Learning about tubercle bacilli is quick and easy

- neither gram negative nor gram positive
- acid fast. resembles gram negative

• very thick
• has mycolic acid

- membrane is even less fluid than some of the other membranes
- infection by inhalation or ingestion
- invades macrophages
- tubercle (nodule) is primary lesion. Forms at initial site of infection
- eventually, more macrophages attracted by cytokines will be able to fight the pathogen

• will destroy (or at least arrest) the bacilli
• will also destroy tissue and exacerbate disease

- diagnosis: lesions are characteristic. However, must culture M. bovis to confirm
- positive test doesn't necessarily indicate dz; probably indicates persistence of bacilli
- vaccines: killed vaccines not effective. BCG most dominent TB vaccine in the world. Animals not vaccinated b/c then would always test positive.
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Bordetella bronchiseptica

- can affect pigs, rabbits, guinea pigs, other rodents

- many afflictions (see notes) but notably rhinitis atrophicans: acute rhinitis progressing to deformations of the turbinate bones, nasal septum and upper jaw

VIRULENCE FACTORS OTHER THAN LPS (toxin), FIMBRIAE (colonizing factor)

- other colonizing factors: filamentous hemagglutinin, pertactin

- other toxins: adenylate cyclase (hemolysin), type 3 secretion system, dermonecrotic (heat-labile) toxin, tracheal cytotoxin, transferrin/lactoferrin binding proteins, siderophore

therapy: susceptibility testing

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Bordetella

- respiratory tract

- strict aerobes

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Actinobacillus lignieresii

- causes "Wooden tongue"

VIRULENCE FACTORS

- proteases

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Actinobacillus (Haemophilus) pleuropneumoniae

- morphology resembles Pasteurella

- hemorrhagic necrotizing pneumonia, fibrinous pleuritis in pigs

- high morbidity; lethality depends on environmental factors

- no healthy carriers

- survivors end up with chronic pneumonia

- transmission: aerosol

VIRULENCE FACTORS OTHER THAN LPS AND CAPSULE

- cytotoxins

- porcine transferin binding protein (lends host specificity)

therapy: penicillin

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Taylorella (Haemophilus) equigenitalis

- stallion = asymptomatic reservoir

- transmission is venereal

- sensitive to desiccation

- therapy: penicillin

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Histophilus somni

- cattle = asymptomatic reservoir

DISEASES

- infections of the respiratory tract (thromboembolic meningoencephalitis)

- endometritis and abortion in cows

VIRULENCE FACTORS IN ADDITION TO LOS

- surface protein that binds bovine transferrin/iron

- Fc receptors have antiphagocytic effect

- resist neutrophils

- can survive w/in macrophages

REQUIRES

- thiamin (vitamin D1) pyrophosphate

- also likes CO2 (capnophilic)

therapy: penicillin

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Haemophilus parasuis

- causes Glasser's dz in 2w.-3mo. old stressed pigs

- therapy: penicillin

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Haemophilus

- facultative anaerobe

- LOS is not LPS, but it has the same function and it's similar

- special requirements: 

• hemin
• NAD (depends on NAD produced by other bacteria)

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Mannheimia (Pasteurella) haemolytica

- respiratory tract infections

• Shipping fever in cattle
• pneumonia, sepsis in lambs
• pneumonia, salpingitis, sepsis in fowl

- mastitis in ewes

- in addition to LPS, capsule, fimbriae, has:

• leukotoxin specific for ruminant leukocytes and platelets
  
• membrane protein that binds ruminant transferrin/ iron

- therapy: susceptibility testing to choose appropriate antibiotics

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Pasteurella

- facultative anerobe
- commensal on mucosa
- opportunist
- hemorrhagic sepsis in cattle
- fowl cholera
- respiratory tract infections (rabbits, cats, calves, pigs)

• rhinitis
• conjunctivitis
• otitis
• bronchitis
• pneumonia

- abscesses in humans, dogs and cats by bites and scratches

• associated with lymphadenitis, sepsis

- therapy: most antimicrobial agents

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Broad overview of this huge packet!

