ICS Flashcards
Define inflammation
Increased vascular permability accompanied by infiltration of inflammatory cells
Response to injury or infection
When is inflammation beneficial?
Destruction of invading microorganisms
Walling off abscess cavity to prevent spread of infection
Good in injury and infection
When is inflammation bad?
Autoimmune reactions
Overreaction
What is the sequence of acute inflammation?
- injury or infection
- neutrophils arrive and phagocytose and release enzymes
- macrophages arrive and phagocytose
- either resolution with clearance of inflammation or progression to chronic inflammation
What is acute inflammation + example?
Initial reaction of tissue to injury
e.g. acute appendicitis, strep throat, frostbite
What are the 5 principal causes of acute inflammation?
Microbial infections
Hypersensitivity reactions
Physical agents
Chemicals
Tissue necrosis
Example of acute inflammation by microbial infection
Pyogenic bacteria
Viruses
Examples of acute inflammation by physical agents
Trauma
Ionising radiation
Heat
Cold
Examples of acute inflammation by chemicals
Corrosives
Acids and alkalis
Reducing agents
Bacterial toxins
Example of acute inflammation by tissue necrosis
Ischaemic infarction
What are the essential macroscopic appearances of acute inflammation?
5 cardinal signs
Redness from dilation
Increase in temp in peripheral parts from increased blood flow
Swelling from oedema
Pain
Loss of function
rubor, calor, tumor, dolor
What cells are involved in inflammation?
Neutrophil polymorphs
Macrophages
Lymphocytes
Endothelial cells
Fibroblasts
What do neutrophil polymorphs do?
First cells to arrive in acute inflammation
Adhesion to microorganisms
Phagocytosis and intracellulara killing of microorganisms
Release lysosomal products
Short lived and die on scene
What accumulates in the early stages of acute inflammation?
Oedema, fibrin and neutrophil polymorphs accumulate in extracellular space
What are the 5 cardinal signs in inflammation?
Rubor
Dolor
Calor in extremeties
Tumour
Loss of function
What are the early stages of acute inflammation?
Changes in vessel calibre and flow
Increased vascular permeability
Formation of fluid exudate
Formation of cellular exudate and emigration of neutrophil polymorphs into extracellular space
Diapedesis
Chemotaxis of neutrophils
What is diapedesis?
in acute inflammation
red cells being passively forced out of vessels by hydrostatic pressure
Lots of RBCs in extravascular space implies severe vascular injury
What is chemotaxis?
of neutrophils in acute inflammation
neutrophil polymorphs attracted to certain chemical substances in solution
What do histamine and thrombin cause in acute inflammation?
upregulation of adhesion molecules on surface of endothelial cells leading to firm neutrophil adhesion to endothelial surface
What do endogenous chemical mediators cause?
Vasodilation
Emigration of neutrophils
Chemotaxis
Increased vascular permeability
Itching and pain
What does histamine cause in acute inflammation?
Vascular dilation and immediate increased vascular permeability
What is the most important source of histamine in humans?
Mast cells
also present in basophil , eosinophil leucocytes and platelets
What is the diagnostic histological feature of acute inflammation?
Accumulation of neutrophil polymorphs in extracellular space
What is in the fluid exudate?
acute inflammation
high protein content
immunoglobulins
coagulation factors (fibrinogen)
What does resolution mean?
Complete restoration of the tissues to normal after acute inflammation
What conditions favour resolution?
Minimal cell death and tissue damage
Organ regenerative capacity
Rapid destruction of causal agent
Rapid removal of fluid and debris
Example of acute inflammatory condition that usually resolves completely
Acute lobar pneumonia
What does excessive exudate lead to in acute inflammation?
Suppuration (formation of pus)
What does excessive necrosis in acute inflammation lead to?
Repair and organisation of tissue
Fibrosis
What does a persistent causal agent in acute inflammation lead to?
Chronic inflammation
Fibrosis
What circumstances favour organisation in acute inflammation?
Large amounts of fibrin formed which can’t be removed
Lots of necrotic tissue
Dead tissue not easily digested
Exudate and debris can’t be removed
What is organisation of tissue in inflammation?
