tolerance and autoimmunity

Question 1

evidence for concept of tolerance against self using cows

Answer 1

cattle have fused placentas and exchange cells and antigen in utero: non-identical twins have different sets of blood group antigens, and as these twins are non-identical, as adult cattle they would normally be expected to react to each others cells and tissues, however due to sharing antigens in utero, can tolerate blood transfusions and skin graft transplants

Question 2

evidence for concept of tolerance against self using mice to show timing is critical

Answer 2

if take cells from adult mouse and give to neonate other mouse, if then conduct skin graft later on in life they accept it; however this is rejected if no cells are given to neonate

Question 3

evidence for concept of tolerance against self using mice to show tolerance has specificity

Answer 3

if take cells from adult mouse and give to neonate other mouse, if then conduct skin graft later on in life with another type of mouse they reject it

Question 4

define immunological tolerance

Answer 4

acquired inability to respond to antigenic stimulus

Question 5

what are the 3 As of immunological tolerance

Answer 5

acquired (acquired immune cells), antigen-specific, active (active process in neonates, with effects maintained through life)

Question 6

how does self tolerance work: 2 types of tolerance and consequence of failure

Answer 6

central (induced during lymphocyte development), peripheral (mechanisms which help control self-reactive lymphocytes in periphery); if one or more mechanisms fail, it may result in autoimmune disease

Question 7

how does self tolerance work: 3 mechanisms of peripheral tolerance

Answer 7

anergy, active suppression (by Treg cells), (ignorance of antigen and immune privelege)

Question 8

central tolerance: describe process

Answer 8

lymphocyte develops in bone marrow but B-cells released immaturely, which secrete Ig, and pre T cells also released, which go to thymus and export mature T-cells to periphery

Question 9

central tolerance: what do T-cells recognise in thymus

Answer 9

peptides presented on MHC of thymic epithelial cells or dendritic cells

Question 10

central tolerance: outcome of thymus selection of useless (can’t see MHC) T-cells

Answer 10

die by apoptosis

Question 11

central tolerance: outcome of thymus selection of useful (see MHC weakly) T-cells

Answer 11

receive signal to survive (positive selection) - only about 5% of thymocytes (MHC restricted)

Question 12

central tolerance: outcome of thymus selection of dangerous (see self strongly) T-cells

Answer 12

die by apoptosis (negative selection) as see self too strongly and could cause autoimmunity

Question 13

central tolerance: where does B-cell tolerance occur

Answer 13

bone marrow

Question 14

central tolerance: immature B cell selection 4 outcomes

Answer 14

no self reaction migrates to periphery and matures; multivalent self molecule undergoes clonal deletion or receptor editing, so undergoes apoptosis or generation of non-autoreactive mature B cell if repaired; soluble self molecule migrates to periphery and becomes anergic B cell (don’t mature properly, don’t upregulate surface IgM - just IgD, have short half-life, and ineffective at generating responses); low-affinity non-cross-linking self molecule migrates to periphery and matures but is clonally ignorant of self-antigen unless something breaks tolerance (potential to lead to autoimmune reactions)

Question 15

what do defects in central tolerance lead to autoimmune disease (APECED) against

Answer 15

self-reaction against endocrine glands

what does induction and maintenance of peripheral tolerance depend on: site of antigen expression (MHC expression, immune privilege), timing of antigen expression, amount of antigen expression, costimulation, T cell help for B cell responses, regulation

Question 16

what causes APECED

Answer 16

failure of central tolerance to delete T-cells in thymus due to mutations in transcription factor AIRE (autoimmune regulator gene), involved in negative selection of self reactive T-cells in thymus (persistence of autoreactive cells instead of clonal deletion or tolerance)

Question 17

what are most autoimmune diseases associated with

Answer 17

mutliple defects and genetic traits e.g. failure to induce tolerance causing autoantibody production, apoptosis failure and failure to clear of antigen (so abundance of autoantigen)

Question 18

3 mechanisms by which mature lymphocytes are prevented from becoming auto-reactive in periphery (as some antigens may not be expressed in thymus or bone marrow)

Answer 18

anergy, suppression by regulatory T cells, ignorance of antigen

Question 19

describe anergy

Answer 19

absence of costimulation by APC to naive T cell as well, so cell proliferation and/or factor production does not proceed, with subsequent stimulation leading to a refractory state “anergy”

Question 20

what does induction and maintenance of peripheral tolerance depend on

Answer 20

site of antigen expression (MHC expression, immune privilege), timing of antigen expression, amount of antigen expression, costimulation, T cell help for B cell responses, regulation

Question 21

what 3 occasions does immunological ignorance occur

Answer 21

when antigen concentration is too low in periphery, when relevant antigen presenting molecule is absent (e.g. no MHC class II, which is common in periphery), at immunologically priveleged sites where immune cells can’t normally penetrate (eye, CNS, PNS, testes)

Question 22

sympathetic ophthalmia as example of failure of immunological ignorance

Answer 22

trauma to one eye results in release of sequestered intraocular protein antigens -> these are carried to lymph nodes and activate T cells -> these return via bloodstream and attack antigen in both eye

Question 23

what regulate/suppress autoreactive T-cells (which are present but don’t respond to autoantigen)

Answer 23

Treg cells: CD25 (IL-2 receptor), CTLA-4 (binds B7 and sends negative signal), FOX P3 (transcription factor required for Treg cell development)

Question 24

what is a syndrome causing a failure in regulation of peripheral tolerance

Answer 24

IPEX

Question 25

what causes IPEX, when and what is the outcome

Answer 25

caused by mutation in FOXP3 gene which encodes transcription factor for Treg cell development, and is therefore fatal recessive in childhood

Question 26

5 symptoms of IPEX due to accumulation of autoreactive T cells

Answer 26

early onset T1DM, severe enteropathy, eczema, variable autoimmune phenomena, severe infections

Question 27

what can “break” peripheral tolerance

Answer 27

specific infections for specific autoimmune diseases e.g. Streptococci causing breaking of peripheral tolerance in rheumatic fever

Question 28

6 ways how infections can affect tolerant state

Answer 28

molecular mimicry of self molecules, induce changes in expression and recognition of self proteins, induction of co-stimulatory molecules/inappropriate MHC class II expression in APCs (pro-inflammatory environment), failure in regulation (effect Treg cells), immune deviation (shift in type of immune response e.g. Th1-Th2), tissue damage at immunologically priveleged sites