- Pasteurella
- Haemophilus
- Actinobacillus
- Bordetella
- Moraxella bovis
- Pseudomonas
- Brucella
- Francisella tularensis
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Pathogenesis of neurologic disease associated with lysosomal storage diseases

(A) Single gene is mutated
(B) Insufficient enzyme activity
(C) Storage of primary substrate

1. neuronal swelling
2. secondary or primary glycolipid substrate accumulation
   --> GM2 ganglioside storage in neurons -->

• neurite sprouting --> abnormal synapses
• meganeurites

(D) both 1 & 2 above lead to neural dysfunction

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Liver: possible causes of fatty change

- toxins (hepatocyte dysfunction causes impaired lipoprotein secretion)
- diabetes mellitus (excessive fat mobilization)
- protein insufficiency (decreased synthesis of apoproteins, leading to lipoprotein insufficiency)
- excessive fat intake/ caloric intake (normal amounts of lipoprotein aren't sufficient to deal with excess fat)
- starvation (excessive fat mobilization + protein insufficiency)

All of the above eventually lead to accumulation of clear cytoplasmic vacuoles in hepatocytes.
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How a normal liver becomes cirrhotic: 3 major components

1. SEVERE, DIFFUSE, HEPATIC FIBROSIS

• a post-necrotic and post-inflammatory response.
• hepatocyte injury causes release of IGF-1, which acts as a mitogen for stellate cells.
• Kupffer (and other) cells make TGF-beta, prompting stellate cells to turn into myofibroblasts
• fibroblasts and myofibroblasts proliferate. Collagen (types I, III, XVIII) and fibronectin are produced.
• because the myofibroblasts produce collagen and ECM in the space of Disse, the normal fenestrations in hepatic endothelium become closed.
• closure of fenestrations causes blood to be shunted through the liver and into the hepatic vein, functionally bypassing hepatocytes.
• eventually fibrosis will connect portal and central areas.

2. NODULAR REGENERATION

• a post-necrotic response.
• 75% of liver can be removed before liver dysfunction occurs
• liver can regenerate up to 80% of its mass and will function if the connective tissue framework remains intact

3. BILE DUCT HYPERPLASIA

• may be associated with necrosis, inflammation, toxins, blockage of bile ducts
• proliferation of bile duct epithelium is concentrated in portal areas.

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Liver: patterns of necrosis

- multifocal random pattern is caused by infectious agents (viruses, protozoa, bacteria)
- massive pattern indicates toxic or nutritional problems
- zonal patterns fall into 3 anatomical categories:

• centrilobular (hypoxia, toxins)
• midzonal (rare)
• periportal (toxins)

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Acute necrotizing pancreatitis: pathogenesis

1. initial insult may be dietary, toxic, hormonal
2. enzymes are stopped from being secreted!
3. "colocalization" of lysosomes and secretory zymogen granules
4. lysosomal hydrolases act on trypsinogen to form trypsin
5. once typsin is activated...
6. other zymogens are activated
7. leads to activation of lipase, amylase, elastase, protease, etc.
8. autodigestion (necrosis) of pancreas and surrounding tissues

• blood vessels --> thrombosis, hemorrhage, edema --> further necrosis b/c of ischemia
• fat necrosis + calcium --> fat saponification
• inflammation (secondary event) --> neutrophil enzymes can cause further necrosis --> fibrosis

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Canine prostate: non-neoplastic lesions

- benign prostatic hyperplasia: proliferation of prostatic epithelium associated with testosterone
- squamous metaplasia: associated with excess estrogen (e.g. Sertoli cell tumor)
- cystic hyperplasia

• usually secondary to benign prostatic hyperplasia or squamous metaplasia
• caused by obstruction of ducts that carry prostatic secretions to urethra
• results in multiple fluid-filled cavities

- paraprostatic cysts

• fluid-filled cysts adjacent to prostate
• develop from abnormal tissue that remains from embryonic development

- bacterial infection (bacterial prostatitis)

• may ascend or descend the urethra (if descending, comes from urinary bladder)
• usually associated with pre-existing prostatic abnormality

- prostatic abscess

• progression of bacterial prostatitis with accumulation of pus and abscess formation.

