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SFM > Immunological Tolerance and Autoimmunity > Flashcards

Immunological Tolerance and Autoimmunity Flashcards

1
Q
  • type of tolerance that is induced in immature self-reactive lymphocytes in the primary lymphoid organs
  • ensures that mature lymphocytes are not reactive to self antigens
A

central tolerance

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2
Q
  • tolerance that is induced in mature self-reactive lymphocytes in the lymph nodes or peripheral sites such as submucosal tissues
  • needed to prevent activation of these potentially dangerous lymphocyte clones in the periphery
A

peripheral tolerance

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3
Q

What are the 3 ways central tolerance is developed?

A
  1. deletion by apoptosis
  2. receptor editing of BCRs (B cells only)
  3. development of Treg cells from CD4+ T cells
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4
Q

What are the 3 ways peripheral tolerance develops?

A
  1. cells are inactivated (anergy)
  2. deletion by apoptosis
  3. suppressed by Treg cells
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5
Q

If a T cell recognizes a self antigen in the thymus, what 2 things can happen?

A
  1. death of cell by negative selection
  2. development into Treg cell
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6
Q

What is the general process of creating central T cell tolerance in the thymus? (5)

A
  1. T cells with strong binding to self antigens are deleted by apoptosis
  2. nonfunctional T cells with no affinity undergo apoptosis
  3. T cells that bind self antigens below a certain threshold are positively selected and migrate into blood as mature T cells
  4. most thymic emigrants develop into CD4+ or CD8+ effector cells
  5. small percentage of positively selected T cells develop into natural CD4+CD25+FOXp3+ Treg cells
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7
Q

Treg cells that are positively selected are on the ______ ____ cusp of the positively selected T cells in terms of avidity to self antigens

A

higher end

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8
Q

What is the role of FOXp3+ in survival of Treg cells?

A
  • if a thymocyte demonstrates high TCR self reactivity and has FOXp3+, it will survive to become a Treg cell
  • if a thymocyte demonstrates high TCR self reactivity and is FOXp3-, it will undergo negative selection and apoptosis
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9
Q

How do Treg cells avoid apoptosis?

A
  • Treg cells produce anti-apoptotic molecules that protect them from negative selection in the thymus
  • IL-2 is critical for survival and functional competence of Treg cells
  • Tregs are long-lived
  • express FOXp3 transcriptional factor that is necessary for their suppressive activity
  • express high levels of CTLA-4 (inhibitory receptor that binds to B7-1 and B7-2 on DC’s with higher affinity/avidity that CD28 (T effector cells))
  • also express CD4 and CD25
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10
Q

How do induced Treg (iTregs) cells differentiate?

A
  • induced Tregs differentiate in the periphery (lymph nodes or GI tract)
  • FOXp3 expression can be induced in naive CD4+ T cells in vitro upon antigen recognition in the presence of TGF-β
  • developmental relationship between iTregs and Th17: antigen recognition in the presence of TGF-B induces FOXp3 expression IF IL-6 IS NOT PRESENT; antigen recognition in the presence of TGF-β and IL-6 prevents FOXp3 expression leading to Th17 differentiation
  • retionoic acid (prod by DC’s) + TGF-β + IL-2 also facilitates the generation of FOXp3+ induced Treg cels from naive CD4+CD25- T cells
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11
Q

What are the interactions/cells that Tregs can inhibit?

How do they inhibit these responses?

A
  • inhibition: DC presenting to naive T cell, effector T cells, B cells, NK cells
  • Tregs can bind to APC’s with greater affinity than naive T cells or effector T cells, they release cytokines (IL-4, IL-10, and TGF-β) that inhibit the APC and suppress the APC’s CD40, CD80/86, IL-12, and increase IL-10
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12
Q

How is T cell anergy and suppression induced? (2 ways)

A
  • antigen recognition without adequate CD80:CD28 costimulation induces anergy
  • these cells survive but are incapable of responding to the antigen
  • the cell may engage inhibitory receptors CTLA-4 or PD-1 that causes suppression of the T cell response
  • both CTLA-4 and PD- 1 are expressed on CD4+ and CD8+ T cells after antigen stimulation
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13
Q

What are the 2 ways T cells will undergo apoptosis?

