Ch7: Hypersensitivity and Autoimmunity Flashcards
What are allergens?
Things that the immune system develops an over-active response to
What are 4 common sources of allergens?
- inhaled materials
- injected materials
- ingested material
- contacted materials
How many types of hypersensitivity are there?
4
Name of each hypersensitivity reaction?
- Type I: Immediate Hypersensitivity
- Type II: Antibody-mediated diseases
- Type III: Immune complex mediated diseases
- Type IV: T cell mediated diseases
What are the steps of Type I Hypersensitivity’s sensitization?
- Allergens taken up by APC’s
- Proteins degraded
- Peptides presented as peptide:MHC to specific T cells
- Th2 cells then produce cytokines to isotype switch to IgE
- IgE binds to Fc-epsilon-RI receptors on Mast cells
- Repeat exposure of allergen causes activation of mast cell and release of mediators
Two kinds of mediators that mast cells release?
- Vasoactive amines and lipid mediators immediately after repeat exposure
- Cytokines released hours later
Does IgE need antigen to bind and coat mast cells?
No
Basophils and mast cells are very similar but differ in what terms?
Mast cells: tissues
Basophils: Blood
5 main classes of products released by mast cells and which are prestored?
- enzymes (prestored)
- toxic mediators (prestored)
- cytokines (TNF-alpha only prestored)
- chemokines
- lipid mediators
Effect of enzymes released by mast cells?
Remodeling of CT matrix
Two main toxic mediators released by mast cells?
Histamine and heparin
Function of histamine and heparin release?
- Toxic to parasites
- leaky vessels
- Smooth muscle contraction
Function of mast cell TNF alpha? 3
- promotes inflammation
- stimulates cytokine production
- activates endothelium
Function of IL4 and IL13 release
Stimulate and amplify TH2 cell response
Function of IL3, IL5, and GM-CSF release?
Promote eosinophil production and activation
Function of CCL-13 release of mast cells?
Chemotactic for phagocytes
Function of leukotriene release of mast cells?
- Smooth muscle contractin
- Increase vessel leakiness
- Cause mucus secretion
Function of platelet activating factor
- Chemotactic for leukocytes
- Amplifies production of lipid mediators
- Activates neutrophils, eosinophils, and platelets
Function of prostaglandins?
Vascular dilation
Function of vasoactive amines?
Vascular dilation
Smooth muscle contraction
IMmediate Phase Type I hypersensitivity involves what cells?
Mast
Late phase Type I hypersensitivity involves what cells?
Eosinophils
What causes the wheal and flare of a Type I reaction?
Mast cell degranulation
Late-phase reaction occurs 6-8 hours later because of what?
Leukotrienes, chemokines, cytokines synthesized by mast cells
Degranulation in GI tract of Type I causes what?2
Diarrhea and vomiting
Degranulation in Airways causes what? 2
Phlegm and coughing
Degranulation in blood vessels causes what? 3
Edema
Inflammation
Increased lymph flow
Treatment for Type I involves what?
Block effects of inflammatory mediators (histamine and leukotrienes)
Can’t stop the cause: IgE crosslinking
When allergen is in skin, what results? (2)
- urticaria
2. angioedema
Where do recruited eosinophils go in Type I?
To the lung
Why is mast cell degranulation bad in the heart and vascular system?
Leakage of fluids into tissue resulting in drop in cardiac output leading to anaphylactic shock and possibly death
Most extreme outcome of hypersensitivity is what?
IgE mediated systemic anaphylaxis
What reverses systemic anaphylaxis?
How? (3)
Epinephrine
- Reforms tight junctions in between cells
- Reduces permeability Preventing fluid loss from blood
- Relaxes constricted bronchial smooth muscle and stimulates heart
Activated mast cells release what to stimulate eosinophils?
IL-5
What is the most important chemokine for eosinophils?
CCL11 (Eotaxin)
Do resting eosinophils express IgE receptors on surface?
No, not first responder
Presence of eosinophils is associated with what?
Chronic allergic inflammation
What is preformed in eosinophils for release?
Enzymes and toxic proteins
Chronic responses involve what?
Th2 cells and eosinophils
Allergic asthma is due to what?
Mast and Th2 cells activating eosinophils to cause damage in the lungs
Chronic asthma is what type of hypersensitivity?
Type 4
Why is chronic asthma different from allergic asthma?
Hyper-responsiveness of airways and exposure to the allergen is no longer needed to initiate attack
Chronic asthma involves what cells?
