Host Defenses and Immunization

Overview of Host Defense Mechanisms

• Host defenses function as a multi-level network consisting of innate, nonspecific protections and specific acquired immunities.
• These defenses are categorized into the first, second, and third lines of defense.
• First Line of Defense:
  • Defined as any barrier that blocks invasion at the portal of entry.
  • Limits access to the internal tissues of the body.
  • It is not considered a true immune response because it does not involve the recognition of foreign substances.
  • Action is categorized as very general.
• Second Line of Defense:
  • An internalized system consisting of protective cells and fluids.
  • Key components include inflammation and phagocytosis.
  • Acts rapidly at both local and systemic levels once the first line of defense is circumvented.
• Third Line of Defense:
  • Acquired on an individual basis as lymphocytes encounter foreign substances.
  • Produces unique protective substances for each different microbe.
  • Provides long-term immunity.
• Most defenses are redundant and overlap in their effects to ensure the survival of invading microbes is unlikely.

The First Line of Defense: Physical and Chemical Barriers

• Physical Barriers:
  • Skin: The most visible barrier; covers the majority of surfaces in contact with the environment.
  • Mucous Membranes: Line the digestive, respiratory, and genitourinary tracts.
  • Mucus constantly bathes these surfaces to wash them. Some membranes use mechanisms to propel microbes and viruses to areas where they can be eliminated.
• Chemical Barriers (Antimicrobial Substances):
  • Lysozyme: An enzyme that degrades peptidoglycan. It is found in tears, saliva, blood, and phagocytes.
  • Peroxidase: Found in saliva, body tissues, and phagocytes. It breaks down hydrogen peroxide ($H_2O_2$) to produce reactive oxygen.
  • Lactoferrin: Found in saliva, phagocytes, blood, and tissue fluids. It sequesters iron ($Fe$) to prevent microbial growth.
  • Defensins: Antimicrobial peptides that insert into microbial membranes. Found on mucous membranes and in phagocytes.
• Normal Flora:
  • Defined as microorganisms growing on the body surfaces of healthy individuals.
  • While not technically part of the immune system, they provide protection through competitive exclusion.
  • They cover binding sites so pathogens cannot bind and compete for nutrients, making them unavailable for pathogens.

The Second Line of Defense: Cells and Sensor Systems

• Hematopoiesis:
  • The formation of blood cells. All blood cells, including immune cells, originate from hematopoietic stem cells in the bone marrow.
  • Differentiation is stimulated by Colony-Stimulating Factors.
• Leukocytes (White Blood Cells):
  • Granulocytes: Contain cytoplasmic granules.
    • Neutrophils: Most abundant and important in the innate response; also called polymorphonuclear neutrophilic leukocytes ($PMNs$).
    • Basophils: Involved in allergic reactions.
    • Eosinophils: Important in expelling parasitic worms and active in allergic reactions.
  • Mononuclear Phagocytes:
    • Monocytes: Circulate in the blood.
    • Macrophages: Differentiated from monocytes; abundant in the liver, spleen, lymph nodes, lungs, and peritoneal cavity.
  • Dendritic Cells: Branched cells that function as "scouts." They engulf materials in tissues and bring them to cells of the adaptive immune system.
• Recognition Mechanisms:
  • Markers: Proteins and/or sugars on cell surfaces used by the immune system to identify threats.
  • Pathogen-Associated Molecular Patterns ($PAMPs$): Markers common to many different kinds of microbes.
  • Pattern Recognition Receptors ($PRRs$): Receptors on host cells (second line of defense) that recognize $PAMPs$.

The Complement System

• Composed of nine proteins, named $C1$ through $C9$ in the order of discovery.
• Proteins can split into "a" and "b" fragments (e.g., $C3$ splits into $C3a$ and $C3b$).
• Pathways of Activation:
  • Classical Pathway: Requires antibodies; antibodies interact with $C1$.
  • Alternative Pathway: Triggered by the binding of $C3b$ to a cell surface. $C3b$ is always circulating in the blood.
  • Lectin Pathway: Requires mannan-binding lectins ($MBL$) which detect mannan (a polymer of mannose found in microbes).
• Outcomes of Activation:
  • Inflammation.
  • Opsonization.
  • Lysis of Foreign Cells: Complexes of $C5b$, $C6$, $C7$, $C8$, and multiple $C9$ units form a Membrane Attack Complex ($MAC$). This creates pores in the membrane. It is most effective on Gram-negative cells.

Phagocytosis, Inflammation, and Fever

• Steps of Phagocytosis:
  1. Chemotaxis: Cells recruited to the infection site.
  2. Recognition/Attachment: Receptors bind to invading microbes.
  3. Engulfment: Phagocyte forms a phagosome.
  4. Phagosome-Lysosome Fusion: Forms a phagolysosome.
  5. Destruction and Digestion: Microbe is killed by lack of oxygen and decreased $pH$.
  6. Exocytosis: Residual debris is expelled.
• Inflammation:
  • Signs: Heat, Pain, Redness, Swelling, and Loss of Function.
  • Process: Initiation leads to dilated blood vessels and fluid leakage. Diapedesis is the leakage of phagocytes from blood vessels into tissues.
• Fever:
  • Induced by Pyrogens. Endogenous pyrogens are host cytokines; exogenous pyrogens are microbial products.
  • Pyrogens reset the hypothalamic thermostat to a higher setting.
  • Benefits: Inhibits pathogen growth by exceeding their maximum growth temperature and speeds up body defenses.