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Tell me about equine herpes virus 1

- an infectious agent that can induce abortion and stillbirth
- involves multifocal necrosis of lung, liver, lymphoid organs
- intranuclear viral inclusion bodies with chromatin margination are pathognomonic
- may also cause respiratory disease, fatal vasculitis, myelopathy secondary to vasculitis
- can also affect South American cammelids
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Female gonadal stromal tumors

GRANULOSA CELL TUMOR
- common in mares, but rarely malignant.
- may be solid or may involve one or more cysts.
- animal exhibits failure to cycle, visible as anestrus.
- contralateral ovary undergoes atrophy.
- 40-50% produce androgens, (result: male behavior)
- 90% produce inhibin, causing

• regression of the contralateral ovary
• lack of progesterone that results in nymphomania.

- may occur in pregnant mares.
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Abnormal gonads: hermaphrodites

- types: bilateral, unilateral, lateral.
- hypospadia: incomplete masculinization of the penis.
- confirm your diagnosis via karyotype, histopathology
- chimera: mosaic, XX (may have SRY), or unknown
- possible causes:

• congenital adrenal gland hyperplasia
• fetal exposure to sex hormones
• testicular feminization syndrome
• XY gonadal dysgenesis
• XY gonadal agenesis
• chromosomal abnormalities

- interruption of DAX-1 expression may lead to hypogonadotropic hypogonadism

- SOX 9 regulates SRY expression

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Abnormal phenotypic gender: pseudohermaphrodites

Pseudohermapthrodites may result from problems with receptors, hormones or enzymes:

• persistent paramesonepthric (Mullerian) duct syndrome involves a receptor abnormality (dogs have Mullerian Inhibiting Substance). Undescended testes are attached to uterine horns, vasa deferentia are located in uterine wall. Bilateral oviducts, complete uterus with cervix, and cranial vagina are present.

• androgen insensitivity (testicular feminization) involves deficiency or abnormality of cytosol receptors for androgen. Complete or partial failure of androgen-dependent masculinization. Wolffian system does not develop or does not develop fully. Uterus, cervix and anterior vagina regress as they do normally.

• steroid 5-alpha-reductase deficiency means that dihydrotestosterone cannot be produced; therefore closure of urethra and scrotum do not occur; also, prostate and penis fail to develop.

• adrenogenital syndrome means that a female can't make adrenal cortical steroids due to enzyme deficiencies. This results in overproduction of adrenal androgens. The female duct system is modified toward the male.

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Malformations in neonatal/ juvenile cats

Broad categories of causes:
- biological agents
- physical agents
- chemical agents
- genetic defects

Certain malformations may/ often result in death.
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Kittens: necropsy is different than adults

- color of skeletal muscle
- presence of thymus
- scant adipose tissue
- prominence of thyroid glands, adrenal glands, mesenteric LNs
- thinner kidney cortex
- softer brain (high water content)
- limited ossification
- histologically evident hematopoesis in liver and spleen (for several weeks after birth)
- (possibly) unseparated eyelids
- (possibly) closed aural canals
- (possibly) prominent urachus (between umbilicus and urinary bladder)
- males have descended testes that can move in/out of scrotum until 5-7 mos.

In addition:
- frequent use of heat lamps may accelerate autolysis
- empty stomach/jejunum may indicate

• mom can't make milk
• mom neglecting baby
• baby is diseased

- full stomach may indicate death due to

• rapidly progressive illness
• trauma

- gas-filled stomach may indicate

• hypothermia (decreased gut motility led to fermentation of ingesta)
• aerophagia (swallowing air) due to pulmonary disease or agonal death

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Toxic substance pneumonia revisited

What is atypical interstitial pneumonia of cattle?
- necrosis of type I pneumocytes
- edema, respiratory distress
- replacement of type I pneumocytes by type II pneumocytes
- septal fibrosis and eventually emphysema

How do cattle get atypical interstitial pneumonia?
- if they eat feed rich in L-tryptophan
- L-tryptophan is converted to 3-methyl indole in the rumen
- Clara cells convert 3-methyl indole to a cytotoxin, resulting in necrosis of type I pneumocytes

Certain plants can be pneumotoxic to cattle: for example, the sweet potato vine, which produces a mycotoxin called ipomeanol. Results are similar to atypical interstitial pneumonia.


