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immunological tolerance and autoimmunity Flashcards

1
Q

immunulogical tolerance? what is challenge of it? mediated by?

A

unspecific unresponsiveness to ag

challenge is to understand how it becomes a pathological process , how T and B cells recognize self ags and contribute to tissue injury

mediated by IL-10

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2
Q

self-tolerance

A

all individuals are tolerant to specific self ag

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3
Q

autoimmunity

A

results from breakdown of self tolerance

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4
Q

negative selection

A

T lymphocytes should be doing this in the thymus, but it is not perfect

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5
Q

auto-reactivity

A

low level of it is crucial to normal immune function

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6
Q

central and peripheral tolerance

A

ag specific

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7
Q

central tolerance

A

induced in self reactive (immature) lymphocytes in primary lymphoid organs

ensures that lymphocytes are not reactive to self ags

results in:

  1. deletion by apoptosis
  2. change of BCR specifitiy
  3. development of Treg cells
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8
Q

peripheral T cell tolerance

A

induced in mature self-reactive lymphocytes in lymph nodes or peripheral sites such as submucosal tissues

needed to prevent activation of potentially dangerous lymphocyte clones in periphery

results in:

  1. inactivated (anergy)
  2. deleted (apoptosis)
  3. suppressed by Treg cells
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9
Q

central T cell tolerance- where does it take place and by what mechanisms

A

takes place in thymus**

T cells that have strong binding of self ags (negatively selected) are deleted by apoptosis

T cells that show no affinity or bind to self ag below threshold are positively selected migrate into blood as mature T cells

most will develop into effector CD4 and CD8 cells, small percent develop into Tregs

**further detail on question for AIRE

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10
Q

Treg cells? what do they do? what do they express? what is needed for their survival? what do they release to what?

A

natural Treg develop in thymus

respond to self ag but still positvely selected for

produce anti-apoptotic molecules which protect them from negative selection

also inhibit CD4 T cell activation and CD8 T cell differentation

prevent T cells from helping B cells in production of Abs

express FOXP3, CD4, CD25, CTLA-4

IL-2 critical for survival and function

long-lived

prevent autoimmune reactions in certain tissues- suppress activation of self reactive lymphocytes in peripheral tissues

release IL-4, IL-10, TGF-B to APC’s through cell to cell contact

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11
Q

Th0 cells- where are they produced?

what do they express?

what are they inhibited by?

A

induced Treg

outside of thymus- produced in GI and lymph nodes

FOXP3 exp induced in CD4 cells upon ag recognition and in presence of TGF-B if IL-16 is not present

if IL-6 is present- FOXP3 exp prevented and induced exp of RAR and RORyt leading to Th17 differentiation

development relationship between iTregs and Th17

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12
Q

anergy

A

functional unresponsive

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13
Q

suppression

A

block in activation by Treg

work through inhibitory receptors CTLA-4 and PD-1 (all CD4 and CD8 cells express these after ag stimulation)

cancer therapy- enhanced antitumor immune respone and tumor regression– checkpoint blockage

checkpoint blockade can form autoimmune reactions

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14
Q

deletion

A

apoptosis

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15
Q

anergy

A

functional unresponsive

is induced when there is no costimulation of CD80:CD28

anergic cells survive but are incapable of responding to ag

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16
Q

apoptosis

A

caused by cell receptor death or ag recognition without co stimulation

apoptotic inducers are released from mt

*two pathways

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17
Q

mitochondrial (intrinsic pathway)

A

cell injury triggers BH3 proteins

BCL-2 upregulated (and effectors Bax, Bak)

cytochrome c and other pro-apoptotic proteins realeased

intiator: caspase 9
executioner: caspases

endonuclease activation and breakdown of cytoskeleton

sends DNA fragments out to surface of cell where ligands signal them for phagocytosis

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18
Q

death receptor (extrinsic pathway)

A

FasL binds to Fas on mt while TNF binds to TNF receptor

intiator: caspase 8
executioner: caspases

endonuclease activation

sends DNA fragments out to surface of cell where ligands signal them for phagocytosis

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19
Q

central B cell tolerance

A

immature B cells that recognize high avidity self ags in bone marrow will undergo receptor editing or apoptosis

low avidity for self ag will lead to anergic B cell

20
Q

receptor editing

A

rearrangment and replacement of Ig light chain gene that will continue to occur until the cell no longer recognizes self ag or cell dies

21
Q

BCR editing

A

all BCR’s that have light chain go through this

already express rearranged heavy chain

first recombines locus that encodes kappa light chain which yields a lymphocyte with autoreactive BCR– RAG1/RAG2 on during this

BCR continues recombination until it leads to IgL chain that lacks self reactivity– RAG1/RAG2 turned off

22
Q

RAG1/RAG2

A

control recombination

23
Q

peripheral B cell tolerance, problem that can occur

A

Mature B cells that recognize ag in the absence of Th cells may be rendered unresponsive or die by apoptosis

