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Immunology > Autoimmunity and Transplantation > Flashcards

Autoimmunity and Transplantation Flashcards

1
Q

what is autoimmunity

A
  • the response to self antigens which leads to tissue damage and disease
  • breakdown of self-tolerance
  • involves the generation of effector T cells and production of autoantibodies to combat auto antigens
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2
Q

what is xenoimmunity

A

autoimmune responses associated with the microbiota

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3
Q

what is alloimmunity

A

responses to nonself antigens or transplanted organs

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4
Q

what determines if we have self tolerance or not?

A

normal lymphocyte development = have self tolerance
autoimmunity = break/failure of self tolerance

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5
Q

what is the make or break step of developing self-tolerance?

A

the development of central tolerance during lymphocyte development (in thymus and bone marrow)

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6
Q

how does autoimmunity arise

A
  • due to the lack of the TF AIRE
  • if mTECs cannot express AIRE, T cells escape negative selection and we get autoimmunity
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7
Q

what is APECED syndrome

A

lack of AIRE in mTECs leads to auto reactive T cells

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8
Q

what are the different types of peripheral tolerance

A

antigen segregation
peripheral anergy
regulatory T cells
functional deviation
activation-induced cell death
immunological ignorance
immunologically privileged sites

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9
Q

how do regulatory T cells (Tregs) function in peripheral tolerance

A

Tregs work in SLOs and sites of inflammation to inhibit other self-reactive T cells and intercellular signals by producing the cytokines IL-10 and TGF-B

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10
Q

what are some autoimmune diseases mediated by T cells

A

Psoriasis
Rheumatoid Arthritis
Crohn’s
Multiple sclerosis
Type 1 diabetes Melitus

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11
Q

what are some autoimmune diseases mediated by autoantibodies (B cells)

A

Graves’ disease
Myasthenia gravis
Systemic lupus erythematosus

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12
Q

What are some autoimmune diseased mediated by both T cells and autoantibodies (B cells)

A

Hashimoto’s thryoiditis
Sjogren’s syndrome
(lupus mostly B cells but could be considered T cells)

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13
Q

examples of organ specific autoimmune diseases

A

Type 1 diabetes mellitus
Goodpasture syndrome
Multiple sclerosis
Crohn’s
Psoriasis
Graves
Myasthenia gravis
Hashimoto’s thyroiditis
Vitiligo

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14
Q

examples of systemic autoimmune diseases

A

rheumatoid arthritis
scleroderma
systemic lupus erythematosusprimary sjogre’s syndrome
polymyositis

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15
Q

some monogenic disorders related to genetic defects can happen in these genes…

A

AIRE
CTLA4
FoxP3
Fas

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16
Q

disorders in the genetic factor AIRE

A
  • disorders in the TF AIRE lead to APECED
  • lack of peripheral tolerance causes decreased TSA expression in the thymus
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17
Q

disorders in the genetic factor CTLA4

A
  • disorders in the TF CTLA4 lead to graves disease, MS, type 1 diabetes and IPEX
  • decreased negative regulation of effector T cells
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18
Q

disorders in the genetic factor FoxP3

A
  • disorders in the TF FoxP3 lead to IPEX
  • lack of functional Tregs
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19
Q

disorders in the genetic factor Fas

A
  • disorders in the Apoptotic marker Fas leads to ALPS
  • no apoptosis in lymphocytes
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20
Q

what are autoantibodies and auto antigens

A

Auto Ab are self-reactive Igs (react to autoantigens)
Auto Ag are antigens from self

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21
Q

how do genetic and environmental factors affect the progression of autoimmune diseases

A
  • both can alter negative selection which induces autoimmunity
  • genetic factors = MHC polymorphisms, non-MHC mutations
  • environmental factors = infections, chemical exposure, physical trauma
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22
Q

what is molecular mimicry

A

occurs when similarities between foreign and self-antigens favour autoreactive T or B cell activation

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23
Q

what is Guillain-Barre Syndrome

A

type of molecular mimicry - infection with gram-negative bacteria Camp. jejune causes immune reaction to gangliosides (lipids on peripheral nerves)

24
Q

how can environmental factors (such as infectious agents) break self-tolerance

A
  • disrupt the cell or tissue barrier and release self antigen
  • molecular mimicry - produces cross-reactive antibodies or T-cells
25
Q

example of diseases caused by molecular mimicry

A

rheumatic fever
reactive arthritis
Lyme arthritis

26
Q

autoimmune diseases involve all aspects of the immune response, these include…

A

T cells, B cells and antibodies

27
Q

what are some autoantibody-mediated autoimmune diseases

A

graves disease
myasthenia gravis
systemic lupus erythematosus

28
Q

what are some T lymphocyte mediated autoimmune diseases

A

Type 1 diabetes mellitus
Multiple sclerosis
Rheumatoid arthritis

29
Q

characteristics of Graves disease

A
  • Autoimmune B cells make antibodies against the TSH receptor
  • thyroid hormones shut down TSH production but have no effect on autoantibody production, so continues to cause excessive thyroid hormone production
  • autoantibodies down regulate the production of TSH (not thyroid hormones)
30
Q

characteristics of Myasthenia gravis

A
  • autoantibodies bind receptors on muscles to block contraction
  • acetylcholine receptors are internalized and degraded
  • muscle cannot respond to ACh, therefore no Na+ influx so muscles remain relaxed
31
Q

