# Lecture 9: Adaptive Immunity
## Anatomy and Physiology II
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## Learning Objectives
By the end of this lecture, students will be able to:
1. Distinguish between humoral and cell-mediated immunity
2. Define antigen and describe the properties of immunogens
3. Explain the role of antigen-presenting cells and MHC molecules
4. Describe the activation, clonal expansion, and effector functions of B lymphocytes
5. Describe the classes and functions of antibodies
6. Describe the activation and effector functions of T lymphocytes (helper and cytotoxic)
7. Explain immunological memory and distinguish between active and passive immunity
8. Discuss hypersensitivity, autoimmunity, and immunodeficiency
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## Lecture Content
### I. Features of Adaptive Immunity
Adaptive immunity is distinguished by four key characteristics. **Specificity** allows it to target particular antigens through unique receptors. **Diversity** ensures a vast repertoire of lymphocyte receptors capable of recognizing virtually any antigen. **Memory** enables faster and stronger responses upon re-exposure to the same antigen. **Self-tolerance** prevents the immune system from attacking the body's own tissues under normal conditions.
Adaptive immunity operates through two interconnected branches. **Humoral (antibody-mediated) immunity** involves B lymphocytes producing antibodies that target extracellular pathogens and their toxins. **Cell-mediated immunity** involves T lymphocytes that directly attack infected cells, cancer cells, and foreign grafts.
### II. Antigens
An **antigen** is any substance that can be recognized by the adaptive immune system. An **immunogen** is an antigen capable of provoking an immune response, and most antigens function as immunogens. Effective immunogens tend to have large molecular size (typically greater than 10 kDa), chemical complexity (proteins are the best immunogens, while polysaccharides, lipids, and nucleic acids are weaker), and foreignness (they are not recognized as self). The specific part of an antigen recognized by a lymphocyte receptor or antibody is called an **epitope** (antigenic determinant), and a single antigen can present multiple epitopes. A **hapten** is a small molecule that is not immunogenic on its own but becomes immunogenic when attached to a carrier protein, as is the case with penicillin and poison ivy urushiol.
### III. Antigen-Presenting Cells (APCs) and MHC
#### Major Histocompatibility Complex (MHC) Molecules
MHC molecules are cell surface glycoproteins that display peptide fragments to T cells. They are encoded by the HLA (human leukocyte antigen) gene complex on chromosome 6 and are highly polymorphic, varying greatly between individuals, which is why they are critically important for transplant compatibility.
**MHC Class I** molecules are found on all nucleated cells and display endogenous antigens, that is, peptides derived from proteins synthesized within the cell. If a cell is infected by a virus or has become cancerous, abnormal peptides will be displayed on MHC I, flagging the cell for destruction. MHC I molecules are recognized by CD8+ cytotoxic T cells, allowing the immune system to monitor the intracellular environment of every nucleated cell. **MHC Class II** molecules are found only on professional antigen-presenting cells (dendritic cells, macrophages, and B cells) and display exogenous antigens, peptides from material that has been phagocytosed or endocytosed from outside the cell. MHC II molecules are recognized by CD4+ helper T cells.
#### Antigen Processing and Presentation
In the **endogenous pathway** (MHC I), intracellular proteins are degraded by the proteasome, and the resulting peptides are transported into the endoplasmic reticulum by TAP transporters, loaded onto MHC I molecules, and displayed on the cell surface. In the **exogenous pathway** (MHC II), a pathogen is engulfed by phagocytosis or endocytosis, digested in a phagolysosome, and the resulting peptides are loaded onto MHC II molecules that have been assembled in the ER and transported to the endosome. The peptide-MHC II complex is then displayed on the cell surface.
A diagram comparing MHC class I and MHC class II antigen processing and presentation. Panel A (left): The endogenous pathway — a virus-infected cell showing viral proteins being degraded by the proteasome, peptide fragments transported by TAP into the endoplasmic reticulum, loaded onto MHC class I molecules, and transported to the cell surface where a CD8+ cytotoxic T cell recognizes the complex via its T cell receptor (TCR). Panel B (right): The exogenous pathway — a dendritic cell engulfing a bacterium, the bacterium being digested in a phagolysosome, peptide fragments loading onto MHC class II molecules (with the invariant chain being removed), and the complex being displayed on the cell surface where a CD4+ helper T cell recognizes it via its TCR. Each step is numbered and arrows indicate the direction of the pathway.