CD22 inhibitory signals is phosphorylated by Lyn which recruits SHP-1 tyrosine phosphatase which reduces BCR signaling

defects in Lyn, SHP-1, or CD22 lead to autoimmunity

24
Q

commensal microbes functions

A

reside in intestinal and respiratory tracts, on skin

  • inhibit pathogen coloinzation
  • supresses pathobionts through Tregs and IL-10
  • aid in deigestion and absorption of foods
  • have anti inflammaotry properties
  • important role in GALT development
25
Q

GALT

A

upregulates Th17 and Th1 development

upregulate barrier function

26
Q

commensal microbe tolerance

A

exxagerated mucosal immunity to normal micrflora

controlled by genetic factors

cause of IBD

27
Q

autoimmunity mechanism

A

mix of suspectibilty genes that fail to create self tolerance of B and T cells and tissue injury, activation of APC’s

activation of self reactive lymphocytes

effector molecule cause tissue injusry and autoimmune disease

28
Q

mutations that can break tolerance

A

AIRE

C4

CTLA-4

Fas/FasL

FoxP3

IL-2/IL-R2

SHP-1

29
Q

AIRE functions

A

autoimmune regulator

tissue-restricted Ag’s (TRA’s) processed are expressed on surface of medullary thymic epithelial cell’s HLA (regulated by AIRE) to bind to T cell to negatively select it

30
Q

AIRE def

A

AIREs are thought to be transcription factors that upregulate protein expression of self ag

without it, decreased expression of self-Ags

self-reactive T cells are not eliminated, enter tissues, cause injury

31
Q

def in CP pathway of complement activation are linked to development of autoimmunity

A

.

32
Q

C4 def

A

usually CR1 binds C3b’s (which ag:ab complexes are bound to) from complement to RBC’s (RBC:CR1) to have RBC’ take to liver and spleen, phagocytically removing it from RBC’s

when this can’t happen, there is a defective clearnace of immune complexes

33
Q

regulation of T cell responses by inhibitory receptors

A

CD28– terminates T cell responses

CTLA-4

34
Q

CTLA-4 role

A

homolog of CD28

inhibitory receptor

terminate immune responses are maintain self tolerance

35
Q

CTLA- def

A

enlarges lymphnodes to fatal level

enhances autoimmune disease

polymorphuism types– type I diabetes and Grave’s

36
Q

two important properties of CTLA-4

A

low on resting T cells

terminates continuing activation of T cells– cell cycle arrest

37
Q

two pathways of CTLA-4

A

cell-intrinsic: delivers inhibitory signals to T cells (feedback)

cell-extrinsic: Treg’s bind to B7 on on APC’s which blocks their binding to CD28 on T cells

38
Q

features of chronic disease autoimmunity

A

no fundamental difference between self and non self ags– composed of same AA

pathological immune response against self ag– immune mediated inflammatory response

activation of T and B cells is absense of infections

hypersensitve reactions

39
Q

how autoimmunity is prevented

A
  1. immunological ignorance– t cells separated from specific antigen
  2. deletion– Fas(CD95) receive signals from FasL– apoptosis
  3. inhibition– CD80 binding B7
  4. suppression– Treg’s release IL-10 and TGF-B
40
Q

immune priviledged sites

A

eye

brain

pregnant uterus

ovary

testis

adrenal cortex

hair follicles

if an allograft is placed in these sites, theyll survive

if barrier is broken on these, autoimmune response

41
Q

general features of autimmone disorders

A

sytemic or organ-specific

various affector molecules to tissue injury

chronic, progressive, self-perpetuating

failure of B or T cell self tolerance

complex polygenic traits

multiple genetic polymorphisms increase disease suspetibility

strongest association with MHC genes (most with class II)

also non-HLA genes

suspeptibility genes interact with environmental factors (tissue damage and infection)

42
Q

role of environmental factors and ex

A
  1. molecular mimicry
    ex: cross reactivity between strep and cardiac myosin
  2. polyclonal activation: autoreactive lymphocrytes in cytokine field
  3. microbes kill cells that cause release of previously sequestered ags from bursted cells
43
Q

inflammatory bowel disease

A

type IV hypersensitivity– bacteria from guts leaks into epithelial tissues, disrupts APC that is being bound to Th cell

44
Q

systemic lupus erythematosus

A

type III hypersensitvity

rashes, arthritis, glomerulonephritis, vasculitis triggered by auto-ab are found- most common anti-DNA abs

anti-nuclear abs serve as diagnostic test

45
Q

Rheumatoid arthritis

A

type IV hypersensitivity

inflammation of synovium associated with destruction of bone and cartilage

auto-ab is rheumatoid factor that reacts with circulating IgM and IgG that react with Fc portion of IgG

rheumatoid factor- diagnostic marker

other cells involved: Th1, Th17, B cells, macrophages, plasma cells

46
Q

FoxP3 def

A

type of peripheral tolerance break

symptoms: multi-organ lymphocytic infiltrates, wasting

47
Q

Fas/FasL def

A

SFM (6 decks)

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