Pathology - unfinished Flashcards
What is acute inflammation?
Response of living tissue to infection/damage
Develops quickly (min-hours) and lasts few hours to days
What are the 3 main processes of acute inflammation?
Vascular dilation
Increased vascular permeability
Neutrophil activation and migration
What is aetiology?
Causes - all aspects
What is pathogenesis?
Progressive changes as disease develops
What is the difference between sign and symptom?
Symptom is a complaint by patient
Sign is identified by examiner
What are the 5 cardinal signs on inflammation?
Rubor (redness) Tumor (swelling) Calor (heat) Dolor (pain) Functio laesa (loss of function)
What are the key organs of the immune system?
Thymus
Bone marrow
Lymph nodes
Spleen
What is the sequence of ‘inflammatory events’
Initiation of reaction - response to pathogen
Progression - containment of pathogen
Amplification - modulation of immune response
Resolution - favourable outcome leading to healing
Failure to resolve –> Chronic inflammation
What can cause acute inflammation?
Microbes
Physical agents - Heat, cold, UV, trauma
Chemicals - Acids, alkalis, ROS
Tissue necrosis - hypoxia
What chemical mediators induce pain?
Bradykinin
Prostaglandins
What does inflammatory exudate provide the tissues?
Fluids and salts - dilute toxins, allow diffusion of mediators
Glucose and O2 - supports macrophages
Complement proteins and antibodies - opsonins
Fibrin - provide scaffold entrapping microbes
What are the chemical mediators of inflammation?
Histamine Bradykinin Leukotrienes Serotonin Prostaglandins
What are the protein mediators of acute inflammation?
Cytokines
Chemokines
What causes degranulation?
C3a, C5a - complement
Antigen - IgE surface immunoglobulin reaction
What is histamine?
A chemical mediator of acute inflammation
Released form mast cells upon degranulation
Role as a neurotransmitter - itching
Causes vascular dilation
What are prostaglandins?
Product of fatty acid metabolism
Most abundant is Prostaglandin E2 (PGE2)
Cause vasodilation
Also regulate cytokine/chemokine production
Acts on nerve fibres - pain
Involved in tissue remodelling
What enzyme regulates prostaglandin release?
Cyclo-oxygenase II (COX II)
What drugs inhibit COX II?
NSAIDs e,g, ibuprofen
What are the 4 enzymatic cascades?
Complement
The kinin system
Coagulation cascade
Fibrinolytic system
What is the kinin system?
Requires activation of Hagemen factor (XIIA) which occurs in response to damage on exposed surfaces
XIIA converts prekallikrein to kallikrein
Kallikrein converts kininogen to bradykinin
What does bradykinin do?
Important complement activation
Stimulates nerves - pain
Increases vascular permeability
What are the 3 pathways of the coagulation pathway?
Intrinsic
Extrinsic
Common - production of thrombin which produced fibrin
What is the fibrinloytic system?
Activation of plasmin
Which is involved in breakdown of blood clots (fibrin) - prevents excess clotting in health
Also activates complement, plasmin cleaves C3
Fibrin breakdown products promote vascular permeability
What causes haemophilia A and B?
A - deficiency in factor VIII
B - deficiency in factor IX
What are two drugs that cause acquired coagulation disorders?
Heparin
Warfarin
What is suppuration?
Formation of pus
Caused by neutrophil infiltration
Pus = bacteria with dead/dying neutrophils
Once pus accumulates it is surrounded by pyogenic membrane
What are the three types of dental abscess?
Gingival
Periodontal
Periapical
How does chronic inflammation differ from acute?
Greater tissue destruction
Inflammatory infiltrate is mixture of macrophages, lymphocytes and plasma cells (neutrophils less prominent than acute)
Reaction more productive than exudative e.g. production of new fibrous tissue rather than exudation of fluid
What are the three main classes of chronic inflammation?
Non-specific
Specific
Granulomatous (subset of specific)
What characterises non-specific chronic inflammation?
Persistent bouts of acute inflammation
Failure to resolve acute inflammation
What characterises specific chronic inflammation?
Can be granulomatous or not
Characterised by excessively activated macrophages
What is specific chronic inflammation induced by?
Non immunological - foreign body reactions, inert noxious materials (asbestos)
Immunological - infective organisms that grow in cells, hypersensitivity reactions, autoimmune reactions, infection by fungi, protozoa or parasites
What are examples of primary granulomatous diseases?
Crohn’s disease, sarcoidosis
What are M1 macrophages?
‘Dark side’ - Classical activation
Induced by: IFNgamma, LPS, TNF-alpha
Causes cytotoxicity tissue injury
What are M2 macrophages?
‘Good side’ - Alternative activation
Induced by: IL-4, IL-13, IL-10, TGF-beta
Immune suppression
Tissue repair
What are activated M1 products that cause tissue injury?
ROS Proteases Neutrophil chemokines Coagulation factors AA metabolites NO
What are activated M2 products that result in fibrosis?
GFs (PDGF, FGF, TGF-beta)
Fibrogenic cytokines
Angiogenesis factors
Remodelling collagenases
How does chronic granulomatous inflammation differ from normal chronic inflammation?
