Lec10-11 Tolerance, Autoimmunity, Hypersensitivity Flashcards Preview

Immunology > Lec10-11 Tolerance, Autoimmunity, Hypersensitivity > Flashcards

Flashcards in Lec10-11 Tolerance, Autoimmunity, Hypersensitivity Deck (58):
1

Immunological Tolerance

Absence of pathological reactivity to self antigens
Can be central [during development] or peripheral [outside development process]

2

Selection of T cells

- T cells with very low affinity for self fail to be positively selected
- T cells with very high affinity are negatively selected and deleted
- T cells with intermediate tolerance are positively selected and survive
- If you eliminated all possible cells that under any circumstance could respond to self, then you would be very limited

3

How does thymus delete T cells reactive to antigens found in specific organs?

AIRE = autoimmune regulator
- protein made in thymus
- allows thymic epithelial cells to express tissue-specific proteins that would otherwise only be expressed in periphery
- Thus, able to test whether T cells are reactive to tissue-specific antigens since thymus is expressing them

4

What happens to a person deficient in AIRE

- no peripheral antigens expressed in thymus
- No central deletion of T cells reactive to these proteins --> will still have high affinity autoreactive T cells
- get Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy [APECED] causes destruction multiple endocrine tissues

5

Central tolerance

deletion editing of autoreactive T cells in thymus and bone marrow

6

Ignorance

Physical barrier by keeping T cells away from possible reactive antigens.
- if antigen not accessible to immune system, won't matter if T or B cells autoreactive

7

Peripheral Anergy

Cellular inactivation by weak signaling without co-stimulus in secondary lymphoid tissue

Cell anergy = paralysis

If T cell sees peptide MHC complex that it recognizes but doesn't have costimulation --> becomes non-responsive/anergic

Naive T cells ONLY activated in presence of costimuli in lymphoid tissue

8

Regulatory T Cells

- Suppress response of other T cells by secreting cytokines and through direct contact
- Foxp3 is one such TF that is a marker of CD4+CD25+ regulatory cells
- produces TGFbeta and IL-10 cytokines that turn effector off
- interacts with APC and turns APC off

9

What is Foxp3? What happens in deficiency?

- transcription factor present in CD4+CD25+ regulatory T cells
- deficiency causes severe autoimmunity

10

What is CTLA4? What happens in deficiency?

- CTLA4 is expressed on cell surface of Foxp3+ Tregs
- It is required for their Treg function
- Transmits off signal to APC
- Deficiency causes lymphoproliferation and diffuse autoimmunity

11

What are examples of cytokines secreted by T regulatory cells that turn off effector T cells?

TGF-Beta
IL-10

12

Central tolerance in B Cells

- B cells tested for interaction with self antigens in bone marrow
- Those with high affinity are negatively selected
- receptor editing = high affinity t cells get a second chance by rearranging their receptor to get different antigen specificity
- If now has lower affinity for self it gets saved otherwise deleted

13

Extrinsic B cell tolerance regulation

In periphery, regulated by cytokines from other cells
- BAFF = B Cell Activating factor, a survival factor that helps B cells of low affinity survive
- APRIL

14

BAFF

B Cell Activating factor, a survival factor that helps B cells of low affinity survive
- overexpression of BAFF causes lupis-like disease

15

Peripheral B Cell Tolerance

- B cell needs help from T cell through CD40/CD154 in order to produce antibody
- Mechansims that keep T cells intact affect B cells indirectly

16

Definition of autoimmune disease

- Clinical syndrome with activation of T and/or B cells in absence of infection and associated with end organ damage
- Can be diffuse or specific to individual organ
- Occurs mech tolerance mech overcome/bypassed

17

What causes autoimmune disease [general]?

- Usually genetic predisposition
- some sort of trigger [usually infection]

18

Goodpasture's syndrome - What type of hypersensitivity? What happens?

Example of Type II hypersensitivity
- genetic predisposition with DR2
- Autoantibody reactive to antigen in glomerular basement membrane
- Causes kidney failure

19

Multiple sclerosis

DR2

20

Grave's disease - What type of hypersensitivity? What happens?

Example of Type II hypersensitivity
- genetic predisposition with DR3
- Normally TSH activated thyroid epithelial cell makes thyroid hormone
- Autoantibody to TSH receptor binds receptor and activates it, causing unregulated release of thyroid hormone
- get hyperthyroidism
- No inflammation

21

Systemic lupus erythematosis -- What type of hypersensitivity? What happens? Treatment?