A
  1. recognition of antigen w/o costimulation: inducers of apoptosis within cell are activated, apoptotic proteins released from mitochondria
  2. egagement of death receptors: death receptor and death receptor ligands are engaged
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14
Q

What is the process of mitochondrial pathway of T cell apoptosis?

A
  • cell injury: deficiency of growth factors or survival signaling, DNA damage, protein misfolding
  • BH3 only proteins
  • Bcl-2 effectors (Bax, Bak) are activated while regulators (Bcl-2, Bcl-XL) are inhibited
  • cytochrome c and other pro-apoptotic proteins are produced/release into cytosol
  • activate initiator caspase: caspase 9
  • activates excecutioner caspases which trigger endonuclease activation and breakdown of cytoskeleton
  • endonuclease activation causes DNA and nuclear fragmentation
  • the cytoskeleton and DNA fragmentation are released into exo-vesicles that have ligands for receptors on phagocytes
  • apoptotic bodies are phagocytosed
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15
Q

What is the process of death receptor (extrinsic) pathway of T cell apoptosis?

A
  • receptor-ligand interactions occur (FAS, TNF receptor)
  • activate initiator caspase: caspase 8
  • activates excecutioner caspases which trigger endonuclease activation and breakdown of cytoskeleton
  • endonuclease activation causes DNA and nuclear fragmentation
  • the cytoskeleton and DNA fragmentation are released into exo-vesicles that have ligands for receptors on phagocytes
  • apoptotic bodies are phagocytosed
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16
Q

How do B cells develop central tolerance? (3 ways)

A
  1. receptor editing: rearrangement and replacement of the IgL-chain genes until non-self recognizing receptors are produced
  2. deletion by apoptosis
  3. weak recognition of self antigens in bone marrow may lead to anergy
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17
Q

How do BCR receptors undergo editing when they are self antigen reactive?

A
  • beforehand: heavy chain is already expressed, thus the locus that encodes for κ light (IgL) chain is recombined, yielding a lymphocyte with an autoreactive BCR
  • RAG1 and RAG2 stay turned on, BCR signaling promotes developmental arrest and continued recombination
  • receptor editing of the IgL chain leads to expression of a distinct IgL chain, generating cell-surface immunoglobulin that lacks self-reactivity

- all B cells with BCR containing the λ light chain underwent BCR editing

18
Q

What are the 3 ways B cells develop peripheral tolerance?

A
  1. anergy
  2. apoptosis
  3. inhibitory regulation: CD22 inhibitory receptor is phosphorylated by Lyn and then recruits SHP-1 tyrosine phosphatase attenuating BCR signaling

(B cells may also be inhibited by Tregs)

19
Q

What are the cells that are mediators of peripheral tolerance?

A

Tregs

  • they may inhibit CD4+ activation by APC’s and inhibit T cell differentiation into CD8+ CTL’s
  • may prevent T cells from providing help to B cells in the production of antibodies
20
Q

What are the mechanisms of autoimmunity?

A
  • susceptibility genes: interfere with pathways of self-tolerance and lead to the persistence of self-reactive T and B cells
  • environmental triggers: infections and other inflammatory stimuli, promote influx of lymphocytes into tissues and activation of APC’s
  • self-reactive lymphocytes: activated by the above APC’s, result in the generation of effector T cells and autoantibodies that are responsbile for autoimmune disease
21
Q

mutations breaking immunological tolerance:

  • gene: AIRE
  • phenotype of mutant:
  • mechanism of failure of tolerance:
  • human disease:
A
  • destruction of endocrine organs by antibodies, lymphocytes
  • failure of central tolerance
  • autoimmune polyendocrine syndrome (APS)
22
Q

mutations breaking immunological tolerance:

