Notes on Host Defenses and Adaptive Immunity (McGraw Hill Transcript)

Three Lines of Defense That Protect The Human Body From Pathogens

• Three lines of defense (Course Outcome 9):

  • First Line of Defense: Barriers that block invasion at the portal of entry; does not involve recognition of foreign substances; general in action; nonspecific.

  • Second Line of Defense: Internalized system of protective cells and fluids; inflammation and phagocytosis; acts rapidly at local and systemic levels; nonspecific.

  • Third Line of Defense: Acquired on an individual basis as each foreign substance is encountered by lymphocytes; produces unique protective substances and cells that can come into play if the microbe is encountered again; provides long-term immunity.

Major Components of Host Defenses

• First Line of Defense

  • Barriers block invasion at portal of entry; non-specific and non-recognition-based.

• Second Line of Defense

  • Internalized system: inflammatory response, phagocytosis, complement, interferons, etc.; rapid, non-specific.

• Third Line of Defense

  • Adaptive immunity: specificity and memory; involves lymphocytes (T and B cells) and their products; long-term immunity.

White Blood Cells: Granulocytes

• Granulocytes are a class of white blood cells with cytoplasmic granules; include:

  • Neutrophils: phagocytic; found in blood; first to respond; increase during bacterial infections; participate in inflammatory events; usually in low numbers in steady state.

  • Eosinophils: elevated in allergic reactions; active in protozoal and helminth reactions; usually found in low numbers.

  • Basophils: found in the tissues (and linked to allergic responses); contain histamine; function in inflammatory responses; present in low numbers.

  • (Note: Some descriptions mention similarities to mast cells in tissues and histamine content when discussing basophil-like effectors.)

White Blood Cells: Agranulocytes

• Monocytes

  • Blood phagocytes that rapidly leave the circulation; mature into macrophages and dendritic cells.

• Macrophages

  • Large phagocytic cells; high capacity for killing microbes and cleaning up dead cells; antigen-presenting cells (APCs).

• Dendritic cells

  • Reside in tissues and MPS (mononuclear phagocyte system); process foreign matter and present it to lymphocytes; antigen-presenting cells.

• Lymphocytes

  • T cells: cell-mediated immunity; assist B cells.

  • B cells: differentiate into plasma cells and release antibodies; antigen-presenting cells.

  • Natural killer (NK) cells: related to T cells but do not act specifically.

Phagocytosis: Phases and Mechanisms

• Step 1: Chemotaxis — Phagocytes move to the site of injury following chemical trails from damaged tissues.

• Step 2: Pattern Recognition Receptors (PRRs) recognize Pathogen-Associated Molecular Patterns (PAMPs) on microbes (e.g., markers common to many microbes).

  • Examples of PAMPs: $ext{Peptidoglycan}, ext{Bacterial flagella}, ext{LPS}, ext{Teichoic acids}$

• Steps 3–4: Engulfment into phagocytic vacuole and formation of phagosome; adhesion of bacteria; PRR on host cell; lysosomes fuse to form phagolysosome; involvement of Golgi apparatus and rough endoplasmic reticulum in processing.

• Step 5: Formation of phagolysosome.

• Step 6: Killing and destruction of bacterial cells via enzymes and reactive oxygen species (ROS):

  • Enzymes: Lysozyme, DNase, RNase, Proteases, Peroxidase.

  • ROS: $\text{Superoxide} (O<em>2^-), \, \text{Hydrogen peroxide} (H</em>2O<em>2), \, \text{Singlet oxygen} (^1O</em>2), \, \text{Hydroxyl radical} (\cdot OH)$

• Step 7: Release of debris (not all debris is released; some is presented to T cells later).

• Not all phagocytosis is perfect: some microbes (e.g., Mycobacterium tuberculosis) can resist degradation due to capsule/structural features that impair phagosome/lysosome fusion.

Antiviral Activity of Interferons

• Virus-infected cells synthesize interferons (IFNs) and release them to nearby cells.

• IFNs bind to receptors on nearby cells and induce expression of antiviral proteins.

• This leads to degradation of viral nucleic acids and blocks viral replication in the neighboring cells.

