Immunity and Stress Lecture Notes

Overview and Core Activities of the Immune System

• Assault and Homeostasis: The biological organism is continuously exposed to potential invasions by foreign pathogenic microbes.
• Systemic Control: The immune system operates as a self-regulated and self-limiting network to prevent uncontrolled damage to host tissues.
• Self versus Nonself Recognition: The foundational requirement of immune function is the absolute capacity to distinguish between host markers (self) and foreign elements (nonself).
• Antigens: Foreign structures or molecular surface markers that trigger an adaptive or innate immune response.
• Primary Activities: The immune system relies on two unified functional pillars:
  • Defense: Shielding host tissues from pathogen entry and colonization.
  • Attack: Actively neutralizing and destroying recognized foreign entities or compromised host cells.

Innate Immunity and Non-Specific Barriers

• Overview of Innate Immunity: Represents the first and second lines of defense. It responds immediately to threats in a non-specific manner, recognizing nonself elements without differentiating between specific pathogen species. It does not require prior antigen exposure.
• Anatomical and Physiological Barriers: Primary physical and chemical shields designed to block entry:
  • Skin and Mucous Membranes: Physical structures that block pathogen entry.
  • Chemical Protections: Secretory substances and enzymes that neutralize microbial agents.
  • Microbiome: Normal flora that outcompete non-commensal microorganisms.
  • Permeability Note: These protective barriers are effective but not completely impenetrable.
• Inflammatory Response Dynamics:
  • Definition: A localized and systemic vascular reaction caused by physical trauma, tissue damage, or biological invasion.
  • Trigger: Mast cells release chemical signals upon tissue damage to initiate the cascade.
  • Nondiscriminatory Pattern: Follows a uniform, predictable sequence regardless of the inciting etiology, manifesting both locally and systemically.
• Phases of Inflammation:
  • Acute Phase: Initiated immediately post-injury and continues until the threat is neutralized. Key physiological mechanisms include vasoconstriction followed by vasodilation, phagocyte recruitment, and fibrinogen deployment to localize the injury.
  • Chronic Phase: Occurs when acute mechanisms fail to resolve the underlying damage or infection. Persists until healing is completed and frequently occurs in the presence of resistant microorganisms.

Vascular and Cellular Steps of the Inflammatory Response

• Function: Acts as the secondary line of defense. The rapid arrival of circulatory clotting factors to the injured area is essential for walling off infection and establishing structural repair.
• Sequential Steps of Inflammation:
  1. Tissue Damage and Histamine Release: Injured tissues immediately release histamines, which stimulate local vasodilation to increase regional blood flow.
  2. Capillary Permeability and Extravasation: Histamines cause capillary endothelial cells to separate, making microvessels permeable ("leaky"). This allows circulating phagocytes and clotting factors to pass into the damaged tissue matrix.
  3. Phagocytosis: Migrated phagocytes active at the injury site engulf foreign bacteria, dead tissue cells, and cellular debris.
  4. Hemostasis and Tissue Sealing: Platelets exit the microvasculature into the wound site to establish a clot, sealing damaged tissue barriers.

Systemic Mediators of Innate Immunity

• Pyrogens:
  • Secreted directly by invading bacteria or activated host immune cells.
  • Target the central nervous system to induce fever (a systemic inflammatory reaction).
  • Elevate core body temperature to create a thermally unfavorable environment for microbial replication.
• Interferons:
  • Specialized regulatory proteins released by virus-infected host cells.
  • Diffusive signaling molecules that bind to membrane receptors on uninfected neighboring cells.
  • Trigger antiviral protein synthesis within uninfected cells to inhibit subsequent viral replication.
• Complement Proteins:
  • Circulating plasma proteins activated in a cascade by microbial surface structures or antibody interaction.
  • Enhance local inflammatory responses, promote direct cell lysis through the membrane attack complex, and opsonize pathogens for enhanced phagocytic destruction.

