W2P1 Flashcards
Histo of skin Wound healing Hypersensitivity Laboratory Immunology Adaptive Immune deficiences Autoimmunity and tolerance Asthma and Rhinits
What are hypersensitivities
- what do they result in
Exaggerated immune mechanisms directed against innocuous antigens
- Resulting in tissue injury
- Causing many known human diseases
- Can be fatal
What classification system is used for hypersensitivities?
Coombs and Gell classification:
Type I: Immediate hypersensitivity (IgE)
Type II: Antibody-dependent cell mediated cytotoxicity (ADCC) (IgG, IgM)
Type III: Immune complex mediated (IgM, IgG)
Type IV: Delayed type (T cell mediated)
Type 1 Hypersensitivity:
Immediate type
most common type. seen in 20% of population
This is an allergic reaction induced by specific antigen/allergen
provoked by RE-EXPOSURE to the same antigen
mediated by IgE antibodies, which activates tissue mast cells to release HISTAMINE [pro-inflammatory] and…. circulating basophiles
to release local or systemic pro-inflammatory mediators
Type 2 Hypersensitivity
- which ABs are involved
- how does it get triggered
Antibody Dependent Cell Mediated Cytotoxicity
- antibodies coating pathogens (usually viruses) are taken up via FcγR111 on NK cells, leading to the killing of the cells the viruses had infected. The viruses must be presented by MHCI.
this involves IgG and IgM produced AGAINST
a. intrinsic Ag (self antigens)
- failure in immune tolerance
- cross reactivity
b. extrinsic Ag absorbed on host cells surface
- i.e. penicillin at the surface of RBC
Once type 2 hypersensitivity antibodies bind to the surface of host cells, what happens?
4 pathways can be initiated by IgG or IgM binding in type 2 hypersensitivity:
Opsonization ( phagocytosis)
Complement activation (MAC, lysis)
NK cell activation (via perforins and Granzymes, by binding to Fc of AB)
Activation or blockage of important cell receptors
One method employed in Type 2 hypersensitivity is the activation or blockage of important cells receptors.
what is an examples of a disease resulting from this specific pathway?
Myastenia gravis
What are examples of type 2 hypersensitivities
ADCC mediated pathologies
AB and Rh blood group incompatibilities (Transfusion reactions)
Autoimmune diseases :
- Idiopathic Thrombocytopenic Purpura
- Myasthenia gravis
- Goodpasture’s
- Graves’
Some drug reactions
Type 3 hypersensitivity
Immune Complex Mediated Hypersensitivity
Caused when Antigen-Antibody complexes form, which happens when there is an antigen excess compared to the amount of antibodies
Immune complexes form in large amounts in the circulation
Deposition in various tissues
Skin
Joints
Kidneys…
caused when soluble antigen-antibody (IgG or IgM) complexes, which are normally removed by macrophages in the spleen and liver, form in large amounts and overwhelm the body These small complexes lodge in the capillaries, pass between the endothelial cells of blood vessels - especially those in the skin, joints, and kidneys - and become trapped on the surrounding basement membrane beneath these cells The antigen/antibody complexes then activate the classical complement pathway
In type 3, activation of the complement pathway may cause:
Lodge in capillaries
Immune complexes activate classical complement pathway
which may cause:
a. massive inflammation, due to complement protein C5a;
b. influx of neutrophils, due to complement protein C5a , resulting in neutrophils discharging their lysosomes and causing tissue destruction and furthers inflammation
c. MAC lysis of surrounding tissue cells, due to the membrane attack complex, C5b6789n; and
d. aggregation of platelets, resulting in more inflammation and the formation of microthrombi that block capillaries
Type 3 examples
Serum sickness Immune Complex Glomerulonephritis Hypersensitivity pneumonitis Extrinsic Allergic Alveolitis (Farmer’s lung) SLE Arthritis?
