# Lecture 23: The Immune System
## General Biology II — Organismal, Evolution & Ecology
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## Learning Objectives
By the end of this lecture, students will be able to:
1. Describe the components and functions of the innate immune system
2. Explain the inflammatory response and its role in defense
3. Distinguish between humoral and cell-mediated adaptive immunity
4. Describe the structure and function of antibodies and how antibody diversity is generated
5. Explain the processes of clonal selection, clonal expansion, and immunological memory
6. Compare the roles of B cells, helper T cells, and cytotoxic T cells in adaptive immunity
7. Explain the basis of vaccination, autoimmune disease, and immunodeficiency
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## Lecture Content
### I. Overview of the Immune System
The immune system defends against pathogens (bacteria, viruses, fungi, parasites) and abnormal cells (cancer) Two interconnected branches: **Innate immunity** — rapid, nonspecific; first and second lines of defense; present from birth; no memory. **Adaptive (acquired) immunity** — slower onset, highly specific; third line of defense; generates immunological memory. All immune cells derive from hematopoietic stem cells in the bone marrow. Key lymphoid organs: Primary: bone marrow (B cell maturation), thymus (T cell maturation) Secondary: lymph nodes, spleen, tonsils, Peyer's patches (sites of immune responses).
### II. Innate Immunity — First and Second Lines of Defense
#### A. First Line of Defense — Physical and Chemical Barriers
Skin — keratinized stratified squamous epithelium; dry, acidic surface (pH ~5.5); antimicrobial peptides (defensins) Mucous membranes — line respiratory, digestive, urogenital tracts; mucus traps microbes. Secretions — lysozyme (in tears, saliva, nasal secretions; degrades bacterial cell wall peptidoglycan), stomach acid (pH ~2), sebum (skin oils), cerumen (earwax) Normal microbiota — compete with pathogens for nutrients and space (competitive exclusion) Ciliated epithelium — mucociliary escalator in the respiratory tract moves trapped particles upward.
#### B. Second Line of Defense — Internal Innate Defenses
**Phagocytes** — engulf and destroy pathogens: Neutrophils — most abundant WBC; first responders; short-lived; phagocytose bacteria. Macrophages — derived from monocytes; phagocytose pathogens and debris; present antigens to T cells (antigen-presenting cells, APCs) Dendritic cells — most effective APCs; reside in tissues exposed to the environment (skin, mucosa); migrate to lymph nodes to activate T cells. **Natural killer (NK) cells** — lymphocytes of the innate system; kill virus-infected cells and tumor cells by inducing apoptosis (perforin/granzyme pathway); recognize cells lacking MHC class I. **Pattern recognition receptors (PRRs)** — recognize conserved molecular patterns on pathogens: **Toll-like receptors (TLRs)** — on macrophages, dendritic cells, neutrophils; recognize PAMPs (pathogen-associated molecular patterns) such as LPS (bacterial), flagellin, dsRNA (viral), CpG DNA. Activation of TLRs → signaling cascades → production of cytokines, chemokines, and antimicrobial molecules. **Complement system** — ~30 plasma proteins; activated in a cascade: Functions: opsonization (coating pathogens to enhance phagocytosis), membrane attack complex (MAC — forms pores in pathogen membranes → lysis), inflammation (recruitment of immune cells) Three activation pathways: classical (antibody-mediated), lectin, and alternative. **Interferons (IFNs)** — cytokines produced by virus-infected cells: Signal neighboring cells to produce antiviral proteins → inhibit viral replication. Activate NK cells and macrophages. Type I interferons: IFN-alpha, IFN-beta.