Adaptive Immune Defenses

• Overview of Adaptive Defenses: Also termed acquired immunity. This secondary defense network targets specific pathogens that manage to escape innate defenses.
• Key Characteristics: Highly specific to individual organisms, differentiates precisely between self/nonself and distinct pathogen strains, and develops robust immunological memory over time.
• Cellular Immunity (Cell-Mediated):
  • Primary Mechanism: Direct destruction of foreign or aberrant antigens by specialized lymphocytes.
  • T Lymphocyte Development: $\text{T cells}$ are produced in the bone marrow and migrate to mature within the thymus.
  • Regulator T Cells: Include Helper $\text{T cells}$ (comprising $4$ distinct sub-types of $\text{T}_h$ cells) and Suppressor $\text{T cells}$.
  • Effector T Cells: Cytotoxic killer $\text{T cells}$ that directly lyse target cells.
  • Target Scenarios: Primary defense against intracellular viruses, malignant tumor cells, hypersensitivity reactions, and organ transplant rejections.
• Humoral Immunity (Antibody-Mediated):
  • Primary Mechanism: B cell activation leading to systemic antibody production targeting specific antigens.
  • B Lymphocyte Dynamics: Comprises memory cells and immunoglobulin-secreting plasma cells. Detectable circulating antibodies are generated approximately $72\,\text{hours}$ following initial antigen exposure.
  • Memory B Cells: Persist indefinitely to drive rapid, robust antibody synthesis upon subsequent exposures to the identical antigen.
  • Classification: Divided into active acquired immunity (direct exposure or vaccination) and passive acquired immunity (transferred antibodies).

Immunity Dynamics Across the Life Span

• Infancy and Early Development:
  • Maternal Transfer: Neonates receive temporary passive immunity via maternal $\text{IgG}$ crossing the placenta, which persists for $3\,\text{to}\,6\,\text{months}$. Transferred maternal antibodies possess relatively low antigen affinity.
  • Mucosal Protection: Breastfeeding transfers maternal $\text{IgA}$ across mucosal surfaces; pediatric vaccinations confer active acquired protection.
  • Functional Limitations: Newborn immune responses are limited; they respond effectively to protein antigens, but show minimal functional responses to glycoproteins or polysaccharides.
• Adolescence:
  • Hormonal Influence: Pubertal endocrine shifts significantly modulate immune reactivity because both $\text{B cells}$ and macrophages express functional surface hormone receptors.
  • Immune Dimorphism: Biological sexes exhibit distinct immunological response profiles to systemic infections and active immunizations.
• Aging and Immunosenescence:
  • Immune Senescence: Age-related decline in overall immune function.
  • Cellular Declines: Characterized by decreased production rates of new $\text{B cells}$ and $\text{T cells}$, alongside elevated rates of lymphocyte apoptosis.
  • Clinical Impacts: Multifactorial aging processes increase baseline susceptibility to inflammatory and autoimmune pathologies. Comorbidities alter signaling pathways, predisposing older adults to autoimmune conditions due to signal misinterpretation.

Hypersensitivity Disorders

• General Classification: Types I, II, and III are mediated by antibodies ($\text{IgE}$, $\text{IgG}$, or $\text{IgM}$); Type IV is mediated exclusively by T lymphocytes.
• Type I: IgE-Mediated (Immediate) Hypersensitivity:
  • System Dynamics: Manifests locally or systemically; requires prior antigen sensitization.
  • Sequence: Allergen exposure $\rightarrow$ $\text{IgE}$ production $\rightarrow$ $\text{IgE}$ binding to mast cells and basophils $\rightarrow$ Rapid cellular activation and histamine release.
• Type II: Cytotoxic (Antibody-Mediated) Hypersensitivity:
  • System Dynamics: Typically immediate; targets specific cell-surface antigens.
  • Sequence: $\text{IgG}$ or $\text{IgM}$ antibodies bind to self-cell membrane antigens $\rightarrow$ Complement cascade activation $\rightarrow$ Direct cell lysis or phagocytic destruction, causing tissue damage and cellular loss.
• Type III: Immune Complex-Mediated Hypersensitivity:
  • System Dynamics: Delayed onset; induces local or systemic pathology.
  • Sequence: Soluble antigen-antibody complexes form in circulation $\rightarrow$ Complexes deposit within microvascular tissues $\rightarrow$ Complement system activation $\rightarrow$ Neutrophil recruitment, severe inflammatory tissue damage, and potential anaphylaxis.
• Type IV: Delayed (Cell-Mediated) Hypersensitivity:
  • System Dynamics: Antibody-independent reaction driven entirely by cellular immunity.
  • Sequence: Sensitized $\text{T cells}$ (helper and cytotoxic $\text{T cells}$) recognize antigens $\rightarrow$ Local cytokine release $\rightarrow$ Macrophage activation $\rightarrow$ Chronic tissue injury and localized fibrosis.

