Chapter 2.4 Autoimmune Disorders (Part 1) Flashcards
What are autoimmune disorders?
What is the prevalence in US?
What is the
1-2 % prevalence in US
characterized by immune-mediated damage of self tissues
immune system reacts against self antigen
What is the underlying principle of autoimmune disorders? (What is lost?) Describe how B and T cells recognize antigen and how this relates to autoimmune disorders.
Involves loss of self-tolerance
B cell - recognize antigen by Ig
T cell- recognizes antigen by TCR
generation of Ig and TCR is random, while we generate them, we generate some Ig and TCR reactive against self
self reactive lymphocytes are regularly generated
How does the body normally take care of self-reactive lymphocytes? What process?
central and peripheral tolerance
central occurs in places where lymphocytes develop, peripherally would be outside the place where lymphocytes develop
Where does central tolerance occur?
where T cells develop = thymus
where B cells develop = bone marrow
Describe the process by which T cells become MHC restricted. Where does this process occur?
Stem cells come from bone marrow, through blood, enter into thymus, eventually become double positive cell (CD4 and CD8 and TCR)
Once express TCR they then will progress to single positive and either express CD4 or CD8.
Single positive will exit as mature naive T cells to go out into periphery
As cells develop they undergo various check points … DP cells undergo positive selection (checked to see if they can bind MHC and antigen) if DP can recognize MHC they can progress to SP if they cannot, they undergo apoptosis and die. (select cells that are MHC restricted)
positive selection occurs in cortex of thymus
What kind of cells undergo negative selection? Single or double positive? Describe this process and where it takes place.
SP undergo negative selection..do SP cells bind self antigen? if they avidly bind they undergo apoptosis …so removing self-reactive lymphocytes
if they don’t bind avidly they can leave thymus
negative selection takes place is the medulla of thymus
What are the implications of an AIRE mutation. Describe why/mechanism of AIRE.
autoimmune polyendocrine syndrome
MEC has AIRE (transcription factor in nucleus) necessary to express some self-antigens, if we cannot express some subset of self antigens then lymphocytes that are reactive against those self antigens (against antigens dependent upon AIRE) can escape out into the periphery and we have self-reactive lymphocytes in periphery
In order for negative selection to occur the lymphocytes must be exposed to antigens present in body, how is this accomplished?
there are dendritic cells in medulla that express wide array of self antigen on MHC to test cells if they bind self antigen
medullary epithelial cell that also express lots of peripheral antigens on MEC
if lymphocyte binds antigen on DC or MEC then cell undergoes apoptosis and dies
MEC has AIRE (transcription factor in nucleus) necessary to express some self-antigens, if we cannot express some subset of self antigens then lymphocytes that are reactive against those self antigens can escape out into the periphery and we have self-reactive lymphocytes in periphery
What are patients with an AIRE mutation susceptible to? Describe the triad seen in patients with an AIRE mutation.
patients develop autoimmunity that destroys endocrine glands
1) hypoparathyroidism
2) adrenal failure
3) chronic candida infections of skin and oral mucosa
Describe the tolerance selection process of B cells.
Where does it take place? (Describe the progression of B cell development as well).
SC generated in bone marrow, progresses to immature B cell, then progresses to exit bone marrow as naive mature B cell
as cell progresses from SC to immature B cell, expresses Ig, then undergoes Negative selection “do u bind self antigen too tightly?” (DC present in bone marrow express self antigens the B cell can bind)
As a B cell progresses from a stem cell to an immature B cell, it expresses Ig, then undergoes negative selection; “do u bind self antigen too tightly?” (DC present in bone marrow express self antigens the B cell can bind). What happens if the B cell binds self antigen too tightly? (2 options)
as cell progresses from SC to immature B cell, expresses Ig, then undergoes Negative selection “do u bind self antigen too tightly?” (DC present in bone marrow express self antigens the B cell can bind) if binds too tightly then the B cell can undergo receptor editing (RAG genes which are essential for development of Ig specificities are re-expressed, allows for editing of the light chain of Ig and hopefully won’t bind self antigen anymore then can go to periphery
or can undergo apoptosis through mitochondria pathway
Describe the process of peripheral tolerance.
if antigen is recognized in peripheral tissues without co-stimulatory signal the lymphocyte will undergo anergy (shut down) or undergo apoptosis
(CD4 cell using TCR to bind MHC II on DC) this first interaction needs 2nd interaction to activate T cell (CD28 on T cell would bind B7 on DC)
self reactive T cell in periphery …if it binds MHC II on a DC you’d expect no second signal because there is no inflammation to generate that second signal so the CD4 T cell will undergo ANERGY (shuts down) or CD4 T cell may undergo apoptosis …
CD4 has CD95 (Fas)= death receptor. if regular binding of TCR to antigen with no second signal the CD4 T cell will begin to express FasL…when it expresses FasL it will bind to CD95 (Fas) and that is death receptor… or FasL can bind CD95/Fas on another B or T cell it can induce apoptosis of those cells
There is a self reactive T cell in periphery …if it binds MHC II on a DC in periphery, what will occur? Describe the two possible outcomes.
expect no second signal because there is no inflammation to generate that second signal so the CD4 T cell
so the CD4 T cell will undergo ANERGY (shuts down) or CD4 T cell may undergo apoptosis …
CD4 has CD95 (Fas)= death receptor. if regular binding of TCR to antigen with no second signal the CD4 T cell will begin to express FasL…when it expresses FasL it will bind to CD95 (Fas) and that is death receptor… or FasL can bind CD95/Fas on another B or T cell it can induce apoptosis of those cells
What is ALPS? Describe what mutations can lead to this disease and the implications.
mutation is Fas apoptosis pathway
CD4 T cell needs CD95 (Fas) receptor, and FasL, and caspases (CAS-10)
if patient has mutation where lose Fas or FasL or cas-10 then cannot undergo apoptosis in periphery and this would allow for survival of some self reactive lymphocytes
autoimmune lympho-proliferative syndrome
(autoimmune= patients have self reactive lymphocytes that generate IgG against cells in blood, can get cytopenias like anemia of thrombocytopenia, proliferation of lymphocytes bc can’t get rid of self reactive lymphocytes, get LAD =lymph adenopathy= enlarged lymph nodes throughout body, also can get hepatosplenomegaly…
bc so much proliferation can get mutations and lymphoma
Describe regulatory T cells and their role.
What are two mechanisms by which they can act?
CD4+ T cells that suppress immune responses
act in 2 ways
1) can block T cell activation
Treg express CTLA4 which can come in and compete and bind B7 so the likelihood of a second signal between CD4+ and DC expressing MHCII is reduced and that self reactive T cell could undergo anergy
2) secrete IL-10 or TGF-beta
(IL10 inhibits macrophages and DC and limits expression of MHC II, limits prod. of costimulatory molecules like B7)
(TGF-beta inhibits activation of macrophages)