#### C. The Inflammatory Response
Triggered by tissue damage or infection. **Cardinal signs**: redness (rubor), heat (calor), swelling (tumor), pain (dolor), loss of function. Steps: Tissue damage/infection → mast cells release **histamine** → vasodilation and increased capillary permeability. Increased blood flow → redness and heat. Plasma and proteins leak into tissue → edema (swelling) → pain. Chemokines attract neutrophils and monocytes → **chemotaxis** → phagocytes migrate to the infection site (diapedesis — squeezing through capillary walls) Phagocytes engulf and destroy pathogens. Pus formation — accumulation of dead neutrophils, fluid, and debris. **Fever** — systemic inflammatory response: Pyrogens (from pathogens or immune cells) → hypothalamus raises body temperature set point. Moderate fever enhances immune function (increases phagocyte activity, inhibits bacterial growth).
A multi-step diagram of the inflammatory response. Panel 1: Intact tissue with a pathogen (bacterium) entering through a break in the skin epithelium. Nearby mast cells are shown releasing histamine granules. Panel 2: Vasodilation — arterioles widen, capillaries become more permeable (gaps between endothelial cells shown), with plasma fluid and complement proteins leaking into the tissue space. Blood flow to the area increases (red arrows). Panel 3: Chemotaxis and diapedesis — neutrophils in the blood vessel respond to chemokines (shown as a gradient of dots), adhere to the endothelial wall via selectins and integrins, squeeze between endothelial cells (diapedesis), and migrate toward the bacteria. Panel 4: Phagocytosis — a macrophage engulfing bacteria via pseudopods, with an intracellular phagolysosome fusing with lysosomes to digest the pathogen. An adjacent panel shows the macrophage displaying antigen fragments on MHC class II molecules on its surface, linking innate to adaptive immunity.
### III. Adaptive Immunity — Overview
**Specificity** — each lymphocyte recognizes a specific antigen via unique receptors. **Diversity** — the immune system can recognize an enormous range of antigens (~10^9 to 10^11 different specificities) **Memory** — faster and stronger secondary response upon re-exposure to the same antigen. **Self/non-self discrimination** — normally does not attack the body's own cells. **Antigen** — any molecule (or portion thereof) that is recognized by the adaptive immune system; typically proteins or polysaccharides on the surface of pathogens. Epitope (antigenic determinant) — the specific region of an antigen that is recognized by a receptor. Two arms of adaptive immunity: **Humoral immunity** — mediated by B cells and antibodies; targets extracellular pathogens and toxins. **Cell-mediated immunity** — mediated by T cells; targets intracellular pathogens (virus-infected cells) and abnormal cells.
### IV. Antigen Recognition and MHC
**Major histocompatibility complex (MHC)** — cell surface glycoproteins that present antigen fragments to T cells. **MHC class I** — found on all nucleated cells; display intracellular (endogenous) antigens (e.g., viral proteins synthesized inside the cell) Recognized by CD8+ cytotoxic T cells. Allow immune system to detect infected or cancerous cells. **MHC class II** — found only on antigen-presenting cells (APCs: dendritic cells, macrophages, B cells); display extracellular (exogenous) antigens (phagocytosed and processed) Recognized by CD4+ helper T cells. **Antigen processing and presentation**: MHC I pathway: intracellular proteins degraded by proteasome → peptide fragments loaded onto MHC I in ER → transported to cell surface. MHC II pathway: extracellular antigens internalized by endocytosis/phagocytosis → degraded in endosomes → peptide fragments loaded onto MHC II → transported to cell surface. MHC molecules are highly polymorphic (many alleles in the population) → each individual presents a unique set of antigens → basis of transplant rejection.
### V. Humoral Immunity — B Cells and Antibodies
#### A. B Cell Activation and Clonal Selection
Each B cell expresses a unique **B cell receptor (BCR)** — a membrane-bound antibody (IgM or IgD) **Clonal selection** — antigen binds to the BCR of a B cell with a complementary receptor → that B cell is selected for activation. Most B cell responses require **T cell help**: B cell binds antigen via BCR → internalizes, processes, and presents antigen on MHC II. Helper T cell (CD4+) recognizes the MHC II-antigen complex → secretes cytokines (IL-2, IL-4, IL-5, IL-6) Cytokines stimulate B cell proliferation (**clonal expansion**) and differentiation into: **Plasma cells** — effector cells; secrete large quantities of antibodies (~2,000 molecules/sec); short-lived (days to weeks) **Memory B cells** — long-lived; persist for years; enable rapid and amplified secondary response upon re-exposure.
