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22 spring: immunology > Unit 4: tolerance > Flashcards

Unit 4: tolerance Flashcards

1
Q

Immune system must distinguish between and react differently to___

A

self antigens vs foreign antigens

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2
Q

State of unresponsiveness to a particular antigenic epitope

A

tolerance

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3
Q

Only cells with ___receptors (B and T cells) can be tolerize

A

antigen-specific

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4
Q

Both immature and mature ____can be tolerized

A

lymphocytes

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5
Q

Tolerance is achieved via ___ and/or deletion

A

anergy

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6
Q

Failure of tolerizing mechanisms can lead to ___

A

autoimmunity

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7
Q

T cell receptor repertoire is generated by ___ with enormous receptor diversity

A

random TCR gene recombinations

makes millions of different T cells a day

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8
Q

PARR

A

is tumor from single cell (neoplastic tumor) or for many (reactive lesion)

PCR for antigen receptor rearrangement

PARR detects clonal receptor gene rearrangement by PCR

  • best used when cytology or biopsy is inconclusive
  • specificity is 95%, 85% in dogs, 65% in cats
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9
Q

___ T cells are generated as an unfortunate consequence of generating massive TCR diversity

A

Auto-reactive

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10
Q

___ must be rendered unresponsive to self antigen; that is they must be tolerized

A

Auto-reactive lymphocytes

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11
Q

central tolerance

A

kill auto reactive T cells in thymus

if they can’t see self MHC will die in positive selection

If they see self antigen will die in negative selection

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12
Q

peripheral tolerance

A

inactive/delete auto reactive T cells in the periphery

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13
Q

problems with central tolerance, Unlikely that___ are represented in the thymus, therefore, elimination (negative selection) of some self-reactive T cells may not occur

A

all self antigens

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14
Q

Possible that some self-reactive T cells may “leak” through the thymus (may escape ____)

A

negative selection

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15
Q

Peripheral tolerance mechanisms exist to ensure that ____T cells present in the periphery are not activated

A

self reactive

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16
Q

three ways to help peripheral tolerance

A

ANERGY (unable to respond to antigen)

IGNORANCE (prevented from “seeing” self antigen)

SUPPRESSION (active process mediated by suppressor T cells)

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17
Q

ANERGY

A

(unable to respond to antigen)

need 2nd and 3rd signal to activate T cell

in the absence of the second signal (co-stimulatory), anergy is induced

Generally survive but are unable to proliferate when re-exposed to antigen

Anergic state is reversible pending on conditions of antigen contact-therefore induction of anergy is a less absolute mechanism for enforcing tolerance

Anergy can be reversed in the presence of IL-2

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18
Q

IGNORANCE

A

(prevented from “seeing” self antigen)

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19
Q

SUPPRESSION

A

(active process mediated by suppressor T cells)

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20
Q

Anergic state is reversible pending on conditions of antigen contact-therefore induction of anergy is a ___mechanism for enforcing tolerance

A

less absolute

need three signals to active T cells

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21
Q

Anergy can be reversed in the presence of ___

A

IL-2

22
Q

Preventing CTLA4 signaling will ___ T cell response

A

enhance

if CTL4 binds to CD80/86 it will turn off Tcell

if you block this with anti-CTLA4, it will allow/activate T cells to work

anti-CTLA4 is used for treating tumors

23
Q

how does ignorance work

A

T cell might never find its match

the antigens might not be there or in very low quantities or in an area that T cells can’t get to (immunologically privileged sites- brain, eye, testis, fetus)

24
Q

how do immunologically privileged sites decrease tissue damage

A

high expression of FasL limits T cell mediated tissue damage

Treg cells also help

privileged sites: brain, eye, testis, fetus

25
Q

dominant tolerance

A

suppression by Treg

actively suppress other T cells and DC

26
Q

___ is a transcription factor required for Treg development in thymus

A

FOXP3

27
Q

___can induce regulatory activity in peripheral T cells

A

FOXP3

28
Q

Two types of Treg

A

Natural or thymic Tregs (CD4+CD25+) produced in thymus

Adaptive or induced (i) Tregs - CD4+ T cells that gain suppressive activity in response to TGF-b (induced by inflammation, auto-immunity, cancer)

29
Q

T regs require ___ for activation but their
suppressive activities is non-specific (bystander!)

