Transcript Mechanism of delayed hypersensitivity

Aims
• Compare and contrast the ABO and Rho(D)
alloantigens.
• Describe an Arthus reaction.
• List the cells involved in a DTH response.
• Describe ocular immune privilege
• Describe the role Anterior Chamber Associated
Immune Deviation (ACAID) is believed to play in an
ocular immune response.
• Readings: Abbas & Lichtman, Chapter 11
Blood Group Antigens
Type A
Type O
Type B
Red Cell Membrane
• There are numerous blood group antigens
– ABO system
• Glycosphingolipids
– Terminal sugars are galactose (B) & N-acetylgalactosamine (A)
• present on the surface of RBCs
• 80% of individuals also secrete these molecules in their
saliva, sweat and other secretions
• three alleles (A,B,O)
Adapted from Roitt’s Essential Immunology 15-15
ABO system
• Human serum usually contains isohemagglutinins
which are antibodies against blood group antigens
– IgM
Genotype
Phenotype
Frequency Isohemagglutinins
AA, AO
A
42%
anti- B
BB, BO
B
8%
anti- A,
AB
AB
3%
None
OO
O
47%
anti-A, anti-B
ABO Transfusion Reactions
• Mediated by isohemagglutinins – Mediated by IgM (highly efficient C’ fixing antibody
isotype)
• Systemically administered antigen
• Reaction Results in:
–
–
–
–
Massive release of anaphylatoxins
Damaged RBCs
Free heme complex in circulation
Fever, chills, angina, hypotension, shock, DIC, renal
failure.
– Fatal in 10-40% occurrences.
Rh (D) System
• Rh antigens are __________________________
• No naturally occurring antibodies to Rh antigens
• Rh antigens are sparse and widely scattered in
the RBC membrane
• Not found on other body cells or fluids
Rh (D) System
• Consist of three genes (CDE) that are closely linked and
inherited as a group
Father cde
CDe
Mother
CDE
CDE/cde (Rh+ )
CDE/CDe (Rh+)
CdE
CdE/cde (Rh_)
CdE/CDe (Rh+)
• Gene “D” is the most clinically important and its presence
confers Rh+ phenotype (~85% of individuals are Rh+).
• ABO and RhD are not the only relevant antigens on
RBCs!
Hemolytic Disease of the Newborn
(HDN)
• erythroblastosis fetalis
• anemia and jaundice
– RBC destruction
• leukopenia and thrombocytopenia
– RBC replacement
• hepatomegaly/splenomegaly
– RBC clearance
• ascites and edema • petechia
Hemolytic Disease of the Newborn
(HDN)
• Erythrocytes from RhD+
fetus leak into the maternal
circulation usually during
birth.
Adapted from Roitt’s Immunology 22-7
Hemolytic Disease of the Newborn
(HDN)
• Stimulating the
production of antiRhD antibody of
the IgG class
postpartum.
Adapted from Roitt’s Immunology 22-7
Hemolytic Disease of the Newborn
(HDN)
• During subsequent pregnancies,
anti-RhD IgG antibodies are
transferred across the placenta
into the fetal circulation.
• If the fetus is again RhD+ the
antibodies cause erythrocyte
destruction.
Next Pregnancy
Adapted from Roitt’s Immunology 22-7
Prevention of HDN
• Prenatal typing of parents
• Administer RhoGam (antiRhD, IgG) within 72 hours of
birth if Rh-incompatible
• MicRhoGam – smaller doses
at 28+ weeks
• RhoGam binds fetal Rh+
RBCs and removes them from
the maternal circulation prior
to initiating an immune
response.
• If HDN is present – exchange
transfusion with O neg. blood
RhoGam
Adapted from Roitt’s Immunology 22-7
Type III Hypersensitivity
• Involves soluble antigen
• Immune complex-mediated
Abbas & Lichtman’s Basic Immunology 11-7B
Type III Hypersensitivity
• Arthus reaction
• Persistent low-grade infection.
– Weak antibody response and chronic immune-complex
formation (malaria).
• Autoimmune disease.
– Constant formation of autoantibody to a self-antigen and
prolonged immune-complex formation (Systemic Lupus
erythematosus).
• Inhalation of antigenic material.
– Immune-complex formation in the lung following repeated
inhalation of mold, plant, or animal (Farmer’s lung) antigens.
Type III Hypersensitivity Mechanism
• Immune complexes can
bind to ________________
receptors on basophils and
platelets resulting in
increased blood vessel
permeability due to the
release of vasoactive
amines (histamine).
Adapted from Roitt’s Immunology 23-5
Arthus Reaction
• Example: Deltoid muscle soreness following tetanus
booster.
• Localized deposition of insoluble IC.
• Sensitization
– usually a result of secondary immunization
– usually high levels of IgG
• Reaction
– localized either i.d. or i.m.
• Time of onset
– earliest reactions are 1-2 hours after injection.
– depends on the amount of Ag and Ab available for complexing.
• Duration
– depend upon severity
Arthus Reaction
• Clinical manifestations
– Local swelling, erythema, edema.
