immune effector mechanisms

IMMUNE EFFECTOR MECHANISMS

Antibody-Mediated Reactions

Immunology - the Double-Edged Sword

Immunoprotection Immunopathology

Both involve the same immune mechanisms!

The balancing act between hyporeactivity and hyperreactivity

Infections and Tumors

Health Immunopathology

Classification of Immune Mechanisms

Handout Gell and General PropertiesCoombs (1963)

Antibody-MediatedInactivation or Activation -- Toxin, virus inactivationCytotoxic or Cytolytic Type II Opsonization, ADCC, C’-mediated lysisImmune Complex Type III Ag-Ab complex formation in tissueAtopic or Anaphylactic Type I IgE mediated allergic reactions

Cell-MediatedT-cell Cytotoxic -- CD8+ T cell-mediated cell lysis Delayed Hypersensitivity Type IV CD4+ T cell-mediated activation of

macrophages

EitherGranulomatous Reactions -- Chronic reaction to poorly degradable

antigens

GranulomatousLymphocytes andMacrophages

Space occupying lesionPersistent antigen

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Lecture: Ab mediated Reactions

Lecture: Cell mediated Reactions

Induction of Different Forms of Immunity

• Type of agent or antigen.• Route of infection/exposure.• Activation of Th1 vs. Th2 cells.• Location/cell type involved in antigen

presentation.• Cytokines expressed by antigen presenting

cells and T cells. • Genetic factors.• Non-genetic factors. (e.g. age and nutritional

status)

1. Inactivation or Neutralization Reactions

Definition - binding of antibody to an epitope resulting in inactivation, neutralization or abnormal activation

Mechanisms – Ab binding to a protein (e.g. toxin) can inhibit binding to

substrate or alter conformation, resulting in loss of activity Ab binding to virus can block receptors, alter viral structure,

or opsonize virus Autoimmune Abs against hormone or neurotransmitter

receptors can either block or activate the receptor

DirectBlockade of active site; orAlteration of structure, function

ToxinViral proteinHost protein

Inactivation or Neutralization Reactions:Medical Aspects (Examples)

• Protective• Toxin inactivation (e.g. C. diphtheriae and C. tetani toxins)

• Virus neutralization (polio, influenza, measles, mumps, rubella)

• Immunopathologic• Myasthenia gravis: autoimmune Ab to ACh receptors, blocks

interaction

• Graves disease: Ab to TSH receptor activate thyroid cells (hyperthyroidism)

Clinical Vignettes – InactivationReactions (Geha and Notarangelo, “Case Studies in Immunology”)

Case 40 Myasthenia Gravisbinding of anti-AchR antibodies results in skeletal muscle weakness (blocks activation)

Three effectsAnti-AchR antibodies block Ach bindingAch receptors internalized and degradedSynaptic clefts decrease in complexity

• Aristotle Onassis • (Jackie Kennedy Onassis’ husband) had this disease.

Graves Disease: Autoantibody to cell surface receptors leading to activation reaction

Normal thyroid activation Autoantibody activation

Graves Disease: Autoimmunity to cell surface receptors

Factoid: George and Barbara Bush AND their dog Millie all had Graves disease while he was President.

Opthamolopathy

2. Cytotoxic Reactions (Type II Hypersensitivity)

Definition - Ab binding to cell surfaces resulting in opsonization, complement activation, or ADCC

Mechanisms Activation of classical complement pathway, MAC formation

Opsonization by IgG or C3b, enhanced phagocytosis

Antibody-Dependent Cellular Cytotoxicity (ADCC) involving null lymphocytes or macrophages

(IgE mediated binding of eosinophils to helminths)

(complement dependent examples)

Cytotoxic Reactions:Medical Aspects (Examples)) Protective

– Ab and complement-mediated killing and opsonization of pyogenic bacteria (e.g. Staph and Strep)

– Ab and complement-mediated killing and opsonization of protozoa, including Plasmodium and Trypanosoma

– ADCC against virus-infected cells, tumor cells, protozoa, and helminths

Immunopathologic– Transfusion reactions - lysis of transfused RBCs– Rh reactions - hemolytic disease of newborns– Hemolytic anemia- autoantibodies lyse, opsonize RBCs– Goodpasture's syndrome - anti-basement membrane Abs– Transplant rejection - recipient Abs cause hyperacute rejection

Immunopathologic

– Transfusion reactions - lysis of transfused RBCs

– Rh reactions - hemolytic disease of newborns

– Hemolytic anemia-autoantibodies lyse, opsonize RBCs

– Transplant rejection -recipient Abs cause hyperacute rejection

Blood Groups

Hemolytic anemia- autoantibodies lyse, opsonize RBCs

Case 46. Geha and Notarangelo

Infections can cause individuals to develop transient serum antibodies to RBC antigens.

