Immune Adaptive

BIO 203 Fall 2025 Class Schedule

Overview of Class Modules

• Introduction to Key Concepts: Fundamental principles of biology, focusing on physiology and biochemistry with relevance to human health.

• Instructional Team:

  • Dr. Collins

  • Dr. Napoli

  • Dr. Watson

Immune System II: Learning Objectives

1. Cell-mediated Immunity vs. Humoral Immunity:

   • Cell-mediated Immunity - involves T cells and is characterized by direct action against infected or abnormal cells, often via contact-dependent signaling.

   • Humoral Immunity - involves B cells and is characterized by the production of antibodies to neutralize pathogens; antibodies are soluble proteins circulating in blood plasma.

2. Distinction Between B and T Cell Receptors:

   • B Cell Receptors (BCRs): Bind to specific antigens and are involved in humoral immunity. Composed of two heavy and two light chains linked by disulfide bonds. Possess a constant region and a variable region, the latter of which undergoes enzymatic gene rearrangement to create a vast array of specific receptors. BCRs are membrane-anchored antibodies and can undergo alternative splicing to remove their transmembrane domain, producing secreted antibodies. They are bivalent, having two antigen-binding sites.

   • T Cell Receptors (TCRs): Recognize antigens presented by MHC molecules and are crucial for cell-mediated immunity. Formed by one alpha and one beta chain linked by disulfide bonds. Also possess constant and variable regions (the variable region undergoes gene rearrangement). Unlike BCRs, TCRs are never secreted.

3. B Cell Response to Foreign Antigens:

   • B cells respond to foreign antigens, such as bacterial proteins, by encountering them, binding via their BCRs, and undergoing clonal expansion (cell division by mitosis). This produces many identical copies of the B cell.

   • Some expanded B cells become long-lived memory B cells, while others differentiate into plasma cells, which are specialized to secrete specific antibodies.

4. Comparison of MHC Class I and II Proteins:

   • MHC Class I: Present on virtually all nucleated cells in the body. They display intracellular antigens (e.g., from viruses inside the cell). Interact with Cytotoxic T cells (Tc) only, requiring a CD8 co-receptor for verification. This interaction leads to the destruction of the infected host cell.

   • MHC Class II: Present only on specialized antigen-presenting cells (APCs) such as macrophages, dendritic cells, and B cells. They display antigens from extracellular pathogens that have been engulfed. Interact with Helper T cells only, requiring a CD4 co-receptor for verification. This interaction promotes the release of cytokines (e.g., Interleukin 2) to enhance the immune system, without killing the APC.

5. Cytotoxic T Cells (Tc) Mechanism of Action:

   • Tc cells recognize and eliminate virus-infected host cells by releasing perforin and granzymes.

   • Perforin proteins form pores in the membrane of the target host cell.

   • Granzymes (e.g., Granzyme B) enter the cell through these pores and activate caspase molecules, which are enzymes that launch a program of programmed cell death called apoptosis. Apoptosis ensures controlled cell death with minimal collateral damage to neighboring cells.

6. Antigen-Presenting Cell (APC) Interaction with Helper T Cells:

   • APCs (macrophages, dendritic cells, and B cells) engulf pathogens (e.g., via pattern recognition receptors for macrophages, or BCRs for B cells), process them into peptide fragments, and present these antigens to Helper T cells via MHC Class II molecules.

   • This interaction, along with the CD4 co-receptor, activates the Helper T cell, leading to its proliferation and cytokine production.

7. Helper T Cells Enhancing Cytotoxic T Cells:

   • Helper T cells secrete cytokines, notably Interleukin 2 (IL-2), which promotes cell division (clonal expansion) not only in B cells but also in cytotoxic T cells, thereby significantly enhancing the overall adaptive immune response.

8. Primary vs. Secondary Immune Responses:

   • Primary Response: The initial response to an antigen; it is slower (takes about $5$ days to detect antibodies, peak at $2$ weeks) and less robust.

   • Secondary Response: Subsequent exposure to the same antigen; it is much faster (antibodies detected quickly, reaching peak faster), stronger (higher peak antibody concentration), and lasts longer due to the presence of memory B and T cells generated during the primary response.

9. Mechanism of Cyclosporine:

   • Cyclosporine is an immunosuppressant drug that specifically blocks the immune system by inhibiting Interleukin 2 (IL-2) gene expression in T cells. This prevents T cell activation and proliferation, thus suppressing the immune response.

Overview of the Immune System: Layers of Defense

First Layer: Barriers

• Physical Barriers:

  • Skin, mucous membranes, and secretions.

• Mechanical Barriers:

  • Flushing mechanisms such as cilia.

• Chemical Barriers:

  • Enzymes, antibodies, and pH levels.

Second Layer: Innate Immune Response

• Nature: Rapid, non-specific, and lacks memory.

• Key Cells:

  • Macrophages, Neutrophils, Natural Killer (NK) cells, Dendritic cells.

• Chemicals:

  • Complement, interferons, inflammatory mediators.

Third Layer: Adaptive Immune Response

• Nature: Slow, specific, and includes memory.

• Key Components:

  • Cell-mediated: Utilizes T lymphocytes, primarily Cytotoxic T cells.

  • Humoral: Utilizes B lymphocytes, leading to antibody production.