• Overall process: synthesis of IFN → signaling to adjacent cells → activation of antiviral genes → antiviral proteins degrade viral nucleic acids and inhibit replication.

The Complement System

• Complement pathways (three main routes) lead to inflammation, opsonization, and lysis of microbes:

  • Classical pathway: activation by antibodies bound to antigen.

  • Lectin pathway: activation by mannose-binding lectin (MBL) binding to carbohydrate patterns on microbes.

  • Alternative pathway: activation on microbial surfaces in the absence of antibodies.

• Key components and outcomes:

  • C3 and C3b mediate opsonization and inflammation; C3 convertases propagate the cascade.

  • C5a acts as a potent inflammatory mediator.

  • C5b–C9 form the Membrane Attack Complex (MAC) that lyses microbes.

• Overall: INFLAMMATION, PHAGOCYTOSIS, and MEMBRANE ATTACK COMPLEX formation against microbes.

Adaptive Immunity: Characteristics of Specific Immunity

• Specificity: Response can be focused on a single antigen.

• Diversity: At least one cell can react against any potential antigen.

• Inducibility: Activation occurs only when triggered.

• Clonality: Millions of cells with the same specificity are generated.

• Tolerance: Immune system does not react with self-antigens.

• Memory: Rapid mobilization of lymphocytes preprogrammed to recall prior antigen exposure.

Antigen, Epitope, and Hapten; Adjuvant

• Antigen: Substances that can be seen and identified by the immune system; sometimes described as the generator of antibodies.

• Epitope: The specific region of an antigen recognized by the immune system.

• Hapten: A small molecule that binds to a carrier molecule to become immunogenic.

• Adjuvant: A small molecule that must bind to a carrier to enhance immunogenicity.

B-Cell (Antibody-Mediated) Immunity: Development, Activation, and Function

• Immunoglobulin (Ig) structure: Variable region, light chain, constant region, heavy chain; the B-cell receptor (BCR) recognizes antigen; B cells mature in the bone marrow; MHC II marker is expressed on B cells for antigen presentation to helper T cells.

• B-Cell development: Occurs in the bone marrow; naive B cells express membrane-bound Ig and MHC II.

• Activation and differentiation:

  • Antigen binding to the BCR (Ig receptor) along with signals from helper T cells leads to B-cell activation.

  • Antigen processing and presentation by B cells on MHC-II to CD4+ T helper cells is a key step (linked recognition).

  • Following activation, B cells proliferate and differentiate into plasma cells (antibody-secreting) and memory B cells; regulatory cells may secrete IL-10 to modulate T-cell responses.

• B-cell lineages after activation: plasma cells, memory B cells, and regulatory cells.

Immunoglobulin Classes: Structures and Functions

• The five major classes of immunoglobulins: $IgM, \ IgA, \ IgD, \ IgG, \ IgE$

• IgM: First to respond to infection or vaccination; can be formed by a fetus; found in secretions; produced in colostrum; protects infant gut.

• IgA: Predominant in secretions; found in mucosal areas and in colostrum; protects mucosal surfaces.

• IgD: BCR on mature B cells; low circulating levels.

• IgG: Dominant in circulation; crosses the placenta; produced in colostrum; neutralizes toxins; long half-life; involved in allergies and parasitic defenses; present on B cells; relatively low in some secretions.

• IgE: Involved in allergies and parasite defense; present on B cells; low in circulation.

Functions and Effects of Antibodies

• Antibodies bind to antigens but do not kill directly; they facilitate other immune mechanisms:

  • Opsonization: Antibodies coat a microbe, enabling macrophages to recognize and engulf more readily. Opsonins enhance phagocytosis by increasing binding affinity.

  • Neutralization: Antibodies bind to viral surface receptors or toxin active sites, blocking attachment and function.

  • Agglutination: Antibodies cross-link antigens, forming large aggregates that immobilize pathogens and enhance phagocytosis.

  • Complement activation: Antibody interaction can activate complement, leading to lysis of microbes.

  • Toxin neutralization: Antibodies neutralize exotoxins produced by bacteria.

  • Cross-linking and aggregation can lead to improved clearance.

• Antibody-mediated agglutination and opsonization are foundational for diagnostic tests in some contexts.

• Toxin-binding antibodies neutralize bacterial toxins.

