(17) Hypersensitivity Reactions (III & IV) + Ocular Immune Privilege

What is an example of a type II hypersensitivity reaction that can occur in the human body but is not associated with an autoimmune disease?

mismatched blood types

There are numerous blood group antigens (ABO) based on what molecules on the plasma membrane of RBCs?

glycosphingolipids

(terminal sugars that are galactose or N-acetylgalactosamine)

glycosphingolipid present on type A RBCs

N-acetylgalactosamine

glycosphingolipid present on type B RBCs

galactose

glycosphingolipid present on type O RBCs

none

antibodies against certain blood group antigens found in human serum

isohemagglutinins

What class of immunoglobulins are isohemagglutinins? (anti-ABO antibodies)

IgM

What is the most common blood type?

type O

What is the least common blood type?

type AB

Which blood type is the universal donor?

type O

Which blood type is the universal recipient?

type AB

What antigen(s) do type A RBCs have?

A

What antigen(s) do type B RBCs have?

B

What antigen(s) do type AB RBCs have?

A, B

What antigen(s) do type O RBCs have?

none

What antibodies attack type A RBCs?

anti-B

What antibodies attack type B RBCs?

anti-A

What antibodies attack type AB RBCs?

none

What antibodies attack type O RBCs?

anti-A, anti-B

What other blood types can type A blood donate to?

A, AB

What other blood types can type B blood donate to?

B, AB

What other blood types can type AB blood donate to?

AB

What other blood types can type O blood donate to?

A, B, AB, O

What can type A blood receive from?

A, O

What can type B blood receive from?

B, O

What can type AB blood receive from?

A, B, AB, O

What can type O blood receive from?

O

Type II hypersensitivity reactions are mediated by antibodies (other than IgE). What specific kind mediates blood transfusion reactions?

isohemagglutinins (IgM)

Type II hypersensitivity reactions result from mismatched blood transfusions, which triggers a massive release of what molecules?

**causes damaged RBCs, free heme complex in circulation, fever, chills, angina, hypotension, shock, disseminated intravascular coagulation, renal failure, death 10-40% of the time

anaphylatoxins

proteins that are sparse and widely scattered in RBC membranes, with no naturally occurring antibodies against them

**found on NO other body cells or fluids

Rh (D) antigens

3 genes that are involved in the Rh (D) system; closely linked and inherited as a group

CDE

Out of the three genes that are involved in the Rh antigen system (CDE), which is the most clinically important?

**its presence confers the Rh+ phenotype

D

two terms for disease in which erythrocytes from an RhD+ fetus enter into maternal circulation, producing antibodies that attack fetal RBCs

results in anemia and jaundice (due to RBC destruction), leukopenia and thrombocytopenia (due to RBC replacement and nothing else), hepatomegaly/splenomegaly (due to RBC clearance), ascites, edema, and petechia

hemolytic disease of the newborn, erythroblastosis fetalis

What are 4 main symptoms of HDN?

anemia, jaundice, hepatomegaly, splenomegaly

(others include leukopenia, thrombocytopenia, ascites, edema, & petechia)

What kind of hypersensitivity reaction is hemolytic disease of the newborn/erythroblastosis fetalis?

type II

HDN pathogenesis 1a: In the first pregnancy, erythrocytes from a [RhD+ or RhD-] fetus leak into maternal circulation.

**usually happens during birth but could be during pregnancy (via IgG)

RhD+

HDN pathogenesis 1b: In the first pregnancy, erythrocytes from a RhD+ fetus leak into maternal circulation, which has what Rh phenotype?

RhD-

HDN pathogenesis 2: When erythrocytes from a RhD+ fetus leak into RhD- maternal circulation, what does the mother's body produce in response during the pregnancy?

IgM

(which CANNOT cross the placenta, which is why the fetus is not affected during the first pregnancy)

HDN pathogenesis 3: After the birth of an RhD+ fetus to an RhD- mother, some of the fetal blood gets mixed in with the maternal blood, stimulating the production of what molecules?

anti-RhD IgG antibodies

(which CAN cross the placenta in future pregnancies)

HDN pathogenesis 4: In subsequent pregnancies, if the fetus is RhD+, how can the anti-RhD IgG antibodies made the first time cause fetal RBC destruction?

cross the placenta into fetal circulation

medication administered to an RhD- mother within 72 hours of birth if Rh-incompatible

binds fetal Rh+ RBCs and removes them from the maternal circulation prior to initiating an immune response

RhoGAM

How can you treat HDN once an infant has it? (i.e. didn't prevent it with RhoGAM)

O- blood transfusion

Which of the following Rh genes will guarantee an Rh+ blood type?