Th2 cells
Role of corticosteroids in type I HS?
Reduce inflammation
Role of leukotriene antagonists in type I HS?
Relax bronchial smooth muscle and reduce inflammation
Desensitization works how in type I?
Giving low doses of allergens may inhibit IgE production and cause production of IgG instead.
What is Anti-IgE antibody used for in type I HS?
Just destroy IgE
What does cromolyn do?
Stabilizes membranes of mast cells so no degranulation
How to induce regulatory T cells for type I?
Give cytokines (IL-10 and IFN-gamma)
How does penicillin become an allergen?
- Binds to bacteria and opens its Beta-lactam ring which forms covalent bond with amino acid residue. B cells recognize this ring or ring with the protein and uptake it. They present the modified peptides to T cells which cause B cells to release IgE and IgG against penicillin
Penicillin allergy is what type of hypersensitivity?
Type 1, 2, and 3
Type II hypersensitivities are mediated by what?
IgG directed at cell surface antigens
Since penicillin binds to erythrocytes, what could happen?
Ab’s attack penicillin epitopes on RBC’s leading to lysis of RBC’s
A person that has A blood is said to have what antibody?
Anti-B antibody
A person that has AB blood is said to have what antibody?
No antibody
A person that has type O blood is said to have what antibody?
A and B antibody
What is the A antigen?
GalNAc
What is the B antigen?
Gal
What does it mean if someone is Rh-?
They possess an anti-Rh antibody so that their blood has no Rh.
What type of hypersensitivity is hemolytic disease of the newborn?
Type II
What is a type III hypersensitivity reaction?
When a antigen-antibody-complement complex forms which deposits into mast cell causing degranulation
Accumulation of immune complexes results in what?
Complement fixation
What are the two molecules that stimulate histamine release?
C3a and C5a (anaphylatoxins)
Type III hypersensitivity reactions involve what antibody?
IgG
What is the arthus reaction?
IgG reacting with mast cells at injection site of inoculations for desensitization
Symptoms of type III HS?
Hemorrhaging in skin and urticarial rashes
What type of HS is serum sickness?
HS
What happens in serum sickness?
First exposure to antibodies from foreign species takes 7-10 days to develop. Subsequent exposure is far faster and stronger.
Apply serum sickness to real life.
Can only use one type of anti-venin in life. Then switch to another animal’s.
Type IV hypersensitivity involves what cells?
T cells
Why is type IV HS so delayed?
Have to develop whole immune response against it and direct T cells
How long does it take for Type IV HS to peak?
2-3 days
What type of HS is contact dermatitis?
Type IV
What causes contact dermatitis?
When hapten pentadecacatechol binds to ECM proteins on skin which are degraded by skin phagocytes which present proteins to Th1 which produce cytokines activating macrophages
Why is it bad is pentadecacatechol penetrates the skin?
Crosses plasma membrane of cells and modifies proteins inside causing CD8 cytotoxic killing of thsoe cells
Key feature of Type IV HS?
Antigens are presented to T cells and effector response is provided by these T cells
Celiac disease is what type of HS?
IV
What happens in celiac disease?
CD4 T cells tell Galt to respond to gluten which activates tissue macrophages, causing inflammation in SI that destroys tissue.
How can celiac disease be controlled?
NO GLUTEN DIET
Allergic response is defined by what?
Presentation of symptoms
What happens in autoimmune hemolytic anemia?
IgM or IgG bind to RBC antigens and cause opsonization which leads to phagocytosis in spleen.
However RBC’s are functional until destroyed
What is autoimmune neutropenia?
IgM or IgG binds to neutrophil antigens and leads to their destruction
What is Good pasture’s syndrome?
IgG forms against alpha3 chain of type IV collagen in BM’s. Is really bad in renal glomeruli leading to loss of kidney function and death
Treatment of Goodpastures?
Plasma exchange to remove antibodies and immunosuppressive drugs
What is Grave’s disease?
Anti-TSH receptor antibody (IgG2) binds to TSH receptors but do not fix complement or bind Fc receptors causing over stimulation of thryoid through Th2 response)
Short term Grave’s disease treatment?
Drugs to inhibit thyroid
Long term grave’s disease treatment?
remove thryoid
Symptoms of Grave’s disease?
Heat intolerance, irrtability, weight loss, bulging of eyes and thyroid
What is Hashimoto’s Thyroiditis?
