Unit 4: tolerance

Question 1

Immune system must distinguish between and react differently to___

Answer 1

self antigens vs foreign antigens

Question 2

State of unresponsiveness to a particular antigenic epitope

Answer 2

tolerance

Question 3

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

Answer 3

antigen-specific

Question 4

Both immature and mature ____can be tolerized

Answer 4

lymphocytes

Question 5

Tolerance is achieved via ___ and/or deletion

Answer 5

anergy

Question 6

Failure of tolerizing mechanisms can lead to ___

Answer 6

autoimmunity

Question 7

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

Answer 7

random TCR gene recombinations

makes millions of different T cells a day

Question 8

PARR

Answer 8

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

Question 9

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

Answer 9

Auto-reactive

Question 10

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

Answer 10

Auto-reactive lymphocytes

Question 11

central tolerance

Answer 11

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

Question 12

peripheral tolerance

Answer 12

inactive/delete auto reactive T cells in the periphery

Question 13

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

Answer 13

all self antigens

Question 14

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

Answer 14

negative selection

Question 15

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

Answer 15

self reactive

Question 16

three ways to help peripheral tolerance

Answer 16

ANERGY (unable to respond to antigen)

IGNORANCE (prevented from “seeing” self antigen)

SUPPRESSION (active process mediated by suppressor T cells)

Question 17

ANERGY

Answer 17

(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

Question 18

IGNORANCE

Answer 18

(prevented from “seeing” self antigen)

Question 19

SUPPRESSION

Answer 19

(active process mediated by suppressor T cells)

Question 20

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

Answer 20

less absolute

need three signals to active T cells

Question 21

Anergy can be reversed in the presence of ___

Answer 21

IL-2

Question 22

Preventing CTLA4 signaling will ___ T cell response

Answer 22

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

Question 23

how does ignorance work

Answer 23

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)

Question 24

how do immunologically privileged sites decrease tissue damage

Answer 24

high expression of FasL limits T cell mediated tissue damage

Treg cells also help

privileged sites: brain, eye, testis, fetus

Question 25

dominant tolerance

Answer 25

suppression by Treg actively suppress other T cells and DC

Question 26

\_\_\_ is a transcription factor required for Treg development in thymus

Answer 26

FOXP3

Question 27

\_\_\_can induce regulatory activity in peripheral T cells

Answer 27

FOXP3

Question 28

Two types of Treg

Answer 28

**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)

Question 29

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

Answer 29

TCR engagement

Question 30

Random rearrangement of BCR genes occurs in the \_\_\_

Answer 30

bone marrow

Question 31

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

Answer 31

bone marrow

Question 32

\_\_\_could be used to treat autoimmunity, suppress allograft rejection

Answer 32

Tregs

Question 33

immature B cells that see ___ are deleted

Answer 33

negative selection self surface antigen and self soluble antigen

Question 34

what other cells besides Treg are suppressive

Answer 34

**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

Question 35

autoimmunity is caused by activation of \_\_\_

Answer 35

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)

Question 36

some mechanisms for autoimmunity

Answer 36

Question 37

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

Answer 37

bystander T

Question 38

bystander activation

Answer 38

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

Question 39

molecular mimicry

Answer 39

get infected by a pathogen it is similar to other pathogen and triggers autoimmunity **EBV(epstein barr virus) and MS connection**

Question 40

antigen non specific lymphocyte activation

Answer 40

toxic shock syndrome ## Footnote **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)

Question 41

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

Answer 41

RA (rheumatoid arthritis) osteoarthritis Identity of autoantigens is **unknown;** IgG, DLA(dog leukocyte antigen) and collagen have been implicated

Question 42

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

Answer 42

laminin and fibronectin

Question 43

Vaccination or immunization with saline induced antibodies against \_\_

Answer 43

myoglobin and myosin

Question 44

genetic susceptibility for autoimmune disease

Answer 44

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

Question 45

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

Answer 45

**polymyositis** in Hungarian Vizsla **hypoadrenocorticism** in various breeds – Nova Scotia Duck Tolling Retriever, Cocker Spaniel, Springer Spaniels, Westies **Chronic Superficial Keratitis** in GSDs

Question 46

drugs can cause auto immunity by

Answer 46

changing target self into non self antigen penicillin can attack RBC→ anemia

Question 47

female and auto immune

Answer 47

hormones? X chromosome?

Question 48

type IV HS cell type

Answer 48

T cell mediated disease

Question 49

lupus is an example of ___ HS

Answer 49

type III → immune complex disease SLE = lupus

Question 50

Treatment for auto immunity

Answer 50

**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)