Skin immunology (psoriasis) Flashcards
(31 cards)
Describe the epidermal barrier of the innate immune system
- The skin forms a barrier to invasion through production of many proteins including FILAGRIN
- Constitutively expressed ANTI-MICROBIAL PEPTIDES (AMPs) like DEFENSINS are also present in the barrier
- normal skin flora are competitive for binding spots on skin (prevent invasive microbes from latching on)
Describe the epidermal induction of local, non-specific immune responses
- The epidermis responds to activation of PROTEASE RECEPTORS and TOLL-LIKE RECEPTORS by producing cytokines that can activate the immune process;
- TUMOR NECROSIS FACTOR alpha
- INTERLEUKIN-1 (IL-1)
- CHEMOKINES (attract increased blood derived cells)
**results in new AMP production and blood borne immune cell activation
What blood derived cells play a major immunological role in skin?
- Blood derived cells are resident in the skin but can also increase in number with chemokine attraction
- __DENDRITIC CELLS
- MACROPHAGES
- MAST CELLS
- NEUTOPHILS
- (also T cells)
What major cytokines interact to promote specific reactions in the skin?
- Dendritic cells produce
- INTERLEUKIN-23 (impacts other blood borne cells such as T cells, neutrophils, and basophils)
- TNF
- IL23 and TNF from DCs induce the production of
- INTERLEUKIN 17 A and F by T cells, mast cells, and neutrophils
- IL-20 and 22 by T cells and macrophages
- These are all increased by the presence of INTERFERON GAMMA produced by T helper cells
What is the epidermal reaction to activation of the innate immune system?
The epidermis thickens, increases barrier proteins, and markedly _increases the number of AMP_s/recruitment of new cells to fight off infection
Describe the role of adaptive immunity in the skin immune response
- T cell activation and B cell production of antibody with specificity
- Much less significant in bacterial infections of the skin than innate immunity
Describe psoriasis (prevalence, comorbidities)
- most common inflammatory disease in adults with approximately 3% of the US population with the condition.
- Can happen at any age, involves men and women equally
- Genetic predisposition. However, about 50% of patients do not have a first degree relative with the condition.
- Increases risk of inflammatory arthritis, diabetes, coronary artery disease (increased risk of MI), and lymphoma.
- Has been found in Egyptian mummies and was likely described in Leviticus with the first report of phototherapy.
Describe the Clinical and Histological presentation of psoriasis
- All related to the epidermal abnormalities
- Skin is thickened (keratinocytes are reproducing too rapidly… Migration to the stratum corneum is 3-7 days as opposed to the normal 28 days)
- Scale (keratinocytes do not mature normally and do not shed properly… Abnormal proteins are produced like keratin 16)
- _Redness (_Blood vessels are nearer to the surface, proliferate, and dilate)
Describe the developing understanding the pathophysiology of psoriasis
- **bedside to bench
- For years thought to be a disease exclusively of the skin.
- With the use of cyclosporine for organ transplants, psoriasis would improve -> T cell model of psoriasis.
- Use of anti-TNF therapy (infliximab and etanercept) were of benefit but there was no good explanation of how the immunological activity changed the skin.
- STAT-3 mouse models caused a murine type of psoriasis.
- The IL-23/IL-17 system put it all together.
Describe the current basic model for psoriasis
**the normal response to infection in overdrive
(Some internal or external stimulus initiates an immune response locally in the skin.)
What do keratinocytes and DCs produce in psoriasis?
- Keratinocytes produce TNFalpha and IL-1.
- Dermal dendritic cells produce IL-23 (activates T cells, mast cells, and neutrophils to produce IL-17 and IL-22)
** Genes associated with psoriasis include those that code for TNF and IL-23 responses.
How do keratinocytes change in psoriasis?
Keratinocytes respond by expressing STAT-3 and changing into psoriatic cells.
What are targeted treatments aimed at in the psoriasis MOA?
- Targeted treatments are being developed to block IL-17, IL-23, along with TNF.
- Different targets give different response characteristics
- IL-23 agents have longer term responses
- IL-17 agents give the fastest responses
What is contraindicated in psoriasis patients?
Oral corticosteroids (prednisone); although the patient will initially get better, stopping treatment will make the patient very sick
What are some possible treatments for psoriasis?
- topical therapies (corticosteroids, vitamin A/D)
- phototherapies (UVB lasers, psoralen + UVA)
- systemic therapies
- methotrexate
- cyclosporine
- retinoids
Contrast the histology of psoriatic and normal skin
Psoriasis on the right;
- perikarytosis (retention of nuclei in the stratum corneum)
- very thick skin
- dilation of blood vessels
- immune cells present
What is PASI?
- Psoriasis Area and Severity Index (PASI)
- the most widely used tool for the measurement of severity of psoriasis
- assessment of the severity of lesions and the area affected into a single score
- ranges 0 (no disease) to 72 (maximal disease).
Describe the initial confusion over whether IL23 or IL12 is upregulated in psoriatic plaques
- p40 subunit shared by IL23 and IL12
- IL12 contains p40 and p35 subunits
- produced by activated DCs and macrophages
- promotes growth/differentiation of naive T cells into Th1 and cytotoxic T cells
- down regulates Th2 cytokines (e.g. IL10)
- observed increase in p40 in psoriasis initially thought to be from IL12
- however, found increased p19 also (the other subunit of IL23) and NO increase in p35
_**IL23 (NOT IL12) mediates psoriasis_
What is the main function of IL23?
Activates local inflammatory cells to produce;
- IL17 family cytokines
- IL20 family cytokines
**epidermal proliferation is dependent on both IL22 and IL17A
Topical corticosteroids are in what family of steroids?
Glucocorticoids
**overall anti-inflammatory effect
What are some side effects of topical corticosteroids?
- Reversible: hypopigmentation, hypertrichosis, skin atrophy, telangiectasia
- Irreversible striae
- On face; acne or perioral dermatitis (a form of rosacea)
- Around the eyes; increased risk of glaucoma and cataracts
- May absorb and increase systemic cortisol levels (when applying potent topical corticosteroids to large body surface areas (especially in infants and young children) or to occluded areas (e.g. diaper region))
Describe the classes of topical corticosteroids
Class I-VII, with class I being the most potent
Describe the vehicles used for topical corticosteroids
**Dermatologists mostly prefer ointment formulation (allows for better penetration of the active ingredient through the stratum corneum, effectively increasing the efficacy)
Describe atopic dermatitis
- the most common chronic inflammatory skin disease
- Onset in infancy is typical, but delayed onset in adulthood may be seen
- TRIAD with allergic rhinoconjunctivitis and asthma
- Mutations in the profilaggrin gene (also responsible for ichthyosis vulgaris!)
- infection with S. aureus is common and can aggravate AD by stimulating the inflammatory cascade