Th1 response against thyroid antigens causing lymphocytes to destroy thyroid tissue leading to hypothyroidism
Treatment for hashimoto’s thyroiditis?
Thyroid hormone replacement
What is multiple sclerosis?
Th1 cells produce IFN-gamma and activated macrophages release proteases to destroy myelin sheaths in CNS.
What can reduce severity of multiple sclerosis?
High doses of immunosuppressives
What is myasthenia gravis?
Antibodies against acetylcholine receptors form leading to loss of NMJ function which causes droopy eyelids, weak face muscles, and impaired breathing
Treatment of myasthenia gravis is?
Azathioprine which prohibits autoantibody production
What is systemic lupus erythematosus?
IgG antibodies against cell surfaces, cytoplasm and nucleus.
Lupus autoantibodies cause what?
Inflammation, tissue destruction, release of soluble cellular components and formation of immune complexes.
What is rheumatoid arthritis?
IgM, IgG, and IgA’s against Fc region of human IgG (called rheumatoid factor) causes leukocyte infiltration into joints resulting in prostaglandin, leukotriene, and enzyme release.
What is Type I diabetes?
Antibody against Beta cells in pancreas in which CD8 cells eliminate Beta cells.
What type of HS is Type I diabetes?
Type IV
When using animal insulin to treat type I diabetes what might develop?
Type III HS
What does autoimmunity tell you about where the problem started?
Problem with central and peripheral tolerance
Autoreactive B cells should undergo peripheral tolerance how?
Stay in lymph node and die.
What removes most autoreactive T cells?
Negative selection/Central tolerance
Tregs produce what cytokines?
Result of these?
IL-4, IL-10, TGF-Beta
Suppress CD4 autoreactive cells
What TF do tregs express?
FoxP3
A problem with FoxP3 leads to what?
Absence of tregs –> Autoimmunity against a number of tissues
What is a dysfunction in FoxP3 called?
IPEX (x linked deficiency of Fox P3)
How are anergic T cells dealt with?
No B7 exposed by APC so no secondary activation of T cells
How are T cells dealt with in suppression?
Regulatory T cells block activation
How are autoreactive T cells dealt with through deletion?
Apoptosis
Is there a genetic predisposition to autoimmunity?
Yes, for example ankylosing spondylitis is due to MHC allele HLA-B27
What does a problem with the AIRE gene result in?
APS-1 or APECED
What is APS-1 or APECED?
No AIRE gene results in no presentation of self antigen to T cells in thymus so autoreactive T cells develop
A deficiency in AIRE is breaking which tolerance?
CENTRAL
How does a B cell break peripheral tolerance?
B cell binds self antigen and is activated by a T cell causing differentiation of B cell into plasma cells secreting self antibody
What is sympathetic opthamalia?
When trauma to eye causes self peptide to get in blood stream where it activates T cells in lymph nodes that return to both eyes and cause tissue damage
How might a mother pass Grave’s disease to fetus?
In grave’s disease, IgM from mother against TSHR crosses placenta and stimulates babies Thyroid
What can remove maternal antibodies?
Plasmapheresis
Will Type IV HS cross to the fetus?
No, T cells can’t cross barrier
Explain acute rheumatic fever?
Antibodies toward bacterial cell wall of strep pyogenes react with epitopes in heart, joints, and kidneys causing widespread inflammation leading to heart failure
Why might acute rheumatic fever occur?
A pathogenic antigen might very very similar to a self peptide so when an immune response occurs against bacteria, it also occurs against self.
What cells that don’t express MHC-II, will do so after IFN-gamma upregulates it?
Thyroid cells, Pancreatic Beta cells, astrocytes and microglia
What is pemphigus vulgaris?
Develop Ab’s against desmogleins of keratinocyte cell junctions. First the EC5 which is symptomless and then EC1 and EC2 causing disease.
How does the response toward DNA in SLE develop?
CD4 cells recognize specific pieces of self DNA and will all stimulate the same B cells so that the B cell initiates attacks against all different antigens of DNA.
Treatment for rheumatism is what?
Ab against TNF-alpha called infliximab
What does rituximab do?
Initiates ADCC (NK Cells) against CD20 on B cells thus alleviating rheumatoid
How does one treat B cells in autoimmunity?
CD20 mAB
In MS, how would one attack HMG-CoA reductase?
Statins
How would one attack T cells in autoimmunity?
CD3 mAB
