lecture 10 disorders of the immune response

X-linked (Bruton) agammaglobulinemia (XLA)

• X-linked → ↑ in boys

• Arrest of development in bone marrow of pre-B cells

• Profound hypogammaglobulinemia (↓ immunoglobulins of all classes)

• Recurrent bacterial and enteroviral infections after 6 months (↓ maternal IgG)

• Especially susceptible to encapsulated bacteria

DiGeorge Syndrome

• Partial or complete failure of development of thymus and parathyroid glands (hypoplasia/aplasia)

• Facial characteristics:

  • Hypertelorism (increased distance between eyes), low set ears

  • Micrognathia (abnormally small jaw), underdeveloped chin

  • High-arched or cleft palate

• Hypocalcemia and tetany develop within 24 hours of birth

  • Absent/hypoplastic parathyroid glands = ↓ PTH → ↓ Ca²⁺

• Low/no circulating T-cells

• Normal B cell numbers

• ↓ antibody production

Severe Combined Immunodeficiency Disorders (SCID)

• Characterized by profound deficiencies of T and B lymphocytes and NK cells

• Defective maturation of T helper cells and NK cells

• B-cell production unaffected but antibody production impaired

• Lack of T-cell help (TH cell) → immature B cells not responding to antigen

• ↓ IgM, IgA and IgG (after 6 months)

• Hypoplastic thymus (underdeveloped)

no T cells + weak B cells + no NK cells → severe infections

Leukocyte Adhesion Deficiency (LAD)

• Defective chemotaxis, margination and adherence

• Clinical hallmarks:

  • Recurrent skin and mucosal bacterial infections

  • Absent pus/abscess

  • Absence of neutrophils at infection sites

lack of WBCs -WBCs can’t stick or move into tissues → infections + no pus

Chronic Granulomatous Disease (CGD)

• Defects in microbicidal oxidant production (respiratory burst)

• Defect of NADPH oxidase → ↓ ROS and H₂O₂ → no intracellular killing

phagocytes eat bacteria but can’t kill them (no respiratory burst)

Type I HSR-allergic reaction

Cells involved:

• Th2 lymphocytes

  • Differentiate in response to allergens → cytokine secretion (IL-4)

  • Stimulates differentiation of B cells into IgE-producing plasma cells

• Mast cells

  • Degranulate (release mediators – histamine)

  • Initiate early events

allergen → Th2 → IgE → mast cells → histamine → allergy symptoms

Type II Antibody-Mediated (Cytotoxic) HSR

Mediated by IgG or IgM antibodies directed against target antigens on cell surfaces or tissues

• antibodies attack cells → cells get destroyed

Type II HSR – Mechanisms

1. Complement-activated cell destruction

• Opsonization and MAC

2. Complement- and ab-mediated inflammation

• Leukocytes

3. Antibody-dependent cell cytotoxicity (ADCC)

• NK cells

4. Antibody-dependent modulation of normal cell surface receptors

Kill (MAC, NK cells), Eat (opsonization), Inflame (leukocytes), Mess up receptors

Type III Immune Complex-Mediated HSR

• Formation of insoluble antigen-antibody (immune) complexes in blood

• Immune complexes = aggregation (clumps) of antigens and antibodies

• Immune complexes deposit on vascular epithelium or tissue → activate complement system

• Attract neutrophils → inflammation and tissue damage

• Alterations in blood flow

• Increased vascular permeability

• Destructive action of inflammatory cells → tissue damage and necrosis

antigen + antibody clumps → get stuck → cause inflammation and tissue damage - “Clumps cause damage”

Type IV Delayed Cell-Mediated HSR

• Antibody-independent T cell-mediated reactions

• Delayed-type HSR

  • Exs:

    • Tuberculin skin test (PPD)

    • Allergic contact dermatitis

• Hallmarks:

  • Delay in time required for reaction to develop

  • Recruitment of macrophages (vs. neutrophils in type III HSR)

T cells (no antibodies) → delayed reaction → macrophages cause inflammation- “Type IV = delayed & T cells”

types

ACID

• A = Type I → Allergy (IgE)

• C = Type II → Cytotoxic (cells destroyed)

• I = Type III → Immune complexes

• D = Type IV → Delayed (T cells)

• Type I: IgE, immediate allergy

• Type II: IgG/IgM attack cells

• Type III: immune complexes cause inflammation

• Type IV: delayed T-cell response

Hyperacute Graft Rejection

• Antibody-mediated or humoral rejection; rapid

• Preformed antibodies against graft antigens on vascular endothelial cells initiate a type III HSR

• Activates complement and clotting systems → vessel occlusion → stasis of blood flow

• Graft turns white immediately

pre-existing antibodies → immediate attack → no blood flow → graft dies quickly

Acute Rejection

• Cell-mediated immune response

• Occurs within days – months after transplantation

T cells attack graft over time

Chronic Rejection

• Occurs over a prolonged period (months – years)

• Immune-mediated inflammatory injury to a graft

slow, long-term immune attack → gradual damage → graft failure

Graft Versus Host Disease (GVHD)

• 3 requirements for development:

  1. Graft has functional cellular immune component

  2. Recipient’s cells express antigens foreign to donor cells

  3. Immunocompromised recipient tissue incapable of mounting an effective immune response

• Involves:

  1. Donor’s T cells recognize recipient’s cells as foreign

  2. Activation of donor T lymphocytes

  3. Target tissue destruction (type IV HSR)

donor T cells attack the recipient’s body