18 Immunology and Defense Systems
18.1 Learning Objectives
By the end of this chapter, you should be able to:
- Describe the three lines of defense against pathogens and how they interact
- Distinguish between innate and adaptive immunity and their components
- Explain how the lymphatic system supports immune function
- Describe how B cells and T cells recognize antigens and mount immune responses
- Explain the mechanisms of immunological memory and vaccination
- Analyze how immune system malfunctions lead to autoimmune diseases, allergies, and immunodeficiencies
- Describe how the immune system interacts with other body systems
- Apply immunological principles to understand infectious diseases, cancer, and transplantation
18.2 Introduction
The immune system is the body’s defense network against pathogens, cancer cells, and other threats. This remarkable system can distinguish self from non-self, remember past infections, and mount targeted responses while maintaining tolerance to the body’s own tissues. Understanding immunology is essential for combating infectious diseases, developing vaccines, treating autoimmune disorders, and advancing cancer therapies. This chapter explores how the immune system protects us while maintaining the delicate balance required for health.
18.3 Overview of Host Defenses
18.3.1 Three Lines of Defense
First line: Physical and chemical barriers
- Skin: Physical barrier, acidic pH, antimicrobial peptides
- Mucous membranes: Mucus trapping, ciliary clearance
- Chemical barriers: Stomach acid, lysozyme, defensins
Second line: Innate immunity
- Cells: Phagocytes, natural killer cells
- Proteins: Complement, interferons, acute phase proteins
- Processes: Inflammation, fever
Third line: Adaptive immunity
- Cells: B lymphocytes, T lymphocytes
- Features: Specificity, memory, self-tolerance
18.3.2 Pathogens and Threats
Types of pathogens:
- Bacteria: Prokaryotes (tuberculosis, strep throat)
- Viruses: Require host cells (influenza, HIV)
- Fungi: Eukaryotes (candida, athlete’s foot)
- Parasites: Protozoa (malaria), helminths (tapeworms)
- Prions: Misfolded proteins (mad cow disease)
Other threats: Cancer cells, transplanted tissues, allergens
18.3.3 Lymphatic System
Components:
- Lymph: Fluid similar to plasma
- Lymph vessels: Transport lymph
- Lymph nodes: Filter lymph, contain immune cells
- Spleen: Filters blood
- Thymus: T cell maturation
- Tonsils/adenoids: Protect respiratory/digestive entry
- Peyer’s patches: In intestinal wall
Functions: Immune cell transport, antigen presentation, fluid balance
18.4 Innate Immunity
18.4.1 Characteristics
Present from birth: No prior exposure needed
Rapid response: Minutes to hours
No memory: Same response each time
Limited specificity: Recognizes patterns
18.4.2 Cellular Components
Phagocytes: Engulf and destroy pathogens
- Neutrophils: Most abundant, first responders
- Macrophages: Tissue-resident, antigen presentation
- Dendritic cells: Best antigen presenters
Natural killer (NK) cells: Kill virus-infected and cancer cells
- Mechanism: Release perforins and granzymes
- Recognition: Missing self (lack of MHC I)
Mast cells: Release histamine in inflammation Basophils/Eosinophils: Attack parasites, allergic responses
18.4.3 Molecular Components
Complement system: >30 proteins that enhance immunity
- Pathways: Classical, alternative, lectin
- Functions: Opsonization, inflammation, membrane attack
Interferons: Antiviral proteins (α, β, γ)
Acute phase proteins: CRP, fibrinogen (increase during infection)
Cytokines: Chemical messengers (interleukins, chemokines)
18.4.4 Inflammatory Response
Cardinal signs: Redness, heat, swelling, pain, loss of function
Steps:
- Recognition: Pathogen-associated molecular patterns (PAMPs)
- Vasodilation: Increased blood flow
- Increased permeability: Leakage of fluid and proteins
- Phagocyte migration: Chemotaxis to site
- Phagocytosis: Engulfment and destruction
- Tissue repair: Resolution phase
Fever: Elevated body temperature
