Hypersensitivity Rxns 2

Front 1

Type I hypersensitivity rxn--think ____.

Type 2 hypersensitivity rxn--think ____.

Back 1

IgE

IgM or IgG

Front 2

What's a good way to remember what's a type 2 rxn and what's a type 3 rxn?

Back 2

-Type 2 involves SURFACE stuff; antigens can be intrinsic to the cell membrane or exogenous, like a drug metabolite adsorbed onto the cell surface.

Front 3

4 main mechanisms of Type 2 hypersensitivity:

Back 3

A. Opsonization and Phagocytosis (Used to be known as “Complement Dependent Reactions”)
1. Complement-induced lysis
2. Complement & Fc receptor-mediated phagocytosis

B. Complement & Fc Receptor-Mediated Inflammation

C. ADCC (Antibody-Dependent Cell-Mediated Cytotoxicity)

D. Antibody-Mediated Cellular Dysfunction

Front 4

Discuss Opsonization and Phagocytosis in Type 2 hypersensitivity:

2 ways it happens

Back 4

1. Complement-induced lysis (Direct lysis)

2. Opsonization by fixation of antibody or complement to cell surface.

Front 5

Direct lysis:

What's a common example of something that would cause this?

Back 5

-IgM or IgG antibodies react with an antigen present on the cell surface, causing complement activation, and resulting in the assembly of MAC, that “drills” holes through the lipid bilayer, resulting in cell lysis.

-Example: Acute hemolytic transfusion reaction (due to ABO mismatch) --> lysis of transfused rbcs.

Front 6

List the Blood types and the plasma ABs expressed with each:

Which is universal donor? Why
Which is universal recepient? Why

Back 6

universal donor: O; rbcs express no antigen
universal recipient: AB; plasma expresses no Abs.

Front 7

What happens when you give someone a blood type you shouldn't?

Back 7

-Acute hemolytic transfusion reaction --> direct cell lysis (INTRAVASCULAR hemolysis)

-Fever, hypotension, tachypnea, tachycardia, flank pain, hemoglobinemia

*this is a type 2 hypersensitivity rxn.

Front 8

Opsonization by fixation of antibody or C3b to the cell surface:

Back 8

-IgG or IgM Ab deposited on cell surface.

--> Complement activation
--> deposition of C3b on cell surface --> phagocytosis

Front 9

What's an example of a type 2 hypersensitivity rxn involving opsonization?

Back 9

-Minor Transfusion Reaction (minor blood group antigens --> EXTRAVASCULAR hemolysis)

Front 10

∆ b/t positive and negative blood types:

Back 10

-Rh antigen

A+ = antigen A & the Rh antigen
A- = antigen A

~15% of Caucasian Americans are Rh negative. (5-7% of the African-American population, and virtually none of the Asian population)

Front 11

Why is Rh compatibility imoprtant in pregnancy?

Back 11

-Rh Incompatibility Disease of the Newborn“Hemolytic Disease of the Newborn” (Erythroblastosis Fetalis)

-2nd Rh+ newborn is in trouble. CP, MR

Front 12

How can sensitization to fetal Rh+ blood cells be avoided?

Back 12

-“Rhogam”: IV human immune globulin containing antibodies against Rh+ rbcs destroys Rh+ rbcs before the maternal bloodstream can react by producing its own anti-Rh antibodies.

-Needs to be administered within 72 hours after delivery.

-Prevents formation of maternal anti-Rh antibodies.

-Delivered before and after delivery.

Front 13

Discuss Autoimmune Hemolytic Anemia, Leukopenia, Thrombocytopenia

Back 13

-Individuals produce antibodies to their own blood cells, which are then destroyed

-Example of a type 2 hypersensitivity run.

Front 14

Discuss Drug-Induced type 2 runs:

Back 14

Hapten - an incomplete antigen that can stimulate antibody production only in combination with a particular protein.

*Results in destruction of RBCs.

Front 15

Discuss Complement & Fc Receptor-Mediated Inflammation:

Back 15

-Ag on a surface; it's too big to be phagocytosed.
-Ab deposits in extracellular tissues (BM, matrix)
-Resultant injury is due to inflammation (not due to phagocytosis or lysis!)

-Deposited Abs activate complement -> C5a and C3a recruits neutrophils and monocytes -> activation of leukocytes -> release of enzymes, ROS -> damage to tissues

Front 16

What is Anti-Glomerular BM nephritis?
-AKA?
-who does it effect

Back 16

-AKA Goodpasture Syndrome.

