Immune Pathology II - Basic Mechanisms Flashcards Preview

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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)


What does allergy mean?

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


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

direct involvement of ANTIBODIES


Type IV Hypersensitivity is characterized by what immune mechanism?

T CELLS are the main effector cells


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).


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)


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)


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.


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.


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

Within minutes of encountering the allergen you can trigger a response


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.


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

autoimmune diseases


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)


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


What are the two types of tolerance?

Central and Peripheral


Why is self-tolerance needed?

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


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.


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



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.


This is called negative selection

Central tolerance


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

multi-organ autoimmunity


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


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


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

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


What is anergy?

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


Anergy can occur when T cells encounter antigen without _____.

subsequent activation


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
-engagement of inhibitory receptors on these cells (don't need to know this path)


What are additional tolerance mechanisms?

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


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


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


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



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)


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

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


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)


Self tolerance

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


induction of costimulators on APCs

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


molecular mimicry

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


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


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


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


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


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


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


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)


Describe immune privilege (mechanism of self-tolerance)

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


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


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


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


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)


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