immune effector mechanisms

50
IMMUNE EFFECTOR MECHANISMS Antibody-Mediated Reactions

Upload: buiduong

Post on 14-Dec-2016

226 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: IMMUNE EFFECTOR MECHANISMS

IMMUNE EFFECTOR MECHANISMS

Antibody-Mediated Reactions

Page 2: IMMUNE EFFECTOR MECHANISMS

Immunology - the Double-Edged Sword

Immunoprotection Immunopathology

Both involve the same immune mechanisms!

Page 3: IMMUNE EFFECTOR MECHANISMS

The balancing act between hyporeactivity and hyperreactivity

Infections and Tumors

Health Immunopathology

Page 4: IMMUNE EFFECTOR MECHANISMS

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

Page 5: IMMUNE EFFECTOR MECHANISMS

GranulomatousLymphocytes andMacrophages

Space occupying lesionPersistent antigen

1234

6

5

7

Lecture: Ab mediated Reactions

Lecture: Cell mediated Reactions

Page 6: IMMUNE EFFECTOR MECHANISMS

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)

Page 7: IMMUNE EFFECTOR MECHANISMS

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

Page 8: IMMUNE EFFECTOR MECHANISMS

DirectBlockade of active site; orAlteration of structure, function

ToxinViral proteinHost protein

Page 9: IMMUNE EFFECTOR MECHANISMS

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)

Page 10: IMMUNE EFFECTOR MECHANISMS

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.

Page 11: IMMUNE EFFECTOR MECHANISMS

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

Normal thyroid activation Autoantibody activation

Page 12: IMMUNE EFFECTOR MECHANISMS

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

Page 13: IMMUNE EFFECTOR MECHANISMS
Page 14: IMMUNE EFFECTOR MECHANISMS
Page 15: IMMUNE EFFECTOR MECHANISMS

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)

Page 16: IMMUNE EFFECTOR MECHANISMS

(complement dependent examples)

Page 17: IMMUNE EFFECTOR MECHANISMS
Page 18: IMMUNE EFFECTOR MECHANISMS

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

Page 19: IMMUNE EFFECTOR MECHANISMS

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

Page 20: IMMUNE EFFECTOR MECHANISMS

Blood Groups

Page 21: IMMUNE EFFECTOR MECHANISMS
Page 22: IMMUNE EFFECTOR MECHANISMS

Hemolytic anemia- autoantibodies lyse, opsonize RBCs

Case 46. Geha and Notarangelo

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

Page 23: IMMUNE EFFECTOR MECHANISMS

Hyperacute Rejection – KidneyPreformed antibodies available to rapidly destroy transplanted tissue

Page 24: IMMUNE EFFECTOR MECHANISMS

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

Page 25: IMMUNE EFFECTOR MECHANISMS
Page 26: IMMUNE EFFECTOR MECHANISMS
Page 27: IMMUNE EFFECTOR MECHANISMS
Page 28: IMMUNE EFFECTOR MECHANISMS

and influx of PMNs, monocytes

Occurring in Tissue

Page 29: IMMUNE EFFECTOR MECHANISMS

• hemorrhagic appearance (purpura)

• Neutrophilic infiltrate around vascular beds

• Requires 2 to 6 hours to occur

Page 30: IMMUNE EFFECTOR MECHANISMS

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

Page 31: IMMUNE EFFECTOR MECHANISMS

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

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

Page 32: IMMUNE EFFECTOR MECHANISMS

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

Page 33: IMMUNE EFFECTOR MECHANISMS

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

Page 34: IMMUNE EFFECTOR MECHANISMS

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

Page 35: IMMUNE EFFECTOR MECHANISMS

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

Page 36: IMMUNE EFFECTOR MECHANISMS

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

Basophils – found in blood

Page 37: IMMUNE EFFECTOR MECHANISMS

Protective Response to Parasitic Worms

Page 38: IMMUNE EFFECTOR MECHANISMS
Page 39: IMMUNE EFFECTOR MECHANISMS

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.

Page 40: IMMUNE EFFECTOR MECHANISMS

Sensitization Phase

Page 41: IMMUNE EFFECTOR MECHANISMS
Page 42: IMMUNE EFFECTOR MECHANISMS

IgE-Mediated Reactions

Page 43: IMMUNE EFFECTOR MECHANISMS
Page 44: IMMUNE EFFECTOR MECHANISMS
Page 45: IMMUNE EFFECTOR MECHANISMS

Effector Phase with released mediators

Page 46: IMMUNE EFFECTOR MECHANISMS

Clinical Presentations of Type I Hypersensitive Reactions

Page 47: IMMUNE EFFECTOR MECHANISMS

Roitt 19.2

Anaphylactic Reaction to a Bee Sting

Page 48: IMMUNE EFFECTOR MECHANISMS

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

Page 49: IMMUNE EFFECTOR MECHANISMS

GranulomatousLymphocytes andMacrophages

Space occupying lesionPersistent antigen

1234

6

5

7

Lecture: Ab mediated Rxns

Lecture: Cell mediated Rxns

Page 50: IMMUNE EFFECTOR MECHANISMS

Late Phase Reaction with released mediators

(constant stimulation leads to pathology; occurs in ASTHMA)