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Foundations Week 3 > Immune Pathology II - Basic Mechanisms > Flashcards

Immune Pathology II - Basic Mechanisms Flashcards

1
Q

What is hypersensitivity?

A

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

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2
Q

What does allergy mean?

A

Altered reactivity

  • immune response against an otherwise harmless substance
  • allergy incidence has risen sharply in recent years
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3
Q

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

A

direct involvement of ANTIBODIES

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4
Q

Type IV Hypersensitivity is characterized by what immune mechanism?

A

T CELLS are the main effector cells

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5
Q

Type I (Immediate Hypersensitivity) involves…

A

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).

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5
Q

Type II, antibody-mediated, hypersensitivity involves…

A

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)

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6
Q

Type II (antibody-mediated) hypersensitivity involves…

A

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)

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8
Q

Type III (immune complex) hypersensitivity involves…

A

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.

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8
Q

Type IV (T cell-mediated) hypersensitivity involves…

A

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.

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10
Q

Why are type I hypersensitivity reactions considered “immediate hypersensitivity”?

A

Within minutes of encountering the allergen you can trigger a response

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11
Q

Why is type IV hypersensitivity sometimes called “delayed-type hypersensitivity”?

A

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.

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12
Q

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

A

autoimmune diseases

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13
Q

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

A

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)
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14
Q

What are the general features of autoimmunity?

A
  • 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
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15
Q

What are the two types of tolerance?

A

Central and Peripheral

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16
Q

Why is self-tolerance needed?

A

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

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17
Q

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

A

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

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18
Q

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

A

tolerance

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19
Q

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

A

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.

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20
Q

This is called negative selection

A

Central tolerance

20
Q

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

A

multi-organ autoimmunity

22
Q

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

A

APECED

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

23
Q

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

A

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

24
Q

What is anergy?

A

silencing of T cells

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

25
Q

Anergy can occur when T cells encounter antigen without _____.

A

subsequent activation

26
Q

Describe the T cell anergy response

A

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
Q

What are additional tolerance mechanisms?

A
  • Regulatory T cells (Tregs)

- immune-privilenged sites

28
Q

How do regulatory T cells work

A

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
Q

Immune-privileged sites

A

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
Q

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

A

Trauma

31
Q

What two things can break tolerance for autoimmunity?

A
  • genes (maybe cause defects in self-tolerance pathways?)

- environmental stimuli (this can lead to activation of self-reactive lymphocytes)

32
Q

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

A

HLA genes

-mainly mapped to MHC I and II genes within HLA

33
Q

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

A
  • self-tolerance (anergy or deletion)
  • induction of costimulators on APCs (autoimmunity)
  • molecular mimicry (autoimmunity)
34
Q

Self tolerance

A

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

35
Q

induction of costimulators on APCs

A

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

36
Q

molecular mimicry

A

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

37
Q

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

A
  • 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
Q

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

A
  • type II
  • the self antigen is the thyroid-stimulating hormone receptor
  • pathway is the same as for pemphigus vulgaris
38
Q

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

A
  • 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
Q

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

A
  • 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
Q

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

A
  • type IV
  • antigen is myelin basic protein and a proteolipid protein
  • same pathway as for Rheumatoid arthritis
41
Q

Distinguish between autoreactivity and autoimmunity

A

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
Q

Describe central tolerance (mechanism of self-tolerance)

A
  • 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
Q

Describe immune privilege (mechanism of self-tolerance)

A

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

44
Q

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

A
  • 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
Q

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

A
  • 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
Q

Describe how tolerance can be broken to produce autoimmunity - HLA

A
  • HLA, the MHC gene, greatly affects susceptibility to autoimmune disease
  • certain alleles have greater risk than those without for particular autoimmune diseases
47
Q

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

A
  • 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
Q

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

A
  • 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

Foundations Week 3 (12 decks)

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