Benefits: Inhibits pathogen growth, enhances immune responses
Pyrogens: Substances that cause fever
18.5 Adaptive Immunity
18.5.1 Characteristics
Specificity: Recognizes specific antigens
Memory: Faster, stronger response upon re-exposure
Self-tolerance: Normally doesn’t attack self
Requires prior exposure: Initial response takes days
18.5.2 Antigens and Epitopes
Antigen: Substance that elicits immune response
Epitope: Specific part of antigen recognized
Hapten: Small molecule that becomes antigenic when attached to carrier
18.5.3 Major Histocompatibility Complex (MHC)
MHC class I: Present on all nucleated cells
- Presents: Endogenous antigens (viral proteins, tumor antigens)
- Recognized by: CD8+ T cells
MHC class II: Present on antigen-presenting cells (APCs)
- Presents: Exogenous antigens (bacterial proteins)
- Recognized by: CD4+ T cells
MHC polymorphism: Many alleles in population → diverse recognition
18.5.4 B Lymphocytes (Humoral Immunity)
Development: Bone marrow
Maturation: Bone marrow (mammals), bursa (birds)
Antigen receptor: B cell receptor (BCR) = membrane-bound antibody
Activation: 1. Antigen binding to BCR 2. T helper cell help (for protein antigens) 3. Differentiation: Into plasma cells and memory B cells
Antibody structure:
- Heavy and light chains: Constant and variable regions
- Fab: Antigen-binding fragment
- Fc: Constant fragment (determines class)
Antibody classes:
- IgM: First response, pentamer
- IgG: Most abundant, crosses placenta
- IgA: Secretions (mucus, milk)
- IgE: Allergies, parasites
- IgD: B cell receptor
Antibody functions:
- Neutralization: Blocks binding sites
- Opsonization: Enhances phagocytosis
- Complement activation: Classical pathway
- ADCC: Antibody-dependent cellular cytotoxicity
18.5.5 T Lymphocytes (Cell-mediated Immunity)
Development: Bone marrow
Maturation: Thymus (positive and negative selection)
Types:
- Helper T cells (CD4+): Activate other cells (Th1, Th2, Th17, Treg)
- Cytotoxic T cells (CD8+): Kill infected/cancer cells
- Memory T cells: Long-lived protection
- Regulatory T cells (Treg): Suppress immune responses
T cell receptor (TCR): Recognizes antigen + MHC
Co-receptors: CD4 (MHC II), CD8 (MHC I)
Activation:
- Antigen presentation by APC
- Co-stimulation (e.g., CD28-B7 interaction)
- Cytokine signals
Effector functions:
- Cytotoxic T cells: Release perforin, granzymes, Fas ligand
- Helper T cells: Release cytokines that activate other cells
18.5.6 Immune Response Dynamics
Primary response: First exposure, lag phase, IgM then IgG
Secondary response: Memory cells respond faster, higher affinity IgG
Clonal selection: Specific clones expand upon antigen encounter
Affinity maturation: Somatic hypermutation improves antibody affinity
18.6 Immunological Memory and Vaccination
18.6.1 Basis of Immunological Memory
Memory cells: Long-lived B and T cells
- More numerous than naive cells
- Lower activation threshold
- Faster proliferation and differentiation
Characteristics of memory:
- Specificity: Same antigen
- Duration: Years to lifetime
- Enhanced response: Higher magnitude, faster
18.6.2 Types of Immunity
Active immunity: Individual produces own immune response
- Natural: Infection
- Artificial: Vaccination
Passive immunity: Receiving pre-formed antibodies
- Natural: Maternal antibodies (placenta, breast milk)
- Artificial: Immune globulin, antivenom
18.6.3 Vaccination Principles
Goals: Induce memory without causing disease
Types of vaccines:
- Live attenuated: Weakened pathogen (MMR, oral polio)
- Inactivated/killed: Dead pathogen (influenza, polio injection)
- Subunit: Parts of pathogen (hepatitis B, HPV)
- Toxoid: Inactivated toxin (tetanus, diphtheria)
- mRNA/DNA: Genetic material encoding antigen (COVID-19 mRNA vaccines)
Herd immunity: Protection of unvaccinated when enough population immune
Vaccination schedules: Based on immune system development, pathogen exposure risk
18.7 Immunological Disorders
18.7.1 Autoimmune Diseases
Failure of self-tolerance: Immune system attacks self
Mechanisms:
