ED Lecture Autoimmune Diseases PDF

Immune System Diseases Jakub Jóźwicki, MD PhD Department of Clinical Pathomorphology, CM NCU Hypersensitivity: Immunologically mediated tissue damage Immune reactions, which are usually protective, can also cause tissue damage. Hypersensitivity refers to a group of immune reactions that resul...

Immune System Diseases Jakub Jóźwicki, MD PhD Department of Clinical Pathomorphology, CM NCU Hypersensitivity: Immunologically mediated tissue damage Immune reactions, which are usually protective, can also cause tissue damage. Hypersensitivity refers to a group of immune reactions that result in tissue damage. Diseases associated with hypersensitivity are the result of excessive or improperly directed immune system responses. Mechanism of Hypersensitivity The immune system typically operates on a principle of balance – eliminating pathogens without damaging tissues. However, sometimes immune responses become uncontrolled or are directed against harmless antigens, or even the body's own tissues. In such cases, these responses become a source of disease rather than providing protection. Causes of Hypersensitivity Reactions Autoimmunization: Reactions against self-antigens. Normally, the immune system "tolerates" self-antigens (known as self-tolerance). When self-tolerance fails, autoimmunization occurs – an attack on the body’s own cells and tissues. Reactions to microorganisms: Excessive responses to microbial antigens or their prolonged presence can lead to tissue damage. Examples: Tuberculosis (granuloma formation), post-streptococcal glomerulonephritis. Cross-reactions: For example, rheumatic fever, where antibodies react with both the microorganism and the host tissue. Reactions to environmental antigens: Allergies to pollen, animal dander, dust mites, or metals. Reactions to substances that are harmless to most people, e.g., drug allergies. Mechanisms of Tissue Damage In hypersensitivity, tissues are damaged by mechanisms that normally serve to combat pathogens: Antibodies Effector T lymphocytes Cells such as macrophages and eosinophils. The main issue lies in the improper activation and persistence of immune responses. Why Are Hypersensitivity Diseases Difficult to Treat? It is difficult to eliminate the triggers of hypersensitivity reactions: Self-antigens (autoimmunization) Persistent microorganisms (e.g., Mycobacterium tuberculosis) Environmental antigens (allergens) The immune system has self-reinforcing mechanisms that, under normal conditions, support protective responses. Once a hypersensitivity reaction begins, it is challenging to control and often becomes chronic. Summary Hypersensitivity refers to abnormal immune responses that, instead of providing protection, cause tissue damage. Depending on the cause, it may involve reactions to self-antigens, microorganisms, or allergens. These diseases are chronic and pose a therapeutic challenge due to the difficulty in eliminating the factors that trigger them. Classification of Hypersensitivity Reactions Hypersensitivity reactions are divided into four types based on the immune mechanism causing the damage. Three of these involve antibodies, while one is mediated by T lymphocytes. Understanding the mechanism is crucial for predicting clinical symptoms and selecting appropriate therapy. Type I – Immediate Hypersensitivity (Allergy) Mechanism: Th2 cells, IgE, mast cells, and other leukocytes. Process: - IgE binds to mast cells. - Mast cells release mediators that act on blood vessels and smooth muscles. - Cytokines recruit inflammatory cells. Examples: Asthma, allergic rhinitis. Type II – Antibody-Mediated Disorders Mechanism: IgG and IgM antibodies bind to antigens on the surface of cells or within tissues. Process: - Antibodies promote phagocytosis or cell lysis. - They induce inflammation and can disrupt cell functions without causing destruction. Examples: Hemolytic disease of the newborn, pemphigus. Type III – Immune Complex-Mediated Disorders Mechanism: Immune complexes (antigen-antibody complexes) deposit in tissues, triggering inflammation. Process: - Antigen-antibody complexes