Immune Regulation and Autoimmunity Flashcards
Decreased expression of ___renders immune effector cells more susceptible to apoptosis in the absence of survival signals
anti-apoptotic Bcl-2
What is antigenic competition?
competing antigen can regulate the immune response to an unrelated antigen
- by cytokine crossregulation for example
What is at the centre of the immune regulatory process? why?
Antigen because humoral and cell-mediated immune responses diminish as antigen concentration decreases
What is the more simple role of antibody in the regulation of the immune response?
clearance of antigen by freely circulating antibody via the formation of immune complexes
Followed by phagocytosis
What is the role of secreted IgG in the regulation of the immune response?
inhibits continued activation of B cells by forming immune complexes that cross- link surface immunoglobulin and IgG Fc receptors on B cells
what is antibody feedback?
activation of a phosphatase that prevents further signalling through the B cells antigen receptor
give an example of an active regulatory mechanism for T cells?
CTLA-4 binding to B7 molecules deprives T cells of essential costimulatory signaling through CD28
What does ACID stand for? what is it important for?
Activation induced cell death
Important for the maintenance of T cell homeostasis
How does ACID work?
activated T cells express FASL on their surface as well as Fas
Trimerization of Fas can occur by interacting with FASL on neighbouring T cells
Leads to death by apoptosis
Mutant mice that lack functional Fas/FASL on T cells ..
had excessive numbers of T cells and spontaneously develop autoimmune disease.
When do Treg cells develop?
after persistent antigenic stimulation of T cells
What could be a clinical use of increased Treg activity?
diminish unwanted immune responses (lie autoimmunity) and promote desirable ones (like anti tumour)
Are Treg cells antigen specific?
Yes
What are the 4 mechanisms of Treg cell action?
- Cytokine deprivation
- usually of IL-2 - release of inhibitory cytokines (IL-10 and TGFß)
- Inhibit APC cells by preventing them from up regulating B7 fam members
- cytotoxicity by secreting perforin and granzyme
Treg cells that interact with DCs via CTLA-4 (on T cell) and CD80-86 results in activation of a pathway leading to…
Induction of indoleamine-2,30dioxyenase (IDO) and decreased expression of inflammation-promoting cytokines and costimulatory molecules
What kinds of inflammatory cytokines and co-stimulatory molecules would be downregulated with CTLA-4/B7 interactions
inhibition of IL-6 and TNF alpha and downregulation of CD80/86
what is PGE2 an example of and what do they do? what are they secreted by?
PGE2 is an example of a prostaglandin secreted by macrophages
they inhibit immune responses in a non-specific manner
How do prostaglandins inhibit immune responses?
promote cAMP accumulation in T cells, which inhibits IL-2 synthesis and IL-2 receptor signaling.
Define: idiotope
Each antigenic determinant in the variable region
Define: idiotype
The sum of the individual idiotopes
Define: tolerance
active state of specific immunologic unresponsiveness exhibiting antigen specificity and memory that is induced by prior exposure to an antigen
What kind of lymphocytes is tolerance more easily induced in ?
immature ones
What are 4 factors that make an antigen prone to tolerance
- high doses
- introduced via oral or intravenous route
- absence of adjuvants and/or low levels of co-stimulation
- If the antigen is soluble
What is central tolerance?
deletion of self-reactive lymphocytes by apoptosis during their maturation in the bone marrow or thymus
Autoreactive T cells are eliminated in the ___ while autoreactive B cells are eliminated in the ___
thymus; bone marrow
What is peripheral tolerance?
inactivation of self-reactive lymphocytes in peripheral lymphoid tissues.
T regulatory cells (CD4+CD25+) act in ___tissues and ___ to down-regulate autoimmune responses by other T cell subsets
secondary lymphoid tissues; sites of inflammation
autoimmunity affect ___% of the population
5-7
significantly more of which sex is affected by autoimmune diseases? why ?
more women because they tend to mount a more robust and Th1 type immune response
What are the two broad categories that autoimmune diseases fit into?
organ specific and systemic
What are the 2 examples of organ specific autoimmune diseases that we talked about?
Grave’s disease and insulin dependent diabetes mellitus
What occurs during organ specific autoimmunity?
ymphocytes or antibodies bind to cell- membrane antigens, causing cell lysis and/or an inflammatory response, damaging the organ
What causes Insulin-dependent diabetes mellitus?
Autoimmune response to insulin producing beta cells in the islets of Langerhans in the pancreas
What attacks the beta cells?
activated CTLs
What pro-inflammatory cytokines are produced in Insulin-dependent diabetes mellitus? what do they activate? what does this lead to?
IFN-γ, IL-1, TNF-α
activate macrophages leading to a DTH response
What other factor can contribute to islet cell destruction?
autoantibodies
What is the cause of Grave’s disease?
autoantibodies directed against specific receptors on thyroid cells mimic the effect of thyroid- stimulating hormone (TSH)
What is the result of the autoantibodies binding to the thyroid cells?
they activate receptor-coupled adenylate cyclase and stimulate the production of thyroid hormones thyroxine and triiodothyronine
Why is it that the overstimulation of the thyroid cannot be controlled in Grave’s disease?
