Wk 2 TBL 2 Type I Hypersensitivity Flashcards
What are 2 types of tolerance with regards to the adaptive immune system?
- Central - occurs in thymus
- Peripheral - circulating T cells
How does central tolerance manifest?
In thymus, negative selection of self-reactive T cells - undergo apoptosis OR some develop into Treg cells
How does peripheral tolerance manifest?
- Circulating T cells: Activated DCs (signal 1+signal 2) -> T cell activation
- W/o inflammation, immature DCs can generate signal 1 but no signal 2 w/ T cells -> either T cell death or anergy
- Tregs- convert activated DCs into regulatory DCs
-secrete immunosuppressive cytokines (IL-10, TGFbeta)
What is anergy?
Fxnal state in which T cell has lost ability to respond to T cell receptor signals
Central vs peripheral tolerance
Central tolerance mechanisms eliminate self-reactive lymphocytes during their initial development in the bone marrow and thymus.
Peripheral tolerance mechanisms eliminate self-reactive lymphocytes that escape the radar of central mechanisms; in the peripheral tissues and secondary lymphoid organs.
Where do Tregs develop?
thymus
-to suppress autoimmune responses
-constantly circulating
When are Tregs induced?
During immune responses (to suppress immunopathology)
-also constantly circulating
What regulates Tregs?
FoxP3, a transcription factor, expressed by tTregs and pTregs
What happens w/ FoxP3 mutations?
can lead to IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome)
-autoimmune disease in endocrine organs
-complete loss of fxn of FoxP3 not observed, but -> overwhelming autoimmunity and death in experimental animals
What is IPEX?
=immunodysregulation polyendocrinopathy enteropathy X-linked syndrome
-autoimmune disease in endocrine organs
-complete loss of fxn of FoxP3 not observed, but -> overwhelming autoimmunity and death in experimental animals
Define hypersensitivty reactions
=immune responses that damage human tissues
-tolerance systems don’t fxn well
When do hypersensitivty reactions occur?
- Response to foreign antigen (ie. Penicillin covalently attaches to surface of RBCs. penicillin-specific antibodies can develop and cause destruction of RBCs)
- Response to self antigen (autoimmunity) - ie RBC-specific antibody (self antigen)
When do hypersensitivty reactions occur?
- Response to foreign antigen (ie. Penicillin covalently attaches to surface of RBCs. penicillin-specific antibodies can develop and cause destruction of RBCs)
- Response to self antigen (autoimmunity) - ie RBC-specific antibody (self antigen)
What are the 4 types of hypersensitivity reactions?
- Type I - mediated by IgE on mast cells (ie allergic reactions)
- Type II -mediated by IgG (cell-associated antigens)
- Type III - mediated by IgG:antigen immune complexes - can be specific for autoantigens or foreign antigens
- Type IV - mediated by T cells (T helper cells that secrete cytokines like IFN gamma, TNF OR CTLs)
Why do tolerance mechanisms break down? AKA why do we get hypersensitivity reactions?
- genetics - HLA, sex, genes associated w/ immune regulation
- Environmental factors (smoking, weight, age, diet, etc)
- Infectious history (similarity b/w foreign and self antigens = molecular mimicry, which can -> destruction of self tissues)
How are autoimmune diseases inherited?
Most have complex inheritance w/ multiple loci and variable penetrance
Some driven by single gene, usually ones centrally involved in immune tolerance: CTLA-4, PD-1, Fas, FoxP3, AIRE
What locus is most strongly linked to autoimmune diseases?
HLA
MHC Class II
What locus is most strongly linked to autoimmune diseases?
HLA
MHC Class II
What locus is most strongly linked to autoimmune diseases?
HLA
MHC Class II
What diseases is HLA-B27 linked to?
Ankylosing spondylitis
Psoriasis
IBD
Reactive Arthritis
-strong contributor to relative risk and used as a diagnostic
What are some autoimmune consequences of infections?
Rheumatic fever (carditis, polyarthritis)
Reactive arthritis
Chronic arthritis in Lyme disease
Type I diabetes
-can -> molucular mimicry and autoimmune responses
What demographic is more susceptible to many autoimmune diseases?
Females
-onset often begins in 3rd, 4th or 5th decade of life
-poorly understood
Summary
What cells drive type I hypersensitivity?
