Immunological tolerance and Autoimmune disease Flashcards
what is immunological tolerance
failure to repsond to an antigen
Is immunological tolerance an active or passive response ?
Active and specfic response to particular epitope
what are the 2 broad types of immunological tolerance
- natural “self” tolerance
- induced tolerance
why is natural tolerance a good thing ?
This is what tells the immune system to not attack body’s own proteins and self/antigens
if they do attack self-Ag = autoimmune disease
what is the most important concept to remember about tolerance
self-tolerance
-prevents body from mounting immune response on its tissues
what is the diff. b/w central and peripheral tolerance
central - occurs in the organs where lymphocytes dev. so involves immature lymphocytes
peripheral - occurs at peripheral sites involving mature lymphocytes
In what organs do B and T cells develop and mature
B cells - bone marrow
T cells - thymus
when a lymphoid progenitor cell encounters a self-Ag in the thymus, it can undergo Positive or Negative selection. What is the difference b/w these
Positive selection of T cell - progenitor cell binds MHC and binds self-Ag w/low avidity
Negative selection - progenitor cell binds MHC BUT binds self-Ag w/high avidity
what part of the thymus does positive selection occur
cortex region
what part of the thymus does negative selection occur
medulla region
the basis of central tolerance follows what strategy
A) negative selection or B) positive selection
A ) negative selection
-b/c if bind to self-Ag then its deleted via apoptosis
In certain cases there are some self-reactive ______ t cells that are NOT deleted, but instead differentiate into ______ T cells
CD4 helper t cells
-become regulatory t cells
Peripheral tolerance in T cells occurs if an auto-reactive T cell escapes the thymus, and becomes mature. When this mature t cell binds self-Ag what 4 mechanism can occur ?
1 - Deletion
2 - Anergy
3 -Supression
4 - Ignorance
what is T cell clonal anergy, a mechanism of peripheral tolerance
cell becomes non active, b/c co-stimulatory molecule activation is down regulated
what molecules are neccesary for normal co-stimulatory molecule activation
CD28 binds to B7
what molecules cause co-stimulatory activation to be downregulated in anergy, a mechanism of peripheral tolerance
CTLA-4 competes with CD28 ….. thus CTLA-4 binds to B7
CTLA-4 binds w/higher affinity than CD28
what is T cell suppression, a mechanism of peripheral tolerance
inhibition of cell activity (can inhibit in various ways)
in T cell supression, there are 3 ways in which the t cell activity can be inhibited. What are they ?
1 - inhibit Ag recognition
2 - inhibit proliferation
3 - inhibit effector functions
T cell ignorance, a mechanism of peripheral tolerance, is also known as ?
passive tolerance
-simply a RARE nonresponsiveness of t cell
what can cause t cell ignorance (mechanism of peripheral tolerance) ?
- sequestered Ag
- Ag not expressed on MHC molecules
- Ag cant get across some sort of barrier
Central tolerance in B cells occurs differently than in T cells. If lymphiod progenitor cells bind a self-Ag w/high avidity, what 2 things can happen
1 - deletion (basis of central tolerance)
2 - receptor editing
what is receptor editing ?
it is the process of restructuring the gene segments on the B receptor, in an attempt to make them NOT bind to self-Ag w/high avidity
what are the 2 outcomes of receptor editing in B cells
- still bind self-Ag w/high avidity = deletion
- bind w/self-Ag w/low avidity = maturation
_____ and ______ of the self-Ag determine the fate of B cells survival
nature (multivalent Ag) and concentration
High concentrations of self-Ag would induce B cell ______, whereas low concentrations of self-Ag would induce __________.
high = apoptosis low = anergy
T/F Self reactive B cells never escape the bone marrow, so there is no need for B cell peripheral tolerance ?
F, there is B cell peripheral tolerance
In order for B cells to become activated, they need the assistance of what cells ?
Helper T cells
How do Helper T cells affect the outcome of B cell activation in the periphery ?
Two signal Hypothesis
* B cells need both signals to become activated*
what are the signals that Helper T cells provide to B cells in the Two Signal Hypothesis
Signal 1 - Via Ag receptor
Signal 2 - Via CD40 and CD40L
what is the result of the B cell only recieves ONE of the signals from the T cell ?
Result in B cell anergy
administering foreign Ag can preferentially result in “induced tolerance.” What are 3 of the most common administering routes to get induced tolerance.
- Oral tolerance
- Ag administered subcutaneously
- Ag administered intradermally
Usually, a state of immune _____________ follows oral administration of an Ag
hyporesponsiveness
in general how do autoimmune diseases result ?
when central and peripheral tolerance is BROKEN
there are many factors that can predispose an individual for an autoimmune disease, these vary greatly amongst individuals, what are some of these factors ?
- genetics
- gender
- environment (climate)
- immune regulation (or there of)
autoimmune diseases can differ b/w gender, in what two ways ?
- Incidence (women get more typically)
- severity (differs b/w diseases)
incomplete deletion of self reactive cells, and/or altered regulation which stimulates previously anergic self-reactive cells are both common ways to do what ?
initiate and autoimmune response
what are the 2 theories of what activates autoimmunity
Induction of costimulators on APC (bystander activation)
Molecular mimicry
what are the 2 categories of autoimmune disease, and what is a example disease of each
systemic
organ specific
Lupus (SLE) and Rheumatoid arthritis R(A) are both examples of what category of autoimmune disease ? What about multiple sclerosis (MS) and Insulin Dep. Diabetes Mellitus (IDDM) ?
Systemic - Lupus and RA
Organ specific - MS and IDDM
what are some characterisitics of SLE, a systemic autoimmune disease
- multisystem disorder
- 10:1 female predominance
- onset b/w 15-25
- multiple sympotms making hard to diagnose
what are some characteristics of MS, an organ specific autoimmune disease
- most common inflammatory disease of CNS
- 3:2 female predominance
- loss of myelin and depletion of oligodendrocytes which impairs nerve conduction
what are the two ends of the spectrum of autoimmune disease, and how do they relate to each other
systemic(non organ specific) vs. organ specific
* ind. may develop more than one autoimmune disease but will NOT be one from opposite sides of spectrum*
