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Basic Immunology- Module 1 > Models of AI disease > Flashcards

Models of AI disease Flashcards

1
Q

What can happen to self-reactive cells in self tolerance?

A

may merely become anergic

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2
Q

What are the pros of in vitro research models?

A

simple; inexpensive; answers about olecular/cellular interactions; immortalised cells; ethical

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3
Q

What are the cons of in vitro research models?

A

cannot stidy systemic interactions; growing cells; hayflick number-limited number of cell divisions; need to make assumptions about disease

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4
Q

What are the pros of using mice models?

A

mammalian; very well characterised; inbred strains-reliable, consistent and reproducible; genetic modification easy; many similarities; inexpensive; lots of reagents

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5
Q

What are the cons of mice?

A

incred strains (humans arent inbred!); essentially naive immunologically; many differences

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6
Q

What is the key initiating event in an autoimmune repsonse?

A

recognition of a peptide from self tissue bound to an MHC and then presented to an autoreactive T cells which becomes activated

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7
Q

Give examples of cellular autoimmunity?

A

T1DM; MS

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8
Q

What mediates cellular autoimmunity?

A

CD4 and CD8 T cells; macrophages

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9
Q

What mouse model is used to mimic T1DM?

A

non-obese diabetic mouse (NOD)

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10
Q

What are the features of the NOD model?

A

spontaneous disease phenotype affecting AI infiltration of the islets; thyroid and salivary glands and with many genetic immunological and pathological similarities to human T1DM

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11
Q

What is seen in Tregs in NOD diabetes?

A

reduced numbers and function of Tregs in the periphery

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12
Q

What happens if you transfer small numbers of Tregs to NOD mice?

A

reverses even ongoing disease

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13
Q

Why if many individuals carry AI T cells does the clinical disease only sometimes develop?

A

failure to regulate the immune repsonse properly; contributory role of multiple predisposing genes; role of infectious disease

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14
Q

What is central tolerance?

A

deleting cells found during differentiation in the thymus to be self reactive

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15
Q

what is peripheral tolerance?

A

regulating any self-reactive cells that have entered the immune repetoire

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16
Q

If negative selectin of self-reactive T cells depends on engagement of self antigens during passaage through teh thymus, how can this work for proteins specifically expressed at other sites?

A

autoimmune regulatory protein gives T cells a chance to see proteins across body whilst in thymus by expressing different proteins

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17
Q

What disease is caused by mutation in AIRE?

A

APECED: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

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18
Q

What is the function of natural Tregs?

A

curb autoreactive T cells by subduing their function wtihout killing them

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19
Q

What happens to CTLA-4 and FoxP3 knockout mice?

A

fatal aroudn 3 weeks of AI lymphoproliferative disease

20
Q

What happens in TGFb knockout mice?

A

wasting syndrome; multifocal, mixed inflammatory cell response and tissue necrosis leading to organ failure and death

21
Q

Waht happens to Cbl-b knockout mice?

A

auto-antibody production, infiltration of activated T and B cells into multiple organs and parenchymal damage

22
Q

Why is PTPN22 involved in so many AI disease?

A

sets threshold for T cell activation vs tolerance

23
Q

What is epitope spread?

A

autoimmunity starts with reactivity to one epitope then in inflammatory environemnt, start responding to other epitopes

24
Q

How does microbiome modulate susceptibility to autoimmunity?

A

shapes T cell subset responses

25
Q

Where is AIRE mainly expressed?

A

in lymphoid organs especially the thymus

26
Q

Which cells express AIRE in the thymus?

A

meduallry epithelial cells and to a small extent DCs

27
Q

What is the function of medullary epithelial cells?

A

involved in the negative selection of self-reactive thymocytes

28
Q

What is a special feature of medullary epithelail cells?

A

transcripts enocding peripheral tissue antiegns are extopically expressed by MECs

29
Q

What is the function of clonal deviation of PTA-reactive thymocytes?

A

allows them to survive whil acquiring protective characteristics eg. as FOXP3 Treg cells

30
Q

What are mice lacking FOXP3 known as?

A

scurfy mice

31
Q

What proteins are PHD motifs often found in?

A

nuclear transcriptional regulators

32
Q

What is different about the start sites of ectopic PTA gene transcripts in MECs from those for the genes in the tissue they are principally expressed?

A

very different

33
Q

Give an example of another disease aside from APECED where central tolerance mechanisms may play a role in development?

A

polymorphisms in the number of variable nucleotide repeats in the promoter region of hte gene encoding insulin promotes susceptibility to T1DM

34
Q

Which chromosome encodes FOXP3?

A

X chromosome

35
Q

What is scrufy analogous to in humans?

A

IPEX (immune dysregulation, polyendocrinopathy enteropathy X-linked

36
Q

What is FOXP3 required for?

A

establishment as well as maintenance of Treg cell suppressor function

37
Q

How does the differentiation of hte majority of peripheral Treg cells start?

A

in the thymus upon induction of FOXP3 expression in a subset of thymocytes expressing ab TCRs having increased affinity for self peptide-
MHC complexes

38
Q

Why is Treg survival and proliferation reliant on IL-2 produced by activated nonregulatory T cells?

A

express low levels of IL-7Ra- cant compete with naive and memory cells for the survivla factor IL-7; have a high quantity of CD25 on surface but cannot produce IL2

39
Q

How does FOXP3 facilitate Treg cell lineage commitment?

A

amplifyinf and stabilising its own expressiong and repressing alternative cell fates by inhibiting T-bet; GATA3 and RORyt

40
Q

What are the characteristic hallmarks of patients with acute and relapsing disease?

A

formation of focal inflammatory demyelinating lesions in the white matter

41
Q

what is seen in patietns wqith progressive MS?

A

brain is afected more globally with diffuse but widespread damage in the normal appearing whitematter and massive demyelination also in the grey amtter

42
Q

Why is EAE not a good model for MS?

A

MS is spontaneous whereas EAE is induced by active sensitisation with brain tissue antigens and usually need strong immune adjuvants which doesn’t occur in physiological conditions; EAE is studied in inbred animals and genetic heterogeniety is massive in MS population

43
Q

What type of T cells is thought to be mainly responsible for initiating the inflammatory reponse in the CNS in MS?

A

Th1

44
Q

What specific molecular abnormalities are seen in chronically demyelinated axons in MS?

A

redistribution of ion channels resulting in changes in intra-axonal ionic homeostasis

45
Q

What supports the finding that axonal loss results in axonal damage?

A

axonal loss is significantly reduced by pharmacological agents that reduce sodium and calcium entry across the axolemma

46
Q

What soluble factors do maceophages produce that may play a role in functional blockade and /or structural damage in axons ?

A

nitric oxide; ROS; excitotoxins; proteases

47
Q

What is needed to better amalgamate EAE and MS?

A

MS is domainted by CD8 whereas CD4 is dominanat in EAE models

Basic Immunology- Module 1 (31 decks)

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