  • gene: C4
  • phenotype of mutant:
  • mechanism of failure of tolerance:
  • human disease:
A
  • SLE
  • defective clearance of immune complexes; failure of B cell tolerance?
  • SLE
23
Q

mutations breaking immunological tolerance:

  • gene: CTLA-4
  • phenotype of mutant:
  • mechanism of failure of tolerance:
  • human disease:
A
  • lymphoproliferation; T cell infiltrates in multiple organs, especially heart; lethal by 3-4 weeks
  • failure of anergy in CD4+ T cells
  • CTLA-4 polymorphisms a/w several autoimmune dz’s
24
Q

mutations breaking immunological tolerance:

  • gene: Fas/FasL
  • phenotype of mutant:
  • mechanism of failure of tolerance:
  • human disease:
A
  • anti-DNA and other autoantibodies; immune complex nephritis; arthritis; lymphoproliferation
  • defective deletion of anergic self-reactive B cells; reduced deletion of mature CD4+ T cells
  • autoimmune lympho-proliferative syndrome (ALPS)
25
Q

mutations breaking immunological tolerance:

  • gene: FoxP3
  • phenotype of mutant:
  • mechanism of failure of tolerance:
  • human disease:
A
  • multi-organ lymphocytic infiltrates, wasting
  • deficiency of regulatory T cells
  • IPEX
26
Q

mutations breaking immunological tolerance:

  • gene: IL-2; IL-2alpha/beta
  • phenotype of mutant:
  • mechanism of failure of tolerance:
  • human disease:
A
  • inflammatory bowel disease; anti-erythrocyte and anti-DNA autoantibodies
  • defective development, survival or function of regulatory T cells
  • none known
27
Q

mutations breaking immunological tolerance:

  • gene: SHP-1
  • phenotype of mutant:
  • mechanism of failure of tolerance:
  • human disease:
A
  • multiple autoantibodies
  • failure of negative regulation of B cells
  • none known
28
Q

What is the role of AIRE in central tolerance?

A
  • negative selection in T cells in thymus is necessary for self-tolerance
  • medullary thymic epithelial cells function as APC’s and express a large number of peripheral tissues-restricted self antigens that are presented to developing T cells
  • mutations in AIRE (autoimmune regulator) protein cause breakdown of central tolerance
  • AIRE is proposed to function as a transcription factor
  • mutations in AIRE are a/w decreased expression of peripheral tissues self antigens in the thymus
29
Q

How is the mutation/absence of funtional AIRE proteins lead to autoimmunity?

A

self-reactive T cells are not eliminated through negative selection, thus they can enter tissues and cause tissue injury

30
Q

What is the role of CTLA-4 receptor in peripheral tolerance?

A
  • CTLA-4 is a homolog of CD28 and an inhibitory receptor
  • CTLA-4 binds with higher affinity/avidity to B7 than CD28
  • provides signals that terminates immune responses and maintains self-tolerance
31
Q

What are the 2 important properties of CTLA-4?

A
  1. expression is low on resting T cells until the cells are activated by antigen
  2. once expressed, CTLA-4 terminates continuing activation of the responding T cells

(CTLA-4 is expressed on Tregs and mediates the suppressive function of these cells by inhibiting the activation of naive T cells)

32
Q

What are some manifestations of CTLA-4 malfunction? (3)

A
  1. uncontrolled lymphocyte activation: massively enlarged LN’s and spleen, fatal multi-organ lymphocytic infiltrates
  2. blocking of CTLA-4: enchances autoimmune dz’s
  3. polymorphisms of CTLA-4: a/w several autoimmune dz’s in humans (type 1 diabetes and Graves’ dz)
33
Q

What are the 2 modes of action of CTLA-4 receptor?

A
  1. intrinsic: engagement of CTLA-4 on a T cell may deliver inhibitory signals that terminate further action of the cell
  2. extrinsic: CTLA-4 on Treg cells or responding T cells bind to B7 molecules on APC’s or makes the B7 unavailable to CD28 and blocks T cell activation
34
Q

What are the 4 ways autoimmunity is prevented?