Because autoantibody production is not regulated
What causes rheumatoid arthritis? (ie. what two antibody classes react together)
autoantibodies of the IgM class (rheumatoid factor) that react with the Fc portion of self IgG
- form immune complexes
Where do the IgM-IgG immune complexes deposit?
in the synovia of the joints
what is the result of IgM-IgG immune complex deposition? what are the 3 hallmarks of this response?
chronic inflammatory response characterized by:
- infiltration of the joints by granulocytes and monocytes
- destruction of cartilage and collagen by hydrolytic enzymes
- joint fusion
what causes MS?
demyelinization of central nervous system tissue by T cells
What is the result of CNS demyelinization?
progressive paralysis
the MS lesions that are caused by the T cells resemble which kind of immune response ? what is involved?
A DTH reaction
- autoreactive Th1 cells specific for myelin basic protein produce cytokines that attract and activate monocytes, which do the actual damage to the myelin sheath of nerve fibers
Are autoantibodies and CTLs involved in the MS pathology?
Yes
The balance of what 2 factors is often a determining factor in development of autoimmunity?
Th1/Th2
In most cases, organ specific autoimmunity is linked to autoreactive ____
CD4+ T cells
Th1 cells tend to promote…
the development of autoimmunity
Th2 cells tend to…
prevent the induction of autoimmunity and may also halt the progression of established autoimmune disease
How are HLA specificities involved in autoimmunity?
Autoimmune diseases are often associated with the expression of certain HLA allelic specificities
if you have one autoimmune disorder you tend to be at greater risk for….
an additional one
preferential expression of certain _____ is also associated with autoimmune diseases
T cell receptor variable regions
autoimmunity is most likely when an individual has __ and __ that can bind self peptide
MHC and TCRs
Briefly, what are the 4 mechanisms accounting for T cell mediated generation of autoimmune disease?
- Release of sequestered autoantigens
- Molecular mimicry
- Inappropriate expression of class II MHC molecules
- Polyclonal B cell activation
how does release of sequestered autoantigens lead to an autoimmune response?
T cells are exposed to antigens normally sequestered in the body and to which they were never rendered tolerant
How does molecular mimicry lead to development of an autoimmune response?
tends to occur following exposure to a pathogen
those that express molecules closely resembling self antigen
- ex: heat shock antigens
can be found is both bacteria (like mycobacteria) and viruses (like measles P3)
How does inappropriate expression of class II MHC lead to an autoimmune response
cells that don’t normally have class II MHC and also have co-stim molecules can present autoantigens to Th cells
What is an example of inappropriate MHC II presentation
pancreatic beta cells from individuals with autoimmune diabetes express high levels of class I and class II MHC molecules
How does IFN-γ promote development of an autoimmune reaction? when is it produced?
Produced following trauma or viral infection
up-regulating class II MHC expression
What does IFN-y induce the expression of that can provide a costimulatory signal to autoreactive T helper cells reacting with self antigen- class II MHC complexes on pancreatic beta islet cells.
IL-1
What occurs during polyclonal B cell activation? how does this lead to an autoimmune response?
LPS and EB virus are polyclonal activators of B cells
- dont require Th cells
Self reactive B cells that are activated in this manner can synthesize autoantibodies that contribute to autoimmune disease
After the 4 ways of autoimmune induction, what are the 3 ways the tissue damage occurs?
- Th cells activate macrophages leading to inflammation and a DTH response
- Th cells secrete IFN-y inflaming target tissue and IL-2 which stimulates CTLs to attack tissue
- activate B cells to create and secrete mass amounts of autoantibodies
What are 7 treatments for autoimmune diseases? (briefly)
- Plasmapheresis
- Immunosuppressive drugs
- Neutralizing antibodies
- Induced tolerance via oral administration of autoantigens
- Peptide blocking of T receptors recognizing self antigen/class II MHC
- administer monoclonal antibodies that target activated T cells
- targeted immunotherapy by vaccinating with autoreactive Th cells
How does Plasmapheresis work? what disease types is it effective for?
removes autoantibodies and immune complexes from the plasma
temporary relief from the symptoms of autoantibody-mediated autoimmune disease
What are 2 examples of immunosuppressive drugs? what doe they reduce the severity of?
cyclosporin A or FK506 can reduce the severity of T cell-mediated autoimmune diseases
What do neutralizing antibodies target?
molecules involved in chronic inflammation
e.g., TNF-α and adhesion molecules
How does administering autoantigens induce tolerance?
possibly by the induction of T regulatory cells that produce immunosuppressive cytokines such as transforming growth factor-ß.
how does vaccinating with autoreactive T cells suppress autoimmunity
suppress the activity of the autoreactive T cells that cause autoimmune disease while sparing T cells with other antigenic specificities
