Immune Pathology II - Basic Mechanisms Flashcards Preview

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Flashcards in Immune Pathology II - Basic Mechanisms Deck (49):
0

What is hypersensitivity?

An injurious, typically excessive immune response directed against foreign or self antigens
-the foreign antigens can be dangerous (pathogens) or normally harmless (plant pollen)

2

What does allergy mean?

Altered reactivity
-immune response against an otherwise harmless substance
-allergy incidence has risen sharply in recent years

3

Types I-III Hypersensitivity are characterized by what immunologic mechanism?

direct involvement of ANTIBODIES

4

Type IV Hypersensitivity is characterized by what immune mechanism?

T CELLS are the main effector cells

5

Type I (Immediate Hypersensitivity) involves...

Mast cells (specific for allergen) bind IgE via their Fc receptors. On encountering antigen the IgE becomes cross-linked, causing degranulation and release of inflammatory mediators (granules and cytokines).

5

Type II, antibody-mediated, hypersensitivity involves...

Antibody is directed against antigens on an individual's own cells (target cell). This may lead to cytotoxic action by NK cells, complement-mediated lysis, or receptor modulation (ex, hormone receptor signaling)

6

Type II (antibody-mediated) hypersensitivity involves...

Antibody (IgG or IgM) is directed against antigens on an individual's own cells (target cell). This may lead to cytotoxic action by NK cells, complement-mediated lysis (activation of leukocytes), or receptor modulation (ex, hormone receptor signaling)

8

Type III (immune complex) hypersensitivity involves...

Antigen/antibody (IgG or IgM) complexes are deposited in the tissue. Complement is activated and neutrophils are attracted to the site of deposition, causing local damage.

8

Type IV (T cell-mediated) hypersensitivity involves...

Antigen-sensitized T cells release cytokines following a secondary contact with the same antigen. This induces INFLAMMATORY REACTIONS and activates MACROPHAGES which release additional mediators.

10

Why are type I hypersensitivity reactions considered "immediate hypersensitivity"?

Within minutes of encountering the allergen you can trigger a response

11

Why is type IV hypersensitivity sometimes called "delayed-type hypersensitivity"?

During the delay phase there are additional steps after antigen recognition. The T-cells that are going to respond to the antigen are somewhere else in the body, so you need B-cells, release of signals, and T cell activation. These are memory T cells responding, so a little faster than initial response.

12

Adaptive immune responses directed against healthy cells and tissues of the body can produce __________.

autoimmune diseases

13

Autoimmunity results from a _____ of the mechanisms that produce and maintain ______.

Autoimmunity results from a FAILURE of the mechanisms that produce and maintain SELF-TOLERANCE.
- genetic and/or environmental factors contribute
- may be organ-specific or affect many organs (systemic)

14

What are the general features of autoimmunity?

-Genetic factors and environmental factors
-->strong links between MHC I and II alleles and certain diseases, but these susceptibility alleles do not guarantee that disease will develop

-Disease frequency differs between sexes
--> overall higher incidence in of most diseases in females, unclear why

-Diseases "wax and wane"
--> checks and balances of immune system

-Mechanisms of tissue injury classified according to those for hypersensitivity.
-->many autoimmune disease fit into several hypersensitivity types, but they are classified by their initial type

15

What are the two types of tolerance?

Central and Peripheral

16

Why is self-tolerance needed?

byproduct of the mechanism to create vast antigen receptor diversity is the production of auto-reactive lymphocytes

17

Tolerance is the _____ and _____ lack of immunological reactivity to a particular antigen.

Tolerance is the ACQUIRED and SPECIFIC lack of immunological reactivity to a particular antigen.

18

Autoimmunity results from a failure to establish _____ (or a break in it).

tolerance

19

Central tolerance: B cells in the __________ and T cells in the _______ may be ______ if their ______ receptors are strongly self-reactive.

Central tolerance: B cells in the BONE MARROW and T cells in the THYMUS may be DELETED if their ANTIGEN receptors are strongly self-reactive.
This is called negative selection.
Also involves development int he thymus of regulatory T cells.

20

This is called negative selection

Central tolerance

20

If mice lacked the AIRE (autoimmune regulator gene), they also developed ___________.

multi-organ autoimmunity

22

AIRE (autoimmune regulator gene) was identified in some patients with systemic autoimmunity, a disease called

APECED

AIRE permits expression of tissue-restricted antigens in the thymus for sampling by developing T cells as they are 'educated'

23

Why is peripheral tolerance also needed, in addition to central tolerance?

Because some self-reactive lymphocytes make it out into the periphery

24

What is anergy?

silencing of T cells
this is an active state of non-responsiveness; in some cases cells eliminated via apoptosis

25

Anergy can occur when T cells encounter antigen without _____.

subsequent activation

26

Describe the T cell anergy response

Immature APCs present self antigen recognized well by naive T cell - this produces anergic (unresponsive) T cells via either:
-signaling block
OR
-engagement of inhibitory receptors on these cells (don't need to know this path)

27

What are additional tolerance mechanisms?

- Regulatory T cells (Tregs)
- immune-privilenged sites

28

How do regulatory T cells work

They produce a number of suppressive factors that inhibit the function of other T cells, as well as virtually all other immune cell types
Tregs are CRITICAL in the prevention of autoimmunity

29

Immune-privileged sites

lymphocytes do not typically enter some tissues (such as brain, eyes, testis, placenta/fetus). Therefore, they do not encounter some tissue-restricted antigens
Mechanisms are in place to tightly regulate immune cells in these locations, but not super strict as each tissue must have some capacity for immunity

30

_____ to the tissue can release antigens that the immune system has never "seen" before.

Trauma

31

What two things can break tolerance for autoimmunity?

