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

Lec10-11 Tolerance, Autoimmunity, Hypersensitivity Flashcards

1
Q

Immunological Tolerance

A

Absence of pathological reactivity to self antigens

Can be central [during development] or peripheral [outside development process]

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2
Q

Selection of T cells

A
  • 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
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3
Q

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

A

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
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4
Q

What happens to a person deficient in AIRE

A
  • 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
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5
Q

Central tolerance

A

deletion editing of autoreactive T cells in thymus and bone marrow

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6
Q

Ignorance

A

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

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7
Q

Peripheral Anergy

A

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

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8
Q

Regulatory T Cells

A
  • 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
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9
Q

What is Foxp3? What happens in deficiency?

A
  • transcription factor present in CD4+CD25+ regulatory T cells
  • deficiency causes severe autoimmunity
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10
Q

What is CTLA4? What happens in deficiency?

A
  • 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
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11
Q

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

A

TGF-Beta

IL-10

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12
Q

Central tolerance in B Cells

A
  • 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
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13
Q

Extrinsic B cell tolerance regulation

A

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
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14
Q

BAFF

A

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

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15
Q

Peripheral B Cell Tolerance

A
  • 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
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16
Q

Definition of autoimmune disease

A
  • 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
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17
Q

What causes autoimmune disease [general]?

A
  • Usually genetic predisposition

- some sort of trigger [usually infection]

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18
Q

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

A

Example of Type II hypersensitivity

  • genetic predisposition with DR2
  • Autoantibody reactive to antigen in glomerular basement membrane
  • Causes kidney failure
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19
Q

Multiple sclerosis

A

DR2

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20
Q

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

A

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
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21
Q

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

A

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
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22
Q

Diabetes I – What type of hypersensitivity?

A

Type IV hypersensitivity

  • genetic predisposition with DR3/DR4
  • autoreactive T cells target pancreatic islets
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23
Q

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

A
  • 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
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24
Q

What are 5 common triggers of autoimmune disease?

A
  • Infection [most common]
  • Puberty/Estrogen
  • Drugs [procainamid, penicillin]
  • Loss of T-regulatory function
  • Organ damage leading to exposure to antigens not normally released
25
Q

How can organ damage be a trigger for autoimmune disease?

A
  • organ damage from hydrocarbon [smoking] or other source causes exposure to antigens not normally released/available to T Cell
  • overcomes ignorance
26
Q

What are the 4 classes of hypersensitivity response?

A

Type I: Immediate hypersensitivity

Type II: Antibody mediated

Type III: Immune Complex mediated

Type IV: T cell mediated

27
Q

What is the mechanism of antibody mediated hypersensitivity?

A

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

28
Q

How does antibody-mediated hypersensitivity cause tissue injury?

A
  • 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
Q

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

A
  • 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
Q

Describe Type II hypersensitivity and acetylcholine receptor?

A
  • 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
Q

What is the mechanism for Type III Hypersensitivity response?

A
  • 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
Q

How does Type III Hypersensitivity cause tissue damage?

A

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

33
Q

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

A

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
Q

What diseases are associated with Type IV hypersensitivity

A
  • T cell mediated autoimmune diseases
  • – ex. Diabetes type I
  • Contact dermatitis
  • Granuloma formation
35
Q

What are the mech of type IV hypersensitivity?

A

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
Q

T cell and macrophages working in delayed type hypersensitivity?

A
  • T cells activate macrophages
  • activated macrophages produce mediators of inflammation and are better antigen presenting cells
  • activated macrophage amplifies signal
37
Q

Chemokines in delayed type hypersensitivity [type IV]?

A
  • released by CD4+ T cell

- recruit macrophages to site

38
Q

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

A
  • released by CD4+ T cell
  • induces expression of vascular adhesion molec
  • Activates macrophages –> increases release of inflammatory mediators
39
Q

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

A
  • released by CD4+ T cell
  • causes local tissue destruction
  • increases expression of adhesion molec on local blood vessels
40
Q

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

A
  • stimulate monocyte production by bone marrow stem cells
41
Q

Epitope spreading in Type IV hypersensitivity

A
  • 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
Q

What is contact hypersensitivity?

A

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
Q

PPD reaction as an example of DTH [Type IV]

A
  • delayed onset [48-72 hrs]
  • Th1 regulated
  • IFN-gamma, TNF-alpha mediated
44
Q

What causes granuloma formation?

A

Chronic delayed type hypersensitivity [type IV]

45
Q

What is the mechanism of type I hypersensitivity?

A
  • 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
Q

Histamine/Heparin in Type I resposne

A
  • increases vascular permeability
  • causes smooth muscle contraction
  • toxic to parasites
  • released from mast cells
47
Q

IL-4/IL-13 in Type I response

A
  • stimulate and amplify TH2 cell response
48
Q

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

A
  • promote eosinophil production and activation
49
Q

TNF-a in type I response

A
  • promote inflammation, stimulate cytokine production by many cell types, activates endothelium
50
Q

Platelet activation factor in type I response

A
  • attracts leukocytes
  • amplifies production of lipid mediators
  • activates neutrophils, eosinophils, platelets
  • released by mast cells
51
Q

Leukotrienes C4, D4, E4 in type I response

A
  • vasodilation + increase vascular permeability
  • stimulate mucus secretion
  • released by mast cells
52
Q

Affect of mast cell degranulation on systems

A

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
Q

Anaphylaxis

A
  • fall in blood pressure [shock] by vascular dilation, airway obstruction due to laryngeal edema
  • due to drugs, bee sting, food, etc
54
Q

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

A
  • 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
Q

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

A

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

56
Q

Type II hypersensitivity - immune reactant, antigen, effector mech

hint: two types of antigen

A

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

57
Q

Type III hypersensitivity - immune reactant, antigen, effector mech

A

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

58
Q

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

hint: 3 different immune reactants and corresponding paths

A

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

Immunology (17 decks)

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