form in the bloodstream or tissues. - These complexes activate the complement system and recruit inflammatory cells. - The resulting inflammation causes tissue damage. Examples: Systemic lupus erythematosus (SLE), post-streptococcal glomerulonephritis. Type IV – T Cell-Mediated Hypersensitivity Mechanism: Mediated by CD4+ helper T cells (Th1 and Th17) and CD8+ cytotoxic T lymphocytes (CTLs). Process: - CD4+ T cells: Recognize antigens presented by APCs and release cytokines, leading to macrophage activation and inflammation. - CD8+ T cells: Directly kill target cells displaying antigens. - Tissue damage results from prolonged inflammation or direct cytotoxicity. Examples: Contact dermatitis, type 1 diabetes, tuberculosis (granuloma formation). Summary of Hypersensitivity Classification Type I: Allergy – IgE, mast cells. Type II: Antibodies – IgG/IgM, inflammation. Type III: Immune complexes – IgG/IgM, deposition in vessels. Type IV: T cells – Th1, Th17, CD8+. Understanding these mechanisms aids in the diagnosis and treatment of hypersensitivity diseases. Type I Hypersensitivity (Immediate) A tissue reaction occurs rapidly (usually within minutes) after an antigen comes into contact with IgE on the surface of mast cells. The antigen (allergen) triggers the allergic reaction. Examples: Hay fever, asthma, anaphylaxis. Course of Type I Hypersensitivity Reaction Activation of Th2 Cells and IgE Production: Th2 cells produce IL-4, IL-5, and IL-13. IL-4 and IL-13 stimulate class switching in B cells to produce IgE. IL-5 activates eosinophils. Sensitization of Mast Cells by IgE: Mast cells express FcεRI receptors for IgE, enabling them to respond to allergens. Basophils have similar functions. Mast Cell Activation and Release of Mediators: Allergens bind to IgE on mast cells, leading to degranulation and the release of inflammatory mediators. Mediators in Type I Hypersensitivity Reaction Vasoactive Amines: Histamine: Causes vasodilation, increased vascular permeability, smooth muscle contraction, and mucus secretion. Neutral proteases: Contribute to tissue damage and kinin generation. Newly Synthesized Lipid Mediators: Prostaglandin D2: Causes bronchoconstriction and increased mucus secretion. Leukotrienes LTC4, LTD4: Potent bronchoconstrictors and vasodilators. LTB4: Chemotactic for neutrophils and eosinophils. Cytokines: TNF and chemokines: Recruit leukocytes during the late phase of the reaction. Development of Allergy and Genetic Predispositions Atopy: Genetic predisposition to allergic reactions. Characterized by higher levels of IgE and Th2 cells. 50% of individuals with atopy have a positive family history. Genes Associated with Predisposition: HLA, cytokine-related genes, FcεRI, and ADAM33. Environmental Factors: Pollution, viral infections, and lack of exposure to microorganisms (hygiene hypothesis). Phases of Type I Hypersensitivity Reaction Sensitization Phase: Initial exposure to an allergen. Antigen-presenting cells (APCs) present the allergen to naive T cells, promoting their differentiation into Th2 cells. Th2 cells produce cytokines (IL-4, IL-5, IL-13), stimulating B cells to produce allergen-specific IgE. IgE binds to FcεRI receptors on mast cells and basophils, sensitizing them for future exposures. Phases of Type I Hypersensitivity Reaction 2. Immediate Phase (Effector Phase): Occurs within minutes of re-exposure to the allergen. Allergen cross-links IgE on mast cells, triggering degranulation and release of preformed mediators: ○ Histamine: Causes vasodilation, increased vascular permeability, smooth muscle contraction, and mucus secretion. ○ Neutral proteases: Damage tissues and generate kinins. Newly synthesized lipid mediators (e.g., prostaglandins and leukotrienes) amplify the response, causing bronchoconstriction and increased inflammation. 