#### B. Antibody Structure and Function
**Antibody (immunoglobulin, Ig)** — Y-shaped protein composed of: Two identical heavy chains + two identical light chains, linked by disulfide bonds. **Variable (V) region** — the antigen-binding site (at the tips of the Y); unique to each antibody; determines specificity. **Constant (C) region** — the stem of the Y; determines the antibody class and effector function. Each antibody has two identical antigen-binding sites → can cross-link antigens (agglutination) **Antibody classes (isotypes)**: **IgM** — first antibody produced; pentamer form in blood; strong agglutination; activates complement. **IgG** — most abundant in blood; crosses the placenta (passive immunity to fetus); opsonization; complement activation; long-lasting. **IgA** — dimer form in secretions (saliva, breast milk, mucus); mucosal immunity. **IgE** — binds to mast cells and basophils; triggers histamine release; involved in allergic responses and defense against parasites. **IgD** — found on B cell surface; functions as BCR; role in B cell activation. Antibody effector mechanisms: **Neutralization** — antibodies bind to pathogen surface or toxins → block their ability to infect cells or cause damage. **Opsonization** — antibody coating marks pathogens for phagocytosis (Fc receptors on phagocytes bind the constant region) **Agglutination** — antibodies cross-link pathogens into clumps → easier phagocytosis. **Complement activation** — classical pathway; antibody-antigen complex activates complement → MAC, opsonization, inflammation.
#### C. Antibody Diversity
**V(D)J recombination** — during B cell development, gene segments encoding the variable region are randomly rearranged: Heavy chain: V, D, and J segments recombine. Light chain: V and J segments recombine. Random combination of different V, D, J segments → enormous diversity. **Combinatorial diversity** — random pairing of heavy and light chains. **Junctional diversity** — imprecise joining at V-D-J boundaries adds/removes nucleotides. **Somatic hypermutation** — point mutations introduced in V regions during B cell proliferation in germinal centers → variants with higher affinity are selected (affinity maturation) **Class switching (isotype switching)** — activated B cells change the constant region of their antibody (e.g., IgM → IgG) while retaining the same antigen specificity; directed by cytokines from helper T cells.
A detailed diagram of antibody structure and function. The main panel shows the Y-shaped antibody molecule with two heavy chains (blue) and two light chains (green), connected by disulfide bonds (shown as S-S links). The variable regions at the tips of the Y are highlighted in a different shade, with the antigen-binding sites (paratopes) labeled where they interact with an antigen epitope. The constant regions form the stem (Fc region), labeled with the antibody class designation. An upper inset shows the five antibody classes: IgG (monomer, most abundant), IgM (pentamer linked by J chain), IgA (dimer with secretory component), IgE (monomer bound to a mast cell surface via Fc receptor), and IgD (monomer on B cell surface). A lower panel illustrates four effector mechanisms: neutralization (antibodies blocking a virus from binding a host cell receptor), opsonization (antibody-coated bacterium being engulfed by a macrophage via Fc receptor binding), agglutination (antibodies cross-linking multiple bacteria into a clump), and complement activation (antibody-antigen complex triggering the complement cascade leading to MAC pore formation in a bacterial membrane).
### VI. Cell-Mediated Immunity — T Cells
T cells mature in the **thymus**; undergo positive selection (must recognize self-MHC) and negative selection (must not react strongly to self-antigens) **T cell receptor (TCR)** — recognizes antigen fragments presented on MHC molecules (not free antigen).