T Cells and Cell-Mediated Immunity

• T-Cell Lineages:

  • Helper T cells (CD4+): assist other immune cells; activate B cells and cytotoxic T cells; can differentiate into TH1 or TH2 subsets; memory T cells form after activation.

  • Cytotoxic T cells (CD8+): recognize and kill infected host cells presenting antigen with MHC I; generation of memory cytotoxic T cells.

  • Regulatory T cells (subset not detailed here) help modulate immune responses.

• Antigen presentation and T-cell activation:

  • Antigen-presenting cells (APCs) process antigen and present to helper and cytotoxic T cells via MHC molecules.

  • Most B cells require stimulation from helper T cells activated by antigen.

• MHC restriction:

  • CD8+ T cells recognize antigens presented on MHC class I molecules.

  • CD4+ T cells recognize antigens presented on MHC class II molecules.

Major Histocompatibility Complex (MHC)

• MHC Class I: On all nucleated cells; recognized by CD8+ cytotoxic T cells.

• MHC Class II: On antigen-presenting cells (macrophages, dendritic cells, monocytes, B cells); recognized by CD4+ helper T cells.

B-Cell and T-Cell Cooperation (Linked Recognition)

• Activated B cells require help from T helper cells that have been activated by the same antigen.

• Process:
  1) Antigen binding and processing by B cell; presentation on MHC-II to a helper T cell.
  2) Helper T cell activation and production of growth factors (e.g., interleukins) that stimulate B-cell growth and activation.
  3) B cell activation and clonal expansion.

• Result: production of antibodies by plasma cells, formation of memory B cells, and continued T-cell help.

Helper T Cells and Memory

• Activated helper T cells can generate memory helper T cells (CD4+); they help drive B-cell maturation and antibody production.

• Cytokines involved include IL-4, IL-2, IFN-γ, among others that promote B-cell growth and differentiation.

T Cells: Activation of Cytotoxic T Cells and Memory

• Activated helper T cells aid in the activation of cytotoxic T cells.

• Activated cytotoxic T cells differentiate into memory T cells and fully functional effector CTLs to destroy infected host cells.

Antibody Titer and Primary vs Secondary Immune Responses

• Primary response: after first exposure to an antigen; a latent period precedes detectable antibodies; gradual build-up of IgM followed by IgG.

• Secondary response: upon subsequent exposure; faster and stronger antibody production due to memory cells; higher titer and faster clearance.

• Antibody titer reflects concentration of antibodies in serum and correlates with protection.

Acquired Immunity: Four Types (Passive vs Active; Natural vs Artificial)

• Passive Immunity

  • Individuals receive antibodies produced outside their own body; no memory; short-term protection.

  • Natural: antibodies transferred from mother to fetus (placental transfer) or via breast milk; Artificial: immune globulin injections.

• Active Immunity

  • Individual produces their own immune response with memory; long-lasting protection.

  • Natural: infection with pathogen; Artificial: vaccines or administered antiserum to stimulate immunity.

• Summary examples:

  • Natural Passive: mother’s antibodies protect the fetus or newborn.

  • Artificial Passive: immune globulin given after exposure.

  • Natural Active: recovery from infection leading to immunity.

  • Artificial Active: vaccination creating memory without disease.

Integumentary System and Eye Diseases (Selected Topics)

• Necrotizing fasciitis: polymicrobial infection with rapid tissue destruction; can be caused by multiple bacteria including Clostridium perfringens, Streptococcus pyogenes, Staphylococcus aureus; rapid progression due to tissue-destructive enzymes and bacterial spread; superantigen-mediated T-cell activation; high mortality; treatment with broad-spectrum antibiotics.

• Chickenpox and Shingles: Varicella Zoster Virus (VZV); itchy rash with fluid-filled vesicles; shingles is reactivation of latent VZV.

• Smallpox: Variola virus; fever, vomiting, mouth ulcers, a characteristic vesicular/pustular rash; eradicated via vaccination; historic context.

• Hand, Foot, and Mouth Disease (HFMD): Coxsackievirus infections; fever, sore throat, malaise; painful oral/blister lesions on hands, feet, and possibly genitals.