3. Late Phase: Develops 4–6 hours after the immediate reaction and can persist for 12–24 hours. Involves recruitment of inflammatory cells (eosinophils, neutrophils, Th2 cells) by cytokines (TNF, IL-5) and chemokines. Causes prolonged inflammation, tissue damage, and chronic symptoms, such as those seen in asthma or chronic allergic conditions. Examples and Clinical Symptoms of Type I Hypersensitivity Therapy Type II Hypersensitivity (Antibody-Mediated) Caused by antibodies directed against antigens on the surface of cells or within tissues. Antigens can be: Endogenous: e.g., in cell membranes. Exogenous: e.g., drug metabolites. Examples of diseases: Autoimmune hemolytic anemia, pemphigus vulgaris, Goodpasture's syndrome. Mechanisms of Type II Hypersensitivity Opsonization and Phagocytosis: Mechanism: ○ IgG/IgM antibodies coat cells (e.g., erythrocytes), marking them for destruction. ○ Opsonized cells are phagocytosed by macrophages, primarily in the spleen. Example: Autoimmune hemolytic anemia. Treatment: Splenectomy may be considered to reduce the destruction of antibody-coated cells by splenic macrophages. Mechanisms of Type II Hypersensitivity Complement Activation and Inflammation: Mechanism: Antibodies activate the complement system, leading to the recruitment of leukocytes (e.g., neutrophils, macrophages). This results in inflammation and tissue damage. Examples: ○ Goodpasture's syndrome. ○ Certain forms of glomerulonephritis. ○ Transplant rejection. Mechanisms of Type II Hypersensitivity Antibody-Induced Cellular Dysfunction: Antibodies block or excessively activate cellular functions. Examples: Myasthenia gravis: Blocking of acetylcholine receptors. Graves' disease: Excessive stimulation of TSH receptors, leading to hyperthyroidism. Treatment: May include complement inhibitors or targeted therapies against antibodies. Examples of Antibody-Mediated Diseases Goodpasture's Syndrome/Goodpasture's Disease A syndrome classified as a systemic vasculitis caused by antibodies against the basement membrane of capillaries located in renal glomeruli and pulmonary alveoli. It is characterized by rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage. The first case was described by Ernest Goodpasture in 1919. The association with anti-basement membrane antibodies was discovered in 1965. Ernest William Goodpasture 1886 - 1960 Morbidity 1–2 cases per million per year. Primarily affects young white males under 40 years of age, although it can also occur in older adults. Women over 50 years of age typically develop a form of the disease that affects only the kidneys. Accounts for 10% of cases of rapidly progressive glomerulonephritis (RPGN). The second leading cause of alveolar hemorrhage (after cases associated with pulmonary hypertension). Etiopathogenesis Autoantibodies: Immunoglobulins of the IgG class (rarely other classes) target the C-terminal NC1 domain of the α3 chain of type IV collagen, a key component of the basement membrane. These autoantibodies bind to antigens in the basement membrane of: - Pulmonary capillaries (alveoli). - Renal glomeruli (glomerular basement membrane). Complement Activation: Binding of autoantibodies activates the complement system, leading to the formation of the membrane attack complex (MAC). This results in destruction of the basement membrane and subsequent tissue damage. Role of ANCA Antibodies: In some cases, ANCA antibodies (anti-neutrophil cytoplasmic antibodies) amplify the inflammatory response, worsening the damage. Genetic Predisposition: An association with the major histocompatibility complex (MHC) is observed, particularly in individuals with: - HLA-DRB1*1501. - HLA-DRW2 and HLA-B7 (reported in other studies). This genetic susceptibility increases the likelihood of an autoimmune response against type IV collagen. Symptoms Systemic Symptoms: Flu-like symptoms (e.g., fever, malaise). Weight loss. Gastrointestinal symptoms (nausea, vomiting, diarrhea). Pulmonary Symptoms: Symptoms of alveolar hemorrhage: Cough, Dyspnea (shortness of breath), Hemoptysis (coughing up blood). Auscultatory findings: crackles heard over the lungs. Renal Symptoms: Rapidly progressive glomerulonephritis (RPGN): Nephritic syndrome, characterized by: - Proteinuria, Hematuria, Oliguria, Hypertension. Progression to renal failure. Neurological Symptoms: Very rarely, involvement of the central nervous system (CNS). Additional Test Results in Goodpasture's Syndrome Laboratory