There are toxic gases.
What type of toxic gases are we talking?

• nitrogen dioxide
• hydrogen sulfate (derived from bacterial growth on manure)
• ammonia (derived from bacterial growth on urine, manure; causes ciliostasis and loss of cilia, a.k.a. ciliocyophthoria)
• ozone (irritant)
• sulfur dioxide (irritant)
• carbon monoxide (not a pneumotoxin, but causes formation of carboxyhemoglobin, which results in hypoxia)
• volatile fluoropolymers (e.g. overheated Teflon; cause death by peracute pulmonary hemorrhage)

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2 types of emphysema

- emphysema involves trapped air (either in alveoli or lymphatic vessels)
- alveolar emphysema has a bubble wrap appearance (bullae). It involves destruction of alveolar septa. It is uncommon in animals, but is common in humans due to chronic smoking or elastase induction.
- interstitial emphysema involves distended lymphatics between lobules. It is common in cattle with pneumonia; can occur due to gasping while dying. : (
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COPD: an allergic phenomenon

- chronic obstructive pulmonary disease is a chronic bronchiolitis that involves airway constriction and expiratory effort. It involves:

• hyperplasia and hypertrophy of bronchiolar epithelium
• goblet cell metaplasia and increased airway secretions
• excessive mucus retention in airways

- another allergic phenomenon is extrinsic allergic alveolitis; it is uncommon in animals.
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Pulmonary cytology

- tracheobronchial lavage, bronchoalveolar lavage can be used to recover mucus, cells and debris from the respiratory tract. Fluid is centrifuged, smeared onto a slide and examined. Components of normal washes:

• mucus. Inspissated mucus indicates poor ventilation of alveoli; granular mucus has been altered by neutrophil enzymes.
• epithelial cells. Some are present. Squamous epithelium coated with bacteria is from the oropharynx.
• leukocytes. Activated pulmonary alveolar macrophages are normal. More than 20% neutrophils is excessive. Eosinophils, lymphocytes and multinucleated giant cells indicate pathology.
• debris. Should be a small component. If excessive, may indicate aspiration pneumonia.

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Neoplasms of the respiratory tract

- primary pulmonary neoplasms:

• uncommon in animals
• examples: bronchiolar-alveolar adenoma, carcinoma, carcinoid, pulmonary adenomatosis of sheep

- remember that granulomatous pneumonias can look like pulmonary neoplasms
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Pneumonia, pneumonia and more pneumonia

- bronchopneumonia occurs when an animal inhales aerosols that then leave bacteria or particles in the airways.

• inflammatory exudates start in the airways and spill into the alveoli. Inflammation centers are on the bronchi and bronchioles.
• produces a cranioventral pattern of lung injury
• affected areas are consolidated, firm
• diagnosis made by gross exam

- interstitial pneumonia happens via hematogenous delivery of bacteria, viruses, allergens, toxins

• inflammation of insterstitium, alveolus
• type I cells are destroyed! type II cells proliferate
• alveolar septa become thickened
• diagnosis made by histological exam

- embolic pneumonia occurs when bacteria or septic emboli travel via the blood.

• can usually be diagnosed by gross exam

- granulomatous pneumonia can be due to varying agents, including fungi, mycobacteria, foreign body response, etc.

• nodular pattern
• chronic by definition
• grossly, similar to neoplasia

- bronchointerstitial pneumonia is caused by viruses; diagnosis must be confirmed by histological exam.

