Autoimmune diseases and transplantation Flashcards
What is tolerance?
= prevents our immune system from attacking our own cells and tissues
= central and peripheral tolerance
= prevent autoimmunity
What is Central Tolerance
Central tolerance
= elimination of strongly self-reactive T-cell or B-cell clones before they are allowed to mature
e.g. Negative selection of T cells in thymus
= T cells with TCRs that bind strongly to self antigens are eliminated by apoptosis
e.g. Negative selection of B cells in bone marrow
= by clonal deletion of B cells with self-reactive B cell receptor and by receptor editing
= some self reactive B and T cells not eliminated by central tolerance
= cus not all antigens are expressed in thymus / bone marrow
+
some B or T cells that bind weakly to antigen are not eliminated
What is Peripheral Tolerance?
= controls activity of self-reactive T and B cells in the tissues
Tolerance is favoured by antigens that:
= are present at high doses
= show long-term persistence
= are introduced orally or intravenously
= are not accompanied by adjuvants (PAMPs)
= induce low levels of co-stimulation
= are presented by immature or unactivated APCs
Antigen sequestration
= the retention of antigens in compartments without significant immune cell access that are immunologically privileged
= e.g. eye, uterus, testes, brain
What are the mechanisms of Peripheral Tolerance?
Some antigens located in immunoprivileged sites
= e.g. eye, brain, uterus, testes
= leads to B and T cell ignorance of these tissue-specific antigens
= but immune privilege can be compromised by infection and injury
= when T cell recognises an antigen from an APC in the absence of co-stimulatory signals
(CD80/86 binding to CD28 / CD40 binding to CD40L)
= can lead to T cell anergy (unresponsiveness)
= or activation-induced death of the T cell
How are Tregs involved in Peripheral Tolerance?
Tregs
= specific T cell subset
= can be CD4+ or CD8+
Have 2 origins:
natural TREG (nTREG)
= develop in the thymus during normal T cell development
induced TREG (iTREG)
= develop in the periphery from conventional T cells
TREG cells help turn off immune responses and prevent autoimmunity by:
= secreting anti-inflammatory cytokines: IL-10 , TGFß
= inhibiting function of APCs when CTLA-4 on the TREG surface binds CD80/86 on APCs (sends inhibitory signal to APC)
(bystander suppression occurs when one APC engages several T cells of different specificity and the TREG cell inhibits the activity of the other T cells
What is Autoimmunity?
= caused by failure of tolerance mechanisms which protect tissues from destruction by own immune system
= if T cells or antibodies recognise own proteins - can lead to cell lysis / organ damage
= can be caused by self-reactive antibodies (autoantibodies) or self-reactive T cells
(sometimes contributions from innate immunity and complement)
= incidence of autoimmune disorders is rising
(>80 different diseases - can be organ specific or systemic)
What is Type I Diabetes Mellitus?
= organ-specific autoimmune disease affecting pancreas
= insulin-producing ß cells in pancreas are attacked
= normally diagnosed before 14 y.o
= leads to increased blood glucose levels
= can be treated with daily insulin injections
= cytotoxic T cells, autoantibodies and macrophages contribute to destruction of ß cells
What is Myasthenia Gravia?
= organ-specific autoimmune disease
= motor end plate cells of skeletal muscle are destroyed
= caused by autoantibodies to Ach receptors
= tiggers complement-mediated lysis of cells with these receptors
= results in progressive loss of muscle function
= can lead to severe problems with eating and movement
= can be treated with immunosuppressants (corticosteroids) or with cholinesterase inhibitors
What is SLE?
= systemic lupus erythematous
= systemic autoimmune disease
= affected individuals produce autoantibodies to wide range of tissue antignes
= common targets are proteins associated with self DNA and RNA
= thought that detection of self nucleic acids by PRRs play role
= characteristic sign is the “butterfly rash” on face
= other symptoms: fever, weakness, arthritis and kidney dysfunction
(due to deposition of immune complexes containing antibodies and complement)
What is MS?
= multiple sclerosis
= due to action of auto-reactive T cells that attack the myelin sheath of nerve fibres and the spinal cord
= symptoms include: numbness, paralysis and loss of vision
= causes unknown, include genetic risk factors and associated infections
(possible due to molecular mimicry)
What causes autoimmunity?
= most are multifactorial diseases
(many genes and environmental factors have a role)
Genetic factors that increase susceptibility:
= certain kinds of MHC variants
(e.g. HLA-B27 in ankylosing spondylitis)
= genes for immune cell surface protein
(e.g. IL-2 receptor and CTLA4 in T1DM, IL-23 receptor in Crohn’s disease)
= genes for innate immune signalling factors
(e.g. TLRs and RNA receptors in SLE)
= sometimes a single mutation
(e.g. in FoxP3 in IPEX)
Others:
= hygiene hypothesis
= diet microbiome hypothesis
= sex hormones (e.g. oestrogen promotes inflammation)
= injury can reveal antigens from immunoprivileged sites
= infections containing antigens that are similar to self antigens can cause autoimmunity (molecular mimicry)
What are the challenges of transplantation?
= availability of organs
= surgical techniques
= graft rejection
What are the different types of graft?
Autograft
= tissue transplanted from one site of body to another
= e.g. skin after burns, fat tissue for breast reconstruction
(never rejected)
Isograft
= graft of tissue from one genetically identical individual to another
= e.g. monozygotic twins
Allograft
= graft of tissue from a donor to a recipient
= needs good genetic match and immunsuppression
Xenograft
= transplantation of organs from animals to humans
= currently not possible in clinic, being researched
= immunologically complex
Graft Acceptance vs Rejection
Acceptance:
= grafted epidermis
= revascularisation
= healing
= resolution
Rejection
= grafted epidermis
= revascularisation
= cellular infiltration
= thrombosis and necrosis
= rejection displays specificity and memory
= “first set” rejection takes 12-14 days
= “second set” only takes few days due to memory response
= graft destruction occurs by effector mechanisms
How does Allograft donor matching work?
Autografts / isografts are not usually rejected
Allografts
= need to minimise genetic differences between donor and recipient
= major antigens to match: ABO blood type, MHC molecules (HLA)
= MHC proteins often very polymorphic
(so vary a lot between individuals - can be recognised as foreign in graft)
2 types of recognition of the graft as foreign:
= Direct allorecognition
(recognition of intact donor MHC on donor cells)
= Indirect allorecognition
(recognition of donor MHC peptide presented by self cells)
How is immunosuppression for transplantation used?
= transplant recipients often need to undergo immunosuppressive therapy for many years
= the treatments cause general (rather than antigen-specific) immunosuppression
= therefore, transplant recipients are more susceptible to infections and some cancers