Findings Imaging Findings Histopathology Laboratory Findings Inflammatory Markers: Elevated ESR (erythrocyte sedimentation rate). Elevated CRP (C-reactive protein). Blood Tests: Hypochromic anemia (often due to chronic blood loss or alveolar hemorrhage). Leukocytosis and eosinophilia. Increased serum creatinine and blood urea nitrogen (BUN) levels, indicating kidney dysfunction. Hyperkalemia, due to impaired kidney function. Urinalysis: Hematuria (red blood cells in urine). Proteinuria (indicative of glomerular damage). Serology: Presence of anti-GBM antibodies (specific marker of Goodpasture’s syndrome). Presence of p-ANCA antibodies (anti-neutrophil cytoplasmic antibodies), especially in overlapping syndromes. Bronchoalveolar Lavage (BAL): Presence of hemosiderin-laden macrophages in ≥20% of macrophages, confirming alveolar hemorrhage. Imaging Findings Chest CT/HRCT: Changes consistent with alveolar hemorrhage, such as ground-glass opacities or diffuse infiltrates. Histopathology Kidney Biopsy: Features of rapidly progressive glomerulonephritis (RPGN) with crescent formation. Lung Biopsy: Evidence of alveolar hemorrhage (e.g., red blood cells, hemosiderin deposits). Note: The diagnosis of Goodpasture’s syndrome requires concurrent involvement of both kidneys and lungs. Changes in the lungs must be accompanied by kidney damage to confirm the disease. Treatment Immunosuppressive Therapy: Corticosteroids: High-dose intravenous methylprednisolone to reduce inflammation. Cytotoxic drugs: Cyclophosphamide to suppress antibody production. Plasmapheresis (Plasma Exchange): Removes circulating anti-GBM antibodies and inflammatory mediators from the bloodstream. Typically performed daily for 1–2 weeks, combined with immunosuppressive therapy. Supportive Care: For renal failure: Dialysis may be required for acute or chronic kidney injury. For respiratory symptoms: Oxygen therapy or mechanical ventilation in cases of severe pulmonary hemorrhage. Adjunctive Treatments: Antihypertensives: To manage hypertension due to kidney damage. Prophylaxis against infections: Particularly for patients on long-term immunosuppressive therapy. Prognosis Favorable Prognosis: ○ Early diagnosis and treatment improve outcomes significantly. ○ Cases without severe kidney damage or those caught before the onset of end-stage renal disease (ESRD) have better recovery rates. Poor Prognosis: ○ Patients with severe renal failure at presentation or requiring dialysis have a higher likelihood of permanent kidney damage. ○ Pulmonary hemorrhage can be life-threatening without prompt intervention. Long-Term Outcomes: ○ Many patients with severe kidney involvement progress to ESRD and require lifelong dialysis or kidney transplantation. ○ The risk of relapse is low but can occur, particularly in overlapping syndromes (e.g., with ANCA-associated vasculitis). Overall Mortality (within the 1st year after the diagnosis) : Mortality rates have significantly decreased with modern therapies, from 90% historically to less than 20% with timely and aggressive treatment. Summary of Type II Hypersensitivity (Antibody-Mediated) Mechanisms: Opsonization and phagocytosis Complement activation and inflammation Cellular dysfunction Key examples of diseases: Hemolytic anemia, Goodpasture’s syndrome, myasthenia. Therapies aimed at inhibiting antibodies and reducing inflammation. Type III Hypersensitivity (Immune Complex-Mediated) Antigen-antibody complexes formed in the circulation can deposit in blood vessels. This leads to complement activation and acute inflammation. The complexes can be exogenous (e.g., foreign proteins) or endogenous (e.g., autoimmunization).  Pathogenesis of Type III Hypersensitivity 1. Formation of Immune Complexes: ○ Antigen-antibody complexes (IgG or IgM) form in the circulation after exposure to antigens. 2. Deposition of Complexes: ○ The immune complexes deposit in tissues, particularly in blood vessels, glomeruli, or synovial membranes. 3. Complement Activation: ○ Deposited complexes activate the complement system, generating C3a, C4a, and C5a (anaphylatoxins). ○ These fragments recruit neutrophils and mast cells to the site of deposition. 