A

TCR engagement

30
Q

Random rearrangement of BCR genes occurs in the ___

A

bone marrow

31
Q

Mechanisms to induce B cell tolerance are present in the___ (central) and in the periphery (peripheral tolerance)

A

bone marrow

32
Q

___could be used to treat autoimmunity, suppress allograft rejection

A

Tregs

33
Q

immature B cells that see ___ are deleted

A

negative selection

self surface antigen and self soluble antigen

34
Q

what other cells besides Treg are suppressive

A

regulatory immune cells

TAM: M2 macrophages that make IL10, TGFbeta- work in tissue repair and angiogenesis, tumor promotion, down regulation of M1 and adaptive immunity

MDSC(myeloid derived suppressor cell)

immune suppressive cytokines → IL10, TGFB, IDO, arginase

Checkpoint molecules → CTLA4, PD1, PDL1

35
Q

autoimmunity is caused by activation of ___

A

auto reactive T cells that

1) support the production of auto-antibody by B cells (CD4+ Th cells)
2) damage tissues directly (CD4+ and CD8+ T cells)

36
Q

some mechanisms for autoimmunity

A
37
Q

Infections can induce autoimmunity via ___ cell activation (breakdown of peripheral tolerance), molecular mimicry and non-specific lymphocyte activation

A

bystander T

38
Q

bystander activation

A

other T cells, slides in and binds to activated APC and cause unwanted down steam reactions

bystander is activated in the absence of specific TCR stimulation

39
Q

molecular mimicry

A

get infected by a pathogen

it is similar to other pathogen and triggers autoimmunity

EBV(epstein barr virus) and MS connection

40
Q

antigen non specific lymphocyte activation

A

toxic shock syndrome

Superantigens activate T cells non-specifically (will bind randomly)

Produced by viruses and bacteria

Superantigens are not processed

Result in polyclonal T cell activation and massive cytokine release

Massive amounts of IFN-γ are produced which lead to cytokine production by macrophages (IL-1, IL-6 and TNF-alpha)

41
Q

CDV proteins and antibodies against CDV are present in the synovial fluid of dogs with __ (not present in dogs with __)

A

RA (rheumatoid arthritis)

osteoarthritis

Identity of autoantigens is unknown; IgG, DLA(dog leukocyte antigen) and collagen have been implicated

42
Q

Vaccination against CPV, CDV and rabies induced auto-antibodies to ___

A

laminin and fibronectin

43
Q

Vaccination or immunization with saline induced antibodies against __

A

myoglobin and myosin

44
Q

genetic susceptibility for autoimmune disease

A

increased in twins

associated with certain MHC class II- does not always develop disease and siblings don’t need the identical MHC to also have increased rick

Higher prevalence of AI amongst monozygotic twins

Pattern of inheritance is complex – multiple genes interact leading to increased genetic susceptibility to AI

Autoimmune diseases associated with c**ertain MHCII type**s include SLE, MG, TypeI DM, MS, RA
• Exactly how certain MHC types influence disease risk is **unknown** but certain. HLA class II alleles may be better at presenting self antigen than others

• People with predisposing MHC types do not always develop disease -
therefore other factors must be involved

• Non-MHC identical siblings have an increased risk of developing these
diseases indicating a role for non-MHC components in disease risk

45
Q

what are some common auto immune diseases associated with DLA class II haplotypes

A

polymyositis in Hungarian Vizsla

hypoadrenocorticism in various breeds – Nova Scotia Duck
Tolling Retriever, Cocker Spaniel, Springer Spaniels, Westies

Chronic Superficial Keratitis in GSDs

46
Q

drugs can cause auto immunity by

A

changing target

self into non self antigen

penicillin can attack RBC→ anemia

47
Q

female and auto immune

A

hormones?

X chromosome?

48
Q

type IV HS cell type

A

T cell mediated disease

49
Q

lupus is an example of ___ HS

A

type III → immune complex disease

SLE = lupus

50
Q

Treatment for auto immunity

A

Corticosteroids
• Cytotoxic agents
• Cyclosporin or FK506 - blocks T cell signaling pathways
• Anti-cytokine therapies
• Anti-TNFα (RA and IBD)
• Anti-IL-12/23 (Psoriasis)

• Small molecule inhibitors of JAK/STAT pathway (RA)
• Monoclonal antibodies (Mabs)
• anti-BAFF (prevents BAFF maintenance of autoreactive B cells)
• anti-CD20 – eliminates B cells (pemphigus, RA)
• anti-integrins
• Genetically engineered T cells to eliminate autoreactive B cells (CAR T cells)

22 spring: immunology (23 decks)

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