tolerance and autoimmunity

Question 1

what is autoimmunity *

Answer 1

adaptive immune responses with specificity for self ag - autoantigens

innate immune system is also involved - complent activation and inflammation involved in disease but autoimmunity kicks it off

Question 2

describe the transition from normal autoimmunity to autoimmune disease*

Answer 2

random recombination of genes segments mean all have have lymphocytes that recognise self

tolerance means that the normal autoimmunity doesnt cause disease

genetic and environmental factors eg diet and infection cause a breakdown of self tolerance = autoimmune disease

Question 3

what are the criteria for something to be autoimmune*

Answer 3

evidence of disease specific adaptive response in the affected target tissue, organ or blood

passive transfer of autoreactive cells or ab replicates the disease

elimination of the autoimmune response modifies the disease - however for many conditions you cant eliminate the autoimmune response

history of autoimmune disease - personal or family, and MHC associations

Question 4

describe the genetic and environmental factors that determine contribute to autoimmune disease *

Answer 4

genes - twin and family studies - GWAS eg 40 loci in SLE, identical twins 50% concordance, non-identical 10%

sex - women are generally more suseptible

infections - the inflammatory environment promotes autoimmune

diet - obesity, high fats, effects on gut microbiome (regulates the autoimmune response) - diet modification might alter autoimmune disease

stress - physcal and psychological, stress hormones

microbiome - helps shape and develop immunity, perturbation (dysbiosis) may help trigger autoimmune disease - there are sex differences in microbiome - may contribute to the sex difference in autoimmune disease

Question 5

summarise the mechanisms of autoimmunity *

Answer 5

adaptive immune reactions against self use same mechanisms as immune reactions against opathogens

involves breaking T cell tolerance - even when have Ab need to overcome T cell tolerance because IgG needs class switch which is helped by T cells

because self tissue is always present - they are chronic conditions - periods of control and relapse

effector mechanisms resemble hypersensitivity type 2 3 4

Question 6

summarise the importance of autoimmune disease

Answer 6

approx 100 conditions

approx 8% people affected

80% affected are female

incidence is increasing - hygiene hypothesis - environement now is different to when immune system evolved - so get lss exposure to ag = immune system not developing how it should - respond to things that we shouldnt

Question 7

describe sex differences in autoimmune diseases *

Answer 7

usually female more

but eg dm - males more

some symptoms better in preg and some worse

• switch in immune response against inflammation - dont want inflammation during pregnancy
• favours Th2 Ab response rather than Th1 cell mediated
• therefore rheumatoid arthritis symptoms better - cell mediated
• SLE worse - Ab mediated
• after pregnancy have worse RA

Question 8

list common autoimmune diseases *

Answer 8

rheumatoid arthritis

t1dm

MS

SLE
autoimmune thyroid disease - hasimoto’s and grave’sn

Question 9

how do you classify autoimmune responses

Answer 9

organs effected

involvement of specific auto-ag - for many dont know what ag causes disease

types of immune response - hypersensitivity type

Question 10

describe the target organs for auto-immune disease *

Answer 10

range from very organ specific eg Grave’s to multi-systemic autoimmune disease - SLE (immune complex mediated - circulate and are deposited at various points)

some have main organs but are also systemic so classifying diseases this way isnt very usefil

Question 11

describe 2 cases where auto-ag play a direct role in the immunopathies *

Answer 11

autoimmune haemolytic anaemia - auto-ab against rbc = clearance or complemented mediated lysis of autologous erythrocytes = anaemia

neonatal grave’s - IgG in graves crosses placenta - causes graves in baby until the ab have turned over

Question 12

describe the different immune reactions known to play a role in autoimmunity *

Answer 12

ab response to cellular or ECM - against something that is insoluble - type 2 - activates complement and inflammatory cells

immune complex formed by ab against soluble ag - type 3

T-cell mediated disease - delayed type hypersensitivity reaction - type 4 - involves cells

Question 13

describe goodpasture’s syndrome *

Answer 13

autoag is the non-collagenous domain of bm collagen type 4

causes glomerulonephritis and pumonary haemorrhage

there is infiltration of immune cells

type 2 hypersensitivity

Question 14

describe grave’s disease *

Answer 14

anti-TSH R ab binds to TSH R - stimulate thyroid hormone release

no negative feedback = uncontrolled thyroid hormone release = hyperthyroidism

type 2 hypersensitivity

Question 15

describe SLE *

Answer 15

type 3 hypersensitivity

autoags = dsDNA, ribosomes, snRNP, scRNP ie nuclear ag

IgG Ab against these nuclear components

causes glomerulnephritis, vasculitis and arthritis

immune complex circulates in blood - deposited in kidney, joints and skin

Question 16

summarise the mechanism of type 2 hypersensitivity *

Answer 16

ag in ECM - injury is caused by antitissue Ab

usually IgG binds to something insoluble = complement and Fc receptor mediated recruitment and activation of inflammatory cell = tissue injury