- Molecular mimicry: Pathogen antigen resembles self
- Release of sequestered antigens: From privileged sites
- Polyclonal B cell activation: Non-specific stimulation
- Genetic predisposition: HLA associations
Examples:
- Type 1 diabetes: Anti-islet cell antibodies
- Rheumatoid arthritis: Anti-IgG antibodies (rheumatoid factor)
- Multiple sclerosis: Anti-myelin antibodies
- Systemic lupus erythematosus: Anti-nuclear antibodies
18.7.2 Hypersensitivities (Allergies)
Type I (Immediate): IgE-mediated (anaphylaxis, hay fever)
- Sensitization: IgE production to allergen
- Re-exposure: Allergen cross-links IgE on mast cells → degranulation
- Mediators: Histamine, leukotrienes, prostaglandins
- Treatment: Antihistamines, epinephrine, desensitization
Type II (Cytotoxic): Antibody-mediated cell destruction (blood transfusion reactions)
Type III (Immune complex): Antigen-antibody complexes deposit in tissues (serum sickness)
Type IV (Delayed): T cell-mediated (contact dermatitis, TB test)
18.7.3 Immunodeficiencies
Primary (congenital): Genetic defects present at birth
- Severe combined immunodeficiency (SCID): Defective T and B cells (“bubble boy” disease)
- X-linked agammaglobulinemia: Defective B cell development
- Chronic granulomatous disease: Defective phagocyte oxidative burst
- DiGeorge syndrome: Thymic aplasia
Secondary (acquired): Caused by external factors
- HIV/AIDS: CD4+ T cell depletion
- Malnutrition: Protein-energy malnutrition impairs immunity
- Medications: Chemotherapy, immunosuppressants
- Aging: Thymic involution, decreased immune function
Treatment: Antibiotics, immunoglobulin replacement, stem cell transplantation, gene therapy
18.8 Immune System Interactions
18.8.1 Neuroendocrine-Immune Axis
Bidirectional communication:
- Stress effects: Cortisol suppresses immune function
- Sickness behavior: Cytokines induce fever, fatigue, social withdrawal
- Psychoneuroimmunology: Mind-body connections in health and disease
Hormonal regulation:
- Sex hormones: Estrogen enhances, testosterone suppresses immunity
- Growth hormone/IGF-1: Enhance immune function
- Melatonin: Modulates circadian rhythms of immune cells
18.8.2 Microbiome and Immunity
Gut microbiome: Trillions of microbes influence immune development
Functions:
- Training: Educates immune system to distinguish pathogens from commensals
- Competition: Commensals outcompete pathogens for resources
- Metabolites: Short-chain fatty acids regulate immune responses
- Barrier function: Maintains intestinal epithelial integrity
Dysbiosis: Imbalanced microbiome linked to autoimmune diseases, allergies
18.8.3 Cancer Immunology
Cancer immunosurveillance: Immune system detects and eliminates cancer cells
Evasion mechanisms:
- Loss of antigenicity: Reduced MHC expression
- Immunosuppression: Secretion of TGF-β, IL-10
- Checkpoint expression: PD-L1 binds PD-1 on T cells, inhibiting them
Immunotherapies:
- Checkpoint inhibitors: Anti-PD-1, anti-CTLA-4 antibodies
- CAR-T cells: Engineered T cells with chimeric antigen receptors
- Cancer vaccines: Stimulate immune response against tumor antigens
18.9 Transplantation Immunology
18.9.1 Histocompatibility
Major histocompatibility antigens: MHC proteins (HLA in humans)
Minor histocompatibility antigens: Other polymorphic proteins
ABO blood group antigens: Important in organ transplantation
18.9.2 Types of Transplants
Autograft: Self to self (skin grafts, bone marrow autotransplant)
Isograft: Genetically identical donor (identical twins)
Allograft: Same species, different genetics (most organ transplants)
Xenograft: Different species (pig heart valves, experimental)
18.9.3 Rejection Mechanisms
Hyperacute rejection: Minutes to hours, pre-existing antibodies
Acute rejection: Days to weeks, T cell-mediated
Chronic rejection: Months to years, vascular changes, fibrosis
18.9.4 Immunosuppression
Drugs:
- Calcineurin inhibitors: Cyclosporine, tacrolimus
- Antiproliferatives: Azathioprine, mycophenolate
- mTOR inhibitors: Sirolimus, everolimus