### IV. Humoral Immunity — B Lymphocytes
#### B Cell Activation
B cell activation requires both antigen binding and co-stimulation. First, the B cell receptor (BCR), which is a membrane-bound antibody, binds to a specific epitope on the native antigen. For most antigens (T-dependent antigens), a second signal from helper T cells is required: the B cell internalizes, processes, and presents the antigen on MHC II. A helper T cell that has already been activated by the same antigen recognizes the MHC II-peptide complex and releases cytokines (IL-2, IL-4, IL-5) that fully activate the B cell. Some antigens, such as polysaccharides with repetitive epitopes (T-independent antigens), can activate B cells without T cell help, though the resulting response is weaker and produces less memory.
#### Clonal Selection and Expansion
Once activated, a B cell undergoes rapid mitosis in a process called clonal expansion, producing large numbers of daughter cells. These daughters differentiate into two populations. **Plasma cells** are antibody-secreting factories that produce approximately 2,000 antibodies per second but are short-lived, surviving only days to weeks. **Memory B cells** are long-lived and remain dormant until re-exposure to the same antigen, at which point they mount a faster and stronger secondary response.
#### Antibodies (Immunoglobulins)
Each antibody is a Y-shaped protein composed of four polypeptide chains: two identical heavy chains and two identical light chains, held together by disulfide bonds. The tips of the Y form the **variable (V) region**, containing two identical antigen-binding sites (the Fab region) that are unique to each antibody. The stem of the Y is the **constant (C) region** (Fc region), which determines the antibody class and its effector function. A flexible hinge region connects the arms to the stem.
There are five classes (isotypes) of antibodies. **IgG** is the most abundant, comprising 75 to 80% of serum antibodies. It is the only antibody that crosses the placenta, providing passive immunity to the fetus, and it participates in opsonization, complement activation, and neutralization. It dominates the secondary immune response. **IgA** accounts for 10 to 15% and is the principal antibody in secretions such as saliva, tears, breast milk, and mucus. It exists as a dimer in secretions and protects mucosal surfaces. **IgM** represents 5 to 10% and is the first antibody produced in a primary immune response. Its pentameric form in blood makes it very effective at agglutination and complement activation. It also serves as part of the B cell receptor on the cell surface. **IgD** constitutes less than 1% and is found on B cell surfaces along with IgM as part of the BCR, functioning in B cell activation. **IgE** is present in only trace amounts but plays an outsized role in allergic responses. It binds to mast cells and basophils via its Fc region, and when antigen cross-links the bound IgE, it triggers histamine release. IgE also provides defense against parasitic worms.
Antibodies eliminate pathogens through several effector mechanisms. **Neutralization** blocks pathogen surface proteins or toxins from binding to host cells. **Agglutination** cross-links particulate antigens like bacteria, clumping them for easier phagocytosis. **Precipitation** cross-links soluble antigens into insoluble complexes. **Opsonization** coats pathogens with antibody, enhancing phagocyte binding and ingestion. **Complement activation** through the classical pathway triggers the cascade leading to MAC formation, opsonization, and inflammation. **Antibody-dependent cellular cytotoxicity (ADCC)** allows NK cells to bind to antibody-coated target cells via Fc receptors and kill them.
A diagram of antibody structure and function. Panel A: A detailed Y-shaped antibody molecule showing two heavy chains and two light chains connected by disulfide bonds, with the variable regions (antigen-binding sites/Fab fragments) at the tips highlighted in one color and the constant region (Fc fragment) at the stem in another color. The hinge region is indicated. Panel B: A comparison chart of the five antibody classes (IgG as a monomer, IgA as a dimer with secretory component, IgM as a pentamer with J chain, IgD as a monomer, IgE as a monomer) showing their structures, locations, and primary functions. Panel C: Four small illustrations showing antibody effector mechanisms — neutralization (antibodies blocking virus attachment), agglutination (antibodies cross-linking bacteria), opsonization (antibody-coated bacterium being phagocytosed), and complement activation (antibody-antigen complex triggering MAC formation on a cell membrane).
### V. Cell-Mediated Immunity — T Lymphocytes
#### T Cell Activation
T cell activation requires two signals. First, the T cell receptor (TCR) binds to an MHC-peptide complex on an APC. CD4+ helper T cells recognize antigen presented on MHC II, while CD8+ cytotoxic T cells recognize antigen on MHC I. Second, co-stimulatory molecules must interact, such as B7 on the APC binding to CD28 on the T cell. Without this co-stimulation, the T cell becomes anergic (unresponsive), a safeguard that prevents unwanted immune responses. Activated T cells undergo clonal expansion, producing effector cells and memory T cells.