4. Inflammation and Tissue Damage: ○ Neutrophils attempt to phagocytose the immune complexes but release inflammatory mediators (e.g., proteases, reactive oxygen species), causing tissue damage. 5. Antigen Sources: ○ Exogenous Antigens: Foreign proteins (e.g., microbial antigens, drugs). ○ Endogenous Antigens: Autoantigens in autoimmune diseases. Examples of affected tissues: blood vessels (vasculitis), kidneys (glomerulonephritis), joints (arthritis). Examples Inflammation and Tissue Damage Activation of Complement by Immune Complexes: Immune complexes activate the complement system, leading to inflammation and tissue damage. Complement consumption reduces serum levels of C3, which serves as a marker of disease activity. Complement-Dependent Damage: Vasculitis: Inflammation of blood vessels caused by immune complex deposition. Glomerulonephritis: Immune complexes in glomeruli cause kidney inflammation, leading to hematuria and proteinuria. Arthritis: Immune complexes in joint spaces trigger inflammation, resulting in pain and swelling. Serum sickness Mechanism: Caused by the formation of immune complexes between circulating antigens (e.g., foreign proteins, drugs) and antibodies. Complexes deposit in tissues, activating the complement system and triggering inflammation. Clinical Features: Systemic symptoms: Fever, malaise, rash, and lymphadenopathy. Arthralgia: Joint pain due to immune complex deposition in synovial membranes. Renal involvement: Proteinuria or hematuria in severe cases. Onset occurs 7–10 days after antigen exposure. Examples of Triggers: Antitoxins (e.g., diphtheria antitoxin). Monoclonal antibodies or certain antibiotics. Arthus Reaction Mechanism: A localized Type III hypersensitivity reaction caused by pre-existing antibodies reacting with an injected antigen. Immune complexes form at the site of injection, activating complement and causing localized inflammation. Clinical Features: Occurs within hours of antigen exposure. Localized redness, swelling, warmth, and pain. Severe cases can result in tissue necrosis at the injection site. Examples: After booster vaccinations (e.g., tetanus toxoid). Both conditions demonstrate the pathological effects of immune complex deposition and complement activation but differ in their systemic versus localized presentation. Morphology of Immune Complex Deposition Vasculitis: The main morphological manifestation of immune complex deposition in vessels. Characterized by fibrinoid necrosis of the vessel wall and neutrophilic infiltration. Glomerulonephritis: Immune complex deposition in glomeruli leads to kidney inflammation. Immunofluorescence microscopy: Granular deposits of immunoglobulins and complement. Electron microscopy: Electron-dense deposits along the glomerular basement membrane. Summary of Type III Hypersensitivity (Immune Complex-Mediated) Immune complexes can cause systemic or localized damage. Complement activation and inflammation lead to clinical symptoms. Examples include SLE, post-streptococcal glomerulonephritis, and serum sickness. Type IV Hypersensitivity (T Cell-Mediated) Mediated by T lymphocytes, not antibodies. Two key processes: 1. Delayed-type hypersensitivity (DTH): Mediated by CD4+ Th1 or Th17 cells, which release cytokines to recruit and activate macrophages and neutrophils, causing inflammation. 2. Direct cytotoxicity: Mediated by CD8+ cytotoxic T lymphocytes (CTLs), which kill target cells expressing the antigen. Examples  Inflammation mediated by CD4+ T lymphocytes Mechanism of CD4+ T Cell Activation: Antigen-presenting cells (APCs) present antigens to CD4+ T cells via MHC class II molecules. Naive T cells differentiate into specific subsets (Th1, Th17) based on cytokine signals: ○ Th1 cells: Secrete IFN-γ, activating macrophages. ○ Th17 cells: Produce IL-17 and IL-22, recruiting neutrophils and promoting inflammation. Role of Cytokines: IFN-γ: Enhances macrophage microbicidal activity and upregulates MHC expression. IL-17: Attracts neutrophils and stimulates production of pro-inflammatory cytokines. TNF-α: Amplifies the inflammatory response. Tissue