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
Which receptor is upregulated by DC2 as they mature, which guides them to the lymph node
CCR7
Which cells express CCR7
DC2, T cells, B cells, Treg,
CCR7 function
Receptor that binds CCL19, CCL22
Brings lymphocytes, DCs to lymph node
Ligands for CCR7
CCL19, CCL22
Which receptor on lymphocytes & DCs hones them to the lymph node
CCR7
Which cell helps B cells produce IgE
Tfh2 cells via IL-4
Th2 also help
Which cytokine helps B cells produce IgE
IL-4
Which cytokines are produced by Type 2 CD8+ cells
IFNgamma
IL-4
IL-6
IL-13
IL-31
Which cytokines are produced by cutaneous Type 2 T cells and B cells
IL-4
IL-6
IL-13
IL-31
Which receptors do T cells have to hone them to the skin
1) CLA (cutaneous lymphocyte antigen)
2) CCR4 (binds TARC/MDC)
3) PgD2R2/CRTH2 (binds prostaglandin D2 for chemotaxis)
Which receptors do eosinophils express?
1) PgD2R2/CRTH2 (binds prostaglandin D2 for chemotaxis)
2) H4R
Which cytokine is implicated in inducing epidermal hyperplasia in more chronic disease
IL-22
Which cell is implicated in inducing epidermal hyperplasia in more chronic disease
Th22
May be protective against Staphylococcus overgrowth
Blocking _____ and _____ cytokines has the biggest impact on skin INFLAMMATION
IL-4
IL-13
Blocking _____ cytokine has the best control for ITCH
IL-31
In addition to keratinocyte, epidermal lipid, and inflammatory cells changes, which other cell is affected by atopic dermatitis
Nerves! Hyperinnervation
Which 3 cell signals are implicated in hyperinnervation in cAD?
1) IL-31
2) NGF
3) Artemin (made when AHR is bound to pollutants)
Other than itch, what other sensation is experienced with severe cAD?
Pain
Receptors for which cytokines are present on neurons (5)
1) IL-31
2) IL-4
3) IL-13
4) TSLP
5) IL-33
How do TRegs work? (5)
1) Produce inhibitory cytokines (IL-10, TGFbeta)
2) Suppress antigen presentation and ILCs via CTLA-4, ICOSL (inhibitory surface molecules)
3) Inhibit target cell metabolism
4) Induce cytolysis with Granzyme A and B
5) Impair B cell production of IgE
What does IgE bind to?
IgE has two types of receptors: FcεRI, which is high-affinity, and FcεRII, which is low-affinity.
T or F: IgE can be heat inactivated
True at 56C
Which cell is increased in dogs with cAD that may produce IL-22 (epidermal hyperplasia) and IL-17A (attract neutrophils); help control dysbiosis
γδ T cells
Which 2 cytokines do γδ T cells produce that may increase epidermal hyperplasia and neutrophil attraction in dogs?
IL-22 (epidermal hyperplasia)
IL-17 (neuts)
Name the Staphylococcus virulence factors (7)
1) Delta toxin: mast. cell degranulation
2) Protein A: (Protein A binds to the Fc region of Igs)
3) Toxins: SEA-U enterotoxin, TTST-1 exotoxin
4) Adhesins
5) Invasins: hyaluronidase, coagulase, staphylokinase
6) Microcapsule
7) Cell wall
Which cytokines does Th1 make? (viral, intracellular pathogens)
TNF alpha
IFN gamma
LT
Which cytokines does Th2 make? (allergy, parasites)
IL-4
IL-6
IL-13
IL-31
Which cytokines does Th17 make (extracellular pathogens; NEUTROPHILS, autoimmunity)
IL-17
IL-22
TNF alpha
Which cytokines does Th22 make? (Epidermal hyperplasia, resistance to staphylococcus overgrowth)
IL-22
TNF alpha
Which cytokines does Th9 make? (Chronic inflammation, potential role in food allergy)
IL-9 = mast cell growth factor
IL-10
Which cytokines does Tfh2 make? (induce IgE, B cell function in LN)
IL-4
IL-6
IL-21
Which cytokines does ILC2 make?
IL-4
IL-5 (eos)
IL-13
IL-9 (chronic inflam, food allergy?)
Enhance Type 2 immune response in cAD
What stimulates ILC2 cells?
Epidermal alarmins (IL-25, IL-33, TSLP)
T or F: Filaggrin mutations are necessary and sufficient to induce cAD
False.
Filaggrin is neither necessary nor sufficient to induce cAD
How does Staphylococcus affect basophils?
Enterotoxin can stimulate basophils to make IL-4
T or F: histamine is the most important molecule for induction of itch in atopic dermatitis
FALSE
NONhistaminergic pathway is more important (TSLP, IL4, IL13, IL31, IL33)
Which cytokine has a vaccine against it, which shows some efficacy against IBH in horses
IL-5
IL-31 (itch not assessed, but decreased lesional scores)
Does medication during ASIT affect its efficacy?
We don’t know.
In human medicine, it seems like it may help with efficacy of ASIT
How does SLIT work to induce tolerance?
Antigen bound by sublingual oral DC –> presented to naive CD4+ T cell in LN –> naive T cell converted to FoxP3 Treg cell –> goes to tissue to induce tolerance
What blocking antibodies are induced by ASIT, which limit IgE binding to Fc on MC, baso
IgG4, IgG1
What makes IgE different than IgG
IgE has an extra portion on Fc region (3)
Heat inactivated
What is IgD
BCR
Neurogenic cytokines
TSLP, IL-4, IL-13, IL-31, IL-33
Adhesion molecule downregulated in cAD skin
Claudin –> skin barrier damage
Tight junction
What are the 2 signals helper T cells need to be activated
1) MHC cl 2 to TCR
2) CD28 to CD80/CD86
How do superantigens contribute to Staphylococcal hypersensitivity
Dogs develop IgE AGAINST SUPERANTIGENS
Superantigen presented to CD4+ by LC –> develop IgE against Staph superantigen –> Staph hypersensitivity
What category of virulence factor are Staphylococcal superantigens
Enterotoxins
Itch ion channels (2)
- TRPV1
- TRPA1
What are the SEA-U and TSST1 impacts as superantigens
*Basophil activation –> release IL-4 –> more Th2 response
*Activate T cell mediated inflammation (Th2)
What do superantigens bind
Beta subunit of TCR
Activate up to 20% of T cells
May be involved in CAFR
Main transcription factor for Th2 cells
GATA3
Main transcription factor for Th1 cells
TBet