What is Serum Sickness
(systemic reaction):
In the pre-antibiotic era, antiserum made by immunizing horses used to treat pneumococcal pneumonia
If a course needed, in some individuals, would lead to a systemic type III hypersensitivity reaction on first exposure
7–10 days after the injection of the horse serum
chills, fever, rash, arthritis, sometimes glomerulonephritis
- self limiting disease
after a second dose of antigen, it would follow the kinetics of secondary antibody response and the onset of disease occurs typically within a day or two
What are some manifestations that are present when the ration of antigens is greater than the ratio of antibodies
antigen:antibody COMPLEXES
lead to:
Fever
Vasculitis
Arthritis
Nephritis
Example of a type 4 hypersensitivity test
Delayed type Hypersensitivity
T- cell mediated
- i.e. Tuberculin test (PPD), used to determine previous exposure by exposing pt to PPD, eliciting a T4 reaction if patient is positive (2nd exposure)
Purified Proteine Derivative
Small amounts of tuberculin—a complex mixture of peptides and carbohydrates derived from M. tuberculosis—are injected intradermally. In individuals who have previously been exposed to the bacterium, either by infection with the pathogen or by immunization with BCG, an attenuated form of M. tuberculosis, a local T cell-mediated inflammatory reaction evolves over 24–72 hours
Type 4
Response mediated by TH1 cells
- Recognize complexes of peptide: MHC class II on APCs
- Releasing IFN-γ and TNF-β…
- Stimulating the expression of adhesion molecules on endothelium and increase local blood vessel permeability
Attracting, retaining and activating macrophages
- Allowing plasma and inflammatory cells to enter the site
- Causing swelling (Induration)
- Each phase takes several hours
- Response appears only 24–48H later
What are some examples of type 4 hypersensitivities
Type IV hypersensitivity reaction to poison ivy
Contact dermatitis with poison ivy
- Response to a chemical in the poison ivy leaf
- Caused by direct exposure- first time exposure
- Mediated by T lymphocytes (CD4, CD8)
Can also occur upon exposure to
Other plants Nickel or other metals Medications Rubber Cosmetics Fabrics and clothing Detergents Solvents Adhesives …
IgE
- what are they produced by
- where are they predominantely located?
- What receptor are they tightly bound to
- IgE produced by plasma cells
IgE located predominantly in tissues
IgE tightly bound to FcE expressed at the surface of
- Tissue mast-cells
- Circulating basophils and activated eosinophils
What is the typical sequence of events for Allergic reaction?
Typical sequence of events:
- Re-Exposure to Antigen (Allergen)
- Presentation through APC
- Activation of TH2
- Production of IgE
Role of Histamine
- causes bronchoconstriction = difficulty breathing
- vasodilation and permeability = edema, uriticaria/hives
What are some treatments to type 1 sensitivities
- anti-histamines: to broncho dilate and decrease vascular permeability
- corticosteroids: decrease inflammatory response
- Epi: Intramuscularily in emerg situations during severe attacks. to constrict blood vessels and prevent anaphylactic shock.
Is immediate hypersensitivity symptoms localized or systemic?
IT DEPENDS on:
nature of allergen
route of introduction of allergen
several host factors
What does it mean to be atopic?
denoting a form of allergy in which a hypersensitivity rxn such as dermatitis or asthma may occur in a part of the body not in contact with the allergen
- it is an increased tendency to mount an IgE response to innocuous antigen
- has a strong familial bias
What cytokines are released by TH2 cells?
TH2 are derived from CD4 naive T cells
they release: IL-4, IL-5, IL-13, IL-31
their function: to recruit more immune cells: mast cells, T cells, eosinophils
Initial environmental/hygiene hypothesis vs modified hypothesis
less hygenic environments predisposing you to infections PROTECTS us against ATOPIC diseases
but how? following hypothesis
initial: Infections that evoke TH1 response early in life might REDUCE the likelihood of TH2 response later in life
modified: there has been an increase in incidence of TH2? mediated autoimmune disease
so really what we need is the development of TREG cytokines that result from infections that MIGHT be able to protect use from atopy.
because too high T1/T2 = atopic/autoimmune diseases
What are the three effector mechanisms for an allergic reaction?
Mast cells: histamine, heparin, proteases. They release IL3 and IL4 to continue the stimulation of TH2 cells.
