Hypersensitivity Rxns 4

Front 1

What's unique about type 4 hypersensitivity?

Back 1

-it's cell-mediated
-AKA delayed type hypersensitivity

-Type IV hypersensitivity disorders involve tissue injury in which cell-mediated immune responses with sensitized T lymphocytes are the cause of the cellular and tissue injury

Front 2

What does normal cell-mediated immunity do?
4

Back 2

Cell mediated immune responses are the principal pattern of immunological defense against a variety of intracellular pathogens including:

mycobacterium tuberculosis
many viruses
protozoa
parasites

Front 3

Two main mechanisms of Type IV Hypersensitivity Reactions:

Back 3

1. Delayed-Type Hypersensitivity (CD4-mediated)
- prototypes: host response to tuberculosis; tuberculin reaction (ppd)
- contact dermatitis (ex. poison ivy)

2. T Cell-Mediated Cytotoxicity (CD8-mediated)
- Resistance to viral infections (e.g. viral hepatitis)
- Some autoimmune diseases
- Graft rejection and Graft-versus-Host Disease
- Tumor immunity

Front 4

Describe the host response to Tuberculosis infection:

Back 4

First exposure to mycobacterium tuberculosis: macrophages engulf mycobacteria and try to kill the organism, but don’t succeed.

Macrophages process and present antigen peptides in association with MHC Class II molecules on their cell surfaces.

They “call in” reinforcements: the T helper cells, which secrete TNF, IFN-g, IL-2

Front 5

How do granulomas form in TB?

Back 5

-With persistent/non-degradable Ags (such as TB), the initial perivascular lymphocytic infiltrate is replaced by macrophages over 2-3 weeks.

-Accumulated macrophages undergo morphologic transformation to epithelioid cells, surrounded by a collar of lymphs = “granuloma”

-Resulting injury iscaused by the T lymphocytes themselves, the macrophages, or both…

Front 6

Back 6

A section that shows several granulomas, each made up of an aggregate of epithelioid cells and surrounded by lymphocytes. Giant cells present.
-A type 4 response!

Front 7

-How long does it take to form a granuloma in TB?

Back 7

~3 weeks to battle mycobacteria & then “mount a Th1 response”

~3 weeks to activate and recruit macrophages -> granuloma formation

Front 8

How does the Tb skin test work?

Back 8

-In previously sensitized person:
injection of tuberculin subcutaneously 

-8-12 hours: reddening & induration begin

-Peaks at 24-72 hours; thereafter subsides

Front 9

Back 9

-Stain for Th1 cells; this is a positive ppd! DTH in Skin. Immunoperoxidase staining reveals a predominantly perivascular cellular infiltrate that marks positively with anti-CD4 antibodies.

1. Accumulation of mononuclear cells – mostly CD4 T lymphs - around small veins & venules (perivascular “cuffing”)

2. Increased microvascular permeability -> escape of plasma proteins (dermal edema & deposition of fibrin in interstitium are main cause of induration)

Front 10

Why is the ppd test sometimes given in as a “two-step” ppd?

Back 10

-Typical example: elderly adult (may have had earlier infection)

-Infected in childhood -> first time ppd as an elderly adult may be negative (“waning reaction”)

-However, the ppd may boost the hypersensitivity, and a repeat ppd 1-3 weeks later may be positive -> “boosted reaction” (NOT a sign of a NEW infection)

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Back 11

-Contact Dermatitis from poison ivy.
-first exposure: take a week to 10 days
-second exposure: is much quicker

Front 12

Haptens:

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-Several allergens that induce contact hypersensitivity reactions are haptens that react with normal self-proteins in the skin. When presented in this way, these antigens induce a cell-mediated response.

-Haptens:
- resins in poison ivy and poison oak
- metals such as nickel
- acetylates & chemicals in rubber

Front 13

Back 13

-Contact dermatitis showing an epidermal blister (vesicle) with dermal and epidermal mononuclear infiltrates.

-(TH1 cells accumulate, releasing cytokines -> damage keratinocytes causing separation of these cells)

*a type 4 response!

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Second Category of Type IV Hypersensitivity:
has important role in what? 4

Back 14

-T Cell-Mediated Cytotoxicity

-Killing of antigen-bearing target cells by cytotoxic T lymphocytes (CTLs).

-Important role:
Resistance to viral infections (e.g. viral hepatitis)
Some autoimmune diseases
Graft rejection and Graft-versus-Host Disease
Tumor immunity

Front 15

Viral Hepatatis:

Back 15

-example of T Cell-Mediated Cytotoxicity (type 4 rxn)

-HBV replication isn’t injurious to the host cell

-Liver injury results primarily from host immune response to viral Ags displayed on infected hepatocytes (CTLs play key role!)

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Back 16

Acute Viral Hepatitis; an example of a type 4 hypersensitivity rxn. T Cell-Mediated Cytotoxicity.

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Various type 4 hypersensitivity diseases:

Back 17

-Type I Diabetes
-MS
-GBS

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Type I Diabetes

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-Type I Diabetes (autoimmune disease in which immune effector cells react against self b-cell antigens).

-Fundamental abnormality: failure of self-tolerance in T-cells

-Damage to b cells:
- Th1 cells (by secreting cytokines including IFN-g and TNF)
- CD8+ CTLs (which directly kill b cells)

-There are also autoantibodies formed against islet antigens (but their role in causing injury is uncertain).

*cytotoxic type 4 response

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MS:

Back 19

*delayed type type 4 response

-autoimmune disease in which immune effector cells react against components of the myelin sheath.

-Available evidence suggests that the disease is initiated by CD4+ Th1 and Th17 T cells that react against self myelin antigens and secrete cytokines.
Th1 -> IFNg -> activates macrophages
Th17 -> promotes recruitment of leukocytes

Damage: activated leukocytes and their “injurious products”

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GBS:

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-acute onset immune-mediated demyelinating neuropathy

-Association with preceding infections (influenza, campylobacter jejuni, CMV, EBV etc).

-Damage: T cell-mediated immune response, activated macrophages -> segmental demyelination

Evidence:
- Transfer of these T cells to a naïve animal results in comparable lesions.
- Lymphocytes from individuals with GB -> produce demyelination in tissue cultures of myelinated nerves

Caveat: Circulating antibodies may also play a part
(plasmapheresis can be an effective treatment).

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T cell role in graft rejection and graft-versus-host disease:

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1) Graft Rejection
(Host-versus Graft Disease) Host T cells recognize graft as foreign -> attack

2) Graft-versus-Host Disease: (seen after bone marrow transplantation)
-Graft contains mature donor T cells -> recognize host cells as non-self -> attack -> organ dysfunction

*type 4 rxn

Front 22

Why does Hashimoto's Thyroiditis produce a complicated picture?

Back 22

-Involves both type II and type IV hypersensitivity reactions.