Th2 cells
What defines allergens?
- usually inert (non-immunogenic)
- inhaled: pollen, dander, mold
- injected: insect venom
- ingested: shellfish, nuts
- skin: latex
How does a type I hypersensitivity reaction occur?
If T cell gets activated by allergen epitopes in the presence of IL-4, it induces a Th2 response
-some genetic susceptibility
-occurs during first sensitizing exposore to an allergen
-mast cells get “armed” with allergen-specific IgE
What antibodies is activated?
IgE on mast cells
What is the role of IL-4 in type I hypersensitivity?
Induces class switching of B cells to IgE
-> IgE-secreting plasma cells
What do the IgE antibodies do after formation?
Bind to mast cells that express the Fc epsilon receptor -> mast cells become coated w/ allergen-specific IgE
What other cytokines do Th2 cells make?
IL-4
IL-5
IL-10
What does IL-5 do?
activates eosinophils
What do eosinophils do in allergic response?
Release prostagladins, cytokines
What happens on second exposure?
-mast cell can crosslink antibodies on surface -> degranulation mediated by IgE-> release of histamine, leukotrienes and proteases (enhance inflammation during tissue invasion)
What is the role of histamine?
acts in the early phase allergic reaction (w/in minutes of 2nd exposure)
-induces vasodilation, allowing fluid and cells to escape into tissues -> edema, urticaria, and rhinitis
-induces bronchoconstriction -> asthmatic reaction
What is early phase allergic reaction AKA?
immediate hypersensitivity
When is late phase allergic reaction?
8-12 hrs after initial allergen exposure
What mediates a late phase allergic reaction?
leukotrienes
cytokines: IL-4, IL-5, TNF produced by mast cells
-cytokines activate Th2, eosinophils, basophils, and neutrophils
What are leukotrienes?
vasoactive lipids derived from arachadonic acid
-induce vasodilation, bronchoconstriction, and activation of many cell types (Th2, basophil, eosinophils, neutrophils)
What is anaphylaxis?
Usually occurs w/ a high dose of allergens via injection (ie. bee venom) or ingested (ie peanuts, shellfish)
-> systemic effects: vasodilation, bronchoconstriction, edema, urticaria, GI distress
can -> drop in BP, poor organ perfusion, shock, eventually organ failure, death
What is the tx for anaphylaxis?
Epi
Type I hypersensitivity tx
- epinephrine
- anti-histamines
- albuterol
- corticosteroids
What are the actions of epinephrine?
increase vasoconstriction
increase ventricular contraction
-> increase HR, BP
What are the actions of anti-histamines?
- vasoconstriction
- bronchodilation
What is the action of albuterol?
- -> bronchodilation
- inhibits mast cell activation
for asthmatic reactions
-is a beta-2 adrenergic receptor agonist
Actionsof corticosteroids?
Non-specific immunosuppression
nasal spray
allergic rhinitis
Summary
What is tryptase?
the most abundant protein component of mast cell secretory granules
-basophils also produce a small amount
-used as a diagnostic marker
What is tryptase?
the most abundant protein component of mast cell secretory granules
-basophils also produce a small amount
-used as a diagnostic marker
What is allergic rhinitis?
-Pollens, grasses, dust mites, etc
-> increased mucus secretion, inflammation of upper airways and sinuses, urticaria, and eczema
Tx: anti-histamines, desensitization, anti-IgE antibodies, Cromolyn
What is desensitization?
repeated administration of low doses of antigen to induce tolerance
What is Cromolyn
drug that inhibits mast cell degranulation
Asthma
=smooth muscle hyper-reactivity w/ inflammation and tissues injury caused by late-phase reaction
Tx: glucocorticoids to reduce inflammation, leukotriene antagonists and phosphodiesterase inhibitors to relax bronchial smooth muscle
-albuterol
How is anaphylaxis diagnosed?
- rapid onset of symptoms involving skin or mucosa
- respiratory compromise (dyspnea, wheeze/bronchospasm, stridor, reduced peak expiratory flow, hypoxemia)
- reduced BP or associated symptoms and signs of end-organ malperfusions (hypotonia (collapse), syncope, incontinence
- persistent GI sx (crampy abd pain, vomiting)
-can be biphasic w/ recurrence of symptoms w/in 12 hrs w/o additional exposire to causative agent