characteristics of Systemic lupus erythematosus

A
  • nucleic acid-containing immune complexes generated from dying cells activate DCs to produce IFN-a
  • IFN-a stimulates BAFF production (survival signal), which enhances survival of autoantibody production to continue autoimmunity
  • common in kidney cells
32
Q

characteristics of type 1 diabetes mellitus

A
  • organ-specific - pancreas
  • an effector T cell recognizes peptides from a beta cell-specific protein and kills the beta cell is the islets of langerhans
  • insulin can no longer be made by the beta cell
  • glucagon and somatostatin are still produced
33
Q

characteristics of multiple sclerosis

A
  • unknown trigger causes BBB to become locally permeable to leukocytes and blood proteins
  • activated T cells specific for CNS antigen reencounter antigen presented on microglia (brain DC)
  • inflammatory reaction occurs in the brain due to mast-cell activation, antibodies and cytokines
  • demyelination of neurons occurs
34
Q

characteristics of rheumatoid arthritis

A
  • unknown trigger causes inflammation is synovial membrane, attracting leukocytes into the tissues
  • auto reactive CD4 T cells activate macrophages, producing pro-inflammatory cytokines
  • cytokines induce production of MMP and RANK ligand by fibroblasts
  • MMPs attack tissues, activation of bone-destroying osteoclasts by RANK ligand results in joint destruction
35
Q

what are some therapies for autoimmune diseases

A

corticosteroids
NSAIDs
Anti-TNFa (TNF blockers)

36
Q

treatment of autoimmune diseases with corticosteroids

A
  • mimic the effects of cortisol
  • inhibit production of cytokines, chemokines, ROS and prostaglandins
  • block macrophages from allowing adhesion, apoptosis and phagocytosis
37
Q

treatment of autoimmune diseases with NSAIDs

A
  • inhibit COX1/COX2 to inhibit production of prostaglandins
  • Prostaglandin E2 is a pro-inflammatory factor
38
Q

treatment of autoimmune diseases with TNFa blockers

A
  • binds TNF receptor on cell to block the activity of TNF
  • No NFkB can cause transcription of autoimmune DNA
39
Q

which organs have higher vs lower transplant survival rates

A

higher = kidney, heart, HSC, cornea
lower = liver, pancreas, lung, intestine

40
Q

what are alloantigens

A
  • proteins expressed by graft tissue received as foreign by the recipient
  • major types: blood group Ags and histocompatibility Ags
41
Q

what are the different types of grafts in transplantation

A

autograft: graft between different sites on the SAME person
syngeneic graft: between genetically identical people (identical twins)
allograft: between unrelated individuals - higher rejection rate, depends on T-cell response

42
Q

transplant rejection is mediated primarily by…

A

T-cell responses to MHC molecules

43
Q

skin graft rejection is a result of…

A

T-cell mediated anti-graft response

44
Q

skin graft to synergetic recipient, allogeneic recipient and 2nd skin graft to allogeneic recipient

A

syngeneic = 100% survival rate
allogenic = graft is rejected b/c different MHC
2nd allogenic = graft shows accelerated rejection b/c different MHC and memory

45
Q

T cells transfer accelerated rejection from a sensitized donor to a…

A

naive recipient

46
Q

what are minor histocompatibility Ags

A

alloantigens bound to MHC graft molecules

47
Q

even complete matching at the MHC locus does not ensure graft survival because…

A

minor histocompatibility antigens are presented on the MHC and cause slow rejection

48
Q

MHC independent transplant rejection

A

happens when there is and MHC match but minor histocompatibility antigens are present in MHC

49
Q

direct pathway of allorecognition example - acute rejection of a kidney graft

A
  • kidney graft with donor’s dendritic cells is transplanted
  • dendritic cells or their exosomes migrate to lymph node and spleen via blood and activate alloreactive T cells
  • effector T cells migrate to graft via blood
  • graft is destroyed by effector T cells
50
Q

indirect pathway of allorecognition

A
  • donor cells from graft are transplanted
  • DCs from the recipients own cells migrate to lymph node and active alloreactive T cells
51
Q

what is the difference between direct and indirect allorecognition

A

direct = T cells recognize MHC on donors DC - acute rejection
indirect = recipients DCs present donors antigens - chronic rejection

52
Q

what is the goal of immunosuppressive drugs to prevent transplant rejection

A

to delay the rejection for as long as possible
solution = suppress the immune system (suppress TCR signalling for T cells)

53
Q

examples of immunosuppressive drugs acting at different stages in the activation of alloreactive T cells

A

belatacept: blocks costimulatory signals (B7:CD28)
anti-CD3 mAB: blocks signal transduction by inhibiting CD3
cyclosporine A/tacrolimus: blocks Ca2+ release. from CD3
mycophenolate/ azathioprine: blocks cell cycle
basiliximab: blocks IL-2 from binding receptor

54
Q

graft-vs-host disease occurs when donor T cells in the graft attack the recipient’s tissues…

A
  • common in hematopoietic stem cell transplantation
  • donors mature and memory T cells circulate in blood and can attack recipient tissues
  • alloreactive cells interact with DCs and proliferate
55
Q

when does graft-vs-host disease occur most often?

A

following HSC transplantation - bone marrow, peripheral blood and cord blood

56
Q

what are transplant success factors

A
  • MHC matching between donor and recipient (but perfect matching only possible when donor and recipient are closely related)
  • immunosuppressive therapy

Immunology (22 decks)

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