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 Properties
Coombs (1963)
Antibody-Mediated
Inactivation or Activation
Cytotoxic or Cytolytic
Immune Complex
Atopic or Anaphylactic
-Type II
Type III
Type I
Toxin, virus inactivation
Opsonization, ADCC, C’-mediated lysis
Ag-Ab complex formation in tissue
IgE mediated allergic reactions
Cell-Mediated
T-cell Cytotoxic
Delayed Hypersensitivity
-Type IV
CD8+ T cell-mediated cell lysis
CD4+ T cell-mediated activation of
macrophages
Either
Granulomatous Reactions
--
Chronic reaction to poorly degradable
antigens
Lecture: Ab mediated Reactions
1
2
3
4
6
5
Granulomatous
Persistent antigen
Lymphocytes and
Macrophages
Space occupying
lesion
Lecture: Cell mediated Reactions
7
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
Toxin
Viral protein
Host protein
Direct
Blockade of active site; or
Alteration of structure, function
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 – Inactivation
Reactions (Geha and Notarangelo,
“Case Studies in Immunology”)
Case 40 Myasthenia Gravis
binding of anti-AchR antibodies
results in skeletal muscle weakness
(blocks activation)
Three effects
Anti-AchR antibodies block Ach binding
Ach receptors internalized and degraded
Synaptic 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
Opthamolopathy
Factoid: George and Barbara Bush AND their dog Millie
all had Graves disease while he was President.
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 anemiaautoantibodies 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 – Kidney
Preformed 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
Occurring in Tissue
and influx of PMNs,
monocytes
• 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, 'lumpybumpy' 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_cells
http://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
Anaphylactic Reaction to a Bee Sting
Roitt 19.2
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
Lecture: Ab mediated Rxns
1
2
3
4
6
5
Granulomatous
Persistent antigen
Lymphocytes and
Macrophages
Space occupying
lesion
Lecture: Cell mediated Rxns
7
Late Phase Reaction with released
mediators
(constant stimulation leads to pathology;
occurs in ASTHMA)