Dr. Cyr - Th2 Immunity Flashcards
what type of pathogen is targeted in type 2 response?
helminth parasite
describe the evolution of the type 2 response
we evolved with parasites so we needed this special response for a large pathogen
now we experience less parasites, so when type 2 response is triggered and dysregulated, hard to bring it down and leads to inflammatory disease
what 4 types of innate cells are involved in type 2 response?
- ILC2
- Mast cell
- Basophil
- Eosinophil
what 2 types of adaptive cells are involved in type 2 response?
- Th2
- Tc2
patients with one Type 2 inflammatory disease have an increased risk of ________? why?
patients with one Type 2 inflammatory disease have an increased risk of developing other diseases driven by Type 2 inflammation
helminths infected everywhere so the immune response was all over body
what are 4 types of Type 2 inflammatory diseases?
- Atopic dermatitis
- Chronic rhinosinusitis with nasal polyps
- Allergic rhinitis
- Asthma
what are 6 common pathophysiological features of Type 2 inflammatory diseases?
- tissue remodeling
- epithelial barrier dysfunction
- sensitivity to environmental/microbial allergens
- reduced diversity of skin microbiota
- infiltration of immune cells (granulocytes) and IgE
- vascular permeability
describe the production of antibodies in the type 2 immune response
- allergen breaches barrier
- DC activates T cell to become TH2 (via IL-4)
- IL-4 and IL-13 stimulate proliferation and B cell activation
- B cell makes antibodies that respond to the allergen upon next exposure
describe the receptors of IL-4 and IL-13
Type I receptor –> for IL-4
Type II receptor –> for IL-4 and IL-13
what does the location of IL-4/IL-13 receptor determine?
determines the role of the cytokine
describe the roles of IL-4 and IL-13?
have overlapping and distinct roles for inflammation and skin barrier dysfunction
describe the itch-scratch cycle and its evolution
cytokines lower threshold of sensitization of skin –> gets itchy –> further damage barrier
evolved for physical removal of parasite
what are 3 targets that can be used for monoclonal antibodies against type 2 inflammation?
- IgE
- cytokines
- cytokine receptors
what is the function of DUPILUMAB?
monoclonal ab that binds IL-4Ralpha
- directly inhibits IL-4 in Type I receptor
- inhibits IL-13 via steric hindrance in Type II receptor
what are 4 results of dupilumab?
- reduced IgE-mediated response
- reduced decline of lung function
- reduced lung inflammation
- reduced lung infiltration
what are the 3 stages of Atopic Dermatitis and what happens at each stage?
- NON-LESIONAL STAGE
- allergens breach bc of poor barrier
- Th2 differentiates and proliferates
- IL-4 and IL-13 released - ACUTE STATE
- IL-4 and IL-13 stimulate barrier disruption by suppressing differentiation and lipid metabolism
- IL-4 and IL-13 induce itch via sensitization, leads to scratch and further disrupts barrier - CHRONIC STATE
- IL-4 and IL-13 causes barrier inhibition and epidermal hyperplasia
how are the stages of atopic dermatitis affected by dupilumab?
since IL-4 and IL-13 are blocked, there is no barrier disruption, no itch/scratch, no barrier inhibition, no epidermal hyperplasia, etc.
what are the approved and failed monoclonal targets for asthma?
approved: target IL-5, IL-4/IL-13, IgE
failed: target IL-13 alone
what are the approved and failed monoclonal targets for atopic dermatitis?
approved: target IL-4/IL-13, IL-13 alone
failed: target IL-5, IgE
how are human mouse antibodies produced in genetically engineered mice?
mouse antibody gene silenced, human antibody gene added
then injected with antigen and will produce fully human antibodies
what is the upscaling process for producing monoclonal antibodies?
make cell lines from mice that produce the monoclonal antibodies and upscale the culture to industrial scale
what is the downscaling process for monoclonal antibodies?
collect antibodies by centrifuge, filtration, etc. until therapeutic is packaged and can be injected into person
