Innate Immunopathologies of Skin Flashcards
Innate immune system components of the skin
- The physical barrier itself (keratin, keratinocytes, tight junctions)
- Antimicrobial peptides
- PRRs
- Sentinel cells (Tissue-resident macrophages, mast cells, NK cells, ILCs)
- Innate immune responder cells (neutrophils, monocytes, monocyte-derived macrophages)
- Complement
Antimicrobial peptides in the skin
Released from the skin in response to damage or infection. Strongly positively charged and form salts with acidic phospholipids in bacterial membranes, but not the zweiterionic phospholipids of mammalian membranes.
“Microbicidal”
Pokes holes in the bacterial cell membrane
In addition to providing immune defense against bacteria, antimicrobial peptides govern ___.
In addition to providing immune defense against bacteria, antimicrobial peptides govern which commensal bacteria are capable of colonizing our epithelial surfaces.
This is because skin is full of antimicrobial peptides! These kill non-commensal bacteria and prevent buildup or transmission.
Cathelicidin
Antimicrobial peptide precursor stored in epithelial cell, macrophage, and PMN lysosomes. Cleaved to its active form, LL-37, by Kallikerin 5.
Also promotes acute inflammation.
Autoimmune diseases which result from antimicrobial peptide dysregulation
- Atopic dermatitis
- Psoriasis
- Rosacea
Complement in Lupus
Rosacea epidemiology
- More prevalent in women
- Most patients between 30 and 50
- More commonly seen in Northern Europeans
Rosacea characteristics
- Chronic inflammatory disease of skin
- Central facial redness or prolonged flushing
- Facial papules or pustules (often confused for acne)
- Persistent or intermittent, depending on patient
- Sometimes associated with burning or stinging pain at papules/pustules
Rhinophyma
Manifestation of Rosacea in the nose tissue. More common in male patients.
Diagnosing Rosacea
- Clinical diagnosis made by observation and history taking
- No defacto clinical tests for rosacea
- Biopsy non-specific as well. Usually displays dilated blood vessels and inflammation consisting of neutrophils, lymphocytes, and plasma cells.
Triggers of rosacea
- Stress
- Spicy food
- Caffeine
- Alcohol (especially red wine)
- Hot beverages
- Hot or cold exposure
- UV light exposure (potent trigger)
- Certain skin microbes (Demodex folliculorum, Staphylococcus epidermidis)
Rosacea is associated with a higher level of ___ in the skin.
Rosacea is associated with a higher level of cathelicidin, TLR2, kallikrein 5, and LL-37 in the skin.
LL-37 may be converted to ____, especially in Rosacea.
LL-37 may be converted to smaller active fragments which trigger acute inflammation, especially in Rosacea.
Regulation of cathelicidin in Rosacea vs in patients without Rosacea
___ may induce Kallkrein 5.
TLR2 may induce Kallkrein 5.
Antimicrobial peptides may be induced by ____ within the skin.
Antimicrobial peptides may be induced by Vitamin D synthesis within the skin.
In this way, vitamin D serves as a sort of ultraviolet light sensor, bringing immune cells to the epithelial surface when potentially barrier-damaging UV light is present to preempt infection.
Treatment of Rosacea
- Counsel patient on avoiding potential triggers
- Counsel patients on sun protection, specifically
- Perscribe topical and oral anti-inflammatories and anti-biotics
- Topical
- Metronidazole (nitroimidazole)
- Azelaic acid
- Benzoyl peroxide
- Tretinoin
- Sodium sulfacetamide
- Oral
- Tetracycline antibiotics
- Metronidazole
- Ciprofloxacin
- Trimethoprim/sulfamethoxazole (antifolate)
- isotretinoin
- Topical
“Neutrophilic Dermatosis”
- Umbrella term used to describe an array of heterogeneous, non-infectious inflammatory skin diseases
- Histopathology characterized by acute neutrophilic infiltrate
- Similar pathogenesis, respond to similar treatments
Manifestations of Neutrophilic Dermatosis
- Variable cutaneous lesions: Pustules, plaques, bullae, nodules, sometimes ulcerations
- Localized or widespread lesion distribution
- Extra-cutaneous involvement may occur (most commonly lungs)
Diseases or medications associated with Neutrophilic Dermatosis
Note that ND may occur alone, but the following are also commonly seen:
- Blood disorders (leukemia, monoclonal gammopathy, myelodysplastic syndrome)
- IBD (UC, Crohn’s)
- Systemic autoimmune disease (Lupus, Grave’s, Rheumatoid arthritis)
- Infections (HIV, Hep B, many more)
Neutrophilic dermatosis is associated with higher levels of ___ in the skin and blood.