• Measles: measles virus; Koplik’s spots early; red maculopapular rash; risk of subacute sclerosing panencephalitis as a serious complication.

• Rubella: rubella virus; mild flat rash; risk to fetus if contracted during pregnancy; vaccination with MMR reduces risk.

• Ocular Trachoma: caused by Chlamydia trachomatis; major global cause of blindness; chronic infection leads to inflammatory damage.

Nervous System Diseases

• Meningitis: inflammation of meninges; various microbes can cause meningitis but produce a similar syndrome; common causative agents include Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, Listeria monocytogenes; signs include photophobia, headache, neck stiffness, fever, and increased WBC in CSF.

• Creutzfeldt–Jakob Disease (CJD): prions cause transmissible spongiform encephalopathies and neurological degeneration; examples include CJD, Kuru, fatal familial insomnia; transmission via contaminated instruments or consumption of infected meat.

• Rabies: caused by Rabies virus; two forms: furious (agitation, hydrophobia, seizures) and paralytic (paralysis, stupor); progresses to coma and death.

• Tetanus: caused by Clostridium tetani; neurotoxin tetanospasmin leads to spastic paralysis by blocking inhibition of muscle contraction; death from respiratory failure.

• Wound Botulism: caused by Clostridium botulinum; forms include foodborne, infant, and wound botulism; botulinum toxin blocks acetylcholine release causing flaccid paralysis; treatment and prevention strategies.

Cardiovascular and Lymphatic System Diseases

• Sepsis: bacterial infection in the blood; septicemia with bacteria thriving in the bloodstream; can lead to decreased blood pressure and septic shock; signs include fever, chills, rapid breathing, and GI symptoms; progression can involve vascular leakage and organ dysfunction.

• COVID-19: caused by SARS-CoV-2; prominent respiratory symptoms; can trigger cytokine storm and hyperinflammation affecting lungs and other organs (skin, muscle, heart, GI); neurotropic features include loss of taste and smell and potential long-term cognitive effects.

• Endocarditis: infection of heart valves; commonly caused by Staphylococcus aureus, Streptococcus species; acute signs include fever, anemia, petechiae, abnormal heart rhythm.

• Lyme Disease: Borrelia burgdorferi; early bull’s-eye rash; fever, headache, stiff neck, dizziness; may progress to cardiac and neurological symptoms and later to crippling polyarthritis.

• Human Immunodeficiency Virus (HIV)/AIDS: retrovirus causing immune deficiency; associated with opportunistic infections such as Pneumocystis jiroveci pneumonia and Kaposi’s sarcoma; systemic symptoms include weight loss, swollen lymph nodes, and immune dysfunction; signs/symptoms correlate with CD4+ T-cell counts.

Respiratory System Diseases

• Pharyngitis: inflammation of the throat; causative agents include viruses (common cold) and Streptococcus pyogenes; may lead to scarlet fever, rheumatic fever, or glomerulonephritis if untreated.

• Influenza: caused by influenza A, B, or C viruses; symptoms include fever, headache, dry cough, myalgia, fatigue; potential for secondary pneumonia; virulence factors include:

  • Hemagglutinin (H): mediates binding to host receptors; agglutination of RBCs;

  • Neuraminidase (N): aids viral release and spread; helps in host cell fusion.

  • Antigenic drift: small, frequent antigen changes reducing memory recognition.

  • Antigenic shift: major reassortment events often causing pandemics.

  • Treatments: Tamiflu; vaccines (three major types in the US); vaccines generally do not cause influenza; ongoing development of universal vaccines targeting conserved H regions.

• Whooping Cough (Pertussis): Bordetella pertussis; phases include Catarrhal (cold-like symptoms) and Paroxysmal (severe coughing with whoop); virulence factors include filamentous hemagglutinin (attachment), pertussis toxin (mucus overproduction), tracheal cytotoxin (ciliated cell damage), endotoxin; treatment with Azithromycin; prevention via vaccination with boosters after age 11.

• Tuberculosis: caused by Mycobacterium tuberculosis; transmitted by aerosol droplets; infectious dose ≈ $10$ bacteria; primary TB often asymptomatic; secondary (reactivation) TB is more severe with violent coughing, sputum production, night sweats, and weight loss; waxy cell wall resists phagolysosome formation, aiding persistence.