Detailed Mechanics of Hypersensitivity Reactions

• Type II Examples:
  • ABO Blood Transfusion Reaction:
    1. Donated Type A blood carrying Type A surface antigens is transfused into a Type B recipient.
    2. Pre-existing Anti-A antibodies in the Type B recipient's plasma bind directly to donor Type A red blood cells.
    3. Antibody engagement activates the complement cascade, causing rapid intravascular hemolysis and massive release of free hemoglobin.
  • Erythroblastosis Fetalis (Hemolytic Disease of the Newborn):
    1. First Pregnancy: During a primary pregnancy with an $\text{Rh}^+$ fetus, fetal $\text{Rh}^+$ red blood cells cross the placenta into the circulation of an $\text{Rh}^-$ mother.
    2. Sensitization: Maternal exposure to fetal $\text{Rh}$ antigens triggers the synthesis of maternal anti-$\text{Rh}$ antibodies.
    3. Second Pregnancy: During a subsequent pregnancy with an $\text{Rh}^+$ fetus, maternal anti-$\text{Rh}$ antibodies persist in circulation and freely cross the placenta.
    4. Hemolysis: Maternal anti-$\text{Rh}$ antibodies attack fetal $\text{Rh}^+$ erythrocytes, leading to severe fetal hemolysis.
• Type IV Mechanics (e.g., Poison Ivy / Hapten Exposure):
  • Sensitization Phase (First Exposure):
    • Hapten penetrates the skin barrier and activates helper $\text{T cells}$ without causing visible skin lesions.
    • Induces the formation of sensitized memory $\text{T cells}$.
  • Effector Phase (Re-Exposure):
    • Re-exposure reactivates circulating memory $\text{T cells}$.
    • Reactivated cells release inflammatory cytokines, recruiting macrophages and activating cytotoxic $\text{T cells}$.
    • A delayed inflammatory skin lesion develops. Reactions progressively worsen with repeated exposures.

Principles of Tissue Transplants and Rejection Reactions

• Transplant Compatibility: Clinical success requires close matching of tissue human leukocyte antigens from living or deceased donors.
• Transplant Categories:
  • Allogeneic: Transfer between genetically distinct donor and recipient of the same species sharing similar tissue types (most common clinical method).
  • Syngeneic: Transfer between genetically identical twins.
  • Autologous: Transfer of tissue from one site to another within the same individual (highest success rate).
  • Xenogenic: Transfer of tissue between different biological species.
• Tissue Rejection Patterns:
  • Hyperacute Tissue Rejection: Occurs almost immediately post-transplant; mediated by pre-existing antibodies activating the complement system, leading to tissue ischemia and necrosis.
  • Acute Tissue Rejection: Occurs within $3\,\text{months}$ post-transplant; treatable cell-mediated response characterized by fever, graft edema, and localized inflammation.
  • Chronic Tissue Rejection: Occurs from $4\,\text{months}$ onward; antibody-mediated response causing progressive arterial ischemia and fibrosis of graft tissues.
• Graft versus Host Dynamics: Graft-versus-host disease (donor cells attack recipient tissue) or host-versus-graft disease (recipient cells attack donor graft) may occur. Both conditions require lifelong immunosuppressive therapy when tissue matching is incomplete.

Autoimmunity and Systemic Lupus Erythematosus

• General Autoimmunity Principles:
  • Occurs when the immune system loses self-tolerance and mounts destructive immune responses against host tissues.
  • Exact triggering mechanisms remain unclear, but can affect any tissue or organ system.
  • Known Predictors: Genetic susceptibility, female sex, and exposure to abnormal stressors.
  • Clinical Trajectory: Typically presents as a progressive relapsing-remitting disorder featuring alternating acute exacerbations and remissions.
  • Diagnosis: Frequently relies on excluding other pathologies.
• Systemic Lupus Erythematosus (SLE):
  • A chronic, stress-linked inflammatory autoimmune disorder affecting generalized connective tissues.
  • Systemic stressors regularly initiate disease exacerbations.
  • Epidemiology: Displays a significantly higher prevalence in women and specific racial/ethnic groups, including African American and Asian populations.
  • Pathophysiology: Hyperactive $\text{B cells}$ produce autoantibodies targeting cellular autoantigens, causing widespread inflammation.
  • Target Organs: Frequently damages the heart, joints, skin, lungs, blood vessels, liver, kidneys, and central nervous system.