- Corticosteroids: Prednisone
Complications: Increased infection risk, cancer, drug toxicity
18.9.5 Graft-versus-Host Disease (GVHD)
Occurs when: Donor immune cells attack recipient tissues
Common in: Bone marrow transplantation
Prevention: HLA matching, T cell depletion, immunosuppression
18.10 Emerging Topics in Immunology
18.10.1 Systems Immunology
High-throughput approaches: Transcriptomics, proteomics, metabolomics
Single-cell analysis: Reveals heterogeneity within immune cell populations
Computational modeling: Predicts immune responses, vaccine efficacy
18.10.2 Trained Immunity
Innate immune memory: Epigenetic reprogramming of innate cells
Mechanisms: Metabolic changes, histone modifications
Implications: Vaccines that protect beyond specific pathogens
18.10.3 Precision Immunology
Personalized vaccines: Based on individual immune profiles
Biomarkers: Predict disease susceptibility, treatment response
Theragnostic approaches: Combine diagnosis and treatment
18.10.4 One Health Immunology
Zoonotic diseases: Understanding spillover from animals to humans
Environmental immunology: Effects of pollution, climate change
Planetary health: Global approaches to infectious diseases
18.11 Chapter Summary
18.11.1 Key Concepts
- Immune system protects against pathogens through layered defenses
- Innate immunity provides rapid, non-specific protection
- Adaptive immunity provides specific, memory-based protection
- B cells mediate humoral immunity via antibodies
- T cells mediate cellular immunity via direct killing and helper functions
- Immunological memory enables faster, stronger responses upon re-exposure
- Vaccination harnesses immunological memory to prevent disease
- Immunological disorders include autoimmune diseases, allergies, and immunodeficiencies
- Immune system interacts with nervous, endocrine systems and microbiome
- Immunology applications include cancer therapy, transplantation, and emerging fields
18.11.2 Three Lines of Defense
| Line | Components | Response Time | Specificity | Memory |
|---|---|---|---|---|
| First | Skin, mucous membranes, chemical barriers | Immediate | Non-specific | None |
| Second | Phagocytes, NK cells, complement, inflammation | Minutes-hours | Pattern recognition | None |
| Third | B cells, T cells, antibodies | Days (first), hours (memory) | Highly specific | Yes |
18.11.3 Immune Cell Types
| Cell Type | Origin | Major Functions | Key Features |
|---|---|---|---|
| Neutrophil | Bone marrow | Phagocytosis, first responder | Most abundant, multilobed nucleus |
| Macrophage | Monocyte (blood) | Phagocytosis, antigen presentation, tissue repair | Tissue-resident, versatile |
| Dendritic cell | Bone marrow | Antigen presentation (best APC) | Many processes, link innate/adaptive |
| Natural killer cell | Bone marrow | Kill virus-infected/cancer cells | No prior sensitization needed |
| B cell | Bone marrow | Antibody production, antigen presentation | Surface immunoglobulin, memory cells |
| Helper T cell | Thymus (via bone marrow) | Activate other immune cells | CD4+, multiple subsets (Th1, Th2, etc.) |
| Cytotoxic T cell | Thymus (via bone marrow) | Kill infected/cancer cells | CD8+, perforin/granzyme release |
| Regulatory T cell | Thymus (via bone marrow) | Suppress immune responses | CD4+CD25+FoxP3+, prevent autoimmunity |
18.11.4 Antibody Classes
| Class | Structure | Location | Functions | Special Features |
|---|---|---|---|---|
| IgM | Pentamer | Blood, lymph | First response, complement activation | Largest, 10 binding sites |
| IgG | Monomer | Blood, tissue fluids | Main blood antibody, crosses placenta | Most abundant, longest half-life |
| IgA | Dimer | Secretions (mucus, milk) | Mucosal immunity, neutralization | Secretory component protects from enzymes |
| IgE | Monomer | Bound to mast cells/basophils | Allergies, parasite defense | Lowest concentration, binds Fcε receptors |
| IgD | Monomer | B cell surface | B cell receptor | Function not fully understood |
18.11.5 Hypersensitivity Types