Damage: Activated macrophages and recruited neutrophils release reactive oxygen species (ROS), nitric oxide (NO), and proteolytic enzymes. Chronic inflammation can lead to tissue remodeling, fibrosis, and granuloma formation in certain diseases. Examples of CD4+ T Cell-Mediated Inflammation Tuberculosis: ○ Th1 response forms granulomas to contain Mycobacterium tuberculosis. ○ Tissue necrosis occurs due to excessive macrophage activation. Rheumatoid Arthritis: ○ Th17 cells drive neutrophilic inflammation in joints, causing synovial damage. Contact Dermatitis: ○ Th1 cells mediate localized inflammation in response to environmental antigens (e.g., nickel, poison ivy). Multiple Sclerosis: ○ Th1 and Th17 cells target myelin, causing demyelination in the central nervous system. Clinical Manifestations: Localized Symptoms: Redness, swelling, pain, tissue induration (e.g., contact dermatitis). Systemic Symptoms: Fever, fatigue, and weight loss in chronic conditions (e.g., tuberculosis, rheumatoid arthritis).  Cytotoxicity mediated by CD8+ T lymphocytes Antigen Presentation: CD8+ T cells recognize antigens presented on MHC class I molecules by infected, tumor, or otherwise abnormal cells. Activation requires co-stimulation from antigen-presenting cells (APCs). Effector Functions of CD8+ T Cells: Once activated, CD8+ T cells (cytotoxic T lymphocytes, CTLs) destroy target cells through: ○ Perforin and Granzyme Pathway: Perforin: Forms pores in the target cell membrane. Granzymes: Enter through these pores, activating caspases and inducing apoptosis. ○ Fas-FasL Pathway: FasL on CTLs binds to Fas receptors on target cells, triggering apoptosis. ○ Release of cytokines (e.g., IFN-γ, TNF-α), enhancing macrophage activity and inflammation. Consequences of CD8+ T Cell Cytotoxicity Target Cell Death: Elimination of infected, neoplastic, or foreign cells. Collateral Tissue Damage: Excessive CTL activity can lead to bystander tissue injury. Examples of CD8+ T Cell-Mediated Diseases Type 1 Diabetes: CD8+ T cells target pancreatic β-cells, causing loss of insulin production. Viral Infections: CTLs kill virus-infected cells, limiting viral replication (e.g., hepatitis B, cytomegalovirus). Graft Rejection (Transplant): CTLs attack donor cells expressing non-self MHC class I molecules, causing acute rejection. Some Autoimmune Diseases: CTLs attack self-cells expressing specific antigens, contributing to tissue destruction (e.g., Hashimoto’s thyroiditis). Therapeutic Targets Immunosuppressive drugs: Tacrolimus, cyclosporine, or corticosteroids to reduce T cell activation. Biologics: Anti-CD8 antibodies or cytokine inhibitors to limit cytotoxic activity. Summary of Type IV Hypersensitivity (T Cell-Mediated) Main Mechanisms: Th1/Th17 Cytokines: Lead to chronic inflammation. CTLs: Cause direct cell damage. Clinical Examples: Type 1 Diabetes. Multiple Sclerosis. Contact Dermatitis. Targeted Therapies: Include drugs that modulate T cell responses. Immune tolerance Tolerance: The ability of the immune system to avoid reacting to self-antigens. Key Role: Essential for preventing autoimmunity. Mechanisms: Includes the elimination, suppression, and control of self-reactive lymphocytes. Mechanisms of Tolerance – Elimination of Autoreactive Lymphocytes Negative Selection in the Thymus (T Cells) and Bone Marrow (B Cells): Mechanism: Lymphocytes recognizing self-antigens with high affinity are eliminated through apoptosis. Key Features: 1. T Cells (Thymus): ○ Negative selection removes autoreactive T cells during their development in the thymus. ○ AIRE Protein: Facilitates the expression of peripheral self-antigens in the thymus, allowing negative selection. Mutations in AIRE: Lead to autoimmune polyendocrine syndrome (APS), characterized by multi-organ autoimmunity. 