17,18,19 Flashcards
What do patterns recognition receptors recognise
Recognise antigens and have diversity of type
what are the 2 themes of PRRs
Recognsiing PAMPS and DAMPS
Recognise foreign cells accordingly but not the exact type
What does the TLR-4 receptor recognise
LPS
What does the TLR-5 receptor recognise
Flagellin
What does the TLR-9 receptor recognise
DNA fragments (intracelluar)
What does NLRP3 and RLRs recogneis
IL-1 the first pro-inflammatory cytokine produced in infection
What do collections recorgnise
Complex carbohydrates in microbes
e.g. MBL, surfactant protein A & B
How to the carbohydrates bind to the callectns in the C-type Lectin family
Via Carbohydrate Recognition Domains
Role of the C-typle Lectin familias
Neutrilisng pathogen in recruitment of adaptive response
Antimicrobial peptide examples
Defensins, cathelins, protegrins, probiotics
What do plasmocytoid dendritic cells produce
IFN –> an anti tumour and antibviral
what do mast cells and basophils release in response to PAMPS
Il-6, TNF and IFN
What do epithelial cells produce
Antibmicrobial peptides and local mediation of innate immunity
What does surfactant protein in the lungs bind
Microbes and promote their clearance
What IL causes muscle ache and drowsiness
IL-1
What cytokines are classically produced initially and important for the adaptive immune response to occur
IL-1, IL-6 and TNF
What is IL-23 used for
By macrophages and dendritic cells to target T lymphocytes
What happens when a lymphocyte encounters an antigen
Undergoes clonal expansion!
Where t and B cells first meet infection
In the lymph nodes
How is the diversity of antigen receptors increased
By the VJD recombination of genes
Why is there still some auto-reactivity of T cells
Although we delete T cells that recognise our own cells there are still similar structures in pathogens and human cells (but this amount is small)
What happens in antigen presentation
Antigen internalised and broken down by proteasome Peptides associated with newly synhtesised class II molecules and brought to the surface Foreign peptides recognised by T helper cells and these are activated and produce cytokines needed by B cells
What are histocompatibility NTIGENS
Glycoproteins on the surface of mammalian cells
What are class 1 HLA
HLA-A,B.C
What are class 2 HLA’s
HLA-DQ,DP,DR
What do MHC1 present to
Cytotoxic T cells
What do MHC2 present to
Helper T cells
How is a T cell activated
B cell presents antigen to it, needs a signal from a T cell receptor and a second signal from another CD protein to go any further
What are the roles of antigens
Neutrilisation, agglutination and precipitation of dissolved antigens
Enhances phagocytosis
What does activation of the complement system cause
Cell lysis
How do cytotoxic T lymphocytes kill cells
Bind to infected cells
Perforin makes hole in cell membrane
Enzyme enters promoting apoptosis
What are the targets of HIV
CD4 cells
What do suppressor T lymphocytes do?
Dampen down the immune response
What is the significance of IL-17
Produced by t-lymphocytes and plays an important role in autoimmune conditions
What is immunodefeciency
lack of an efficient immune system –> susceptible to infection
What disease are you susceptible to if PRRs aren’t working
Pneumococcus and HSV (don’t get an inflammatory response)
What disease are you susceptible to if Effector T cells aren’t working
SCID and opportunistic infections
What disease are you susceptible to if complement proteins aren’t working
meningococcus
What disease are you susceptible to if macrophages/neutrophils aren’t working
GCD, aspergillus, staphylococcus
What disease are you susceptible to if cytokines aren’t working
Mycobacterium
What disease are you susceptible to if B cells aren’t working
recurrent sino-pulmonary infections
What is hypersensitivity
Undesirable reactions produced by normal immune system against innocuous antigens in a pre-sensitised (immune host_
What type is type 1 hypersensitivity
anaphylactic - IgE mediated
Common antigens in type 1 hypersensitivity
pollen, bee venom, anaimal danader
Onset of type 1 hypersensitivity
15-30 munutes
What happens in type 1 hypersensitivity
IgE mediated mast cell and basophil deranulation
What is IgE produced under
By B cells under the control of Il-4 and CD40-L-CD40 interaction
What receptor does IgE attach to
FC13 receptor on mast cells has a high affinity for it
How do mast cells activate
Fc3R1 receptor in high densities on the surface binds IgE, crss linking by he allergen activates the mast cell
Causese degranulation of synthesis of lipid mediators
What mediators are pre formed
histamine
Kallikrin
Tryptase
What does histamine do
increases vascular permeability (vasodilation), smooth muscle contraction and stimulates irritant nerve receptors
What does kallikrein do
activates bradykinin (similar role to histamines)
What are the lipid mediators and how are they formed
Formed from arachidonic acid
Leukotrienes (formed due to 5lipooxygenase enzyme)
Prostaglandins (formed due to COX enzyme)
Takes 4-6 hours to produce these lipid mediators
What causes the late phase repose and what is their role
Basophils - similar role to mast cells but longer term
Eosinophils - Make granules containing cytotoxic proteins –> release granule content in tissues causing tissue damage. Also make cheekiness to attract cells to site of inflammation