| Type | Name | Mechanism | Time Course | Examples |
|---|---|---|---|---|
| I | Immediate (allergic) | IgE, mast cell degranulation | Minutes | Anaphylaxis, hay fever, asthma |
| II | Cytotoxic | Antibody vs. cell surface antigens | Hours-days | Blood transfusion reactions, hemolytic disease |
| III | Immune complex | Antigen-antibody complexes deposit | Days-weeks | Serum sickness, lupus nephritis |
| IV | Delayed | T cell-mediated | 2-3 days | Contact dermatitis, TB test, graft rejection |
18.11.6 Immunodeficiency Types
| Type | Cause | Examples | Key Features |
|---|---|---|---|
| Primary | Genetic defects | SCID, X-linked agammaglobulinemia | Present from birth, often severe |
| Secondary | External factors | HIV/AIDS, malnutrition, drugs | Acquired, may be reversible |
| Combined | T and B cell defects | SCID, Wiskott-Aldrich syndrome | Severe infections, poor prognosis |
| Humoral | B cell/antibody defects | X-linked agammaglobulinemia, CVID | Bacterial infections |
| Cellular | T cell defects | DiGeorge syndrome, HIV (late) | Viral/fungal infections, cancer |
| Phagocytic | Phagocyte defects | Chronic granulomatous disease | Bacterial/fungal infections, granulomas |
| Complement | Complement defects | C1-C9 deficiencies | Bacterial infections, autoimmune-like |
18.12 Review Questions
18.12.1 Level 1: Recall and Understanding
- List and describe the three lines of defense against pathogens.
- What are the main differences between innate and adaptive immunity?
- Describe the structure of an antibody and the functions of its different regions.
- What are the four types of hypersensitivity reactions, and what mechanisms underlie each?
- Explain the difference between active and passive immunity, giving examples of each.
18.12.2 Level 2: Application and Analysis
- A patient has recurrent bacterial infections but normal viral resistance. What type of immunodeficiency might this suggest, and why?
- Explain why a booster shot is often needed for vaccines, referring to immunological memory.
- How do cytotoxic T cells recognize and kill virus-infected cells?
- Compare and contrast the primary and secondary immune responses in terms of timing, antibody classes produced, and antibody affinity.
- Why might an immunosuppressed transplant recipient be at increased risk for certain cancers?
18.12.3 Level 3: Synthesis and Evaluation
- Design an experiment to determine whether a new vaccine candidate induces both humoral and cellular immunity.
- Evaluate the ethical considerations of using fetal tissues in vaccine development and testing.
- How has our understanding of checkpoint molecules in cancer immunology transformed cancer treatment?
- Propose a strategy for developing a universal flu vaccine that would provide protection against multiple strains.
18.13 Key Terms
- Antigen: Substance that elicits an immune response
- Antibody: Protein produced by B cells that binds specifically to antigens
- Pathogen: Disease-causing organism
- Phagocytosis: Engulfment and destruction of particles by cells
- Inflammation: Local response to tissue damage or infection
- Cytokine: Signaling protein that mediates immune responses
- Major histocompatibility complex (MHC): Cell surface proteins that present antigens to T cells
- B cell: Lymphocyte that produces antibodies
- T cell: Lymphocyte that mediates cellular immunity
- Immunological memory: Ability to mount faster, stronger response upon re-exposure
- Vaccination: Administration of antigen to induce protective immunity
- Autoimmunity: Immune response against self-antigens
- Hypersensitivity: Excessive immune response causing tissue damage
- Immunodeficiency: Impaired immune function
- Tolerance: Lack of immune response to specific antigens
- Complement: Group of plasma proteins that enhance immune responses
18.14 Further Reading
18.14.1 Books
- Janeway, C. A., Travers, P., Walport, M., & Shlomchik, M. J. (2001). Immunobiology: The Immune System in Health and Disease (5th ed.). Garland Science.
