Autoimmunity

Question 1

Autoimmunity

Answer 1

loss of self tolerance due to combo of factors (we don’t tolerate self antigens)

genetic susceptibility
environmental triggers
inflammation (at the core of disease)

Question 2

Genetic susceptibility

Answer 2

Defective regulatory proteins (Fas ligand + receptor)
MHC inheritance (vigorously present self peptides)
TCR and BCR inheritance (TC = increased killing of self; BC = increased antibodies against self)

Question 3

Hypotheses for autoimmunity

Answer 3

Sequestered antigen
Defective peripheral tolerance
Molecular mimicry
Co-stimulator induction
Survival of self-reactive lymphocyte during clonal selection

Question 4

What is at the core of autoimmune processes

Answer 4

inflammation

Question 5

Sequestered antigen

Answer 5

self peptide that is not introduced to T or B cells during maturation so the T and B cells who respond to these antigens can’t be deleted

think about ocular and brain tissue

Question 6

Defective peripheral tolerance

Answer 6

breakdown in the system that generally can suppress self reactive cells

Question 7

Autoimmune diseases usually follow –

Answer 7

an infection

Question 8

Molecular mimicry + examples

Answer 8

antigens of infectious pathogens closely resemble self peptides – T and B cells begin to recognize self peptides as foreign and attack it

Ex: rheumatic heart disease or T1DM

Question 9

Costimulator induction

Answer 9

APC endocytoses microbes and vigorously present self peptides + have B7 costimulator which activates T cells

Question 10

B cells need costimulation by

Answer 10

T reg or T helper cell

Question 11

Cytotoxic T cell needs costimulation by

Answer 11

B7

Question 12

Inflammation in autoimmunity

Answer 12

Cytokines amplify response
APCs activated
MHC 1 unregulated (located on all cells) –> increases number of self peptide targets

Question 13

Allergy

Answer 13

exaggerated response to environmental antigens

Question 14

Autoimmunity

Answer 14

misdirection of immune response against host’s own cells

Question 15

Alloimmunity

Answer 15

immune response directed against beneficial foreign tissue (transplant or transfusion)

Question 16

immune deficiency

Answer 16

insufficient response to protect host

Question 17

Type 1 hypersensitivity

Answer 17

IgE-mediated (activates mast cells, basophils, eosinophils)

Question 18

Type 2 hypersensitivity

Answer 18

Tissue specific (antigens against tissue)

Other than IgE

Question 19

Type 3 hypersensitivity

Answer 19

immune complex mediated (Ag-Ab deposits)

Question 20

Type 4 hypersensitivity

Answer 20

Cell-mediated (T cells)

Question 21

Type 1 rxn: exposure to environmental antigen/allergen

Answer 21

dendritic cell –> TH cell
TH cell –> TH2 –> IL4, IL5, IL13
IL4—> cause B cells to class switch to IgE plasma cells to produce significant amount of IgE

Question 22

Type 1 rxn: immediate rxn

Answer 22

Allergen w IgE attracts mast cells and basophils
IgE Fc region binds to Fc receptor on mast cells and basophils –> degranulation + histamine release

1st exposure: relatively few receptors
subsequent exposures: greater number of receptors

Question 23

Type 1 rxn: Delayed rxn

Answer 23

TH2 cells recruited –> secrete IL5
IL5 –> bone marrow –> eosinophils released
Eosinophils are attracted to IgE opsonized allergen & release contents
Mast cell nucleus triggers synthesis of cytokines –> released hours later

Question 24

Type 1: anaphylaxis

Answer 24

prior sensitization to allergen
Mast cells armed with IgE

Mast cells are triggered systemically
Capillaries become leaky causing decreased blood volume
Smooth muscle constriction –> bronchoconstriction

Question 25

Type 2 hypersensitivity examples

Answer 25

RBC transfusion rxn Graves disease Myasthenia gravis Goodpasture's syndrome

Question 26

Difference between Type 2 and Type 3

Answer 26

Type 2: binds to cell surface antigens Type 3: binds to soluble antigen in blood or body fluids and LATER deposits into tissue

Question 27

Is type 3 organ specific

Answer 27

NO

Question 28

Type 3 reactions can cause decreases in what?

Answer 28

complement proteins Ex: post-streptococcal glomerulonephritis, SLE

Question 29

Examples of Type 4 hypersensitivity

Answer 29

Type 1 DM (against pancreatic beta cells) Rheumatoid arthritis (action against type 2 collage in joints) IBD Multiple sclerosis - myelin sheath Contact dermatitis (not autoimmune)

Question 30

What T cells are most implicated in Type 4

Answer 30

Cytotoxic T cells = destroy target cells directly Th1 = released cytokines that recruit phagocytic cells --> cell death

Question 31

Carcinogen

Answer 31

capability to alter or disable DNA within a cell --> mutagenic activity

Question 32

Oncogene

Answer 32

mutated gene --> regulatory protein mutations

Question 33

Proto-oncogene

Answer 33

potential to become an oncogene through accelerated or positively regulated proliferation growth factor or growth factor receptors

Question 34

Tumor suppressor genes (anti-oncogenes)

Answer 34

negatively regulate proliferations P53

Question 35

Malignancy occurs when mutations in both

Answer 35

oncogenes maintain and not suppressed

Question 36

Results in abnormal cellular functions --> promote cancer

Answer 36

growth promotion of mutated cells disabled feedback decreased apoptosis increased angiogenesis (increase blood supply to that area) cell/tissue barriers breached Altered immunity

Question 37

Metastases

Answer 37

invasion of distant tissues

Question 38

Macrophages against tumor

Answer 38

synthesize TNF --> destroy blood vessels supply growing tumor Macrophage needs to be hyper activated to react --> might not happen until much later

Question 39

Viruses linked to cancer

Answer 39

HBV & liver HPV & cervix H pylori & stomach

Question 40

NK cells against tumor

Answer 40

in a state of constant inhibition but lose inhibition when MHC class 1 molecules are damaged/mutated produce interferon may not happen until later

Question 41

Checkpoint proteins

Answer 41

programmed death 1 (PD-1) Cytotoxic T cell associated protein 4 (CTLA-4)

Question 42

CTLA-4

Answer 42

down regulates cytotoxic T cell response active when on T cell membrane

Question 43

PD-1

Answer 43

protein on T cells that deactivates T cells when it binds to PD-1 ligand down regulates cytotoxic T cell response

Question 44

Tumors can produce PD-1 ligand

Answer 44

normally, this can prevent overstimulation and autoimmune process BUT in cancer, inhibits TCR mediated positive signaling --> reduced proliferation and reduced T cell survival --> cancer wins

Question 45

Dual therapy cancer

Answer 45

CTLA-4 blockade: activation and proliferation of T cells; reduces Treg mediatied immunosuppression PD-1 pathway blockade: restores activity of anti tumor T cells

Question 46

Autoimmune therapy goals

Answer 46

decrease autoimmune response; so increase CTLA-4 etc

Question 47

Cancer therapy goals

Answer 47

increase immune response so block CTLA-4 etc.