Type III hypersensitivity
- genetic predisposition with DR3
- autoantibodies develop to DNA, histones, and others
- Antibodies bind to antigens in serum, form immune complexes
- Excess immune complexes can't be cleared and deposit in tissue
- Antibodies trigger effector functions [Fc, complement]
- Can treat with anti-BAFF

22

Diabetes I -- What type of hypersensitivity?

Type IV hypersensitivity
- genetic predisposition with DR3/DR4
- autoreactive T cells target pancreatic islets

23

How does a trigger [ie virus] stimulate autoimmune disease?

- virus turns on immune system through TLRs --> activates T cells through APCs --> make T cells that would have normally not reacted to self start reacting

- Molecular mimcry: peptide in virus similar to peptide in self --> get reaction to both virus and to self

- Inability to clear immune complexes produced by infection

24

What are 5 common triggers of autoimmune disease?

- Infection [most common]
- Puberty/Estrogen
- Drugs [procainamid, penicillin]
- Loss of T-regulatory function
- Organ damage leading to exposure to antigens not normally released

25

How can organ damage be a trigger for autoimmune disease?

- organ damage from hydrocarbon [smoking] or other source causes exposure to antigens not normally released/available to T Cell
- overcomes ignorance

26

What are the 4 classes of hypersensitivity response?

Type I: Immediate hypersensitivity

Type II: Antibody mediated

Type III: Immune Complex mediated

Type IV: T cell mediated

27

What is the mechanism of antibody mediated hypersensitivity?

IgM and IgG antibodies bind antigens on cell surface or extracellular matrix

28

How does antibody-mediated hypersensitivity cause tissue injury?

- Autoantibody binds to the collagen/autoantigen that it recognizes on basement membrane causes:
---- Opsonization and phagocytosis of cells expressing antigen
---- Complement- and Fc receptor–mediated inflammation via neutrophil activation

- Abnormalities in cellular functions, e.g., abnormal hormone receptor signaling [think TSH]

29

How do autoantibodies alter cellular function in type II hypersensitivity without causing injury? Two examples.

- Grave's disease: autoantibody to TSH receptor
--- binds and activates, stimulates unregulated release of thyroid hormone = hyperthryoidism

- Autoantibody to acetylcholine receptor
--- binds acetylcholine receptor in at neuromuscular junction causing them to be internalized and degraded
--- blocks ability of neuronal impulse to reach acetylcholine receptor

- No inflammation in either case

30

Describe Type II hypersensitivity and acetylcholine receptor?

- Autoantibody to acetylcholine receptor
--- binds acetylcholine receptor in at neuromuscular junction causing them to be internalized and degraded
--- blocks ability of neuronal impulse to reach acetylcholine receptor

- No inflammation just blocks function

31

What is the mechanism for Type III Hypersensitivity response?

- Immune complex forms in blood and deposited in tissue OR antigen deposited first then antibody and form complex in tissue
- Different from Type II because complex not on cell surface, in a place it wasn't supposed to be
- Activates Fc and Complement pathways

32

How does Type III Hypersensitivity cause tissue damage?

Complement and Fc receptor mediated recruitment and activation of leukocytes [neutrophils, macrophages]

33

What is Post streptococcal glomerulo-nephritis? What type of hypersensitivity?

Type III hypersensitivity
- child gets throat infection with strep
- develops antibodies to strep proteins
- excess bacterial proteins deposited in kidney
- antibodies bind to them and trigger effector mech [complement, Fc gamma]

34

What diseases are associated with Type IV hypersensitivity

- T cell mediated autoimmune diseases
--- ex. Diabetes type I
- Contact dermatitis
- Granuloma formation

35

What are the mech of type IV hypersensitivity?

T cell mediated
- CD4 [or CD8] --> cytokine-mediated inflammation
- CD8 CTLs --> T cell mediated cytolysis [kill cells]
- also called delayed type - takes 2-3 days to develop

36

T cell and macrophages working in delayed type hypersensitivity?

- T cells activate macrophages
- activated macrophages produce mediators of inflammation and are better antigen presenting cells
- activated macrophage amplifies signal

37

Chemokines in delayed type hypersensitivity [type IV]?

- released by CD4+ T cell
- recruit macrophages to site

38

IFN-gamma in delayed type hypersensitivity [type IV]?

