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OD2 S1 > M: Immuno2 Autoimmune - Week 5 > Flashcards

M: Immuno2 Autoimmune - Week 5 Flashcards

1
Q

Why does autoimmune disease occur?

A

because of the tissue damage due to the activation of self-reactive T and B cells (i.e. failure of T and B cell tolerance)

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2
Q

What mediates autoimmune disease?

A

Type II-IV hypersensitivity responses

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3
Q

Regarding autoimmune diseases:
A) does genetic background determine development and severity?
B) Are they organ specific or non-organ specific

A

A: yes
B: can be either, depends on the disease

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4
Q

What central tolerance mechanism is in place for T cells to control how the react? (1)

A
  • deletion of T cells which recognise self peptide
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5
Q

How can self-peptides be derived? (so that we can test T cell reactivity to them) (2)

A

May be derived from:
- thymic dendritic cell associated proteins
- ectopically expressed proteins on thymic epithelium (AIRE)

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6
Q

What does AIRE stand for?

A

autoimmune regulator gene

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7
Q

Why might T cell tolerance fail?

A

May fail if antigens are not expressed in the thymus to react with

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8
Q

Name 2 types of proteins that are ocular specific antigens against which circulating T and B cells have been detected

A
  1. retinal proteins
  2. iris/choroid proteins - melanin assoc. proteins
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9
Q

Name 4 retinal proteins

A
  1. S-antigen (arrestin)
  2. IRBP (interphotoreceptor retinoid binding protein)
  3. Rhodopsin
  4. Recoverin
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10
Q

Name 4 peripheral tolerance mechanisms for T cells

A
  • Ignorance
  • Deletion
  • Anergy
  • Suppression
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11
Q

Explain Ignorance (the peripheral tolerance mechanism)

A

Mature T cells do not enter healthy tissues, so do not meet their antigen

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12
Q

Explain Deletion (the peripheral tolerance mechanism)

A

corneal endothelium and pigmented epithelial cells express Fas-L which binds Fas expressing activated lymphocytes – lead to apoptosis

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13
Q

Explain Anergy (the peripheral tolerance mechanism)

A

T cell recognition of peptides in the absence of co-stimulation leads to “anergy” of the T cell

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14
Q

Define Anergy

A

absence of the normal immune response to a particular antigen or allergin

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15
Q

Explain Suppression (the peripheral tolerance mechanism)

A

suppression of T cells due to expansion of specific regulatory T cells (Tregs)

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16
Q

What does failure of co-stimulation of T cells lead to?

A

T cell anergy

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17
Q

Why might there be a failure of co-stimulation of T cells?

A

due to absence of PAMPs and/or DAMPs

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18
Q

Name 2 co-stimulatory molecules essential for T cell activation

A

CD80 and CD86

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19
Q

What must APCs do in order to activate CD4 T cells effectively?

A

Differentiate

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20
Q

What is considered a “critical checkpoint” in adaptive immunity?

A

co-stimulation

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21
Q

Briefly describe a normal adaptive immune response

A
  1. Antigen is uptaken and the PAMPs bind the TLR, which activates the APC
  2. Activated APC migrates to LN and expresses co-stimulatory molecules as well as expressing peptides with MHC – this is done to activate CD4 T cells
  3. activated CD4 T cells can now proliferate and differentiate
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22
Q

What happens to the CD4 T cells when co-stimulatory molecules are not induced?

A

Anergy and apoptosis

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23
Q

What is the function of TGF-beta signal? How is this useful

A

suppression of the inflammation response in the target tissue. Useful when you have a sustained inflammation and want to suppress it

24
Q

Describe 3 features of Tregs

A
  • multiple subsets
  • thymus derived and peripherally induced
  • Treg TCRs have higher affinity for self peptides
25
Q

What can Tregs express? Divide Tregs into 3 groups and state what they express or secrete

A
  1. CD4+CD25+ T cells: express FoxP3
  2. Other Tregs (e.g. TH3): secrete TGF-beta
  3. Some other Tregs: express CTLA-4, FAS-L
26
Q

Provide and explain 5 proposed ideas/mechanisms by which tolerance is broken to cause autoimmune disease

A
  1. Molecular mimicry: some retinal antigens have amino acid sequences similar to bacterial/viral antigens
  2. Bystander activation due to infection: upregulation of co-stimulatory molecules nearby allows activation of self-reactive T cells
  3. Polyclonal B cell activation: induction of self-reactive B cells
  4. Failure of regulatory cell activity: defects in TGFbeta production
  5. MHC (HLA) genotype: presentation of the autoantigen
27
Q

List 3 mechanisms in which the eye is protected from autoimmune disease

A
  1. blood ocular barrier
  2. absence of well developed lymphatic drainage
  3. intraocular immunosuppresive env. (ACAID_
28
Q

What does ACAID stand for?

A

Anterior Chamber Associated Immune Deviation

29
Q

What is ACAID induced by?

A

induced by pigment epithelial cells that interact with antigen-loaded APCs in the Ant. Chamber

(The APCs that migrate to the spleen will induce a systemic regulatory immune response)

30
Q

What regulates ACAID? (1)

A

TGFbeta

31
Q

What does ACAID induce (1) and suppress? (3)

A

Induce:
- differentiation of Tregs
Suppress:
- antigen specific CD4 and CD8 T cells
- IL12, CD40, CD40L
- DTH responses

32
Q

In vitro, what was aqueous humour found to inhibit?