- aspiration (inhalation) pneumonia is a bronchopneumonia that can occur due to various reasons, including chemical or bacterial injury, sedation, anesthesia, gastric intubation, ingestion of petroleum products, or cleft palate.

• grossly, resembles bronchopneumonia
• histological proof: particles from diet in terminal airways (tertiary bronchi and bronchioles)

- toxic substance pneumonia can occur because type I pneumocytes have few defenses. Clara cells may produce toxic metabolites in certain circumstances.

- lipid "pneumonia" is probably caused by a mixture of surfactants and cell debris. Foamy macrophages and cholesterol crystals are visible in alveoli on histological exam. Grossly, white subpleural spots can be seen. Lipid pneumonia is an incidental finding.

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Let's break down respiratory to make it less scary

Broad overview of the respiratory tract:
- form and function
- special anatomic considerations
- diseases

PLAN:
- skim through first 2 sections without taking notes
- read through diseases, taking brief notes
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Openings

lesions characterized by parting or break in the skin without loss of epidermis.
examples: comedo, follicular cast, fissure, sinus

- comedo (blackhead) is keratin plug of infundibulum
- follicular cast is a superficial comedo that extends above the skin
- fissure is linear
- sinus is an inflammatory tract that exits externally
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Depressions

lesions below the level of the skin.
examples: erosion, ulcer
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Elevations

lesions above the level of the skin.
examples: papule, plaque, lichenification, wheal, nodule (tumor), cyst, vesicle, bulla, pustule, papilloma, scale, epidermal collarette, crust, vegetation, eschar

- papule is less than 1 cm in diameter; plaque is more
- lichenification is thickening of skin due to rubbing
- wheal is softer than papule or plaque due to edema
- nodule extends into deeper layers of dermis
- cyst contains fluid or semi-solid material
- vesicle is fluid-filled cavity beneath epidermis
- scale is composed of loose stratum corneum
- crust (scab) is a dried exudate; often preceded by pustules
- vegetation is multiple crusts layered on top of each other
- eschar is a type of crust associated with ulceration; adheres tightly to skin due to incorporation of dermal collagen
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Planes

lesions flush with the level of the skin.
examples: macule, patch

- atopic dermatitis is characterized by macules.
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Nodular and diffuse dermatitis: possible causes

- bacterial skin diseases

• Mycobacterial granulomas, Actinomycosis, Nocardiosis

- systemic fungal diseases with cutaneous forms

• Blastomycosis

- protozoal disease

• Leishmania spp.

- non-infectious skin disorder

eosinophilic granuloma

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Derm: concluding odds and ends

- perifolliculitis is inflammation around the hair follicle

- folliculitis is inflammation within the lumen

- furunculosis is follicle rupture

- ringworm is a type of fungus that uses keratin in hair and epidermis (decays it)

- demodex mites are part of normal canine facial flora. They proliferate when the immune system is suppressed.

- vasculitis must have 2 components

• inflammatory cell infiltrate (in or around vessel wall)


• vascular injury

- panniculitis results in damage to adiopocytes. Fatty acids are potent inflammatory mediators.

- hyperadrenocoricism occurs due to increased glucocorticoids, either endogenous or exogenous

• hallmark lesion is calcinosis cutis: mineralization of dermal collagen

dermal fibrosis: involves loss of all adnexal units

• fibroplasia is the proliferation of granulation tissue


• fibrosis is the end stage of fibroplasia; involves increased collagen deposition with altered arrangement.

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Subepidermal vesicular and pustular dermatitis

Possible causes:
- autoimmune disorders

• unlike pemphigus vulgaris, bullous pemphigoid involves hemidesmosomes. Autoantibody against pemphigoid antigen, an antigen in the basement membrane, is produced. No acantholytic cells present.

• epidermolysis bullosa is a group of mechanobullous disorders that affect structural integrity of the epidermal basement membrane zone. Most disorders that fall under this category are hereditary.