#### CD4+ Helper T Cells (Th cells)
Helper T cells serve as the "directors" of the immune response and do not directly kill pathogens. Instead, they release cytokines that coordinate immune activities. **Th1 cells** activate macrophages and cytotoxic T cells, promoting cell-mediated immunity through IFN-gamma and IL-2. **Th2 cells** stimulate B cell activation, class switching, and antibody production, promoting humoral immunity through IL-4, IL-5, and IL-10. **Th17 cells** promote inflammation and recruit neutrophils through IL-17. **Tfh (follicular helper T cells)** help B cells in germinal centers.
#### CD8+ Cytotoxic T Cells (Tc cells / CTLs)
Cytotoxic T cells directly kill target cells, including virus-infected cells, cancer cells, and foreign graft cells. They recognize abnormal peptides displayed on MHC I and employ two killing mechanisms. The **perforin-granzyme pathway** involves releasing perforin to form pores in the target cell membrane and granzymes that enter through the pores to trigger apoptosis. The **Fas-FasL pathway** involves FasL on the CTL binding to Fas on the target cell, directly triggering apoptosis. Cytotoxic T cells are activated by helper T cell cytokines, particularly IL-2.
#### Regulatory T Cells (Tregs)
Regulatory T cells suppress immune responses to maintain self-tolerance and prevent autoimmunity. They express CD4, CD25, and the transcription factor FoxP3, and release immunosuppressive cytokines including IL-10 and TGF-beta.
### VI. Immunological Memory
The **primary immune response** occurs upon first exposure to an antigen. After a lag period of 3 to 6 days, IgM is produced first, followed by IgG through class switching. Antibody levels peak at about 10 to 17 days and then decline. Crucially, this response generates memory cells. The **secondary immune response** upon re-exposure is dramatically different: it occurs within 1 to 3 days, produces much higher antibody titers, is predominantly IgG, and is longer-lasting. This rapid, amplified response is mediated by memory B and T cells and is the basis of vaccination.
### VII. Active vs. Passive Immunity
**Active immunity** develops when the body produces its own antibodies and memory cells. It can be acquired naturally through exposure to a pathogen (getting sick) or artificially through vaccination using attenuated, inactivated, subunit, or mRNA vaccines. Active immunity develops slowly but provides long-lasting protection. **Passive immunity** involves the transfer of preformed antibodies from another source. It occurs naturally when maternal IgG crosses the placenta or IgA is delivered in breast milk, and artificially when immune serum (antiserum or antitoxin) is injected. Passive immunity provides immediate but short-lived protection (weeks to months) and does not generate memory.
### VIII. Clinical Correlations
**Hypersensitivity reactions** are excessive immune responses. Type I (immediate/anaphylactic) reactions are IgE-mediated, involving mast cell degranulation and causing allergies and anaphylaxis. Type II (cytotoxic) reactions involve IgG or IgM directed against cell surface antigens, as in transfusion reactions and hemolytic disease of the newborn. Type III (immune complex) reactions occur when antigen-antibody complexes deposit in tissues, causing conditions like serum sickness and lupus nephritis. Type IV (delayed-type) reactions are T cell-mediated and include contact dermatitis, the tuberculin test, and transplant rejection.
**Autoimmune diseases** arise when the immune system attacks the body's own tissues, as in rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus. **Immunodeficiency** can be primary (genetic, such as SCID or DiGeorge syndrome) or secondary/acquired (such as HIV/AIDS, which destroys CD4+ T cells, or immunosuppressive drug therapy).
A graph comparing primary and secondary immune responses. The x-axis represents time (weeks) and the y-axis represents serum antibody concentration (log scale). Panel A: The primary response curve — showing a lag phase of several days after first antigen exposure, a gradual rise in IgM followed by IgG, peak at about 2 weeks, and then decline. Panel B: The secondary response curve — after re-exposure to the same antigen weeks or months later, showing a shorter lag (1–3 days), a much faster and higher rise predominantly in IgG, reaching a higher peak that is sustained longer. The first and second antigen exposures are marked with arrows on the time axis. Memory cell generation is noted after the primary response.
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