Specific Host Defenses

The Interplay of Innate and Adaptive Immunity

• The Necessity of Dual Systems: Animals require both innate and adaptive immunity to survive infections.

  • Innate Immunity Absent: If innate immunity is lacking, pathogen cell numbers rise exponentially and rapidly, leading to the host being overcome by infection before the adaptive system can even begin to respond.

  • Adaptive Immunity Absent: If adaptive immunity is lacking, the innate immune system initially controls or slows the growth of the pathogen, but eventually fails to eliminate it, leading to a steady, high-level increase in pathogen numbers and eventual death.

  • Normal Immunity: With both systems functional, the innate system holds the infection in check during the "latent period," allowing the adaptive response to activate, reach its peak, and eventually clear the pathogen from the body.

• Relative Activity Over Time:

  • Days 0–5: Innate activity peaks via phagocytes, inflammatory cytokines, and antiviral interferons.

  • Days 5–12: Adaptive activity takes over, characterized by T cells, high antibody production, and specific cytokines.

The Third Line of Defense: Specific Immunity

• Definition: Specific immunity is the final line of defense that "adapts" to an infection and "acquires" a memory for specific antigens.

• Immunocompetence: This refers to the inherent ability of the body to react with foreign substances.

• Key Attributes:

  • Specific Antigens: The system reacts to precise molecular markers.

  • Adaptability: The response evolves during the infection.

  • Memory: The system retains the ability to recognize the same pathogen years later.

Antigens and Epitopes

• Antigens: Molecules that stimulate a response by $B$ and $T$ cells.

  • Composition: Generally proteins or sugars.

  • Location: Found on or inside cells and viruses, or produced by them (exotoxins).

  • Specificity: They are highly individual and unique to specific microbes.

  • Requirement: They must not be a normal constituent of the host's body (non-self).

• Epitope (Antigenic Determinant):

  • The specific portion of an antigen molecule to which an immune cell (receptor or antibody) actually binds.

  • It serves as the primary signal to the immune system. A single protein antigen can have multiple different epitopes (Epitope1, Epitope2, etc.), which may be bound by different antibodies ($AB_1$, $AB_2$, etc.).

• Chemical Categories of Antigens:

  • Proteins (most common and potent).

  • Lipoproteins (associated with cell membranes).

  • Glycoproteins (often used as blood cell markers).

  • Nucleoproteins (DNA complexed to proteins).

  • Polysaccharides (found in certain bacterial capsules).

  • Lipopolysaccharides ($LPS$).

The Major Histocompatibility Complex (MHC)

• Overview: A set of cell surface markers found on all nucleated cells (absent on red blood cells). They are essential for recognizing "self" and rejecting foreign tissue or pathogens.

• Classes of MHC:

  • Class I: Located on all nucleated human cells. They display epitopes of self-proteins or intracellular pathogens to indicate the health status of the cell.

  • Class II: Found on specialized white blood cells known as Antigen-Presenting Cells ($APCs$), including macrophages, dendritic cells, and $B$ cells. These present foreign antigens to $T$ cells.

  • Class III: Molecules involved in the complement system.

Antigen Presentation and Cellular Communication

• Antigen-Presenting Cells (APCs): These cells engulf microbes, degrade them into smaller peptides, and transport these pieces to the cell membrane.

• The Presentation Process (Table13.3):

  1. $APCs$ take microbes into intracellular vesicles and degrade them.

  2. Antigen segments are complexed with $MHC-II$ receptors and moved to the cell surface.

  3. The $MHC-II$/antigen complex binds to a specific $T$-cell receptor ($TCR$).

  4. A coreceptor (typically $CD4$) binds to the $MHC-II$ receptor to ensure simultaneous recognition of the antigen (non-self) and the $MHC$ (self).

  5. Identification triggers the $APC$ to secrete $Interleukin-1$ ($IL-1$).

  6. The $T$ helper ($T_H$) cell then produces $Interleukin-2$ ($IL-2$), which acts as a growth factor for other $T$ cells ($T_H$ and $T_{cytotoxic}$) and helps activate $B$ cells.

• Superantigens: Certain bacterial toxins that act as potent stimuli for $T$ cells. They can cause activation levels $100 \times$ greater than normal, leading to an overwhelming release of cytokines (cytokine storm), cell death, Toxic Shock Syndrome, and autoimmune reactions.

Lymphocyte Development and Diversity

• Maturation Sites:

  • $B$ cells: Mature in specialized bone marrow sites.

  • $T$ cells: Mature in the thymus.

  • Both types migrate to separate areas of lymphoid organs and constantly recirculate through the Blood and lymph.

• The Origin of Diversity:

  • Every mature $B$ and $T$ cell is specific to a single antigen.

  • Diversity is achieved through gene rearrangement, where every possible recombination of gene segments occurs to create unique receptors.

  • "Bad" or self-reactive versions are destroyed during development.

  • It is estimated that one individual can produce approximately $10 \text{ trillion}$ ($10^{13}$) different versions of receptors.

• Cluster of Differentiation (CD) Molecules: There are over $300$ identified $CD$ markers. Critical markers include:

  • $CD3$: Found on all $T$ cells; assists in signaling.

  • $CD4$: Found on Helper $T$ cells; binds to $MHC-II$.

  • $CD8$: Found on Cytotoxic $T$ cells; binds to $MHC-I$.

Antibody Structure and Function

• Immunoglobulins (Ig): Large glycoproteins that serve as $B$-cell receptors. When secreted, they are called antibodies.

• Structure:

  • Antigen Binding Sites: Located at the ends of the forks; highly variable.