- genes (maybe cause defects in self-tolerance pathways?)
- environmental stimuli (this can lead to activation of self-reactive lymphocytes)

32

What are the dominant factors linked to autoimmunity (type of gene)?

HLA genes
-mainly mapped to MHC I and II genes within HLA

33

Environmental breakage of tolerance for autoimmunity can occur in three mechanisms:

- self-tolerance (anergy or deletion)
- induction of costimulators on APCs (autoimmunity)
- molecular mimicry (autoimmunity)

34

Self tolerance

Resting tissue APC binds/presents self antigen to T cell --> self-tolerance: anergy or deletion

35

induction of costimulators on APCs

microbe activates APC presenting self-antigen; APC presents self-antigen to self-reactive T cell --> autoimmunity

36

molecular mimicry

microbe taken up by APC, microbial agent presented by APC to self-reactive T cell that also recognizes microbial peptide --> autoimmunity

37

What is the hypersensitivity pathway active in Pemphigus vulgaris (autoimmune disease)?

- type II
- self antigen is the epidermal cadherin
- antibodies are generated to the epidermal cadherin
- antibodies stick to the epidermal cadherin, which is on the surface of the epidermal cells that express it
- the Fc portion of the antibody then binds to a NK cell causing it to release granules to lyse the cell
- or, the antibody fixes complement, ad either form a MAC or opsonize the cell for phagocytosis

37

What is the hypersensitivity pathway active in Graves diseaes (autoimmune disease)?

- type II
- the self antigen is the thyroid-stimulating hormone receptor
- pathway is the same as for pemphigus vulgaris

38

What is the hypersensitivity pathway active in systemic Lupus Erythematosus (autoimmune disease)?

- type III
- the self antigen is DNA, histone, ribosomes, snRNP, scRNP
- B cells produce antibodies against the different autoantigens
- the antibodies form complexes with autoantigens
- these complexes are not soluble and get stuck in various tissues throughout the body, particularly in areas of filtration, like in the glomerulus and choroid plexus
- complement can be activated, which attracts neutrophils to the area (they release enzymes that damage the vessel and adjacent tissue)
- as other immune cells try to destroy the complexes, the tissue in these areas is also destroyed

39

What is the hypersensitivity pathway active in Rheumatoid Arthritis (autoimmune disease)?

- type IV (cytotoxic)
- unknown synovial joint antigen
- antigen is presented by an APC on MHC II to CD4 T cells
-CD4 T cells secrete cytokines to activate macrohpages or recruit neutrophils; macrophages are cytotoxic and destroy the cell, while neutrophils can also injure the tissue
- CD8 T cells can also be activated and will kill cells that present this antigen

40

What is the hypersensitivity pathway active in Multiple Sclerosis (autoimmune disease)?

- type IV
- antigen is myelin basic protein and a proteolipid protein
- same pathway as for Rheumatoid arthritis

41

Distinguish between autoreactivity and autoimmunity

Autoreactivity is recognition of a self antigen
- this can happen as part of the normal physiological process, i.e. lymphocyte recognition of self that causes them to be deleted

Autoimmunity is an immune response against self
- must be the primary source of injury and absence of other well-defined cause of disease
- failure of the mechanisms that produce and maintain self-tolerance

42

Describe central tolerance (mechanism of self-tolerance)

- occurs in bone marrow (B cells) and thymus (T cells)
- negative selection: if a cell recognizes self, it is destroyed
- antigens from peripheral tissues are expressed by certain thymic epithelial cells to train T cells; gene that helps is the autoimmune regulator gene (AIRE)

43

Describe immune privilege (mechanism of self-tolerance)

lymphocytes cannot enter these tissues typically, so do not encounter these antigens

44

Describe the function of regulatory T cells as a mechanism of self-tolerance

- inhibit the activity of virtually all immune cells
- some reactive T cells make it to the periphery; regulatory T cells prevent them from becoming activated or fully functional

45

Describe the function of anergy as a mechanism of self-tolerance

- state of non-responsiveness that can be induced in T and B cells when they encounter their antigens in a low inflammatory context
- body cells lack costimulatory molecules needed to activate T cells

46

Describe how tolerance can be broken to produce autoimmunity - HLA

- HLA, the MHC gene, greatly affects susceptibility to autoimmune disease
- certain alleles have greater risk than those without for particular autoimmune diseases

47

Describe how tolerance can be broken to produce autoimmunity - molecular mimicry

- some diseases have very similar antigens to those of self
- during response to the antigen, T and B cells can be activated against these similar self antigens instead of/in addition to the pathogen
- Rheumatic fever: antibodies develloped against Streptococcus cross-react with heart tissue
- Transient in this case; once pathogen is cleared, the antibody levels will drop and the body will stop attacking the heart (infection provides the proper inflammatory environment to activate T and B cells against self)

48

Describe how tolerance can be broken to produce autoimmunity - Tissue trauma to normally sequestered (hidden) self antigens

- immune system has never been exposed and reacts as if they were foreign, activating T cells
- can then enter the tissue to attack antigen in the normally sequestered area