#### A. Helper T Cells (CD4+)
Recognize antigen presented on MHC class II (by APCs) Upon activation, secrete cytokines that: Activate B cells (humoral immunity) Activate cytotoxic T cells. Enhance macrophage killing ability. Direct the overall immune response. Subtypes: Th1 — promote cell-mediated immunity (activate macrophages, cytotoxic T cells); secrete IFN-gamma, IL-2. Th2 — promote humoral immunity (activate B cells); secrete IL-4, IL-5, IL-13. Th17 — recruit neutrophils; defense against extracellular bacteria and fungi; secrete IL-17. Treg (regulatory T cells) — suppress immune responses; maintain tolerance; prevent autoimmunity; secrete IL-10, TGF-beta.
#### B. Cytotoxic T Cells (CD8+)
Recognize antigen presented on MHC class I (on any nucleated cell) Kill infected or abnormal target cells by: **Perforin/granzyme pathway** — perforin creates pores in the target cell membrane → granzymes enter → activate caspases → apoptosis. **Fas/FasL pathway** — FasL on the cytotoxic T cell binds Fas on the target cell → triggers apoptosis. Critical for defense against intracellular pathogens (viruses) and tumor surveillance.
#### C. Immunological Memory
After an infection is cleared, most effector cells die; a subset persists as **memory cells** (both memory B cells and memory T cells) **Primary immune response** — first exposure to antigen; lag period of 10-17 days; IgM produced first, then IgG; lower antibody titer. **Secondary immune response** — re-exposure to the same antigen; faster (2-7 days), stronger (higher antibody titer), longer-lasting; predominantly IgG; due to rapid activation and expansion of memory cells.
### VII. Immune System Disorders and Applications
#### A. Vaccination (Immunization)
Exposes the immune system to a harmless form of a pathogen or antigen → generates memory cells without causing disease. Types: attenuated (weakened live pathogen), inactivated (killed pathogen), subunit (purified antigen), toxoid (inactivated toxin), mRNA (encode antigen for host cell production), viral vector. **Herd immunity** — when a large fraction of the population is immune, transmission is reduced, protecting unvaccinated individuals.
#### B. Allergies (Hypersensitivity)
**Type I (immediate) hypersensitivity** — IgE-mediated: First exposure: allergen → B cells produce IgE → IgE binds to mast cells (sensitization) Re-exposure: allergen cross-links IgE on mast cells → degranulation → massive histamine release → vasodilation, bronchoconstriction, mucus secretion. Manifestations: hay fever, asthma, hives, anaphylaxis (severe systemic response — life-threatening).
#### C. Autoimmune Diseases
Immune system attacks self-tissues due to failure of self-tolerance. Examples: type 1 diabetes (T cells destroy pancreatic beta cells), rheumatoid arthritis (joints), systemic lupus erythematosus (multiple organs), multiple sclerosis (myelin sheath).
#### D. Immunodeficiency
**Primary (congenital)** — genetic defects (e.g., SCID — severe combined immunodeficiency; no functional T or B cells) **Secondary (acquired)** — caused by infection, drugs, or other factors (e.g., HIV/AIDS — HIV destroys CD4+ helper T cells → collapse of adaptive immunity → opportunistic infections).
A comparison diagram of the primary and secondary immune responses. The x-axis represents time in days, spanning from day 0 to approximately day 56, with two antigen exposure events: the first at day 0 and the second at day 28. The y-axis represents serum antibody concentration on a logarithmic scale. The primary response curve shows a slow rise beginning around day 7-10 after first exposure, peaking at a modest level around day 14-17, with IgM appearing first (dashed line peaking early then declining) followed by IgG (solid line peaking later at a moderate level). The secondary response curve shows a rapid rise beginning 2-3 days after re-exposure at day 28, reaching a peak antibody concentration 10-100 times higher than the primary response, predominantly IgG with minimal IgM, and the elevated antibody level persists much longer. Labels indicate "memory cells activated" at the start of the secondary response, and a text box highlights the key differences: faster onset, higher magnitude, longer duration, and IgG predominance in the secondary response.
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