CH4 – Altered Immunity

Lymphatic & Immune Anatomy

• Lymphatic system is foundational for mounting immune responses
  • Central (primary) lymphoid organs
  • Bone marrow: hematopoiesis; B-cell maturation
  • Thymus: T-cell maturation, positive/negative selection
  • Peripheral (secondary) lymphoid organs
  • Spleen, lymph nodes, mucosa-associated lymphoid tissue (MALT), tonsils, Peyer patches

Lines of Defense

• 1st line: Physical & chemical barriers (skin, mucous membranes, gastric acid, tears, etc.)
• 2nd line: Innate inflammation (phagocytes, complement, NK cells)
• 3rd line: Adaptive (immunity)
  • Key features: specific antigen recognition, neutralization, immunologic memory

Cellular Components of Immunity

• Origin: Lymphoid progenitor (lymphoblast)
• T Lymphocytes
  • Cytotoxic (CD8): directly lyse virus-infected & neoplastic cells
  • Helper (CD4): coordinate immune response via cytokine secretion; activate B- & T-cells, macrophages
  • Regulatory/Suppressor: maintain self-tolerance; prevent autoimmunity
• B Lymphocytes
  • Differentiate → plasma cells that secrete antibodies (immunoglobulins)
  • Membrane-bound antibodies serve as B-cell receptors (BCRs) for antigen detection
• Natural Killer (NK) Cells
  • Part of innate immunity; destroy targets without prior sensitization (missing-self recognition)

Immune Processes

• Innate Immunity
  • Rapid (minutes–hours)
  • Non-specific; relies on epithelial barriers, neutrophils, macrophages, dendritic cells, NK cells, complement, natural antibodies
• Adaptive Immunity
  • Slower onset (days)
  • Antigen-specific; involves clonal expansion of B & T lymphocytes

Active vs. Passive Immunity

• Active Immunity (internal antibody production)
  • Natural: infection with the pathogen
  • Artificial: vaccination with antigenic material
• Passive Immunity (external antibody acquisition)
  • Natural: maternal IgG across placenta, IgA in breast milk
  • Artificial: therapeutic antibody administration (e.g., IVIG, monoclonal Abs)

Humoral Immunity

• Mediated by B-cells & circulating antibodies
• Primary adaptive response
  • Naïve B-cell encounters new antigen → clonal expansion → plasma cells + memory B-cells
• Secondary adaptive response
  • Memory B-cells reactivated on repeat exposure → faster, stronger Ab production
• Five major immunoglobulin (Ig) classes
  • IgA: mucosal secretions (saliva, tears, breast milk); guards mucosal surfaces
  • IgG: \approx 75\% of plasma Ig; only class crossing placenta → neonatal protection; long-term immunity
  • IgM: first Ab produced; pentameric; short-term protection; potent complement activator, BCR component
  • IgE: binds FcεR on mast cells/basophils; mediates allergic (Type I) & antiparasitic responses
  • IgD: mostly membrane-bound; role in B-cell activation/maturation still elucidated

Cell-Mediated Immunity & MHC

• Cytotoxic T (CD8) recognize antigen presented by MHC I → kill infected cells
• Helper T (CD4) recognize antigen on MHC II → orchestrate immune response
• Major Histocompatibility Complex (MHC) = Human Leukocyte Antigen (HLA)
  • Class I: expressed on all nucleated cells; present endogenous peptides → CD8 T cells
  • Class II: on APCs (DCs, macrophages, B cells); present exogenous peptides → CD4 T cells

Mechanisms Altering Immune Function (Overview)

• Host defense failure
  • Antigenic variation (e.g., influenza drift/shift)
  • Viral latency (e.g., HSV hiding in neurons)
  • Immunodeficiency (primary or secondary)
• Hypersensitivity reactions (Type I-IV)
• Autoimmunity (loss of self-tolerance)
• Alloimmunity (immune response to non-self human antigens: grafts, transfusions, fetus)

Hypersensitivity Types

• Type I: Immediate/IgE-mediated (allergy, anaphylaxis)
• Type II: Cytotoxic/IgG & IgM vs. cell surface → complement/phagocytosis (transfusion rxn, hemolytic anemia, hemolytic disease of newborn)
• Type III: Immune complex deposition → inflammation/tissue damage (SLE, rheumatoid arthritis)
• Type IV: Delayed, T-cell mediated (TB skin test, contact dermatitis, graft-vs-host)