-Autoantibodies directed against fixed antigens that are normal components of GBM (“Anti-GBM Abs”)

-Anti-GBM Abs cross-react with other BMs, especially in lung alveoli (lung & kidney lesions)

-Typically affects men in their twenties.

-Characterized by:
rapidly progressive GN (glomerulonephritis) -> severe glomerular damage & rapidly progressive renal failure
necrotizing hemorrhagic interstitial pneumonitis

*example of Complement & Fc Receptor-Mediated Inflammation (a type 2 hypersensitivity rxn)

Front 17

What are antibodies against in Goodpasture Syndrome?
-how are Abs arranged?

Back 17

-Antibodies are directed against Type IV collagen domains (component of the non-collagenous domain, NC1, of the alpha-3 chain of collagen type IV).

-Triggers for antibody formation are unknown

-High prevalence of certain HLA subtypes - genetic susceptibility?

-Autoantibodies are deposited in a linear array along the BM outlining capillary loops of kidney glomerulus & alveolar capillary BM.

-Formation of Ag-Ab complex stimulates inflammatory response & subsequent tissue damage.

Front 18

Back 18

Anti-GBM Antibodies against type IV collagen in Goodpasture Syndrome.

Front 19

Back 19

Immunofluorescence microscopy:

Linear deposition of immune complexes, characteristic of classic Anti-GBM disease.

Anti-GBM Antibodies against type IV collagen in Goodpasture Syndrome.

Front 20

Discuss ADCC: Antibody-Dependent Cell-Mediated Cytotoxicity

Back 20

-A type of type 2 hypersensitivity rxn.

-Doesn’t involve fixation of complement! – instead requires cooperation of leukocytes

-IgG-coated target cells are killed by cells that bear Fc receptors for IgG (eg. NK cells, macrophages, neutrophils)

-IgE-coated target cells are killed by EOSINOPHILS (think of PARASITES)

-ADCC may be relevant to destruction of targets too large to be phagocytosed (ex. parasites, tumor cells)

Front 21

ADCC may be involved in the pathogenesis of some autoimmune diseases such as ____ ____.

Back 21

Hashimoto’s Thyroiditis--Abs against thyroid cells.

(although Type IV CTL damage is also responsible for damage in this disease).

Front 22

Discuss Antibody-Mediated Cellular Dysfunction:

Back 22

-Antibody binding to a specific target cell receptor doesn’t lead to cell death, but rather to change in function without causing cell injury or inflammation

-Myasthenia Gravis - inhibition (Ab blocking) of receptor muscle weakness

-Graves Disease –Ab to TSH receptor results in stimulation of receptor

Front 23

Myasthenia Gravis:

Back 23

An autoimmune disease which is characterized by variable muscular weakness and fatigability of voluntary muscles.

It is caused by the presence of antibodies to Ach receptors in motor end plates of skeletal muscle  impaired neuromuscular transmission.

Front 24

Treatment of MG:

Back 24

-Treatment options:
*Acetylcholinesterase Inhibitors
*Immunosuppression
*Thymectomy
[Up to 85% of patients with MG will improve symptomatically after thymectomy; complete remissions may be seen in up to 30%]

Front 25

Graves' Disease:

Back 25

-An example of Antibody-Mediated Cellular Dysfunction.

-Autoantibody to TSH receptor mimics effect of TSH (stimulation of receptor) -> stimulation of thyroid acinar cells.

-A type 2 hypersensitivity rxn!

Front 26

Key Points: Type II Hypersensitivity Reactions
4

Back 26

1) Antibody-mediated (typically IgG or IgM)

2) Antibodies formed against antigens on cell surfaces or in connective tissues; they are directly or indirectly cytotoxic

3) Injury is mediated by several Ab-dependent mechanisms:
Ab-Complement -> MAC -> Lysis
Ab-Complement & Fc-mediated -> opsonization & phagocytosis
Ab-Complement and Fc-mediated inflammation
ADCC (Ab Dependent DIRECT killing by NK cells)
Ab-mediated cellular dysfunction

4) Complement is required for many of these events (not all – e.g. ADCC; Fc-mediated opsonization and Fc-mediated inflammation; Ab-mediated cellular dysfunction)

Front 27

Human diseases mediated by Type II hypersensitivity reactions:
6 examples

Back 27

Transfusion reactions
Erythroblastosis Fetalis
Autoimmune Hemolytic Anemias
Goodpasture syndrome
Graves disease
Myasthenia Gravis