A. C

B. d

C. c

D. D

D

What mediates type III hypersensitivity reactions?

IgG or IgM immune complexes (deposited on endothelial cells)

What is the basic mechanism of tissue injury (via IgG or IgM ICs) in type III hypersensitivity reactions?

complement activation, phagocyte activity

Type III hypersensitivty reactions involve ____ antigens that are bound by antibodies to get immune complexes, which deposit onto endothelial cells of blood vessels. When they do that, this triggers an inflammatory reaction (vasculitis).

soluble

In type III hypersensitivity reactions, what two things can immune complexes do to induce inflammation and tissue injury?

bind to Fc receptors in neutrophils and macrophages, activate complement cascades

type III hypersensitivity reaction that involves the constant presence of a pathogen that induces a weak antibody response and chronic immune-complex formation (malaria)

persistent low grade infection

type III hypersensitivity reaction involving a constant formation of auto-antibodies to a self-antigen and prolonged immune-complex formation (lupus)

autoimmune disease

If antigenic materials are inhaled, a type III hypersensitivity reaction will occur to form immune complexes where following repeated inhalation of mold, plant, or animal antigens? (farmer's lung)

lungs

located immune complex type III hypersensitivity reaction caused by injection of antigen in previously immunized individuals

**often seen in vaccinations, especially with boosters

Arthus reaction

What is responsible for the soreness of your arm after a booster shot?

Arthus reaction

(type III hypersensitivity)

Where are insoluble immune complexes deposited in the type III Arthus reaction?

wherever antigens were deposited

(depot effect)

The Arthus reaction involves sensitization because it is usually a result of secondary immunization because there are unusually high levels of what Ig present, stemming from the initial vaccination?

IgG

What are the 3 main clinical manifestations of an Arthus reaction?

acute inflammation, thrombus formation, local swelling

What mediates type IV hypersensitivity reactions?

T cells

(activation of CD4+ and CD8+ T cells)

What is the basic mechanism of tissue injury (via T cells) in type IV hypersensitivity reactions?

macrophage activation, lysis of target cells

Why are type IV reactions called "delayed hypersensitivity"?

takes longer than 12 hours to develop

True or false: Type IV hypersensitivity reactions require prior sensitization to an antigen.

true

What are 3 types of type IV delayed hypersensitivity reactions?

contact, tuberculin, granulomatous

type IV primarily epidermal reaction that is typically due to a hapten in something applied to the skin; IC containing hapten causes T cells to be activated

contact dermatitis

What are the principal APCs in skin involved in contact dermatitis?

Langerhans cells

10-14 day stage of contact dermatitis in which the hapten produces a reaction and causes the formation for memory T cells

sensitization

later stage of contact dermatitis in which helper T cells and monocytes are recruited to the antigenic site

elicitation

In the type IV contact mechanism, haptens enter the epidermis, combine with a carrier protein, and then are phagocytized by Langerhans cells.

Those cells then migrate where? What do they present to hapten peptide to? What kind of T cells does the produce?

regional lymph node, MHC class II, memory CD4+ T cells

Upon initial exposure of an antigen in the type IV contact mechanism, memory CD4+ T cells are created.

Upon subsequent exposure, CD4+ T cells secrete what cytokine?

IFN-gamma

Upon initial exposure of an antigen in the type IV contact mechanism, memory CD4+ T cells are created.

Upon subsequent exposure, CD4+ T cells secrete IFN-gamma, which causes keratinocytes and macrophages to release what other 3 cytokines?

IL-1, IL-6, TNF-a

Upon initial exposure of an antigen in the type IV contact mechanism, memory CD4+ T cells are created.

Upon subsequent exposure, CD4+ T cells secrete IFN-gamma, which causes keratinocytes and macrophages to release cytokines like IL-1, IL-6, and TNF-a. These cytokines stimulate the inflammatory response and cause what cells to be recruited to that area, causing the characteristic redness that we see?

more CD4+ T cells, macrophages, neutrophils

Tuberculin-type delayed hypersensitivity is the premise for what disease?

tuberculosis

Tuberculin-type delayed hypersensitivity is similar to contact hypersensitivity in that what phagocytic cells present to which lymphocytes?