  • Variable Regions ($V$): Areas where the amino acid composition varies greatly from one $B$ cell to another.

  • Constant Regions ($C$): Areas that do not vary in amino acid sequence.

  • Chains: Consists of heavy chains and light chains held together by disulfide bonds.

• Antibody Functions (Table13.7):

  • Coating: Covering the surface of a bacterium to prevent normal function and reproduction.

  • Opsonization: Antibodies (opsonins) act as "handles" to help phagocytes grab slippery microbes.

  • Neutralization: Filling surface receptors on a virus or the active site of an enzyme to prevent attachment to host cells. Antitoxins specifically neutralize bacterial exotoxins.

  • Agglutination: Cross-linking cells into large clumps to render them immobile and enhance phagocytosis.

  • Complement Activation: Interaction with complement proteins can lead to the specific rupturing (lysis) of cells and viruses.

Immunoglobulin Isotypes

• $IgG$: The most common ($75 \times$) in circulation. It is the only antibody capable of crossing the placenta. It activates phagocytes and complement and is monitored in diagnostic assays.

• $IgA$: Occurs as a monomer in circulation and a dimer in secretions (tears, saliva, colostrum). Provides immunity against enteric, respiratory, and genitourinary pathogens.

• $IgM$: A large pentamer (or hexamer). It is the first isotype produced during primary exposure. Its size keeps it in the blood; it is very "sticky" and a powerful activator of complement.

• $IgE$: Involved in responses to parasites and mediates allergic reactions/hypersensitivity.

• $IgD$: Acts as a receptor on $B$ cells; often co-expressed with $IgM$.

Clonal Selection and the Immune Curve

• Clonal Selection: A specific $B$ or $T$ cell is activated when its pre-programmed receptor encounters its matching antigen.

• Clonal Expansion: After activation, the cell divides rapidly to produce a large population of identical cells.

• Differentiation:

  • Plasma Cells: Specialized "antibody factories" that secrete large volumes of antibodies.

  • Memory Cells: Long-lived cells that remain in the body to react quickly if the antigen is encountered again.

• Antibody Titer and Timing (Table13.9):

  • Primary Response: Occurs after the first exposure. It has a "latent period" with no measurable antibodies. $IgM$ is produced first, followed by $IgG$.

  • Secondary (Anamnestic) Response: Occurs upon re-exposure. It has no latent period. The response is immediate, much higher in magnitude, and dominated by $IgG$.

T-Cell Mediated Immunity (CMI)

• General Features: $T$-cell actions are dictated by $APCs$ and are $MHC$-restricted. All $T$ cells produce cytokines to mobilize the immune system.

• Types of T Cells:

  • Helper T Cells ($T_H$): Constitute approximately $65 \times$ of the $T$-cell population. They activate macrophages (via $IFNγ$ or direct contact) and stimulate $B$ cells through interleukins ($IL-4$, $IL-5$, $IL-6$).

  • Regulatory T Cells ($T_{reg}$): Act to limit inflammation and prevent autoimmune reactions.

  • Cytotoxic T Cells ($T_C$): Target and destroy virally infected cells, cancer cells, and "foreign" cells (the primary cause of graft rejection).

• Perforin Pathway: $T_C$ cells kill by releasing perforins, which create holes in the target cell membrane, and granzymes, which enter through the holes to induce apoptosis (programmed cell death).

Natural Killer (NK) Cells

• Mechanism: They lack specific antigen receptors but detect the lack of MHC on a cell. They are often the first to attack cancer and virus-infected cells.

• Killing Process:

  1. $NK$ cell releases perforins to polymerize and form a hole in the "enemy" cell membrane.

  2. Granzymes enter the hole and degrade enzymes.

  3. Enemy cell dies by apoptosis.

  4. Macrophages engulf and digest the dying cell.

Categories of Acquired Immunity

• Natural Immunity: Acquired through normal life experiences.

  • Active: Developing host antibodies/memory after recovering from an infection (e.g., lifelong immunity from measles).

  • Passive: Receiving antibodies from the mother via the placenta ($IgG$) or breast milk ($IgA$). Protection lasts months to a year.

• Artificial Immunity: Produced through medical procedures.

  • Active: Vaccination (exposure to a microbial stimulus) to trigger the immune response and memory.

  • Passive: Immunotherapy using pooled human serum (gamma globulin) or immune globulins to provide instantaneous, short-term protection with no memory.

Vaccination Principles and Public Health

• History:

  • Edward Jenner: Used cowpox to protect against smallpox.

  • Louis Pasteur: Developed vaccines for anthrax and rabies.

  • Salk and Sabin: Developed vaccines for polio.

• Adjuvants: Special binding substances (e.g., alum) added to vaccines to enhance immunogenicity, prolong retention at the site, and facilitate contact with $APCs$.

• Vaccine Efficacy Data (Table  55):

  • Diphtheria: Pre-vaccine $21,053$ cases; current reports $0$ ($100 \times$ decrease).

  • Measles: Pre-vaccine $530,217$ cases; current reports $187$ (>99 \times decrease).

  • Polio: Pre-vaccine $16,316$ cases; current reports $1$ (>99 \times decrease).

  • Smallpox: Pre-vaccine $29,005$ cases; current reports $0$ ($100 \times$ decrease).

• Herd Immunity: When a high percentage of the population (e.g., $90 \text{--} 95 \times$) is vaccinated, the microbe cannot spread effectively, protecting those who cannot be vaccinated.

• Safety and Misconceptions: There is no link between the $MMR$ vaccine and autism. The original $1998$ paper was discredited, and the author's medical license was revoked. In $2011$, the Institute of Medicine confirmed that the vaccine does not cause autism.