Autoimmunity and Transplantation Flashcards
what is autoimmunity
- 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
what is xenoimmunity
autoimmune responses associated with the microbiota
what is alloimmunity
responses to nonself antigens or transplanted organs
what determines if we have self tolerance or not?
normal lymphocyte development = have self tolerance
autoimmunity = break/failure of self tolerance
what is the make or break step of developing self-tolerance?
the development of central tolerance during lymphocyte development (in thymus and bone marrow)
how does autoimmunity arise
- due to the lack of the TF AIRE
- if mTECs cannot express AIRE, T cells escape negative selection and we get autoimmunity
what is APECED syndrome
lack of AIRE in mTECs leads to auto reactive T cells
what are the different types of peripheral tolerance
antigen segregation
peripheral anergy
regulatory T cells
functional deviation
activation-induced cell death
immunological ignorance
immunologically privileged sites
how do regulatory T cells (Tregs) function in peripheral tolerance
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
what are some autoimmune diseases mediated by T cells
Psoriasis
Rheumatoid Arthritis
Crohn’s
Multiple sclerosis
Type 1 diabetes Melitus
what are some autoimmune diseases mediated by autoantibodies (B cells)
Graves’ disease
Myasthenia gravis
Systemic lupus erythematosus
What are some autoimmune diseased mediated by both T cells and autoantibodies (B cells)
Hashimoto’s thryoiditis
Sjogren’s syndrome
(lupus mostly B cells but could be considered T cells)
examples of organ specific autoimmune diseases
Type 1 diabetes mellitus
Goodpasture syndrome
Multiple sclerosis
Crohn’s
Psoriasis
Graves
Myasthenia gravis
Hashimoto’s thyroiditis
Vitiligo
examples of systemic autoimmune diseases
rheumatoid arthritis
scleroderma
systemic lupus erythematosusprimary sjogre’s syndrome
polymyositis
some monogenic disorders related to genetic defects can happen in these genes…
AIRE
CTLA4
FoxP3
Fas
disorders in the genetic factor AIRE
- disorders in the TF AIRE lead to APECED
- lack of peripheral tolerance causes decreased TSA expression in the thymus
disorders in the genetic factor CTLA4
- disorders in the TF CTLA4 lead to graves disease, MS, type 1 diabetes and IPEX
- decreased negative regulation of effector T cells
disorders in the genetic factor FoxP3
- disorders in the TF FoxP3 lead to IPEX
- lack of functional Tregs
disorders in the genetic factor Fas
- disorders in the Apoptotic marker Fas leads to ALPS
- no apoptosis in lymphocytes
what are autoantibodies and auto antigens
Auto Ab are self-reactive Igs (react to autoantigens)
Auto Ag are antigens from self
how do genetic and environmental factors affect the progression of autoimmune diseases
- both can alter negative selection which induces autoimmunity
- genetic factors = MHC polymorphisms, non-MHC mutations
- environmental factors = infections, chemical exposure, physical trauma
what is molecular mimicry
occurs when similarities between foreign and self-antigens favour autoreactive T or B cell activation
what is Guillain-Barre Syndrome
type of molecular mimicry - infection with gram-negative bacteria Camp. jejune causes immune reaction to gangliosides (lipids on peripheral nerves)
how can environmental factors (such as infectious agents) break self-tolerance
- disrupt the cell or tissue barrier and release self antigen
- molecular mimicry - produces cross-reactive antibodies or T-cells
example of diseases caused by molecular mimicry
rheumatic fever
reactive arthritis
Lyme arthritis
autoimmune diseases involve all aspects of the immune response, these include…
T cells, B cells and antibodies
what are some autoantibody-mediated autoimmune diseases
graves disease
myasthenia gravis
systemic lupus erythematosus
what are some T lymphocyte mediated autoimmune diseases
Type 1 diabetes mellitus
Multiple sclerosis
Rheumatoid arthritis
characteristics of Graves disease
- 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)
characteristics of Myasthenia gravis
- 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
characteristics of Systemic lupus erythematosus
- 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
characteristics of type 1 diabetes mellitus
- 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
characteristics of multiple sclerosis
- 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
characteristics of rheumatoid arthritis
- 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
what are some therapies for autoimmune diseases
corticosteroids
NSAIDs
Anti-TNFa (TNF blockers)
treatment of autoimmune diseases with corticosteroids
- mimic the effects of cortisol
- inhibit production of cytokines, chemokines, ROS and prostaglandins
- block macrophages from allowing adhesion, apoptosis and phagocytosis
treatment of autoimmune diseases with NSAIDs
- inhibit COX1/COX2 to inhibit production of prostaglandins
- Prostaglandin E2 is a pro-inflammatory factor
treatment of autoimmune diseases with TNFa blockers
- binds TNF receptor on cell to block the activity of TNF
- No NFkB can cause transcription of autoimmune DNA
which organs have higher vs lower transplant survival rates
higher = kidney, heart, HSC, cornea
lower = liver, pancreas, lung, intestine
what are alloantigens
- proteins expressed by graft tissue received as foreign by the recipient
- major types: blood group Ags and histocompatibility Ags
what are the different types of grafts in transplantation
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
transplant rejection is mediated primarily by…
T-cell responses to MHC molecules
skin graft rejection is a result of…
T-cell mediated anti-graft response
skin graft to synergetic recipient, allogeneic recipient and 2nd skin graft to allogeneic recipient
syngeneic = 100% survival rate
allogenic = graft is rejected b/c different MHC
2nd allogenic = graft shows accelerated rejection b/c different MHC and memory
T cells transfer accelerated rejection from a sensitized donor to a…
naive recipient
what are minor histocompatibility Ags
alloantigens bound to MHC graft molecules
even complete matching at the MHC locus does not ensure graft survival because…
minor histocompatibility antigens are presented on the MHC and cause slow rejection
MHC independent transplant rejection
happens when there is and MHC match but minor histocompatibility antigens are present in MHC
direct pathway of allorecognition example - acute rejection of a kidney graft
- 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
indirect pathway of allorecognition
- donor cells from graft are transplanted
- DCs from the recipients own cells migrate to lymph node and active alloreactive T cells
what is the difference between direct and indirect allorecognition
direct = T cells recognize MHC on donors DC - acute rejection
indirect = recipients DCs present donors antigens - chronic rejection
what is the goal of immunosuppressive drugs to prevent transplant rejection
to delay the rejection for as long as possible
solution = suppress the immune system (suppress TCR signalling for T cells)
examples of immunosuppressive drugs acting at different stages in the activation of alloreactive T cells
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
graft-vs-host disease occurs when donor T cells in the graft attack the recipient’s tissues…
- 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
when does graft-vs-host disease occur most often?
following HSC transplantation - bone marrow, peripheral blood and cord blood
what are transplant success factors
- MHC matching between donor and recipient (but perfect matching only possible when donor and recipient are closely related)
- immunosuppressive therapy