2. B Cells (Bone Marrow): ○ Autoreactive B cells are removed or inactivated. ○ Receptor Editing: If a B cell recognizes self-antigens, it can undergo additional rearrangement of immunoglobulin genes to change its antigen receptor. Outcome: These processes ensure that the immune system minimizes the risk of autoimmunity by eliminating or modifying self-reactive lymphocytes during their development. Suppression by Regulatory T Cells (Tregs) Mechanism: Regulatory T cells (Tregs): A specialized subset of CD4+ T cells that suppress immune responses and maintain tolerance to self-antigens. Key Markers: ○ Express CD25 (IL-2 receptor α-chain). ○ Transcription factor FOXP3 is critical for their development and function. ○ Mutations in FOXP3 lead to IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked). Suppressive Actions of Tregs 1. Cytokine Secretion: ○ IL-10: Inhibits pro-inflammatory cytokine production and antigen presentation by dendritic cells. ○ TGF-β: Suppresses T cell proliferation and macrophage activation. 2. Competition for IL-2: ○ Tregs express high levels of CD25, reducing IL-2 availability for effector T cells, thereby limiting their expansion. 3. Direct Contact Suppression: ○ Tregs can interact directly with effector T cells, dendritic cells, and B cells through inhibitory molecules (e.g., CTLA-4), reducing their activation. 4. Modulation of Antigen-Presenting Cells (APCs): ○ Inhibit APC function, reducing their ability to activate effector T cells. Role in Autoimmunity and Tolerance Tregs are crucial for preventing autoimmunity by suppressing self-reactive lymphocytes. Dysfunction or insufficient numbers of Tregs can lead to autoimmune diseases, chronic inflammation, or immune dysregulation. Therapeutic Implications: Enhancing Treg activity: Useful in autoimmune diseases or organ transplantation. Blocking Treg activity: A potential approach in cancer immunotherapy to enhance anti-tumor immunity. Key Inhibitory Pathways 1. Checkpoint Receptors on T Cells: CTLA-4 (Cytotoxic T Lymphocyte Antigen-4): ○ Competes with CD28 for binding to B7 molecules on APCs. ○ Inhibits T cell activation by reducing co-stimulatory signaling. ○ Therapeutic Implication: Blockade by drugs like ipilimumab enhances T cell responses in cancer immunotherapy. PD-1 (Programmed Cell Death Protein-1): ○ Binds to PD-L1/PD-L2 on APCs or tumor cells, suppressing T cell activity. ○ Reduces T cell proliferation, cytokine production, and survival. ○ Therapeutic Implication: Blockade by nivolumab or pembrolizumab for cancer immunotherapy. Key Inhibitory Pathways 2. Secreted Cytokines: IL-10: ○ Secreted by Tregs, macrophages, and dendritic cells. ○ Suppresses pro-inflammatory cytokine production and APC function. TGF-β: ○ Inhibits T cell proliferation and effector functions. ○ Promotes differentiation of Tregs, further enhancing suppression. Key Inhibitory Pathways 3. Inhibitory Molecules on B Cells: FcgRIIB (Inhibitory Fc Receptor): ○ Regulates B cell activation by delivering inhibitory signals upon binding immune complexes. 4. Metabolic Inhibition: IDO (Indoleamine 2,3-dioxygenase): ○ Expressed by dendritic cells and macrophages. ○ Depletes tryptophan, an essential amino acid for T cell proliferation, leading to T cell suppression. Clinical Relevance Autoimmune Diseases: ○ Dysregulation or loss of inhibitory pathways can lead to overactive lymphocyte responses and autoimmunity. Cancer: ○ Tumors exploit inhibitory pathways like PD-1/PD-L1 to evade immune detection, leading to immune tolerance. Therapeutic Modulation: ○ Checkpoint inhibitors (e.g., anti-CTLA-4, anti-PD-1) boost anti-tumor immunity. ○ Treg-enhancing therapies or cytokines (e.g., IL-10) are being explored for autoimmune diseases. Inhibitory pathways are central to balancing immune activation and tolerance, with diverse implications for therapy in cancer, autoimmunity, and transplantation. Summary of Tolerance Mechanisms Tolerance is the immune system's ability to avoid reacting against self-antigens, essential for preventing autoimmunity. It is established through central tolerance (elimination of self-reactive lymphocytes in the thymus and bone marrow) and peripheral tolerance (control of escaped self-reactive cells in secondary lymphoid tissues). Peripheral tolerance mechanisms include anergy, suppression by regulatory T cells (Tregs), and apoptosis of self-reactive cells. Failures in these mechanisms can lead to autoimmune diseases or chronic inflammation. THANK YOU! :D