The Third Line of Defense: Adaptive Immunity

• Primary Response: The first response to a particular antigen; takes $1$ week or more to develop.
• Secondary Response: A faster, stronger response upon subsequent exposure because the immune system "remembers" the pathogen.
• Humoral Immunity: Eliminates extracellular pathogens; mediated by B lymphocytes (B cells).
  • B cells develop in the bone marrow.
  • Triggered to proliferate into Plasma Cells, which produce Antibodies ($Ab$).
• Cellular Immunity (Cell-Mediated): Eliminates intracellular pathogens; mediated by T lymphocytes (T cells).
  • T cells mature in the thymus.

Antigens and Antibodies

• Antigen ($Ag$): Short for "antibody generator." Any compound that elicits an immune response (also called an immunogen).
  • Epitope: The specific antigenic determinant recognized by the immune system.
• Antibody Structure:
  • Monomer structure made of four amino acid chains (two heavy, two light) held by disulfide bonds.
  • Constant Region ($Fc$): Identical for a class of antibody.
  • Variable Region ($Fab$): Unique region that binds to specific antigens.
• Antibody Classes:
  • $IgM$: First $Ab$ produced ($5-13\%$ in circulation); pentamer structure; only $Ab$ formed by a fetus.
  • $IgG$: Dominant $Ab$ ($80-85\%$); monomer; only $Ab$ to cross the placenta; the antibody of memory.
  • $IgA$: Found in secretions (mucus, tears, breast milk); monomer in serum, dimer in secretions ($10-13\%$).
  • $IgD$: ($<1\%$); monomer; involved in maturation of antibody response.
  • $IgE$: Barely detectable; monomer; active in allergic reactions and parasitic infections.
• Binding Outcomes: Neutralization, Immobilization, Agglutination, Opsonization, Complement activation, and Antibody-dependent cellular cytotoxicity ($ADCC$).

T Lymphocyte Functions and Antigen Presentation

• T cells require Antigen-Presenting Cells ($APCs$) such as Macrophages, B cells, and Dendritic cells.
• Major Histocompatibility Complex ($MHC$):
  • $MHC$ Class I: Bind endogenous antigens; recognized by Cytotoxic T cells ($Tc$).
  • $MHC$ Class II: Bind exogenous antigens; recognized by Helper T cells ($Th$).
• T Cell Populations:
  • Cytotoxic T Cells ($CD8$ Marker): Induce apoptosis in infected or cancerous self-cells.
  • Helper T Cells ($CD4$ Marker): Activate B cells and macrophages; orchestrate the immune response.
• Natural Killer ($NK$) Cells: Lack antigen specificity; recognize cells lacking $MHC$ Class I or cells coated with $IgG$ antibodies; augment the adaptive response.

Principles of Immunization and Vaccines

• Immunity Types:
  • Active Immunity: Results from exposure to antigen (natural illness or artificial vaccine).
  • Passive Immunity: Transfer of antibodies. Natural: Breast milk ($IgA$) or placenta ($IgG$). Artificial: Gamma globulin injection.
• Vaccine Types:
  • Inactivated: Killed virus. Needs boosters (e.g., Flu shot, Polio shot).
  • Live-attenuated: Weakened microbe. Provides long-lasting immunity; risky for immunocompromised (e.g., $MMR$, Chicken pox).
  • Subunit/Conjugate: Uses specific pieces (capsid, protein). Needs boosters (e.g., $Hep B$, $HPV$).
  • Toxoid: Targets toxins produced by germs (e.g., Tetanus, Diphtheria).
  • mRNA: Cells produce a protein to elicit an immune response (e.g., COVID-19).
  • Viral Vector: Uses viral technology to deliver genetic instructions (e.g., Ebola, COVID-19).

Questions & Discussion

• Concept Check: Barriers:
  • A. Hydrochloric acid ($HCl$) of stomach: Chemical.
  • B. Sloughing of skin: Physical.
  • C. Lysozyme in saliva: Chemical.
  • D. Mutation in complement genes: Genetic.
  • E. Ciliary escalator: Physical.
• Concept Check: Phagocytosis Order:
  • Correct order: Chemotaxis ($6$), Adhesion ($4$), Engulfment ($1$), Phagosome formation ($3$), Phagolysosome formation ($7$), Killing/Destruction ($2$), Release of debris ($5$). Answer: D.
• Concept Check: Antibody Types:
  • $IgG$: Most prevalent.
  • $IgA$: Secreted in mucous membranes.
  • $IgM$: First antibody produced.
  • $IgD$: Receptor on B cells.
  • $IgE$: Response to allergens/parasites.
• Concept Check: APCs:
  • Which is not an APC? T-helper cell. (Macrophages, Dendritic cells, and B cells are APCs).
• Concept Check: T cell targets:
  • Cytotoxic T cells kill cancer cells, virus-infected cells, and foreign grafted cells, but generally not free bacteria (which are usually handled by phagocytes/humoral immunity).
• Concept Check: Maturation:
  • B cells mature in the bone marrow; T cells mature in the thymus. Both migrate to the lymph nodes and spleen.
• Concept Check: Active vs. Passive:
  • A. Gamma globulin: Passive.
  • B. Influenza recovery: Active.
  • C. Vaccination: Active.
  • D. Breastfeeding: Passive.
• Immunological Testing Terms:
  • Seronegative: No specific antibodies yet.
  • Seropositive: Actively producing antibodies.
  • Titer: The concentration of antibody in serum.