Question 17

summarise type 3 hypersensitivity response *

Answer 17

immune complex mediated tissue injury

immune complex circulates = widespread damage - systemic rather than localised to Ag

immune complexes are deposited in circulation -causes complement and Fc receptor mediated recruitment and activation of inflammatory cells

Question 18

describe Type 4 hypersensitivity *

Answer 18

ab involved eg anti-insulin, however symptoms are mainly caused by T cells

CD8 and CD4 T cells can be involved - against self peptides presented by MHC

Question 19

diseases with type 4 hypersensitivity response *

Answer 19

insulin dependant dm - autoag is panc B cell ag - lead to B cell destruction

rheum ath - unknown synovial joint ag - joint inflamm and destruction

MS - myelin basic protein and proteolipid protein - brain degradation (demyelination), weakness and paralysis

Question 20

describe the normal T cell response to ag *

Answer 20

ag is presented to T cells by MHC expressed on the surface of APC

MHC class 2 to CD4

class 1 to CD8

causes proliferation and function of the T cells

Question 21

what is the dominant genetic factor in determining suseptibility to autoimmune disease *

Answer 21

HLA class 2

polymorphic - different people have different alleles so have different suseptibility

HLA class 2 important means that CD4 t cells are important

Question 22

evidence for tolerance against self *

Answer 22

freemartin cattle have fused placentas and exchange cells and ag in utero

non-identical twins have different sets of blood gp ag

as adult cattle they would be expected to react to each others cells and tissues

however they can tolerate blood transfusions from a non-identical twin and can accept skin grafts from each other

this is because they shared ag in utero and so developed tolerance to each other’s ags

Question 23

evidence that timing of exposure is important for tolerance *

Answer 23

when neonate white mouse is exposed to ag form black mouse - it can accept a skin graft from the black mouse in adulthood - the white mouse developed tolerance to the black ag

when adult recieves the ag - cannot accept the skin graft

Question 24

evidence that tolerance has specificity *

Answer 24

if neonate mouse is exposed to black ag - it will not accept a skin graft from blue mouse - because only seen black ag

tolerance is ag specific

Question 25

explain the concept of immunological tolerance \*

Answer 25

defined as the acquired inability to respond to an antigenic stimulus acquired - involves cells of the acquired immune system and is learned ag specific active process in neonates - the effects of which are maintained through life

Question 26

what are the 2 mechanisms of immunological tolerance \*

Answer 26

central tolerance - duting lymphocyte development in thymus and bone marrow perioheral tolerance - control self reactive lymphocytes that got to periphery - happens via anergy and active suppression (regulatory T cells) immune privalege - area where immune cells dont go - never see the ag so are not going to respond, they are ignorant to the antigen

Question 27

what is the result of failure of a tolerance mechanism \*

Answer 27

autoimmune disease

Question 28

describe central tolerance \*

Answer 28

b cells mature in bm, T cells in thymus they rearrange their gene segments to make their receptors there are mechanisms to delete the cells that are autoreactive so that they dont escape into the periphery

Question 29

describe T cell selection in the thymus - central tolerance \*

Answer 29

T cells are selected on MHC class 1/2 molecules in thymus this is with self ag CD4 selected by MHC class 2 CD8 by class 1 if T cell is useless and cant see self MHC - dies by neglect - useless because wont by MHC restricted, cant see self MHC if useful - sees self MHC weekly - recieves signal to survive - this is positive selection if dangerous - see self strongly - recieve signal to die by apoptosis - negative selection - if these cells went to the periphery they could cause auto-immune disease only 5% of thymocytes survive selection

Question 30

describe B cell selection \*

Answer 30

if no reaction to ag in bm - escape to periphery, mature in the secondary lymphoid organs - express high levels of IgM and IgD if bind to cell surface with multivalent self molecules they get deleted - they do get chance to regenerate their receptor but if this doesnt work they are deleted = apoptosis or generation of non-autoreactive mature B cell if recognise soluble self molecules - even if cross-link, they escape to periphery - they are anergic because they dont mature in secondary lymphoid organs properly, they dont upregulate IgM and have a short half life, they cant ellicit a response because they cant comete with normal health B lymphocytes if recognise non-cross linking soluble ag - migrate to periphery - mature normally expressing IgM and IgD - they are the cells that have the possibility of generating an autoimmune response but they are clonally ignorant in periphery of the ag unless something breaks tolerance