Adaptive Immune System: Functions and Mechanisms

• Antigen Recognition:

  • Antigens are molecules (e.g., proteins, lipids, carbohydrates, nucleic acids), typically proteins, that are recognized by adaptive immune cells (BCRs and TCRs). Epitopes are specific portions of antigens (e.g., $2$ to $6$ amino acids) that BCRs or TCRs bind to. The immune system cannot predict which antigens an individual will encounter but develops a vast array (e.g., $100$ million) of B cells and T cells with specific receptors during development.

• BCRs and TCRs Structure:

  • BCRs: Composed of heavy and light chains, engage in high specificity interactions. The gene encoding the variable region undergoes enzymatic rearrangement to produce diverse receptors. The transmembrane domain can be spliced out to generate secreted antibodies.

  • TCRs: Formed by one alpha and one beta chain linked by disulfide bonds. The gene encoding the variable region also undergoes enzymatic rearrangement to create a vast diversity of receptors. TCRs are always membrane-bound and are never secreted.

Activation of B Cells

• Process:

  1. Antigen binding to BCR leads to activation.

  2. B cell undergoes clonal expansion (mitosis) to produce populations of identical cells.

  3. Differentiated cells include plasma cells (secrete specific antibodies) and memory B cells (long-lived, provide rapid response upon re-exposure).

Activation of T Cells

• Process:

  1. Antigen presented on MHC by an APC (or infected host cell) binds to TCR, along with co-receptor (CD4 or CD8).

  2. Activation of signaling pathways leads to T cell proliferation (clonal expansion) and cytokine production (e.g., IL-2 by helper T cells).

Antibody Functions

• Antibodies are proteins that do not directly kill pathogens. They function primarily by binding to antigens.

• They are bivalent, possessing two antigen-binding sites per molecule.

• Binding Mechanisms:

  • Agglutination (Clumping): Antibodies bind to multiple bacterial cells or viral particles, causing them to clump together. This clumping makes it easier for phagocytic innate immune cells (macrophages, dendritic cells, neutrophils) to engulf and clear the pathogens, and inhibits pathogen spread and replication.

  • Neutralization: Antibodies bind to critical sites on pathogens (e.g., bacterial toxins, viral surface proteins), blocking their ability to bind to host cells or exert toxic effects. This prevents viral entry into cells or neutralizes toxin activity (e.g., bacterial enzymes).

  • Opsonization (Molecular Tagging): Antibodies bind to the surface of pathogens, acting as 'molecular tags'. Phagocytes have specialized Fc receptors that recognize the antibody-coated pathogens, leading to enhanced phagocytosis.

  • Mast Cell Degranulation: Antibodies (e.g., IgE in allergic reactions or against some pathogens) bound to the surface of mast cells can recognize and bind antigens, triggering mast cell degranulation and the release of inflammatory mediators like histamine.

  • Complement Activation: The complement protein C1 can bind to antibodies when they are attached to antigens on the surface of a bacterial cell, initiating the classical pathway of the complement cascade which leads to pathogen destruction.

Cytotoxic T Cells Action and Mechanism

• Mechanism of Action:

  • Utilizes perforin to form pores in infected host cell membranes.

  • Releases granzymes (e.g., Granzyme B) that enter through pores.

  • Granzymes activate cellular death pathways by cleaving caspase molecules, inducing apoptosis (programmed cell death) ensuring minimal tissue damage.

Organ Transplantation Highlights

• Historical Context:

  • Milestones in organ transplantation include the first successful corneal transplant (1905), the first successful kidney transplant between identical twins (1950) demonstrating surgical feasibility, the discovery of cyclosporine (1969), and its widespread use in transplants beginning in the 1980s, leading to sophisticated procedures like double arm and full face transplants.

• Acute Rejection:

  • Mediated by T and B cells; occurs shortly after transplant when the recipient's immune system recognizes the donor organ as foreign and attacks it.

  • Managed with immunosuppressive drugs like cyclosporine.

• Immunosuppressant Risks:

  • Risks include increased susceptibility to infections (e.g., lung transplants are particularly challenging due to constant pathogen inhalation), increased risk of tumor formation (due to suppressed immune surveillance), and the necessity to continue medication for life.

• Xenotransplantation:

  • Recent advancements address the shortage of human organs by transplanting organs from genetically edited animals (e.g., pigs). For example, engineered pigs with 69 genetic modifications have been developed to increase the tolerability of their organs in human recipients. Early clinical trials of pig kidney transplants in humans have shown promise, with some patients surviving for over $6$ months.

Vaccine Functions and Effects

• Purpose of Vaccines:

  • Induce a primary immune response without causing severe illness, thereby generating memory B and T cells. This prepares the immune system for a rapid and robust secondary response upon future encounters with the actual pathogen.

• Mechanism Example (mRNA vaccines for COVID-19):

  • mRNA encoding a viral protein (e.g., the SARS-CoV-2 spike protein) is encapsulated in lipid nanoparticles and delivered (typically via intramuscular injection).

  • Host cells (e.g., muscle cells) take up the mRNA and translate it into the viral protein, which is then released.

  • The immune system recognizes these viral proteins as antigens, initiating a primary immune response and producing specific antibodies and memory B and T cells.

  • Upon subsequent exposure to the actual virus, the immune system mounts a rapid and strong secondary response, with antibodies preventing viral entry into cells and minimizing infection.