Gastrointestinal System Diseases

• Gastritis and Gastric Ulcers: Helicobacter pylori infection; infections may cause sharp/burning abdominal pain and lesions in the stomach or duodenum; infects about $50\%$ of the world’s population; transmission via oral-oral or oral-fecal routes.

• Shiga-toxin-producing Escherichia coli (STEC) O157:H7: range from mild gastroenteritis to bloody diarrhea; can cause hemolytic uremic syndrome (HUS) and kidney injury.

• Traveler’s Diarrhea: Enterotoxigenic E. coli (ETEC); watery diarrhea, low-grade fever, nausea, and vomiting.

• Clostridioides difficile: part of normal intestinal flora; caused by broad-spectrum antibiotic use; produces enterotoxins A and B causing necrosis; treatment includes stopping antibiotics, fluid replacement, and agents like fidaxomicin or vancomycin; fecal microbiota transplant discussed as option.

Genitourinary System Diseases

• Vaginitis due to Candida albicans: inflammation with itching, burning, discharge; candida infection; antifungal treatment.

• Syphilis: caused by Treponema pallidum; stages include:

  • Primary syphilis: chancre at site of entry (genital, oral, or other sites).

  • Secondary syphilis: widespread rash (including palms and soles); often with hair loss.

  • Latent syphilis: bacteria present but undetectable clinically; antibodies detectable.

  • Tertiary syphilis: gummas in liver, skin, bone, cartilage; neurosyphilis (headache, convulsions, blindness, dementia).

• Historical note: USPHS Untreated Syphilis Study at Tuskegee (1932–1972) involved 399 African-American men; participants were not informed of their infection; penicillin G discovered in 1943 but not provided to participants; unethical conduct and public outcry.

Ethical and Practical Implications

• Historical case study: The Tuskegee syphilis study highlights ethical issues in medical research, informed consent, and the obligation to provide effective treatment to participants when it becomes available.

• Public health relevance: Vaccination, herd immunity, and ethical considerations around experimental treatments and access to care.

Key Formulas and Notations Used

• Viral antigens and immune recognition involve multiple components and pathways; representative symbols used in lecture materials include:

  • $H$ (Hemagglutinin) and $N$ (Neuraminidase) as influenza virulence factors.

  • Antibody isotypes represented as $IgM, IgA, IgD, IgG, IgE$.

  • Inflammatory and oxidative species in phagocytosis: $O<em>2^- , H</em>2O<em>2, \; ^1O</em>2, \; \cdot OH$.

  • Percentages and infectious doses cited in slides: e.g., $50\%$ infection prevalence for H. pylori; infectious dose for TB ≈ $10$ bacteria; three major types of vaccines for influenza in the US: $3$.

Connections to Foundational Principles and Real-World Relevance

• Innate vs Adaptive Immunity: Innate responses provide rapid, non-specific defense and help shape adaptive responses, which provide specificity, memory, and long-term protection.

• Antigen presentation and T-B cell cooperation illustrate the importance of cell-cell communication and signaling (cytokines like IL-2, IL-4, IFN-γ) in coordinating immune responses.

• Vaccination and acquired immunity: Immunization strategies mimic natural infections to develop memory without disease, reducing morbidity and mortality from infectious diseases.

• Clinical relevance: Understanding virulence factors (H and N in influenza), immune evasion (e.g., TB’s waxy cell wall), and opportunistic pathogens (C. difficile) informs diagnostics, treatment, and public health interventions.

Quick Recap: Core Concepts to Remember

• Innate vs Adaptive immunity; three lines of defense; roles of barriers, phagocytes, inflammation, and lymphocytes.

• Phagocytosis steps and key molecules (PRRs, PAMPs, lysosomes, ROS).

• Antiviral actions of interferons; complement system pathways and outcomes.

• Antibody structure, classes, and effector functions (opsonization, neutralization, agglutination, complement activation).

• B-cell development, activation, and differentiation into plasma cells and memory B cells; T-cell maturation, MHC restriction; helper vs cytotoxic roles; linked recognition.

• Vaccination concepts and the distinction between primary and secondary immune responses (timing and antibody titers).

• Major infectious diseases across body systems and ethical implications in medical research.

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