Lec10-11 Tolerance, Autoimmunity, Hypersensitivity Flashcards
Immunological Tolerance
Absence of pathological reactivity to self antigens
Can be central [during development] or peripheral [outside development process]
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
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
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
Central tolerance
deletion editing of autoreactive T cells in thymus and bone marrow
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
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
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
What is Foxp3? What happens in deficiency?
- transcription factor present in CD4+CD25+ regulatory T cells
- deficiency causes severe autoimmunity
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
What are examples of cytokines secreted by T regulatory cells that turn off effector T cells?
TGF-Beta
IL-10
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
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
BAFF
B Cell Activating factor, a survival factor that helps B cells of low affinity survive
- overexpression of BAFF causes lupis-like disease
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
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
What causes autoimmune disease [general]?
- Usually genetic predisposition
- some sort of trigger [usually infection]
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
Multiple sclerosis
DR2
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
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
Diabetes I – What type of hypersensitivity?
Type IV hypersensitivity
- genetic predisposition with DR3/DR4
- autoreactive T cells target pancreatic islets
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
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
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
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
What is the mechanism of antibody mediated hypersensitivity?
IgM and IgG antibodies bind antigens on cell surface or extracellular matrix
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]
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
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
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
How does Type III Hypersensitivity cause tissue damage?
Complement and Fc receptor mediated recruitment and activation of leukocytes [neutrophils, macrophages]
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]
What diseases are associated with Type IV hypersensitivity
- T cell mediated autoimmune diseases
- – ex. Diabetes type I
- Contact dermatitis
- Granuloma formation
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
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
Chemokines in delayed type hypersensitivity [type IV]?
- released by CD4+ T cell
- recruit macrophages to site
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
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
IL-3/GM-CSF in delayed type hypersensitivity [type IV]?
- stimulate monocyte production by bone marrow stem cells
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
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
PPD reaction as an example of DTH [Type IV]
- delayed onset [48-72 hrs]
- Th1 regulated
- IFN-gamma, TNF-alpha mediated
What causes granuloma formation?
Chronic delayed type hypersensitivity [type IV]
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
Histamine/Heparin in Type I resposne
- increases vascular permeability
- causes smooth muscle contraction
- toxic to parasites
- released from mast cells
IL-4/IL-13 in Type I response
- stimulate and amplify TH2 cell response
IL-3/IL-5/GM-CSF in Type I response
- promote eosinophil production and activation
TNF-a in type I response
- promote inflammation, stimulate cytokine production by many cell types, activates endothelium
Platelet activation factor in type I response
- attracts leukocytes
- amplifies production of lipid mediators
- activates neutrophils, eosinophils, platelets
- released by mast cells
Leukotrienes C4, D4, E4 in type I response
- vasodilation + increase vascular permeability
- stimulate mucus secretion
- released by mast cells
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
Anaphylaxis
- fall in blood pressure [shock] by vascular dilation, airway obstruction due to laryngeal edema
- due to drugs, bee sting, food, etc
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
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
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
Type III hypersensitivity - immune reactant, antigen, effector mech
immune reactant: IgG
antigen: soluble antigen
effector mech: complement, phagocytes
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