– If severe, could yield hemorrhage and
necrosis
erythema
necrosis
edema
Arthus Reaction
• Histology
– acute inflammation (neutrophil accumulation)
– thrombus formation.
dermis
perivascular
cuffing
(neutrophils
extravasating)
capillary
Type IV “Delayed Hypersensitivity”
• Takes longer than 12 hours to develop.
• Cell-mediated immune response.
– Involving T cells.
• Three types:
– Contact
– Tuberculin
– Granulomatous
Abbas & Lichtman’s Basic Immunology 11-11A
Contact “Delayed Hypersensitivity”
• Primarily a epidermal reaction.
• Due to the hapten (nickel) in the watch buckle.
• Haptens are small molecules which by themselves
cannot be antigenic, but they bind to proteins to become
antigenic.
Contact Mechanism
• Langerhans’ cells
– principal APC
– Express MHC class II,
and receptors for Fc and
complement.
• 2 stages
– Sensitization
• produces memory T cells.
• 10-14 days.
– ____________________
• recruitment of T helper
cells and monocytes.
Adapted from Roitt’s Immunology 24-4
Contact Mechanism: Sensitization
• Haptens enter the
epidermis, combine with a
carrier protein, and then are
phagocytized by
Langerhans’ cells.
• The Langerhans’ cells
migrate to a regional lymph
node and present the
Hapten-peptide in MHC
class II to CD4+ T cells.
• Resulting in a population of
memory CD4+ T cells.
Adapted from Roitt’s Immunology 24-4
Contact Mechanism: Elicitation
• Langerhans’ cells
present haptenpeptide in MHC class
II to CD4+ T cells.
• CD4+ T cells secrete
cytokines (IFNg).
• Keratinocytes release
cytokines (IL-1 and
IL6).
• CD4+ T cells and
macrophages are
attracted to the site.
Adapted from Roitt’s Immunology 24-5
Tuberculin-Type “Delayed
Hypersensitivity”
• Premise for your TB test.
• Similar to contact
hypersensitivity in that the
Langerhans’ cell presents
antigen to CD4+ T cells.
• The resulting IFNg
activates macrophages to
make TNFa and IL-1.
• Adhesion molecules are
made and leukocyte
extravasation occurs.
• Inflammation and edema.
80-90%
macrophages
Adapted from Roitt’s Immunology 24-9
Granulomatous-Type “Delayed
Hypersensitivity
• Usually results from a microorganism
persisting within a macrophage.
• Can also form from a foreign body (talc)
that cannot be phagocytized by
macrophages.
• Result in the formation of granulomas
containing giant cells and epitheloid cells
derived from macrophages.
Immune Privilege
• Sites in the body that are inaccessible
to or that actively suppress immune
responses.
• Examples include:
– The anterior chamber of the eye
– The testes
– The ___________________________
Why is the Anterior Chamber of the
Eye Immune Privileged?
• There is a need to protect the delicate
visual axis from the sight-destroying
potential of immunogenic inflammation.
Proof of Ocular Immune Privilege
• Genetically incompatible tumor cells
transplanted into the anterior chamber can
often grow into tumors, whereas the same
cells do not form tumors when injected
subcutaneously.
• Cornea transplants do not require tissue
matching or immunosuppressive therapy.
Ocular Immune Privilege
• Passive factors
– Blood-ocular barriers (capillaries of the iris and
retina)
– Lack of lymphatic drainage
– ______________________________________ MHC
class I and II expression
– APC without Class II MHC
Ocular Immune Privilege
• Active factors
– the presence of inhibitory cytokines
• TGFb
• IL-10
• MIF
– the expression of FasL resulting in apoptosis of
Fas expressing T cells.
Anterior Chamber Associated Immune
Deviation (ACAID)
Immune Privilege Due to
ACAID
• Selective suppression of effectors of
immunogenic inflammation
– delayed hypersensitivity (Type IV) T cells
– complement-fixing antibodies (IgG and IgM)
• Preservation of other effectors cells
– cytotoxic T cells
– non-complement fixing antibodies (IgA)
Immune Privilege Due to ACAID
• ACAID is initiated by an antigen-specific signal
generated within the anterior chamber via intraocular
dendritic cells and macrophages.
• Under the influence of immunoregulatory factors
(____________________________________) in
aqueous humor, these cells:
– capture antigen
– process it uniquely
– Do not secrete IL-12 or express CD40
– migrate across the trabecular meshwork into the blood and
then to the spleen.
Immune Privilege Due to
ACAID
• In the marginal zone of the spleen, the APC
present antigen to T cells in an environment
that results in them differentiating into T
regulatory cells (Treg).
• Tregs prevent type IV delayed
hypersensitivity reactions (CMI) from
occurring and prevent B cells from making
antibody that activates complement cascade.
Next Time
• Immunizations
• Diagnostic Tests
Objectives
1. Compare and contrast the ABO and Rh(D) alloantigens.
1.
Role in HDN
2. Describe Type III Hypersensitivity reaction.
1. Arthus reaction.
3. Describe Type IV Hypersensitivity reaction.
1.
List the different types and cells involved in this response.
4. Describe ocular immune privilege
5. Describe the role Anterior Chamber Associated Immune
Deviation (ACAID) is believed to play in an ocular
immune response.