Basophiles
Eosinophils
all of these have the FC receptor for IgE
Epinephrine
Stimulation of:
A1 adrenergic receptor
- increase peripheral vascular resistance by promoting vasoconstriction
- Reduces angioedema
- Improves coronary perfusion
B1 adrenergic receptor
- Increased inotropic and chronotropic effect
B2 adrenergic receptor
- Bronchodilation
- Decrease release of inflammatory mediators from mast cells and basophils
Which method of EPI administration is more affective?
intramuscularly> subcutaneously
recommended location of injection during anaphylaxis: anterolateral aspect of the thigh
Mast Cell
Fundamental role in innate immunity
Express multiple “pattern recognition receptors” involved in recognizing broad classes of pathogens
Major growth factor for mast cells
Stem-Cell Factor (SCF), acting on its receptor c-Kit
against they have receptor for IgE
they release histamines
they are tissue based
Basophils
Many similar characteristics than mast cells
Express also IgE receptors
As opposed to mast cells that are more tissue based
Basophils are more circulating in the peripheral blood
Involved in allergic diseases
Play a significant role in the anti-parasitic response
Eosinophils
Eosinophils fight off infectious agents / damage tissues through release of toxic granule proteins such as
- Major Basic Protein
- Eosinophil-Derived Neurotoxin
- Eosinophil Cationic Protein
important against PARASITES
Fighting viral infections through their RNAses contained within their granules.
Ejects DNA of mitochondrial origin producing a sticky network that can capture bacteria and promote their extra-cellular killing
Invaginations of the skin
refer to sweat glands, hair follicles, salivary glands, toot
What are the two forms of epithelial tissue?
Sheet of cell and glands
tissue between a space (fluid/lumen) and the Basement membrane/ basal lamina
What are the derivations of Epithelia
ectoderm - lining of oral and nasal cavities, cornea, skin epidermis & glands of skin
endoderm - lining of GI tract, lining of respiratory tract, liver, pancreas
mesoderm - renal tubules, lining of reproductive tract, lining of blood vessels
What are the functions of epithelia
Function
- protection, thermoregulation
- transport
- secretion
- absorption
- sensations
What are the different nomenclatures for the epithelial layers
Simple Squamous Simple Cuboidal Simple Columnar Stratified squamous (non-keratinized) Stratified squamous (keratinized) Pseudostratified
What percentage of us is made up of skin?
16%
What are the layers of the skin from superficial to deep?
- stratum corneum (cornified or keratinized layer)
- stratum lucidum (clear layer)
- stratum granulosum (granular layer)
- stratum spinosum (spiny layer)
- stratum basale or germinativum (basal layer)
About the Epithelium of Skin
- integument (skin and its appendages)
- skin = epithelium (epidermis) plus dermis (CT) - 16% of body wt
- sits on fatty hypodermis
- dry skin continuous with wet mucous membrane
- skin appendages from epithelium
nails, hair, glands (sweat and sebaceous glands)
What are the layers/parts of the Epidermis-Dermis INTERFACE?
Top/superficial to deeper:
- Tonofilament insertion
- Hemidemosome
- Integrins
- Basement membrane (collagen IV)
- papillary layer
Structures between Stratum Spinosum cells?
These cells are Keratinocytes
- tonofilament bundles converge into the “desmosome” a general term for the structures involved in the attachment
Desmosome includes:
Cadherines: between the cells, attaching them
Tonofilaments and Kerating Filaments
Stratum Spinosum
polyhedral, spiny cells - deeper cells can also be mitotic
- secrete distinct lamellated granules (membrane-coating granules)(mostly glycolipids, not phospholipids)
- intermediate filaments are called tonofilaments
14 keratin (K1 - K14) genes (cytokeratins) in epidermis
70 diseases have been identified with mutated keratin genes
- keratins in spiny processes, insert into desmosomes
Stratum granulosum summary
Stratum granulosum summary
- 3-5 layers of cells
- large keratohyalin granules (no mb, filaggrin protein) assoc. w. tonofibrils (not always present in kerat. epith.)