Hyperacute Rejection – KidneyPreformed antibodies available to rapidly destroy transplanted tissue

3. Immune Complex Reactions (Type III Hypersensitivity)

Definition - deposition of AgAb complexes, leading to attraction of PMNs, inflammation

Mechanisms– Soluble or insoluble (large) complexes form between Ag

and IgG or IgM and are deposited in tissue– Immune complexes fix complement (releasing C3a,

C5a), resulting in mast cell degranulation and attraction of neutrophils

– Inflammatory response can aid in clearing bacteria– Complement activation, release of neutrophil lysosomal

contents can cause tissue damage

and influx of PMNs, monocytes

Occurring in Tissue

• hemorrhagic appearance (purpura)

• Neutrophilic infiltrate around vascular beds

• Requires 2 to 6 hours to occur

Immune Complex Reactions:Medical Aspects (Examples)

Protective– Contribute to acute inflammatory responses,

protection against bacterial infections

Immunopathologic– Serum sickness (‘foreign’ protein or drug-induced)– Systemic lupus erythematosus (SLE) and other

autoimmune diseases – Rheumatic fever– Glomerulonephritis - neutrophil infiltration, 'lumpy-

bumpy' basement membrane deposits

(Geha and Notarangelo, “Case Studies in Immunology”)

Case 52 Drug-Induced Serum Sickness – antibodies against penicillin cause vasculitis, hemorrhage

Case 37 - Systemic Lupus Erythematosus

16 yo Nicole Chawner developed a ‘butterfly’ rash over her cheeks after prolonged exposure to the sun. Also experienced joint pain and had enlarged lymph nodes. She had anti-DNA antibodies and decreased complement C3 levels. Treatment: prednisone and naproxen.

Geha and Notarangelo, Case Studies in Immunology

4. Anaphylactic or Atopic Reactions(Type I Hypersensitivity)

Definition - IgE-mediated activation of mast cells and other cell types and its effects.

Mechanisms– IgE is produced and binds to Fc receptors on mast cells,

basophils, and eosinophils– Ag crosslinking of bound IgE results in mast cell

degranulation and synthesis of leukotrienes & prostaglandins

– Histamine release causes increased vascular permeability, vasodilation, and bronchoconstriction

– ECF-A and NCF attract eosinophils, neutrophils– Leukotrienes and eosinophil factors cause long-term effects

Anaphylactic or Atopic Reactions:Medical Aspects (Examples)

Protective– Helminth infections: expulsion of worms from GI

tract, eosinophil-mediated killing of worms in tissues

Immunopathologic– Hay fever– Asthma– Cutaneous anaphylaxis– Food allergies– Systemic anaphylaxis

Mast Cells

Connective Tissue (Skin) Mucosal (Gut)

http://tu-dresden.de/die_tu_dresden/fakultaeten/medizinische_fakultaet/inst/imm/bilder/mast_cellshttp://www.vetmed.vt.edu/education/curriculum/vm8054/Labs/Lab5/Lab5.htm

Mast cells – found in tissue (EM, color enhanced)

Basophils – found in blood

Protective Response to Parasitic Worms

Problem – IgE made in response to “everyday” antigenic stimuli. These stimuli thus become “allergens”.

Sequence of Events– Sensitization Phase

– Individual exposed to antigen.– B cells produce IgE to allergen.

– Activation Phase– Mast Cells (and Basophils ) recognize Ab-Ag and trigger

activation of cell. Mast cell triggered to release granules and inflammatory mediators.

– Usually due to cross-linking of Fc receptors with antigen.– Effector Phase

– Preformed mediators released.– Newly synthesized mediators made and released.

– Late Phase– Continued tissue damage.

Sensitization Phase

IgE-Mediated Reactions

Effector Phase with released mediators

Clinical Presentations of Type I Hypersensitive Reactions

Roitt 19.2

Anaphylactic Reaction to a Bee Sting

Clinical Vignettes – Anaphylactic Reactions (Geha and Rosen, “Case Studies in Immunology”)

Case 50 Allergic Asthma –14 yo Frank Morgan has rhinitis and persistent wheezing

Case 49 Acute Systemic Anaphylaxis – toddler John Mason has a near-fatal allergic reaction after repeated exposure to cookies containing peanut butter

GranulomatousLymphocytes andMacrophages

Space occupying lesionPersistent antigen

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Lecture: Ab mediated Rxns

Lecture: Cell mediated Rxns

Late Phase Reaction with released mediators

(constant stimulation leads to pathology; occurs in ASTHMA)