A
  1. immunologic ignorance: T cells that are physically separated from their specific antigen (e.g. BBB) cannot become activated
  2. deletion: T cells that express Fas (CD95) can receive their signals from cells that express FasL and undergo apoptosis
  3. inhibition: CTLA-4 (CD152) can bind B7 (CD80) on APC’s and inhibit costimulatory signals that inhibit T cell activation
  4. suppression: Tregs can inhibit through the prod of inhibitory cytokines (IL-10, TGF-β) or through competitive binding between CTLA-4 and CD28 with B7 (APC’s)
35
Q

What are the immune privileged sites? (7) How can they become compromised?

A
  1. eyes: cornea, anterior chamber, vitreous cavity, subretinal space
  2. brain
  3. pregnant uterus
  4. ovary
  5. testis
  6. adrenal cortex
  7. hair follicles

In animal studies, these have become compromised when an allograft in the privileged site suffers mechanical breaking of barriers due to trauma, this results in generation of autoimmune response against normal tissues in the IP site

36
Q

What are the genetics of autoimmunity?

A
  • most autoimmune dz’s are complex polygenic traits
  • affected individuals inherit multiple genetic polymorphisms that contribute to susceptibility to autoimmunity
  • the strongest gene associations are with MHC genes
  • polymorphisms in non-HLA genes (e.g. CTLA-4) can also be a/w autoimmunity
  • susceptibility genes interact w/ environmental factors to cause dz
37
Q

What is the association between having a specific HLA allele and developing autoimmunity?

A
  • most autoimmune dz’s are a/w HLA class II (HLA-DR and HLA-DQ) because class II controls CD4+ T cells
  • a certain HLA allele may increase the risk of developing a particular autoimmune dz, the HLA allele itself does not cause autoimmunity
38
Q

How do genetic and environmental predispositions lead to pathological autoimmune disorder?

A
  • genetic susceptibility, failure of self-tolerance, and functional self-reactive lymphocytes may combine with environmental triggers

- this leads to pathological dz, including activation of self-reactive lymphocytes and immune response against self tissues

39
Q

What are the 3 ways environmental triggers can initiate autoimmune disorders?

A
  1. molecular mimicry: microbe antigen causes a cross-reaction between microbe and self antigens (i.e. rheumatic fever: strep infxn between strep antigens and cardiac myosin; MS: T cells react w/ myelin basic protein and peptides from Epstein-Barr virus, influenza type A, and HPV)
  2. polyclonal (bystander) activation: microbial infection that results in robust inflammatory response, can cause a polyclonal activation of autoreactive lymphocytes in the cytokine field
  3. release of previously sequestered antigens: microbes that kill cells and cause release of sequestered antigens (DAMP’s) leading to development of autoimmunity
40
Q

How can changes in gut microbiota develop into an autoimmune dz (i.e. IBD)?

A

When your immune system tries to fight off an invading virus or bacterium, an abnormal immune response causes the immune system to attack the cells in the digestive tract, too

41
Q
  • prototypic immune-complex mediated dz (type III hypersensitivity)
  • caused by persistent high-level anti-nuclear IgG antibody production
  • immune complexes formed from the auto-antibodies and their antigens are responsible for glomerulonephritis, arthritis, and vasculitis involving small arteries
  • sx: rashes, arthritis, glomerulonephritis
  • dx: presence of anti-nuclear antibodies
A

systemic lupus erythematosus (SLS)

42
Q
  • inflammatory dz involving small and large joints
  • mediated by type IV hypersensitivity rxns in which Th1 and Th17 cells activate B cells, plasma cells, and macrophages against self antigens
  • inflammation of synovium a/w destruction of the joint cartilage and bone
  • patients frequently have circulating IgM or IgG called rheumatoid factor (RF)
  • dx: presence of auto-antibodies (RF)
A

rheumatoid arthritis (RA)

SFM (21 decks)

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