Langerhans cells, CD4+ T cells

In tuberculin-type delayed hypersensitivity, CD4+ T cells (which were presented antigen by Langerhans cells) secrete what cytokine to activate macrophages?

IFN-gamma

In tuberculin-type delayed hypersensitivity, CD4+ T cells (which were presented antigen by Langerhans cells) secrete IFN-y to activate macrophages, which secrete what other 2 cytokines?

TNF-a, IL-1

In tuberculin-type delayed hypersensitivity, CD4+ T cells (which were presented antigen by Langerhans cells) secrete IFN-y to activate macrophages, which secrete TNF-a and IL-1, which cause what process to occur?

adhesion and leukocyte extravasation

(results in inflammation & edema)

Granulomatous type delayed hypersensitivity usually results from what kind of pathogen persisting within a macrophage?

microorganism

(also can form from a foreign body that cannot be phagocytized by macrophages)

A granulomatous type delayed hypersensitivity reaction results from a microorganisms persisting within a macrophage or a foreign body that can't be phagocytized by macrophages. Either way, it results in the formation of granulomas containing what?

giant cells and epitheloid cells (derived from macrophages)

Which type of hypersensitivity would you classify an arthus reaction?

A. Type III

B. Type IV

C. Type I

D. Type II

A

What are 3 sites in the body that are inaccessible to or that actively suppress immune responses? (they have immune privilege)

anterior chamber, testes, brain

Why is the anterior chamber of the eye immune privileged?

need to protect the visual axis from inflammation that can destroy sight

Why do cornea transplants not require tissue matching or immunosuppressive therapy?

immune cells not present to initiate response

Examples of passive factors contributing to ocular immune privilege are blood-ocular barriers, particularly in what two locations?

iris, retina

An example of a passive factor contributing to ocular immune privilege is the corneal endothelium, which has what connections present to prevent things from getting across cornea?

tight junctions

An example of a passive factor contributing to ocular immune privilege is lack of lymphatic drainage. Why is this important?

no chance of antigens getting from eye to systemic immune system to initiate autoimmune response

Cells in the eye have decreased expression of what molecules on their surface?

**passive factor contributing to ocular immune privilege

MHC class I and II

APCs in the eye do not have class II MHC, contributing to its ocular immune privilege. In addition, they are deficient in expression of what ligands?

CD40

(so even if they did come into contact with T cells, APCs couldn't be activated)

What are 3 inhibitory cytokines found in the eye that act as active factors contributing to ocular immune privilege?

TGF-B2, IL-10, MIF

What inhibitory cytokine is specific to the eye?

TGF-B2

inhibitory cytokine in the eye that specifically functions to keep NK cells out; blocks the signal that would normally draw them in

MIF (migration inhibitory factor)

ligand present on ocular cells that can bind to any rogue T cells that might be around to induce apoptosis

FasL

selective suppression of effectors of immunogenic inflammation while preserving other effectors of the immune system so that we can still have an immune response to remove things that may be harmful to the eye

**prevents delayed hypersensitivity and suppresses complement fixing antibodies, but preserves cytotoxic T cells and non-complement fixing antibodies

anterior chamber associated immune deviation (ACAID)

Does ACAID enhance or suppress delayed hypersensitivity (CD4+)?

suppress

Does ACAID enhance or suppress complement fixing antibodies (IgG & IgM)?

suppress

Does ACAID enhance or suppress cytotoxic T cells (CD8+)?

enhance

Does ACAID enhance or suppress non-complement fixing antibodies?

enhance

What kind of T cells are maintained by ACAID: CD4+ or CD8+?

CD8+

What kind of antibodies are maintained by ACAID: complement or non-complement fixing antibodies? (also list specific Ig classes)

non-complement fixing antibodies, IgA

What kind of T cells are suppressed by ACAID: CD4+ or CD8+?

CD4+

What kind of antibodies are suppressed by ACAID: complement or non-complement fixing antibodies? (also list specific Ig classes)

complement fixing antibodies, IgG and IgM

ACAID is initiated by an antigen-specific signal generated within the anterior chamber via what cells?

intraocular dendritic cells and macrophages

Under the influence of immunoregulatory factors (such as TGF-B2) in aqueous humor, intraocular dendritic cells and macrophages capture antigen and process it uniquely. For example, they block secretion/expression of what molecules?

IL-12, CD40

Intraocular dendritic cells and macrophages migrate across the trabecular meshwork into the blood and then to what location, where they inhibit Th1 and Th2 cell formation?

spleen