- Abbas, A. K., Lichtman, A. H., & Pillai, S. (2017). Cellular and Molecular Immunology (9th ed.). Elsevier.
- Murphy, K., & Weaver, C. (2016). Janeway’s Immunobiology (9th ed.). Garland Science.
18.14.2 Scientific Articles
- Burnet, F. M. (1957). A modification of Jerne’s theory of antibody production using the concept of clonal selection. Australian Journal of Science, 20, 67-69.
- Medzhitov, R., & Janeway, C. A. (1997). Innate immunity: The virtues of a nonclonal system of recognition. Cell, 91(3), 295-298.
- Allison, J. P. (2015). Immune checkpoint blockade in cancer therapy: The 2015 Lasker-DeBakey Clinical Medical Research Award. JAMA, 314(11), 1113-1114.
18.14.3 Online Resources
- The Immune System (NIH): https://www.niaid.nih.gov/research/immune-system
- Immunology Online: https://www.immunology.org
- Vaccine Education Center (CHOP): https://www.chop.edu/centers-programs/vaccine-education-center
- American Academy of Allergy, Asthma & Immunology: https://www.aaaai.org
18.15 Quantitative Problems
- Antibody-Antigen Binding: An antibody binds to its antigen with association constant Ka = 10⁸ M⁻¹.
- What is the dissociation constant Kd?
- If the antigen concentration is 10 nM, what fraction of antibody binding sites are occupied?
- What antigen concentration is needed for 90% occupancy?
- How does affinity maturation improve antibody binding (quantitatively)?
- Immune Cell Numbers: A human has approximately 5 liters of blood with 5 × 10⁹ white blood cells per liter.
- How many total white blood cells are in circulation?
- If 70% are neutrophils, 20% are lymphocytes, and 10% are others, how many of each?
- During an infection, neutrophil count increases 5-fold. What is the new total?
- Lymphocytes recirculate between blood and lymph. If they spend 30 minutes in blood per cycle, how many pass through blood per day?
- Vaccine Herd Immunity: Herd immunity threshold = 1 - 1/R₀, where R₀ is basic reproduction number. For measles, R₀ ≈ 15; for polio, R₀ ≈ 6; for COVID-19 (original strain), R₀ ≈ 3.
- Calculate herd immunity threshold for each disease.
- If vaccine efficacy is 95%, what vaccination coverage is needed?
- If a population of 10 million has 85% vaccination with 95% efficacy for measles, how many are susceptible?
- If one case is introduced, how many secondary cases would occur?
18.16 Case Study: HIV/AIDS
Background: HIV (human immunodeficiency virus) causes AIDS (acquired immunodeficiency syndrome) by destroying CD4+ T cells. Since its discovery in the 1980s, HIV has caused over 35 million deaths but is now manageable with antiretroviral therapy.
Questions:
- How does HIV enter and replicate in CD4+ T cells?
- Why does HIV specifically deplete CD4+ T cells, and what are the consequences?
- How do antiretroviral drugs target different stages of the HIV life cycle?
- Why has developing an HIV vaccine been so challenging?
- What are the prospects for an HIV cure (e.g., “Berlin patient,” gene editing)?
Data for analysis:
- Transmission: Sexual contact, blood, mother-to-child
- Progression: Acute infection → clinical latency → AIDS (without treatment)
- Treatment: Combination antiretroviral therapy (cART) suppresses viral load
- Prevention: PrEP (pre-exposure prophylaxis), PEP (post-exposure prophylaxis), condoms
- Epidemiology: ~38 million people living with HIV worldwide (2021)
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