Neutrophilic dermatosis is associated with higher levels of IL-1 in the skin and blood.
Sweet’s syndrome
Prototypic neutrophilic dermatosis. Characterized by acute onset fever, malaise, arthralgia, and painful, erythematous, fluid-filled papules and plaques. May develop bullae or ulcerations. Elevated PMN count.
Often occurs in association with underlying condition, particularly acute myelogenous leukemia.
Bullae (particularly severe, they may be much smaller)
Pyoderma Gangrenosum
Multiple forms. Often begins as papules or plaques, may develop to wide and deep ulcers. Mimicks some infections, but has the unique feature of a rolled, purple-black, metallic looking border aorund the ulcer.
May occur anywhere, but often appears on legs. 50% appear in connection with systemic disease, most commonly IBD.
Behcet’s Disease
Has visceral manifestations as well, but the cutaneous manifestations include buccal, gingival, and genital mocusal plaques and ulcerations.
Subcorneal pustular dermatosis
Numerous soft or flacid pustules found on skin, especially trunk. Often present in skin folds of underarm and groin as well. May appear in circular pattern.
Neutrophilic eccrine hidradenitis
Erythematous or edematous, painful papules and plaques
Associated with malignancy and infection.
Treatment of Neutrophilic Dermatosis
- Systemic anti-inflammatory usually required.
- Oral, topical, or intralesional corticosteroids common
- Dapsone: topical or oral medication with specifically anti-neutrophilic properties
- As many ND are associated with underlying systemic condition, look for and treat this condition. This will help resolve the ND as well.
H and E of a prototypical neutrophilic dermatosis lesion
Note:
- The spongiosus of the epithelium
- The papillary dermal edema
- The diffuse neutrophilic infiltrate under the basement membrane
Spongiosus
Intercellular edema
Papillary edema
Frustrated phagocytosis
When a MΦ cannot fully phagocytose a target, it merges its lysosomes with the “phagosome” anyway, resulting in release of damaging mediators into the extracellular space.
Dry and itchy skin? ____.
Just dry skin? ____.
Dry and itchy skin? The result of an immune reaction involving eosinophils. Perscribe anti-inflammatories.
Just dry skin? Probably not inflammtory. Perscribe moisturizer to hold in water and prevent further damage.
Retinoic acid as addressin
Targets adaptive immune cells to the gut (α4β7)
Macule
small (<1 cm) non-raised discoloration of skin
Patch
Large (>1 cm) non-raised discoloration of skin
Pedunculated
Skin tag
Raised lesion with a stalk
Micaceous
Small, silvery reflective scaling
Like mica
Weeping
Exuding fluid (coming from serum/interstitial fluid)
Eczematous
Weeping and erythematous
Reticulated
Not a solid color, mottled
Circinate
ring-like
Ichthyosis
Plate-like, keratotic plaques
Nodule
Deep, knot-like. You can tell that most of the mass is beneath the surface.
Vesicle
Small (1 cm) fluid filled papule
Pustule
Vesicle filled with pus/dead neutrophils
Blanching
Redness goes away with pressure
This indicates that blood is still within blood vessels, not leaking into tissues
Non-blanching
Redness does not go away with pressure
Means that blood has leaked out of blood vessels
Purpura
Synonymous with non-blanching lesion
Major microbes associated with Rosacea
Staphylococcus aureus and the pneumodex mite
Classical description of pyoderma gangrenosum
Gunmetal gray ulcer with rolled borders
When analyzing a neutrophilic lesion on H and E, beware. . .
. . . degradation. Neutrophilic lesions are basically liquefactive necrosis and so they fall apart really easily and may leave behind large white spaces that look like ulcers, but are really where pus should be.
Autoimmune vs autoinflammatory
Autoimmune = adaptive response
Autoinflammatory = innate response
IL-17 is produced. . .
. . . by more than just Th17! Just because you see a lot of IL-17 doesn’t mean Th17s are involved or the culprit.
Scabbing
Hemorrhagic crust