Replacement of tissue by granulation tissue as part of the repair process
New capillaries grow into exudate
Macrophages migrate into area and fibroblasts proliferate
Fibrosis and scar formation
Example of acute inflammation recurring and leading to chronic
Chronic cholecystitis
normally due to presence of gallstones
What are the main cells in chronic inflammation?
Lymphocytes
Plasma celss
Macrophages
What is a granuloma?
an aggregate of epithelioid histiocytes
What are the systemic effects of inflammation?
Pyrexia
Malaise
Anorexia and nausea
Weight loss
Reactive hyperplasia (lymph node enlargement)
Haematological changes
Amyloidosis
What do fibroblasts do?
(inflammation)
Produce collagenous connective tissue in scarring following
some types of inflammation
What are some conditions associated with granuloma formation?
Sarcoidosis
Crohns
TB
Wegener’s granulomatosis
What specific infections can cause granulomas?
Mycobacterial: TB, leprosy
What is the sequence of chronic inflammation?
either progression from acute inflammation or starts as
‘chronic’ inflammation
no or very few neutrophils
macrophages and lymphocytes, then usually fibroblasts
can resolve if no tissue damage (e.g. viral infection like
glandular fever)
often ends up with repair and formation of scar tissue
What cancers commonly
spread to bone?
breast, lung,
thyroid, kidney, prostate
BLT KP
How can carcinomas spread?
spread to the lymph nodes that drain the site of the carcinoma
spread to bone via blood
What type of carcinoma can’t spread?
Basal cell carcinoma
complete excision = cure
What are carcinogens?
Agents known or suspected to cause tumours
What does carcinogenic mean?
Cancer causing
What does oncogenic mean?
Tumour causing
What % of cancer risk is environmental?
85%
What are the classes of carcinogens?
Chemical
Viral
Ionising and non-ionising radiation
Hormones, parasites and mycotoxins
Miscellaneous
What % of cancers do viruses cause?
10-15%
Examples of chemical carcinogens
Polycyclic aromatic hydrocarbons
Aromatic amines
Nitrosamines
Alkylating agents
What are examples of DNA viral carcinogens?
and what cancers can they cause?
Human herpes virus 8 (causing kaposi sarcoma)
Epstein barr virus (nasopharyngeal carcinoma)
Hep B virus (hepatocellulara carcinoma)
Human papillomavrius (squamous cell carcinomas)
Merkle cell polyomavrius (merkle cell carcinoma)
What are some examples of viral RNA carcinogens?
Human T-lymphotrophic virus (adult T cell leukaemia)
Hep C virus (hepatocellular carcinoma)
What are biological agents that might increase risk of cancer?
Increased oestrogen
Anabolic steroids
Aflatoxin B1 (mycotoxin)
Chlonorchis sinensis (parasites)
Example of radiant energy that might cause cancer?
UV
Examples of miscallenous carcinogens
Metals
Asbestos
What host factors can affect carcinoma risk?
Ethnicity
Diet / Lifestyle
Constitutional factors - age, gender etc.
Premalignant lesions
Transplacental exposure
What are premalignant conditions?
Identifiable local abnormality associated with increase risk of malignancy at that site
What does hyperplasia mean?
Increase in cell number by mitosis (causing increase in tissue size)
e.g. 4 cells become 8
What does hypertrophy mean?
Increase in cell size without cell division (causing increase in tissue size)
e.g. 4 little cells become 4 big cells
What does atrophy mean?
Decrease in size of an organ or cell
may be physiological (uterus after menopause) or pathological (injury)
What does hypoplasia mean?
Failure of development of an organ
e.g. failure of development of the legs in adult spina bifida patients
failure of morphogenesis, similar to atrophy
What does metaplasia mean?
An acquired form of altered differentiation
Transformation of one mature differentiated cell into another
Affects epithelia or mesenchymal cells
Often increased risk of malignancy
What does dysplasia mean?
Increased cell proliferation
Pre-malignant
Presence of atypical morphology
What does ischaemia mean?
Inadequate blood supply to part of or all of an organ
What does neoplasia mean?
‘new growth’
characterised by abnormal, unco-ordinated and excessive cell proliferation
What is a neoplasm?
