Adaptive Immunity

Overview of Adaptive Immunity

Introduction to Adaptive Immunity

·         Adaptive immunity is the third line of defense in the immune system, following innate immunity and inflammation.

·         It is characterized by its specificity and memory, allowing for a stronger response upon subsequent exposures to the same pathogen.

·         Two main forms of adaptive immunity are identified: Antibody-Mediated Immunity (AMI) and Cell-Mediated Immunity (CMI).

·         AMI involves the production of antibodies by B cells, while CMI involves the activation of cytotoxic T cells to destroy infected or cancerous cells.

·         The adaptive immune response is initiated upon exposure to antigens (Ag), which are foreign macromolecules that provoke an immune response.

Antigens and Their Role

  • Antigens are often proteins or polysaccharides found on the surface of pathogens, and they are recognized by the immune system as foreign.

  • The term 'epitope' refers to the specific part of the antigen that is recognized by antibodies or T cell receptors.

  • Larger antigens tend to elicit a stronger immune response due to the increased number of epitopes available for recognition.

  • The immune response to antigens leads to the production of antibodies and the activation of T cells, which are crucial for eliminating pathogens.

Key Cell Types in Adaptive Immunity

  • T Regulatory Cells (TReg): Down-regulate the immune response and are involved in negative selection of T cells, differentiating from naïve CD4 cells.

  • Cytotoxic T Cells (Tc): Also known as CD8 cells, they target cancer and virus-infected cells, forming from naïve CD8 cells and playing a crucial role in cell-mediated immunity.

  • T Memory Cells (TM): Responsible for immunological memory, allowing for a faster response upon re-exposure to the same antigen.

Antigen Presenting Cells (APCs)

  • Dendritic Cells: Considered 'professional APCs', they present antigens to both CD4 (T helper) and CD8 (cytotoxic) T cells, processing extracellular antigens via MHC II.

  • Macrophages: Phagocytize bacteria and present extracellular antigens to CD4 cells using MHC II, playing a vital role in innate and adaptive immunity.

  • B Cells: Capable of presenting large antigens (T-independent antigens) and can also act as APCs, although less efficiently than dendritic cells.

Major Histocompatibility Complex (MHC)

MHC Class I and II

  • MHC molecules are essential for the immune system to recognize foreign molecules; they present antigens to T cells.

  • MHC Class I molecules are found on all nucleated cells and present intracellular antigens to CD8 T cells, leading to the destruction of infected or cancerous cells.

  • MHC Class II molecules are found on antigen-presenting cells (APCs) and present extracellular antigens to CD4 T cells, which help orchestrate the immune response.

  • The unique structure of MHC molecules is crucial for self-recognition and preventing autoimmune responses.

Role of MHC in Immune Response

  • MHC Class I molecules present endogenous antigens, such as viral proteins, to CD8 T cells, triggering a cytotoxic response.

  • MHC Class II molecules present exogenous antigens, such as bacterial proteins, to CD4 T cells, which then activate B cells and other immune cells.

  • The interaction between T cells and MHC molecules is critical for the activation and proliferation of T cells during an immune response.

Antibodies and Their Functions

Structure of Antibodies

  • Antibodies, also known as immunoglobulins (Ig), are Y-shaped proteins composed of four polypeptide chains: two heavy chains and two light chains.

  • The variable regions of antibodies are responsible for binding specific antigens, while the constant regions determine the antibody class and its function.

  • Antibodies can neutralize pathogens, agglutinate cells, and activate the complement system to enhance the immune response.

Classes of Immunoglobulins

The five main classes of immunoglobulins are IgM, IgG, IgA, IgD, and IgE, each with distinct functions and properties.

  • IgM: The first antibody produced during an immune response; it forms a pentamer and is effective in agglutination.

  • IgG: The most abundant antibody in circulation; it provides long-term immunity and can cross the placenta to provide passive immunity to the fetus.

  • IgA: Found in mucosal areas and secretions (e.g., saliva, breast milk); it plays a crucial role in mucosal immunity.

  • IgD: Primarily serves as a receptor on B cells, initiating the immune response.

  • IgE: Involved in allergic reactions and defense against parasitic infections; it binds to mast cells and triggers histamine release.

Lymphocytes and Their Development

B Lymphocytes (B Cells)

  • B cells are responsible for antibody-mediated immunity and originate in the bone marrow.

  • Upon encountering an antigen, B cells undergo clonal selection, proliferating and differentiating into plasma cells that secrete antibodies.

  • Memory B cells are formed during the primary immune response and provide long-lasting immunity for future encounters with the same antigen.

T Lymphocytes (T Cells)

  • T cells develop from precursors in the bone marrow and mature in the thymus, where they undergo selection processes to ensure self-tolerance.

  • There are several types of T cells, including T helper cells (CD4), cytotoxic T cells (CD8), and regulatory T cells, each with specific roles in the immune response.

  • T helper cells are crucial for activating B cells and other immune cells, while cytotoxic T cells directly kill infected or cancerous cells.

Cytokines and Immune Response

Role of Cytokines

  • Cytokines: Proteins that regulate the immune response, many of which are interleukins, produced by various immune cells.

  • Biological Drugs: Many cytokines are genetically engineered for therapeutic use, known as 'biologicals', to enhance or modulate immune responses.

Primary Immune Response

  • Initial Exposure: The primary immune response occurs when the body encounters an antigen for the first time, involving a series of steps including antigen challenge, T helper cell activation, and B cell activation.

  • Clonal Selection: Activated T helper cells stimulate B cells to divide and differentiate into plasma cells that secrete antibodies, primarily IgM initially.

