Immunology (Fadock NAVDF notes) Flashcards
Phenotype vs endotype
Endotypes are disease subtypes that are defined by a specific pathophysiological mechanism and biomarkers.
Phenotypes are clinical descriptions of a disease or patient.
Endotypes are important for precision medicine, to prescribe targeted therapies.
Various amounts of Type 2, Type 1, Type 17, and
Type 22 cells and cytokines in atopic dermatitis depending on endotype.
Epigenetic definition
How the environmental (pollutants, chemicals, drugs, diet) and behaviorial factors (e.g. stress, anxiety) affect gene expression without changing the sequence of the DNA. These changes are known to be passed from pregnant women to their offspring, affecting prevalence of atopic diseases in the children
How does a damaged barrier promote inflammation?
Alarmins from damaged keratinocyte
IL-33, IL-25, TSLP
More allergen penetration to langerhans cells
What are epidermal alarmins?
IL-25, IL-33, TSLP
Endogenous molecules that are released by the epidermis in response to tissue damage
How do epidermal alarmins promote the Type 2 immune response?
Act on ILC2 cells, which release IL-5 (eosinophils) and IL-13 (Th2 inflammation)
Act on Th2 cells to release IL-4 and IL-13 (Th2 molecules)
Act on Langerhan and dermal dendritic cells
What cells are involved in a Type 2 response
*Keratinocytes (alarmins, chemokines, IL-1)
*ILC2 (IL-5, IL-13)
*Th2 (IL-4, IL-13; express CTLA, CCR4, CRTH2)
*DC2 (OX40L)
*B cells (respond to IL-4 to make IgE)
*Eosinophils (express H4R, CRTH2 for prostaglandin binding)
What cytokines are involved in a Type 2 response
IL-4
IL-6
IL-13
IL-31
Path of an allergen from the skin to the lymph node
Allergen → through keratinocyte layers → Langerhan cell or DC2 processed, presented → Th2 stimulated → DC2 migrates to the LN →trains naive T cells to be Th2 → Th2 stimulates B cells to make IgE → Th2 and B cell go back to skin to release Type 2 cytokines
How does the Type 2 response affect the skin barrier?
1) Downregulates ceramide synthesis
2) Downregulates Filaggrin expression
3) Downregulates antimicrobial peptide expression
4) Alters skin protein and lipid content
Define the hygiene hypothesis
Lack of microbial exposure in early life may increase the risk of developing allergies
How does skin dysbiosis contribute to
allergy?
If more pathogenic Staphylococcus, more superantigen release –> abundant nonspecific T cell signaling (IL-4 production!). Also Basophil activation. Can lead to increased Fas expression and keratinocyte apoptosis –> damage to skin barrier
Superantigens promote Type 2 polarization
How does gut dysbiosis contribute to allergy? Is there anything we can do about it?
Western diet
Glycosylation of proteins = more allergenic (from high T cooking!!
The resident microbiota is important in maintaining structural and functional integrity of the gut and in immune system regulation. It is an important driver of host immunity, helps protect against invading enteropathogens, and provides nutritional benefits to the host. Disruption of the microbiota (dysbiosis) may lead to severe health problems.
Yes! Feeding skin barrier fortified diets can improved cAD symptoms
How does the environment contribute to atopic dermatitis?
Several environmental inputs: not only allergens, but pollutants,
temperature, changes in humidity, psychosocial factors
Risk factors:
*Pollutants –> ROS via skin, hair follicles, glands.
*Tobacco smoke associated with cAD
*Urban environment = risk factor for cAD
*Climate change? Changes in duration and severity of pollination; temperature and humidity; UV light
*Western, processed diet
Role of Aryl hydrocarbon receptor (AHR) in cutaneous hypersensitization
*Transcription factor, activated by pollutants
*KC release artemin when AhR is bound
*Artemin induces hyperinnervation of the epidermis –> dog scratches –> skin barrier damage –> cutaneous hypersensitization
How does allergen immunotherapy work? 4 major mechanisms
1) Desensitization of mast cells, basophils, eosinophils (QUICK): increase inhibitory Fc receptors, increase H2 receptors (block action of histamine)
2) Tolerance: generation of Treg, DCreg, IL10+ ILC (ILCreg), Breg, Tfreg; Reduction of Th2 to Th1 ratio
3) Decrease IgE, increase IgG1, IgG2, IgG4, IgA
4) Decreased # mast cells, basophils, eosinophils in tissue
Inhibitory cytokines from Tregs
IL-10, TGFb, IL-35
What is FoxP3
Transcription factor
Binds DNA to induce expression of Treg development and functional proteins
What is atopic-like dermatitis
Failure to identify allergen-specific IgE by intradermal or serum testing
Like “intrinsic” atopic dermatitis in humans
Mechanisms of epigenetics
- DNA methylation
- Histone acetylation and methylation
- miRNAs (repress translation)
How do ROS affect the skin
- Oxidize lipids in cell membranes
- Activate proteases –> damage skin barrier
- Release proinflammatory mediators from WBC
Which topical product binds aryl hydrocarbon receptor?
Tar
Which neurotrophic factor does aryl hydrocarbon receptor induce?
Artemin
What do Staphylococcus have to promote Type 2 inflammation?
Superantigens (endotoxin)
(Forces MHC cl II on APC and TCR on T cells to bind –> activate nonspecific, robust T cell response!)
Cytokines and chemokines released by keratinocytes
IL-1
Alarmins (IL-25, IL-33, TSLP)
Chemokines (TARC/CCL17, MDC/CCL22)
TARC/CCL17: Cell that produces it
Keratinocyte
TARC/CCL17: cell that responds to it
T cells (Th2, Treg)
TARC/CCL17: receptor that binds it
CCR4
MDC/CCL22: cell that produces it
Keratinocyte
MDC/CCL22: cell that responds to it
Macrophages, DC2
MDC/CCL22: receptor that binds it
CCR4
Cytokine made by activated B cells
IL-4
Cytokines made by activated ILC2
IL-5, IL-13
Costimulatory molecule expressed by DC2
OX40L
Role of OX40L on DC2
Induce T cells to make IL-4, IL-5, IL-13