- lamellated bodies/granules increase in number
- ↑ transglutaminase crosslinking
Stratum Lucidum Summary
Stratum lucidum summary
- thin and variable (in thick skin only), and unstained
- no organelles left, including nucleus
- full of keratin tonofibrils
- cells are dead
Stratum Corneum Summary
Stratum corneum summary
- dead cells, full of crosslinked keratin fibrils, amorphous substance
- protein deposits under membrane as cell envelope (involucrin and loricrin)
- intercellular space packed with lipids
- release of desmosomal attachments
- desquamation, sloughing of squames (cornified cells)
the more mature they are, the more stuffed with keratin they get
Epidermolysis Bullosa
Defective epidermal cell adhesion
Ichthyosis
Abnormal Keratinization of glycolipid processing/release
e. g. filaggrins and transglutaminase mutations
- I think the desquamousing process is messed up so there’s patches of skin, darker or more read that remains
What are other cells, non keratinocytes in the epidermis
Melanocytes
Langerhans cells
Merkel cells
Melanocytes
- function
- derived from?
- location?
- connections to keratinocytes?
- pre-melanosomes contain?
- how is melanin made
mature to melanin granules
- melanin, protects DNA
- cells derive from neural crest
- cell body in stratum basale
- hundreds to thousands per mm2
- no desmosomal connections to keratinocytes
- pre-melanosomes contain tyrosine (amino acid)
- melanosome, tyrosine plus tyrosinase (activated by UV, tyrosine → melanin)
- eu (dark brown) or pheo (red, yellow) melanin
- melanin granules in dendritic-like cell processes
- cytocrine release to keratinocytes
What causes Albinism
- albinism, gene mutations in tyrosinase gene (complete or partial), ↑ skin cancer
tryrosinase is what gets activated by UV light to produce protective melanin
Langerhans cell
- also called dendritic cells (long cell processes)
- bind foreign substances - antigens
- migrating immune response cells that are antigen-presenting cells
- migrate to lymph nodes and present to T lymphocytes
- derive from bone marrow, migratory cells, no desmosomal connections
- 800 cells mm2
- Birbeck (vermiform) granules (function unknown)
Merkel cells
- mechanosensing cells, single isolated cells in basal layer, with desmosomal connections to keratinocytes
- unmyelinated sensory nerve endings contact Merkel cells (complex may act as mechanoreceptor, abundant in finger tips).
- dense-cored granules (function unknown)
Functions of Extracellular Matrix (ECM)
Connecting and supporting (typically collagen fibrils)
collagen = 90% by weight of ECM
- Signals for cell proliferation and differentiation
- Cell communication (outside-in / matrix-cell signaling)
- Cell protection
- Transmits, and attenuates, mechanical signals
- Compartment for blood vessels, lymphatics, nerves, etc.
- Transport system (Ca and other ions, nutrients, metabolites)
- Controls diffusion of soluble growth factors
Connective Tissue
Constituents:
Types:
Constituents: Cells and Extracellular (Intercellular) Matrix
Types: CT proper and CT specialized
CT Proper vs CT specialized
CT Proper
Loose CT (very cellular)
Loose CT (cellular)
[Intermediate CT]
Irregular Dense CT (relatively acellular)
Regular / Oriented Dense CT (relatively acellular)
Nutritive and excretory role
“The battlefield for defence reactions”
Lymph, edema, cancer and metastasis
with addition of mineral = CT Specialized:
Bone, Cartilage and Teeth (dentin, cementum)
What are the major cell types of connective tissue
Mesenchymal cell
Fibroblast (also called Fibrocyte)
Adipocyte
Macrophage / Histiocyte
Mast cell
Plasma cell
Which is the most abundant protein in your body?
Collagen
Collagen is synthesized and secreted by?
Fibroblasts
takes an hour
golgi apparatus is organelle of production?
Dense CT is made up of mostly?
Collagen
Scurvy:
Vit C def
Vit C required for hydroxylation
If absent, no stable triple helices of alpha chains - no ordered fibrils- no collagen- can lead to teeth falling out
Ehlers-Danlos Syndrome
Collagen I, III and V mutations
Gives hyperextensive skin, hyper joint mobility and dislocation
Types of Fibers in our skin
Collagen - fibrillar collagens (types I, II, III, V, VII, XI) Reticular fibres (collagen type III) Elastic fibres (lots of recoil)
Protein cross-linking by which enzyme?
Lysyl Oxidase
