Immune Pathology II - Basic Mechanisms Flashcards
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).
tolerance
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
APECED
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
OR
-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.
Trauma
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