T cells - in early and late response –> produce cytokines –> cause inflammmation
What is the type 2 hypersensitivity reaction
Antibodiy mediate cytotoxic reaction
how does type 2 hypersensitivity occur
Antigen binds to antibody on cell membrane
Complement cascade activated
Fc protions of Immunoglobulin/C3b aggregate with FcR5/C3Rb resulting in opposition, phagocytsosis and destruction
Antibodies in type 2 hypersensitivity
IgG (and IgM)
What type of reactions usually occur in type 2 hypersensitivity
usually haemopoietic cells
Blood group incompatibilities, autoimmune haemolysis
What is hypersensitivity type 3 reactions
Immune complex reactions
What happens in hypersensitivity type 3 reactions
Antigen antibody complex formed –> deposited around body causing inflammation
FCR in complex binds to C1q –> activates the complement cascade
What happens in hypersensitivity type 3 reactions when the complement cascade is activated
C5a attracts neutrophils
C3b binds opsonin
Attempted phagocytosis of these complexes –> releases enzymes and oxygen free radicals –> consequence is tissue damage
Types of reactions in hypersensitivity type 3
Vasculitis, nephritis, Arturhs reaction, farmers lung, glomerular nephritis
What is hypersensitivity type 4 reactions
T cell mediated CD4+ reaction
Delayed type reaction
Examples of delayed type reactions
Tuberculin skin test
What happens in hypersensitivity type 4 reaction
Perivascular infiltration of lymphocytes and monocytes
Langerhans cells present antigens to T cells
T cells release cytokines
Cytokines activate macrophages
Macrophages cause tissue damage
What are haptens
small chemicals causing changes to innate proteins
What are Type V Hypersensitivity reactions
Inactivation e.g.
1) Direct –> intrinsic factor B-12 deficiency
2) Indirect –> binding to hormone resulting in clearance antigen antibody complex
3) Receptor blockade –> e.g. inappropriate response to ACHR Receptor in myasthenia gravis
What is T cell mediated cytotoxicity CD8+ T cells
Contact dermatitis
Nickel acts as a happen with epidermal proteins
Keratinocytes may present this to CTL precursors!
What are granulomas
Focal collection of inflammatory cells in tissue
What Th1 cells sectere
IFN and Il-2
IL-2 also released by macrophages crucial for granulomatous response
What are the 2 types of reaction in leprosy
Th1 - protective
Th-2 non-protective
Examples of granulomatous reactions
Mycobacterium: TB, leprosy
Also crowns, sarcoidosis and Wegeners granulomatosis
Features of acute inflammation
Fast onset Neutrophils Prominent signs Mild, self-limiting tissue injury Vessels dilate and leak --> protein rich exudate
Features of chronic inflammation
Slow onset: days to years Macrophages, lymphocytes, plasma cells Subtle signs Severe and progressive Granulation and scar tissue abundant Usually primary but can be sequential from acute
Causes of acute to chronic inflammation
Most common is suppurative acute infection
Pus forms an abscess –> if deep enough the walls thicken
Granulation and fibrous tissue forms
Recurrent acute can lead to chronic e.g. cholecystitis –> gall bladder inflammation due to stones
Macroscopic features of chronic inflammation
Chronic abscess cavity
Granulomatours e.g. Crohns –> non caseating granulomatous
Fibrosis prominent once inflammatory infiltrate has stopped
What is osteomyelitis
Chronic abscess in the bone marrow
Microscopic features of chronic inflammation
Cellular infiltration of mononuclear cells
Exudation of fluid is not prominent
Fibrous tissue produced from granulation tissue
The roll of cytokines in chornic inflammation
Attract macrophages
Attract neutrophils and facts to increase vascular permeability
Perforin kills invading cells
Produceds interferons to activate NK cells and macrophages
Basophils release prostaglandins to increase blood flow
What traps macrophages in the tissue in chronic inflammatoin
Macrophage inhibition factor
What cell is important in chronic inflammation
Macrophages –> they releasee cytokines causing monocytes to enter the endothelium of blood vessels
Macrophages proliferate in tissues and become immobilised
Role of macrophages in chronic inflammation
Attracted by cytokines, phagocyte bacteria and damaged tissue
Proteases released after they debris damaged tissue
What do macrophages do in low oxygen
Released factors to cause angiogenesis
Induces cells to re-epitheliase the wound and create granulation tissue
What is granulation tissue
New connective tissue and blood vessels
It grows from the base of the wound
Aims to replace injured cells by fibrous tissue (appears light red/dark punk due to capillaries)
Where does granulation tissue form from
Forms from the base of the wound
What happens in fibrosis
formation of fibrous connective tissue during repair of damaged tissue
Scarring, macrophage induced lying down of connective tissue
When is it called a fibroma
If it develops from 1 cell line
What is a granuloma
Aggregate of epithelium histiocytes and other cells, lymphocytes and histolytic giant cells
When do histolytic giant cells form
Material is indigestable to macrophages
When do giant multinucleate cells from
Form when 2 or m ore macrophages try to engulf the same particle
No known function!