A

the proliferation and function of Th1 cells

33
Q

What are T cells exposed to as they migrate into the posterior chamber? (2) What do these factors induce? Why do we want this?

A

Soluble factors such as TGF-beta and Thrombospondin-1 (TSP-1). These factors induce the T cell to become a Treg cell.
- this is good because we want the anterior chamber and cornea to be clear of any inflammation

34
Q

What things might take place prior to autoimmune disease development? (3)

A
  • tissue damage, inflammation/infection leading to venule endothelial cell transformation into “high endothelial venules”
  • early upregulation of adhesion molecules on retinal vascular endothelium
  • upregulation of co-stimulatory molecules (CD80, CD86, CD40) on APCs
35
Q

In the eye, where would you expect to see APCs? (5)

A
  • iris (heaps)
  • corneal epithelium (i.e. dendritic cells)
  • peripheral cornea close to limbus
  • choroid
  • uveal tract
36
Q

Between central vs peripheral cornea, where are APCs more abundant?

A

Peripherally

37
Q

Are there any APCs in the retina?

A

NO. However there are loads of similar cells (macrophages) called “microglia”

38
Q

Do Microglia make for good APCs?

A

No they do not. They are not good at presenting antigen

39
Q

Name 4 intraocular inflammatory diseases that are caused by autoimmunity

A
  • uveitis
  • sjogren’s syndrome
  • sympathetic ophthalmia
  • ocular sarcoidosis
40
Q

Name 4 systemic autoimmune diseases that have ocular manifestations (dry eye, red eye, ptosis, etc)

A
  • rheumatoid arthritis
  • sjogren’s syndrome
  • graves disease
  • myasthenia gravis
41
Q

List 2 indications for a corneal transplant

A
  1. keratoconus (31% of cases) and other stromal dystrophies
  2. Keratitis (incl. herpes simplex virus infection)
42
Q

What main factor influences the likelihood of corneal graft success or rejection?

A

The reason for the graft

43
Q

What is the main cause of corneal graft failure?

A

irreversible immunological rejection

44
Q

Describe the trend in the incidence rate of corneal graft rejection over time

A

Number of rejections is increasing

45
Q

What is “tissue matching” and why is it important?

A

When rejection occurs, it’s due to recognition of foreign MHC molecules. Different humans have huge variability in HLA expression. To increase the likelihood of graft success, it’s important to “tissue match”, meaning to provide the recipient with a donor that has HLA alleles as similar to theirs as possible

46
Q

Is HLA matching perfect? What is the consequence of this?

A

HLA matching is not perfect. Therefore, for most grafts, the recipient needs treatment with systemic immunosuppressives to prevent rejection

47
Q

Provide the 5 year graft survival rates for the following solid organs:
Kidney
Heart
Liver
LUng

A

Kidney: 80-90%
Heart: 70%
Liver: 40-50%
Lung: 30-40%

48
Q

Provide the 5 year graft survival rate for bone marrow

A

80%

49
Q

Provide the 5 year graft survival rate for the cornea What is the advantage for corneal grafts over other grafts?

A

73%. Cornea has it’s own built in immunosuppression therefore treatment with systemic immunosuppresives is not required, and tx generally is done without tissue matching

50
Q

IN many cases, despite the transplantation of allogenic corneal tissue, rejection does not occur. List 4 potential reasons why this is

A
  1. due to ACAID
  2. other suppressive cytokines
  3. relative paucity of MHC II+ cells in donor buttons
  4. Expression of FAS-L on corneal, retinal endothelium
51
Q

What might you expect to see when corneal graft rejection occurs? (6)

A
  • inflammation and oedema
  • class I MHC expressed on corneal epithelium, keratinocytes, endothelial cells
  • class II MHC upregulated on DCs in basal epithelia and on endothelial cells
  • upregulated levels of adhesion molecules
  • vascularised grafts have increased numbers of DCs
  • induction of corneal lymphangiogenesis
52
Q

Describe the nature of the anterior chamber when rejection occurs

A

anterior chamber is inflamed. Keratic precipitates (KPs) appear. Waves of leukocytes (many types), seen as a rejection line move across the graft

53
Q

What might influence graft acceptance?

A

The number of donor dendritic cells

54
Q

How does the speed of wound healing affect the likelihood of graft rejection? Provide 2 examples

A

Rapid wound healing is directly related to rejection
- vascularised grafts: heal fast; more likely to reject
- keratoconus graft: heal slow; less likely to reject

55
Q

List 6 determinants of poor graft survival

A
  • prior vasuclarisation (= “hot” recipient bed)
  • previous grafts
  • recurrence of herpetic infection
  • youth
  • increased ocular pressure
  • keratitis
56
Q

How do CD80/86 antagonists and anti-CD40L affect likelihood of graft survival in rodents over 80 days?

A

Increase likelihood of survival. With all 3 drugs, all rodents survived in the 80 day timeframe

OD2 S1 (47 decks)

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