The predominant cell types are modified activated macrophages
- Epithelioid macrophages
- Giant cells (multi-nucleated fused epithelioid Macrophages)
What induces formation of epithelioid macrophages?
T cells release IL-2, IL-2, IFN-gamma
What is an autoimmune disease?
Unwanted response to body’s own cells and tissues or commensal bacteria
Loss of tolerance to self antigen or commensal bacteria
Sustained immune response generates cells and molecules that destroy self tissue
What is Sjogren’s syndrome?
Autoimmune disease of unknown cause
Causes dry eyes (xerophtalmia) and dry mouth (xerostomia)
Chronic inflammation associated with salivary and lacrimal glands
Auto-antibodies against self ribonucleoproteins
What is the ECM?
Extracellular matrix, is a complex structure that supports cells
Made of protein fibres (mainly collagen)
Remodelled by Matrix metalloproteinases (MMPs)
Why remodel the ECM?
Cell migration
Angiogenesis
How are MMPs produced and regulated?
Cytokines regulate production of Pro-MMP
Processed from Pro-MMP to MMP by plasmin
MMPs regulated by TIMPs
What causes tissue destruction in arthritis, caries and periodontal disease?
Matrix Metalloproteinases
Apart from MMPs what other proteins/chemicals can cause collateral damage if unregulated?
ROS/NOS (Reactive nitrogen species)
What is osteoclastogenesis?
Resorption of bone (bone loss)
Mediated by osteoclasts
Activation of Receptor Activator of Nuclear Factor Kappa-B (RANK) by its ligand (RANKL)
RANKL expressed by numerous immune cells
If expression of RANKL not controlled then increased alveolar bone loss
What is osteroblastogenesis?
Osteoblastogenesis leads to bone formation
Mediated by Osteoblasts
Osteoblasts secrete Osteroprotogerin (OPG)
OPG inhbitis RANKL therefore bone resorption
What is important in healthy bone remodelling?
The RANKL/OPG ratio
Excessive immune response is associated with an increase in the RANKL/OPG ratio and tips the balance towards bone loss
What is adaptive immunity?
Consists of cell-mediated responses and antibody (humoral) responses
T cells - cell-mediated
B cells - humoral
What are the 3 main molecules involved in recognition of a foreign antigen in adaptive immune response?
TCR
BCR (surface immunoglobulins)
MHC
What can T cells be divided into and which MHC receptor does each subset bind to?
CD4+ Helper T cells - MHC II
CD8+ Cytotoxic T cells - MHC I
What is CD3?
A co-receptor involved in activation of both CD4 and CD8
What are gamma-delta T cells?
Only 5% in humans, little known about function
How is TCR diversity achieved?
Via VDJ recombination of the variable region, constant region always remains same hence name.
2 gene segments encode variable region of alpha chain - V, J
3 for beta chain - V, D, J
What are the two classes of TCR?
Alpha beta (95%) Gamma delta (5%)
Alpha beta TCR consists of one alpha chain and one beta chain
Where are lymphocytes derived?
Both B and T derived from bone marrow
B educated in bone marrow, T educated in thymus.
How does thymic education occur?
Pre-thymic T cells enter thymus expressing both CD4 and CD8 (low expression), TCR genes also rearranged.
These move into the cortex where they adhere to cortical epithelial cells, TCRs-MHC on epithelial cell - positive selection.
Cells that aren’t selected subject to apoptosis and phagocytosis.
Thymocytes then migrate into the cortex and expression of CD3, CD4/CD8 and TCR increases.
TCRs with self-reactivity are deleted because of contact with autoantigens presented by dendritic cells/macrophages - negative selection.
Cells that express CD4 or CD8 appear and migrate to periphery.
Where do T cells go once they leave the thymus?
T cells ciruclate in lymphatic system and move to lymph nodes, some however remain in circulation
How do T cells become activated?
Immature dendritic cells pick up foreign antigen in the epidermis, once taken up they migrate to lymph nodes whilst differentiating along the way.
Mature dendritic cells have co-stimulatory activity and can prime naive T cells
What is activation and differentiation of naive T cells called and how does it occur?
Priming
3 signals
Signal 1 - APC presents antigen on MHCII to TCR on naive T cell - activation
Signal 2 - CD28 bind CD80/86 - signal for survival and clonal expansion - no signal 2 leads to anergy
Signal 3 - cytokines released by APC direct differentiation into subsets of effector T cells
What are the functions of Th1 and Th2 T cells?
Linked to innate immunity, Th1 activate and promote activity of macrophages (IFN-gamma) and B cells to produce IgG
Th2 activate B cells to produce IgE, also activates mast cells and eosinophils
What do Th17 cells do?
Release IL-17
Supports innate immunity
What do Tfh cells do?
Promote B cell activation and formation of plasma cells
Found in secondary lymphoid organs in B cell zone
What do Treg cells do?
Immune suppression (provide balance)
Release inhibitory cytokines IL-10
Induce active T cells to undergo apoptosis
Inhibit dendritic cell maturation and function
How are cytotoxic t cells activated?
