Module 7 Flashcards
(28 cards)
How does T-cell differentiation contribute to allergy, and roles do th2 and treg cells play?
Allergens presented to MHC class II to naive CD4+ T cells which differentiate into Th2 or Treg cells. Th2 secrete IL4, IL5 and IL13 promoting IgE production, eosinophil production and mucus secretion. Drives allergic immune responses & defends against helminths. Treg cells (expressing CD25 and FoxP3) are promoted by tolerogenic DC’s and secrete IL-10 and TGF-B suppressing excessive immune responses.
How do Th1 and Th2 cells drive different macrophage activation pathways?
- Th1 secrete IFN-y and TNF-a activating macrophages into M1. M1 express iNOS and release NO and function to kill intracellular pathogens, stimulate inflammation and tissue damage.
- Th2 cells secrete IL-4, IL-5, IL-10, and IL-13 which promote M2 (M2a, M2b, M2c). M2 express arginase into L-orthinine for tissue repair. They are anti-inflammatory, tissue repairers, and parasite clearance.
- Th1 and Th2 antagonise each others effect, balancing immune activation vs repair.
What are the four types of hypersensitivity reaction?
Type I (IgE) - allergy
Type II (cell- or ECM-associated antigen - IgG)
Type III - (soluble antigen - IgG)
Type IV (T-cells)
Autoimmunity associated with type II-IV
What is the mechanism in Type I hypersensitivity? (allergy)
Timing is seconds to minutes and mediators are IgE and FCeRI.
- Allergen (pollen, peanuts etc) triggers B-cell to make IgE
- IgE binds to FceRI on mast cells
- On re-exposure, allergen cross-links with the bound IgE
- Mast cell degranulates ->histamines, prostaglandins, leukotrines
- Causes like allergy, asthma, anaphylaxis, eczema
What is the mechanism in Type II hypersensitivity?
Timing is minutes to hours and mediators are IgG or IgM, complement, phagocytes, NK cells.
- Antibodies (IgG/IgM) bind directly to antigens on host cells (eg, RBCs, platelets)
- Leads to complement activation, phagocytosis (via opsonisation, CR2 and C3b interaction).
- Causes hemolytic anemia, blood transfusion reactions.
What is the mechanism in Type III hypersensitivity?
Timing is hours to days and mediators are IgG, immune complexes, complement and neutrophils.
- Soluble antigen binds to antibody-> immune complex forms in circulation
- complexes deposit in tissues (joints, vessels, glomeruli).
- activates complement-> inflammation->tissue damage
- causes are serum sickness, lupus, post-strep
How do CD4+ T cell differentiation contribute to allergy? and what role do Tregs play in regulation?
Allergens contain peptides presented on MHC class II by APCs presented to naive T cells. In presence of IL-4, Th0 differentiate into Th2 cells which secretae IL-4 for IgE class switching, IL-5 for eosinophil recruitment, and IL-13 for mucus production. This Th2 skewed response drives allergic inflammation. The Th2 cells will also undergo autocrine amplification via IL-4 reinforcing this loop.
In contrast Treg (expressing CD4, CD25 and FoxP3) acts as immune “brakes”. Promoted by tissue dendritic cells. They secrete IL-10 and TGF-B to supress Th2 activation.
What type of cell drives type I hypersensitivity?
Th2 and need APC to influence CD4 T cell differentiation.
What antibody class mediates Type I hypersensitivity?
IgE - binds to FceRI on mast cells and basophils, triggering degranulation upon allergen exposure.
What is degranulation?
Degranulation is the process by which immune cells like mast cells, basophils, and eosinophils released performed granules containing inflammatory mediators like histamine in response to stimuli like allergen cross-linking of IgE to FCeRI.
It causes vasodilation, increased permeability, inflammation and smooth muscle contraction.
What cytokine to drive B-cell into plasma IgE -producing cells?
IL-4
Are IgE bound to FCeRI before antigen encounter?
Yes
What are features of the allergens involved?
- Inhaled molecules, food, skin
- Low doses on mucosal cells (where mast cells actively residing) enough to trigger immune response
- proteases (Derp1)
- low molecular weight
- soluble and stable
What are the key steps in Type I sensitation during an allergic response?
- allergen is taken up and processed by APCs (DCs)
- antigen is presented on MHC class II to naive T cells
- In mucosal surfaces the environment promotes Th2 differentiation (tissue dendritic cells)
- Th2 cells release IL-4, Il-5, IL-13 which promote class switching to IgE and activate B cells via CD40 and CD40L binding
- plasma cells produce allergen-specific IgE
- IgE binds to FceRI receptors on mast cells, completing sensitisation
- memory cells also generated ->faster response upon re-exposure
What will trigger mast cell degranulation in Type I?
Re-exposure to same allergen which induces cross-linking of IgE on mast cell surface bound to FceRI leading to Ca influx and degranulation.
What is the difference between immediate vs late phase in Type I hypersensitivity?
The immediate phase is degranulation of mast cells within minutes
The late phase is recruitment of immune cells (eosinophils, macrophages, lymphocytes) over hours -> sustained inflammation and tissue damage.
Do eosinophils express FceRI upon activation?
Yes
What is a key cell important in asthma?
Eosinophils
Where do mast cells like to live?
Residents at mucosal sites (and connective tissues). Many mast cells ready with their extensive cross-links for re-exposure in Type I patients.
What are the two testings for allergies?
Skin testing
Measurement of specific and total IgE by ELISA patient serums.
Treatments of Type I reactions - Symptomatic
- Anti-histamines
- inhibiton of mast cell degranulation - chromolyn
- Leukotrine receptor blockers
What is the function of omalizumab in allergy treatment (causative)?
Omalizumab is an IgE-specific monoclonal antibody that binds free IgE, preventing it from attaching to FceRI on mast cells, thus reducing allergic sensitivity and mast cell activation.
What does allergen immunotherapy (allergy shots) do?
Allergy shots gradually expose the body to small doses of allergen to promote -> Treg induction, switch from Th2 to Th1.
What are some outcomes of switching Th2 to Th1?
Low IgE, low eosinophil and mast cell activation, low tissue inflammation, increased immune tolerance