- released by CD4+ T cell
- induces expression of vascular adhesion molec
- Activates macrophages --> increases release of inflammatory mediators

39

TNF-a and TNF-B in delayed type hypersensitivity [type IV]?

- released by CD4+ T cell
- causes local tissue destruction
- increases expression of adhesion molec on local blood vessels

40

IL-3/GM-CSF in delayed type hypersensitivity [type IV]?

- stimulate monocyte production by bone marrow stem cells

41

Epitope spreading in Type IV hypersensitivity

- initial immune response could be directed at single peptide
- B cell binds self antigen, activated by T cell
- B cells differentiate into plasma cells, secrete lots of self-antigen specific antibody
- self antigen specific antibody initiates inflammatory response so get more cell injury and more release of self antigens
- more B cells bind, amplifying cycle of tissue damage

42

What is contact hypersensitivity?

A type of type IV hypersensitivity
- small molecule haptens [from nickel, poision ivy, etc] bind to self proteins and taken up by langerhans' cells
- langerhans' cells present haptenated self peptides to TH1 cells that secrete IFN-gamma and other cytokines
- activated keratinocytes secrete IL-1, TNF-alpha and chemokines
- cytokines and chemokines activate macrophages to secrete mediators of inflammation

43

PPD reaction as an example of DTH [Type IV]

- delayed onset [48-72 hrs]
- Th1 regulated
- IFN-gamma, TNF-alpha mediated

44

What causes granuloma formation?

Chronic delayed type hypersensitivity [type IV]

45

What is the mechanism of type I hypersensitivity?

- Antigen presented to CD4 Th2 cell specific to that antigen, stimulates B cell produced specific IgE antibody
- IgE binds specific Fc receptor on mast cell
- Mast cells coated by IgE antibodies are sensitised
- Second exposure to same allregen causes cross-linking of bound IgE, leads to mast cell degranulation

46

Histamine/Heparin in Type I resposne

- increases vascular permeability
- causes smooth muscle contraction
- toxic to parasites
- released from mast cells

47

IL-4/IL-13 in Type I response

- stimulate and amplify TH2 cell response

48

IL-3/IL-5/GM-CSF in Type I response

- promote eosinophil production and activation

49

TNF-a in type I response

- promote inflammation, stimulate cytokine production by many cell types, activates endothelium

50

Platelet activation factor in type I response

- attracts leukocytes
- amplifies production of lipid mediators
- activates neutrophils, eosinophils, platelets
- released by mast cells

51

Leukotrienes C4, D4, E4 in type I response

- vasodilation + increase vascular permeability
- stimulate mucus secretion
- released by mast cells

52

Affect of mast cell degranulation on systems

GI
- increase fluid secretion/peristalsis
--> diarrhea and vomiting

Airways
- decreased diameter, increased mucus secretion
--> wheezin, asmtha, coughing, phlegm

Blood vessels
- increase blood flow and permeability
--> hypotension/shock

53

Anaphylaxis

- fall in blood pressure [shock] by vascular dilation, airway obstruction due to laryngeal edema
- due to drugs, bee sting, food, etc

54

How do mediators from mast cells act in type I hypersensitivity [think quick vs slow rxn]

- vasoactive amines and lipid mediators cause intermediate hypersensitivity rxn minutes after repeat exposure to allergen
- cytokines cause late phase reaction 6-24 hrs later

55

Type I hypersensitivity - immune reactant, antigen, effector mech, example

immune reactant: IgE
antigen: soluble antigen
effector mech: mast cell activation, TH2 dependent
example: allergic rhinitis, asthma, systemic anaphylaxis

56

Type II hypersensitivity - immune reactant, antigen, effector mech

hint: two types of antigen

immune reactant: IgG
antigen: cell or matrix associated OR cell surface receptor
effector mech: complement/Fc gamma, antibody alters cell surface signaling

57

Type III hypersensitivity - immune reactant, antigen, effector mech

immune reactant: IgG
antigen: soluble antigen
effector mech: complement, phagocytes

58

Type IV hypersensitivity - immune reactant, antigen, effector mech, example

hint: 3 different immune reactants and corresponding paths

immune reactant: Th1 cells
antigen: soluble antigen
effector mech: macrophage activation
example:contact dermatitis

immune reactant:TH2 cells
antigen: soluble antigen
effector mech: IgE production, eosinophil activation
example: chronic asthma or allergic rhinitis

immune reactant: CTL
antigen: cell-associated antigen
effector mech: cytotoxicity
example: contact dermatitis