- Antigen recognition - MHCI-TCR reaction
2. Clonal selection - Activated cytotoxic t cell and t memory cells created
How do cytotoxic T cells function?
Release contents of granules (granzyme/perforin)
Perforin directs contents through cell wall
Once in cell granzyme targets apoptotic signalling pathways
- Caspase- 3
- Disrupts mitochondrial membrane releasing cytochrome c
What is hypersensitivity?
A state of altered reactivity in which the body reacts with an exaggerated immune response to a foreign agent
What is the Gell and Coomb’s classification?
Different types of hypersensitivity types
Type 1 - IgE mediated
Type 2 - IgG-mediated (cytotoxic)
Type 3 - Immune complex mediated
Type 4 - Cell mediated
New evidence for type 5 in literature
How does type 1 hypersensitivity occur?
Most common type, occurs rapidly in response to allergen
Ag induces crosslinking of IgE bound to mast cells and basophils with release of vasoactive mediators (histamine)
Can cause systemic/localised anaphylaxis such as allergies, eczema, hayfever, hives
What are the 4 common sources of allergens?
Inhaled materials - plant pollens, domestic animal dander, mould spores
Injected materials - insect venom, vaccines, drugs
Ingested materials - food, drugs
Contacted materials - e.g. plant leaves, metals, chemicals
What are the three potentially fatal reactions of systemic anaphylaxis?
Laryngeal oedema - suffocation
Peripheral oedema - fluid loss from blood vessels causes hypotension and heart attack
Bronchiole constriction - suffocation
What are haptens?
Small organic molecules that do not provoke antibodies by themselves
Attach to carrier molecule and induce antibody-mediated allergic reactions e.g. penicillin on RBCs
How does IgE stimulate a response?
IgE producing B cells activated during sensitisation (first exposure)
IgE binds to Fc receptor on mast cells or CD63 on basophils
IgE recognises allergen and next exposure binds rapidly and causes immediate degranulation (elicitation)
What is released from mast cells during degranulation?
Lipid mediators - prostaglandins/leukotrienes
Preformed mediators - histamine/heparin/proteases
Cytokines/Chemokines/Angiogenic and Growth Factors
What is atopy?
Genetic tendency to develop allergic diseases
Cutaneous atopy - shows up as wheal and flare
Urticaria (itchy rash) Allergic rhinitis (hayfever) Atopic dermatitis (eczema) Asthma (lower respiratory tract) Food allergies
What are the allergy tests?
Skin prick test - 1st test to be done
Blood test - specific IgE test
Patch test (skin only) - allergen added to metal disc taped to skin for 20 mins
Food challenge - subject given gradually increasing amounts of food which suspected allergy of, reaction monitored
What are treatments for allergy?
Avoid allergen
Drugs -
Anti-histamines (inactivate histamine receptors) Hydrocortisone (block histamine synthesis)
Cromoglycate (stabilises mast cells stops degranulation)
Epinephrine - best immediate treatment for anaphylactic shock - reverses effect of granules
Immunological treatment
- Hyposensitisation - repeat injections of allergen
What is a type 2 hypersensitivity reaction?
Involves activation of complement by IgG or IgM binding to an antigenic cell
Cell is lysed by:
- MAC (complement)
- Antibody dependent cell mediated cytotoxicity (NK cells)
Common example is transfusion reactions, prevention is by cross-matching, treatment is to stop transfusion and give diuretics
What is a type 3 hypersensitivity reaction?
Involves reactions against soluble antigens circulating in serum
Antibody-antigen immune complexes are deposited in organs and activate complement, induce neutrophil recruitment and cause inflammatory damage
Examples:
- Arthus reaction
- Serum sickness
- Oral erythema multiforme (EM)
What is the major difference between type II and type III hypersensitivity reactions?
Type III involves immune complexes - which is the binding of specific antibody to SOLUBLE antigen
Type II also involves an antibody-antigen complex, however these are not immune complexes as the antigen is on a carrier molecule
Levels of complement also factor, Type II - small amount, Type III - large
What is arthus reaction?
Type III hypersensitivity reaction
Intradermal injection of antigen - insect bite/vaccination
Immune complexes deposited in localised blood vessels
Complement activation - C3a/C5a chemotactic for neutrophils
- Frustrated phagocytes bind C3b on complexes but cant phagocytose so dump granules
- Causes degranulation of mast cells
What is serum sickness?
Type III hypersensitivity reaction
Systemic arthus reaction
Immune complexes circulate and lodge in various tissues
Vasculitis, rash, fever, joint swelling and pain
Mechanism same as arthus - more widespread
Can occur in hypersensitivity to penicillin
What is oral erythema multiforme (OEM)?
Type III hypersensitivity
Crusty blistering of oral mucosa
Deposition of immune complexes in microvasculature of oral mucosa
What is type IV hypersensitivity?
T cell mediated
Delayed as takes time to recruit T cells
Localised T cell reaction at site of encounter of contact antigens
Involves both CD4+ and CD8+
Localised - contact dermatitis
Systemic - Tb, Crohn’s disease, sarcoidosis