Question 31

does central tolerance fail in autoimmune disease \*

Answer 31

yes occaisionally in APECED it is a rare autoimmune disease that effects the endocrine glands- thyroid, kidneys, chronic mucocutaneous candidiasis, ginadal failure, dm, pernicious anaemia results from a failure to delete T cells from thymus caused by mutations in AIRE (autoimmune regulator) gene - AIRE is important for expression of tissue specific genes in the thymus eg insulin, it is involved in the negative selection of T cells - it allows MHC in the thymus to present self peptides - T cell repetoire is selected in these ag if mutated AIRE - dont have selection if T cells on these peptides - the dangerous T cells will exist in the periphery - dont get tolerance

Question 32

what is the action of genes that are involved in SLE \*

Answer 32

they are involved in the lymophocyte response and lymphocyte half life they are involved in apoptosis - Fas and Fas-L = failure in cell death clearance of ag - complement proteins C1q, C1r and C1s - if dont have functional complement to clear the nuclear components from the dying cells - more likely to have immune response involved in induction of tolerance - B cell lymphocyte activation, CD22, SHP-1 - auto-Ab production

Question 33

summarise induction and maintenance of tolerance in the periphery \*

Answer 33

some ag might not be expressed in the thymuis or bm - may only be expressed after immune system has matured mechanisms are required to prevent mature lymphocytes becomung auto-reactive and causing disease - anergy, suppression by regulatory T cells alos ignorance of ag

Question 34

describe anergy \*

Answer 34

it is an absence of constimulation niave T cells need costimulation for full activation - CD80, CD86 and CD40 are costim molecules expressed on APC they are absent on most cells of the body w/o costimulation, cell proliferation and or factor production doesnt proceed subsequent stim leads to refractory state - anergy - this is difficult to reverse

Question 35

describe immunological ignorance \*

Answer 35

occurs when ag conc is too low in the periphery when relevant antigen presenting molecule is absent - most cells in periphery are MHC class 2 negative - so cant activate CD4 * INF gamma can upregulate MHC 2 eg on epi cells in inflammation causing activation of CD 4 T cells also occurs at immunologically preivaleged sites - immune cells cant normally penetrate eg eye, CNS, PNS and testes - in this case cells ahve never been tolerised against the ag

Question 36

describe sympathetic opthalmia\*

Answer 36

failure of ignorance trauma to 1 eye results in release of sequestered intraocular protein ag - ag draun into lymph node the ag then activate T cells via DC - T cells change expression of adhesion molecules effector T cells return via the blood to bith eyes and attack ag in both eyes

Question 37

describe suppression/regulation \*

Answer 37

auto-reactive T cells may be present but dint respond to auto-ag they are controlled by other cell types regulatory T cells - are: CD4+CD25+CTLA-4+FOXP3+ CD25 is IL2 receptor CTLA-4 binds to B7 and sends negative signal Fox-p3 is a TF required for reg T cell development

Question 38

describe IPEX \*

Answer 38

it is a failure in the regulation of peripheral tolerance fatal recessive disorder presenting early in childhood - mutation in FOXP3 which encodes a TF critical for development of reg T cells therefore dont have fuction reg T cells = accumulation of autoreactive T cells symptoms * early onset of insulin dependant dm * severe enteropathy * eczema * variable autoimmune phenomina * severe infections

Question 39

does infection cause autoimmune \*

Answer 39

generally the evidence is lacking Ab against streptococci cause rheumatic fever by attacjing heart ag

Question 40

how can infection cause auto-immune \*

Answer 40

molecular mimicry of self molecules - ag on infectious organism similar to self - cause immune response and so damage to self induce change in expression and recognition of self molecules cytokines cause induction of co-stimulatory molcules so activate APC or inappropriate MHC class 2 expression - pro-inflammatory environment (cytokines, INF - upregulate MHC expression - APC more effective at activating T cells failure in regulation - effect on reg T cells immune deviation - shift in type of immune response eg Th1 - 2 tissue damage at immunologically privileged site - release Ag and cause reaction

Question 41

what is the state of MHC molecules normally and change in infection \*

Answer 41

have self peptide in - otherwise cant get to cell surface they just cant activate the t cells if have infection: * microbe havemolecular patterns that cause innate immunity = release of cytokines = activate APC * APC more effective at co-stimulation * they can present self ag = activation of T cells

Question 42

describe molecular mimicry \*

Answer 42

microbe produce peptide similar to self APC present peptide = activation of lymphocyte in periphery lymophocytes recognise cells presenting self peptide

Question 43

what does induction and maintenace of tolerance depend on \*

Answer 43

site of ag expression - MHC expression, immune privalige timing of ag expression amount of ag expression costim t cell help for b cell response regulation