Note: Mast-cell histamine → vasodilation & ↑capillary permeability → edema, hypotension, itching

Autoimmunity

• Failure to discriminate self/non-self → targeted organ or systemic damage

Alloimmunity

• Graft rejection: host attacks graft
• Graft-vs-host disease: donor T-cells attack recipient (common in bone marrow transplants)

Immune Manipulation in Medicine

• Goals: treat maladaptive immunity, manage disease, prevent illness (vaccines, immunotherapy, immunosuppression)

Applied Disorders

Acquired Immunodeficiency Syndrome (AIDS)

• Pathophysiology
  • Secondary immunodeficiency from HIV infection of CD4 T helper cells
  • Loss of both cell-mediated & humoral immunity
• Clinical Manifestations
  • Immunosuppression → opportunistic infections & malignancies
  • Neurologic: memory loss, disorientation, cryptococcal meningitis, toxoplasmosis encephalitis
  • Respiratory: Pneumocystis jirovecii pneumonia, tuberculosis
  • GI: chronic diarrhea, weight loss, candidiasis
  • Skin/cancer: Kaposi sarcoma, lymphoma
  • Constitutional: fevers, night sweats, lymphadenopathy, fatigue
• Diagnostics
  • Hx & exam with risk assessment
  • Lab: HIV Ab/antigen tests, viral load (RNA copies), CD4 count (<200\,/\mu L = AIDS)
• Treatment
  • Antiretroviral therapy (ART) combinations
  • Goals: suppress viral load, restore/preserve immunity, ↓morbidity/mortality, limit resistance

Anaphylactic Reaction

• Pathophysiology
  • Systemic Type I IgE-mediated reaction in sensitized individual
  • Triggers: insect stings, foods, drugs
  • Mast-cell/basophil degranulation →
  • Vascular smooth muscle dilation (↓BP)
  • Bronchial smooth muscle constriction (wheezing)
  • ↑Vascular permeability (edema)
• Clinical Phases
  • Phase 1: Dyspnea (mild-mod), flushing, pruritus, angioedema
  • Phase 2: Severe dyspnea, profound hypotension/collapse, massive edema
• Diagnostics: clinical history, physical, possible allergy testing
• Treatment
  • Acute: epinephrine (bronchodilation, vasoconstriction), antihistamines, corticosteroids, β-agonists, IV fluids
  • Prevention: allergen avoidance, desensitization immunotherapy

Systemic Lupus Erythematosus (SLE)

• Pathophysiology
  • Chronic systemic autoimmune Type III (immune complex) disease
  • Antigen persistence → B-cell autoantibodies + T-cell–driven inflammation
  • Autoantibodies vs. cell membrane, cytoplasm, nucleus (anti-dsDNA, anti-Smith)
• Clinical Manifestations
  • Local: skin (malar “butterfly” rash, discoid lesions), arthritis, pleuritis, glomerulonephritis
  • Systemic: seizures, psychosis, myocarditis, endocarditis, hemolytic anemia, leukopenia, thrombocytopenia, lymphadenopathy
• Diagnostics
  • Hx & exam
  • Lab: ANA, anti-dsDNA, anti-Smith, low complement (C3, C4), ESR/CRP
• Treatment
  • NSAIDs, corticosteroids, DMARDs, antimalarials (hydroxychloroquine), immunosuppressants (azathioprine, cyclophosphamide)

Rh Isoimmunization

• Pathophysiology
  • Type II cytotoxic reaction to Rh (D) antigen on fetal RBCs
  • Rh-negative mother exposed to Rh-positive fetal blood → anti-D IgG production → hemolysis in subsequent Rh-positive fetuses
• Fetal/Infant Manifestations
  • Fetus: anemia, hydrops fetalis (generalized edema), intrauterine death
  • Infant: kernicterus (bilirubin brain deposition), lethargy, hearing loss, cerebral palsy, learning deficits
• Diagnostics
  • Maternal Ab screening (indirect Coombs) for anti-D, fetal D antigen typing
  • Amniocentesis for bilirubin; fetal blood sampling for anemia
• Treatment & Prevention
  • Prophylactic Rh immunoglobulin (Rho(D)-Ig) to Rh-negative mothers at 28 weeks & postpartum (if infant Rh+)
  • In utero exchange transfusion or postnatal exchange transfusion for affected neonate