Mechanisms of Immune Response

Antibody-Mediated Immunity (AMI)

  • B Cell Activation: Involves interaction with T helper cells, leading to clonal expansion and differentiation into plasma cells that produce antibodies.

  • Antibody Class Switching: B cells can switch the type of antibody they produce (e.g., from IgM to IgG) through a genetic rearrangement process.

Cell-Mediated Immunity (CMI)

  • Cytotoxic T Cells (Tc): Directly attack infected or abnormal cells using T cell receptors (TCR) to recognize MHC I-antigen complexes on target cells.

  • Mechanism of Action: Tc cells release cytotoxic chemicals such as perforin and granzymes to induce apoptosis in target cells.

Regulation and Memory in Immune Response

Down-Regulation of Immune Response

  • T Regulatory Cells: Inhibit the immune response after the antigen is eliminated, playing a role in maintaining self-tolerance and preventing autoimmunity.

  • Inhibitory Cytokines: These cytokines help to down-regulate both AMI and CMI, ensuring that the immune response does not become excessive.

Memory Response

  • B Memory Cells: Formed during the primary immune response, they persist for years and are responsible for a quicker and more robust response upon re-exposure to the same antigen.

  • Secondary Immune Response: Characterized by a faster and stronger antibody production, primarily IgG, due to the presence of memory cells.

Active and Passive Immunity

Active Immunity

  • Definition: Active immunity occurs when an individual’s immune system is stimulated to produce antibodies in response to an antigen (Ag).

  • Natural Active Immunity: Acquired through natural infection, where the individual exhibits symptoms and develops a strong immune response.

  • Artificial Active Immunity: Acquired through vaccination, which introduces a harmless form of the pathogen to stimulate an immune response without causing disease symptoms.

  • Historical Context: Edward Jenner's work in 1796 with smallpox vaccination laid the foundation for modern immunology.

  • Types of Vaccines: Includes dead pathogens, attenuated (weakened) pathogens, and genetically engineered subunit vaccines.

Passive Immunity

  • Definition: Passive immunity is the temporary immunity gained through the acquisition of antibodies from another source.

  • Natural Passive Immunity: Maternal antibodies (IgG) are transferred to the fetus through the placenta and IgA through breast milk.

  • Artificial Passive Immunity: Involves the injection of gamma globulin or monoclonal antibodies to provide immediate protection.

  • Duration: Passive immunity is temporary and does not involve the recipient's immune response.

Vaccination and Herd Immunity

Vaccination Technologies

  • mRNA Vaccines: A new technology used for COVID-19 (e.g., Moderna and Pfizer) that involves splicing the gene for an antigen into a vector to produce mRNA in vitro.

  • Mechanism: The mRNA is encapsulated in lipid nanoparticles, which facilitate entry into cells where it is translated into the spike protein, triggering an immune response.

  • Future Applications: Plans to utilize mRNA technology for vaccines against various cancers.

Herd Immunity

  • Definition: Herd immunity occurs when a significant percentage of a population becomes immune to an infectious agent, reducing its spread.

  • Threshold: Generally requires over 80% of the population to be immune, either through vaccination or natural infection.

  • Importance: Protects vulnerable individuals who cannot be vaccinated, such as those with certain medical conditions.

Tissue Transplantation

Types of Transplants

  • Autograft: Tissue transplanted from one part of the body to another in the same individual, e.g., skin grafts for burns.

  • Isograft: Tissue transplanted between identical twins, minimizing rejection risk.

  • Allograft: Tissue from a genetically non-identical member of the same species, which is the most common type of transplant.

  • Xenograft: Tissue from a different species, such as pig heart valves, often genetically modified to reduce rejection.

Transplant Success Factors

  • MHC Matching: The success of a transplant largely depends on the compatibility of Major Histocompatibility Complex (MHC) molecules between donor and recipient.

  • Immunosuppressive Therapy: Post-transplant, patients often require medications like Azathioprine and Cyclosporine to prevent rejection by suppressing the immune response.

Immunodeficiencies and Autoimmune Diseases

Immunodeficiencies

  • Thymic Aplasia: A congenital defect leading to reduced or absent thymus, resulting in no T cell production.

  • SCID (Severe Combined Immunodeficiency): A genetic disorder characterized by a significant reduction in both T and B cells, leading to severe vulnerability to infections.

  • ADA Deficiency: A genetic deficiency affecting adenosine deaminase, crucial for immune cell function, and one of the first disorders treated with gene therapy.

Autoimmune Diseases

  • Definition: Autoimmune diseases occur when the immune system mistakenly attacks the body’s own tissues, often due to auto-antibodies and T cells.

  • Examples: Conditions like Type I diabetes, multiple sclerosis (MS), and systemic lupus erythematosus (SLE) arise from immune system failures.

  • Mechanisms: Autoimmunity can result from alterations in self-antigens, hidden antigens becoming visible, or cross-reactivity with foreign antigens.

Hypersensitivity Reactions

Types of Hypersensitivity

  • Type I (Immediate Hypersensitivity): Involves IgE antibodies and results in allergic reactions such as anaphylaxis, triggered by allergens like bee stings.

  • Type II (Cytotoxic Reaction): Mediated by IgG and IgM, leading to cell lysis, as seen in blood transfusion reactions.

  • Type III (Immune Complex Disorders): Involves immune complexes causing inflammation, examples include glomerulonephritis and lupus.

  • Type IV (Delayed Hypersensitivity): Mediated by T cells, with symptoms appearing 24-48 hours after exposure, e.g., poison ivy reactions.

Cytokine Storm

  • Definition: A hyper-immune response characterized by the massive release of cytokines, leading to systemic inflammation and potential organ failure.

  • Context: Observed in severe viral infections like COVID-19 and during certain immunotherapy treatments, though the mechanisms are not fully understood.