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Possible causes of intraepidermal pustules/ vesicles

- autoimmune disorders [pustules/ vesicles]
- bacterial diseases [pustules]
- viral disease [vesicles]
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Glands, subcutis and vasculature

- sebaceous glands are holocrine glands that produce sebum
- sweat glands: 2 types, apocrine and eccrine

• apocrine (epitrichial)
• eccrine (atrichial)

- subcutis is composed of fat (panniculus) and loose CT

• functions: metabolic storage, protection

- cutaneous vasculature:

• no direct flow
• 3 intercommunicating plexuses: superficial (dermoepidermal junction), middle (level of sebaceous glands), deep (subQ-dermal junction)

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Folliculitis vs. furrunculosis

IMPORTANT:
- folliculitis is inflammation of the hair follicle, most commonly caused by

• bacteria
• dermatophytes ("ringworm" fungi)
• demodectic mites

- furrunculosis is rupture of a hair follicle

• causes granulomatous inflammation

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Hair follicle: 3 anatomical regions

- infundibulum (opening to sebaceous duct insertion)
- isthmus (sebaceous duct insertion to arrector pili m. insertion)
- inferior portion (below arrector pili insertion)
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Examples of dermal dysfunction

- problems with collagen can be congenital; may also result from vitamin C deficiency (scurvy)
- problems with elastin may occur due to solar exposure
- problems with ground substance may occur due to excessive mucin deposition
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Dermis provides elasticity and tensile strength

...this protects against injury.
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3 main components of the dermis

- proteoglycans

• located in dermal ground substance. Important for cell communication, water balance, wound healing.

- collagen
- elastin

*both collagen and elastin are formed by fibroblasts.

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Basement membrane zone anchors epidermis to dermis

Contains the following components:

- hemidesmosomes

• connected to nuclear membrane by intermediate filaments. This provides structural rigidity.

- lamina lucida
- lamina densa (type IV collagen)
- sublamina densa (type VII collagen)
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Merkel cells are mechanoreceptors

- located in basal layer of tylotrich pads, hair follicles
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Melanocytes make melanin

- make melanin pigment
- only melanocytes in skin transfer melanin pigment to keratinocytes

• other melanocytes are located in the brain and eye

- other functions:

• scavenge free radicals
• act as barrier to UV radiation
• pigment skin (cosmetic/ camouflage)

- located in basal cell layer and within hair follicles

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Langerhans cells are essentially dendritic cells

- antigen-processing cells
- when activated, leave epidermis, enter lymphatic vessels
- lymph takes them to local LNs where they interact with T cells

- so they're actually dendritic cells!
- located in the stratum spinosum and sometimes in the basal cell layer
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Four layers of the epidermis

- stratum basale

• stem cells are here
• hemidesmosomes attach epidermis to dermis
• may contain melanocytes, Langerhans cells

- stratum spinosum

• prominent desmosomal intercellular attachments
• keratinocytes appear larger, flatter
• Langerhans cells typically found here

- stratum granulosum

• keratinocytes have keratohyalin granules w/in cytoplasm
• granules have profillagrin, which is cleaved into filaggrin. Filaggrin is the "filament aggregating protein" that acts to aggregate keratin filaments. It's important for formation of the stratum corneum.

- stratum corneum

• many layers of cornified cells (composed mostly of protein) that lack nuclei

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What do keratinocytes do?

- provide structural support
- contribute to the skin's immune system

• constitutively produce cytokines (e.g. IL-1, IL-7, TGF beta)
• can produce inflammatory mediators
• amplify contact hypersensitivity rxns

- undergo cornification, which helps the barrier
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Skin: it's not just a barrier

The skin has 5 other (main) functions:
- sensory perception
- storage of water, electrolytes, fat, vitamins, proteins, etc
- temperature regulation, bp control
- vitamin D production
- indicator of general health/ internal dz
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The skin has 4 barrier functions.

- prevention of water/ electrolyte/ nutrient loss
- barrier to enviro (microbial, thermal, chemical) insult
- prevention of solar damage
- constant immunosurveillance

As Mad Eye Moody would say, "constant vigilance!"
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