuppressive regimens as involves extensive genetic testing delicate procedure requires precise a careful balance between as needed. This involves regular testing and consideration of other precise timing and coordination to suppressing the immune response regular check-ups, blood tests, and other factors such as blood type coordination to ensure the viability response enough to protect the and sometimes biopsies of the type compatibility. viability of the transplanted organ. the graft while maintaining transplanted organ. organ. sufficient immunity against infections and cancers. preencoded.png Immune Responses in Organ Transplantation Hyperacute Rejection Occurs within minutes to hours after transplantation due to pre-existing Chronic Rejection antibodies in the recipient. This rapid and severe response can lead to A long-term form of rejection occurring over months or years. It involves immediate graft failure and is typically irreversible, emphasizing the involves gradual immune-mediated damage to the blood vessels in the importance of thorough pre-transplant screening. in the transplanted organ, leading to progressive graft dysfunction and dysfunction and eventual failure if left unchecked. 1 2 3 Acute Rejection Develops days to months post-transplant, primarily driven by T-cell cell mediated responses against donor MHC antigens. This process involves process involves the recognition of foreign antigens by recipient T cells, cells, leading to targeted destruction of the graft tissue. preencoded.png Tumor Immunology: The Immune System's Dual Role Immune Surveillance The immune system's ability to detect and destroy tumor cells. This involves recognition of tumor-associated antigens by associated antigens by cytotoxic T cells and natural killer (NK) cells, which can eliminate cancerous cells before they form before they form clinically detectable tumors. Tumor Evasion Mechanisms by which tumors escape immune detection. These include downregulation of MHC molecules, production of immunosuppressive factors like TGF-β, and recruitment of regulatory T cells that suppress anti-tumor immune responses. Immunotherapy Novel treatment approaches that harness the power of the immune system to fight cancer. This includes checkpoint checkpoint inhibitors, CAR-T cell therapy, and cancer vaccines, which aim to enhance the body's natural ability to recognize ability to recognize and destroy tumor cells. preencoded.png Autoimmune Disorders: When Self-Tolerance Fails 1 Genetic Predisposition 2 Environmental Triggers 3 Breakdown of Tolerance Mechanisms Certain HLA genes and other genetic Infections, toxins, or other factors contribute to increased environmental factors can trigger Failure of central or peripheral susceptibility to autoimmune diseases. autoimmune responses in genetically tolerance mechanisms can lead to the For example, HLA-DQ2 and DQ8 are genetically susceptible individuals. This the persistence and activation of self- strongly associated with celiac disease, This may occur through molecular self-reactive immune cells. This while HLA-DR3 and DR4 are linked to mimicry, where immune responses includes defects in regulatory T cell type 1 diabetes. responses against pathogens cross- cell function or aberrant activation of cross-react with self-antigens due to of autoreactive B cells, resulting in the to structural similarities. the production of pathogenic autoantibodies. preencoded.png Exploring Common Autoimmune Disorders Disease Target Key Autoantibodies Common Symptoms Organs/Tissues Autoantibodies Systemic Lupus Multiple organs Anti-dsDNA, Anti-Sm Skin rashes, joint Erythematosus (SLE) pain, kidney damage damage Rheumatoid Arthritis Joints Rheumatoid Factor, Joint inflammation, (RA) Anti-CCP stiffness, deformity Type 1 Diabetes Pancreatic β-cells Anti-insulin, Anti- Hyperglycemia, GAD65 polyuria, weight loss Multiple Sclerosis Central nervous Anti-MOG, Anti-MBP Neurological deficits, (MS) system fatigue, vision problems preencoded.png Advanced Treatments for Autoimmune Disorders Biological Therapies Cell-based Therapies Gene Therapy and Editing Monoclonal antibodies and fusion proteins target Emerging treatments involve modifying or Cutting-edge approaches aim to correct genetic specific components of the immune system. enhancing specific immune cell populations. This defects associated with autoimmune diseases. Examples include anti-TNF agents for rheumatoid includes CAR-T cell therapy adaptations for CRISPR-Cas9 and other gene-editing technologies arthritis and inflammatory bowel diseases, and B- autoimmune diseases and the use of regulatory T show promise in modifying genes involved in cell depleting therapies like rituximab for cell therapies to restore immune tolerance in immune regulation, potentially offering long-term conditions such as lupus and rheumatoid arthritis. conditions like type 1 diabetes. solutions for autoimmune disorders. preencoded.png