Immunodeficiency and Acquired Immunodeficiency Syndrome

• Immunodeficiency Overview:
  • Characterized by a diminished or absent immune response, leaving the host highly vulnerable to opportunistic pathogens.
  • Presents as acute or chronic conditions.
  • Primary Immunodeficiency: Direct intrinsic or genetic defect within immune system components.
  • Secondary Immunodeficiency: Immunosuppression resulting from an extrinsic factor, underlying disease, or environmental stressor.
• Human Immunodeficiency Virus (HIV) and AIDS Pathogenesis:
  • Etiology: Caused by HIV, an obligate intracellular retrovirus that targets host cells expressing $\text{CD4}$ receptors alongside macrophages.
  • Prevalence: $\text{HIV-1}$ is the most prevalent strain in the United States.
  • Transmission: Spreads through contact with infected blood and body fluids, as well as vertical transmission from mother to child. HIV is not transmitted through saliva.
  • Asymptomatic Latency: An extended asymptomatic phase allows viral replication to proceed over several years.
  • Disease Progression: As viral load increases, host $\text{CD4}$ cells are progressively destroyed, worsening symptoms across three potential pathways:
    1. Severe Immunodeficiency (predisposing to opportunistic infections).
    2. Autoimmunity (e.g., inflammatory arthritis).
    3. Neurological Dysfunction (e.g., AIDS dementia complex).
• Diagnostic Testing and Disease Categorization:
  • Testing Modalities:
    • Nucleic Acid Tests (NAT): Directly quantifies plasma viral load; highly precise but expensive and non-routine.
    • Antigen/Antibody Tests: Administered alongside or following screening; available in rapid and home assay formats to detect the viral $\text{p24}$ antigen in blood or saliva.
  • CD4 Laboratory Categorization:
    • Category 1: $\text{CD4}$ count $> 500\,\text{cells}/\mu\text{L}$
    • Category 2: $\text{CD4}$ count $200\text{--}499\,\text{cells}/\mu\text{L}$
    • Category 3: $\text{CD4}$ count $< 200\,\text{cells}/\mu\text{L}$
  • Clinical Presentation Categorization:
    • Category A: Asymptomatic HIV infection.
    • Category B: Symptomatic manifestations of immunodeficiency (non-AIDS defining).
    • Category C: Presence of overt AIDS-defining opportunistic illnesses.

Physiological Stress and Stress Adaptation

• Nature of Stress: A universal biological experience resulting from both positive (eustress) and negative (distress) life experiences. Represents a physiological response to change that challenges internal homeostasis.
• General Adaptation Syndrome (GAS):
  1. Alarm Stage: The immediate emergency neuroendocrine response to an acute threat.
  2. Resistance Stage: Active physiological coping to maintain systemic function under prolonged stress.
  3. Exhaustion Stage: Depletion of adaptive reserve, leading to organ exhaustion and systemic collapse.
• Local Adaptation Syndrome (LAS): Confines inflammatory and defensive responses to a single localized body area.
• Individual Stress Dynamics:
  • Physiological responses follow predictable pathways, but individual responses vary based on specific conditioning factors.
  • Conditioning Factors: Include genetics, age, biological gender, health history, and social support networks.
  • Coping Strategies: Healthy coping mechanisms minimize adverse physiological impacts, whereas unhelpful strategies cause secondary damage.

Systemic Manifestations of Stress

• Nervous System: Anxiety, depression, chronic fatigue, insomnia, loss of motivation, nervous tics, neuropsychological manifestations, overeating.
• Integumentary System: Acne, eczema, hair loss (alopecia), neurodermatitis, psoriasis.
• Cardiovascular System: Coronary artery disease, heart rate and rhythm disturbances (arrhythmias), hypertension, stroke (cerebrovascular accident).
• Gastrointestinal System: Diarrhea, gastritis, irritable bowel syndrome (IBS), persistent nausea and vomiting, ulcerative colitis.
• Respiratory System: Asthma exacerbations, hay fever (allergic rhinitis), increased respiration rate.
• Immune System: Autoimmune disease triggers, state of immunodeficiency, generalized immunosuppression.
• Endocrine System: Diabetes mellitus onset or exacerbation, sustained hyperglycemia.
• Genitourinary System: Diuresis, sexual dysfunction (frigidity, impotence), irritable bladder, menstrual irregularity.
• Musculoskeletal System: Inflammatory connective tissue disease, muscle contraction backache, tension headache, rheumatoid arthritis.

Strategies for Building and Maintaining Immune Health

• Environmental Hygiene: Avoid over-sanitizing the environment to allow appropriate antigen exposure and natural barrier training.
• Substance Modifications: Complete smoking cessation and limitation of alcohol intake to moderate levels.
• Physical Activity: Engaging in regular exercise routines.
• Immunization: Maintaining up-to-date, appropriate vaccination schedules.
• Hydration and Nutrition: Maintaining increased daily fluid intake paired with a well-balanced diet.
• Rest and Weight Management: Getting adequate sleep nightly alongside proactive weight management.
• Stress Management: Actively practicing stress-reduction techniques.