What is epitheliod histiocyte
Large vesicular nuclei and esoninophilic cytoplasm
Granulomatous bacteria disease
TB - lungs, miliary, cough, haemoptysis and night sweats
Leprosy - nerve granulomas, rest, skin, eyes, loss of pain sensation and injury. No autoamputation
Granulomatours parasitic disease
Schistosomiasis
Granulomatous fungal disease
Cryptococcus - risk in immunocompromised
Granulomatous synthetic disease
Silicosis - occupational disease causing scarring and granulations in the lung
Unknown granulomatous diseases
Sarcoidosis and Crohns
Stages of Granuloma formation in TB
Stage 1 - 1 week: Inhale TB, invades alveolar macrophages via mannose receptor. TB multiplies inside macrophage
Stage 2 - 2-3 weeks: exponential TB proliferation - can’t be contained in a single macrophage
Stage 3: After 3 weeks: Phagocytosis and proliferation balanced. 90% of patients stop here and are asymptomatic
Round complex formed macrophages with TB in centre and new macrophages surround it –> TB can survive here for years and immune system may destroy it leaving scar
Stage 4: Reactivation –> Proliferation away from immune cells. Active symptomatic infection, contagious and more likely in immune compromised
What histological features are you likely to see in granulomas
Langerhans giant cells
Caseous necrosis
Epithelioid macrophages
Describe inflammation in CV system post MI
Involved in atheroma formation –> macrophages adhere to epithelium and recuit other cells, process lipids that accumulate in plaques
Describe inflammation in Multiple Sclerosis
Plasma cells and T lymphocytes seen in white matter where macrophages break down myelin
How does H. Pylori produce gastritis
Produces gastritis that damage the intestinal linig
What happens rheumatoid arthritis
Inappropriate immune response
Immune cells accumulate in the joints
What happens in a prolonged exposure to toxic agents (liver)
Cytochrome P450-E1 metabolises ETOH –> oxidation of NADPH produces free radicals
ETOH activates macrophages –> Produces TNF-alpha. Mitochondria produce reactive oxygen species. Both of these mechanisms cause apoptosis and necrosis
What are the mechanisms of healing damaged cells
Healing by regeneration or healing by repair
Types of cell population
Lable
Stable (Quiescent)
Permanent
Describe lable cell populations
High cell turnover
Active stem cell population in the basal zone - proliferation
Excellent regenerative capacity
E.g. epithelia
Describe stable cell population
Low physiological turnover BUT turnover can massively increased if needed
Good regenerative capacity
E.g. liver and renal tubules
Describe permanent cell populations
No physiological turnover
Long life cells
No regenerative capacity –> lost the capacity divided due to their very specialised function
What is essential for the regeneration of cells
The survival of the connective tissue framework –> i.e. in the glomeruli and the lungs
In liver cirrhosis cells can proliferate but can’t rebuild normal tissue architecture
What are reservoirs of stem cells in adult tissues called
Adult stem cell niches
When can stem cell niches be destroyed
Full thickness burn
Radiation
What controls regeneration
Covering defect
Contact inhibition
Complex control by growth factors, cell-cell and cell-matrix interactions
Repair of cells
Healing of cells by non-specialised fibrous tissue scar
basic pathological process of scar formation
Organisation and granulation tissue fundamental for scar formation
3 components of granulation tissue
1) New capillary loops
2) Phagocytic cells - macrophages and neutrophils
3) Myofibroblasts - lays down matrix/connective tissue and can become contractily
What happens as granulation tissue matures
Vascularity and cellularity decreases
Collagen, ECM and wound strength all increase
Factors inhibiting healing: Local
Infection, haematoma, blood supply, foreign okies and mechanical stress
Factors inhibiting healing: Systemic
Age, drugs (steroids), anaemia, diabetes due to the restricted blood supply and metabolic deficit Malnutrtion Catabolic state Vitamin C Defeciency Trace metal defeciency
What are the two types of healing
Healing by first intention
Healing by second intention
What is healing by first intention
Edges of wound opposed
No infection
Clot forms in between edges and phagocytes remove the clot
Healing by process of organisation and granulation converts it to scar
What is healing by second intention
Wound edges not opposed –> extensive tissue loss
Not functionally different to first intention but much more granulation tissue and more extensive scarring
Describe wound strength by day
Day 7 - 10% strength allows sutures to be removed
Week 4 - 70-80% strength
How do bone fractures heal
Haematoma becomes organised
Nectrotic fragments removed
Osteoblasts lay down woven bone - forms a swollen area
Remodelling according to mechanical stress
Replacement by lameallar bone
How does healing in the brain occur
Neutrons are terminally differentiated hence can’t regenerate
Supporting tissue is glial cells NOT collagen/fibroblasts hence no scar tissue forms
INSTEAD
Damage tissue removed leaving a cyst!
Proliferation of astrocytes to form glial cells which line the cysts GLIOSIS OCCURS
Where does gliosis occur
during healing in the brain