An abnormal tissue mass
the excessive growth of which is uncoordinated with normal tissues
persists after the removal of the neoplasm-inducing stimulus
What does infarction mean?
death of tissue due to insufficient blood supply
What is a tumour?
Abnormal swelling
synonymous with neoplasm
What is apoptosis?
A form of normal or pathological individual cell death characterised by activation of endogenous endonucleases
What is necrosis?
Pathological cellular or tissue death in a living organism, irrespective of caurse
Difference between apoptosis and necrosis
Both models of cell death
Apoptosis: active process involving single-cell death, normal and abnormal, cell membrane intact, no inflammatory reaction
Necrosis: response to injury, almost always a group and pathological, cell membrane integrity lost, inflammatory response and repair common
What can activate the intrinsic pathway of apoptosis?
intracellular signals: DNA damage, failure to conduct cell division
What genes regulate the final common pathway of apoptosis?
bcl-2 protein family
What do the bcl-2 protein family do?
Inhibit or activate the death pathway in apoptosis
What inhibits apoptosis?
Growth factors, cell matrix, sex steroids, some viral proteins
What are some apoptosis inducers?
Growth factor withdrawal, loss of matrix attachment, glucocorticoids, some viruses, free radicals, ionising radiation, DNA damage, Fas ligand
What do caspase enzymes do?
Effector molecules for apoptosis
Switched on by internal and external signals (bcl-2 inhibit, bax proteins switch on, Fas ligand binds to fas receptor = switches on)
What diseases are associated with increased apoptosis?
AIDS
Neurodegenerative disorders
What diseases are associated with decreased apoptosis?
Cancer
Autoimmune disease
What tumours commonly metastasise to the lungs?
Sarcomas
Any common cancers
What tumours commonly metastasise to the liver?
colon
stomach
pancreas
carcinoid tumours of intestine
What makes up neoplasms?
Neoplastic cells
Stroma (framework)
What are features of neoplastic cells?
Derived from nucleated cells
Usually monoclonal
Growth pattern and synthetic activity related to parent cells
What does the stroma provide in the neoplasm?
Connective tissue framework
Mechanical support anda nutrition
Why is it important to classify neoplasms?
To determine appropriate treatment
To provide prognostic information
To aid communication
What can neoplasms be classified as?
Benign
Borderline
Malignant
Features of benign neoplasms
Localised, non-invasive
Slow growth rate
Low mitotic activity
Close resemblance to normal tissue
Circumscribed or encapsulated
Why worry about benign neoplasms?
Pressure on adjacent structures
Obstruct flow
Produce hormones
Transform to malignant neoplasm
Anxiety
Features of malignant neoplasms
Invasive
Metastases
Rapid growth rate
Variable resemblance to normal tissue
Poorly defined or irregular border
Histological features of malignant neoplasms
Hyperchromatic nuclei
Pleomorphic nuclei
Increased mitotic activity
Necrosis and ulceration common
Growth on mucosal surfaces and skin often endophytic
Histological features of benign neoplasms?
Nuclear morphometry often normal
Necrosis rare
Ulceration rare
Growth on mucosal surfaces usually exophytic
Why worry about malignant neoplasms?
Destruction of adjacent tissue
Metastases
Blood loss from ulcers
Obstruct flow
Produce hormones
Paraneoplastic effects
Anxiety and pain
Where might neoplasms arise from?
Epithelial cells
Connective tissues
Lymphoid/haematopoietic organs
What is a papilloma?
Benign neoplasm of non-glandular non-secretory epithelium
What is an adenoma?
Benign neoplasm of glandular or secretory epithelium
What is a carcinoma?
Malignant epithelial neoplasm
What are adenocarcinomas?
Carcinomas of glandular epithelium
When is a neoplasm described as anaplastic?
cell type of origin cannot be determined
Example of an inherited predisposition for cancer
Familial adenomatous polyposis risk for colorectal cancer
When is the suffix -oma used + exceptions
Benign connective tissue neoplasms
not neoplasm: granuloma
malignant: melanoma, mesothelioma, teratoma
When is the suffix sarcoma used + exceptions?
Malignant connective tissue neoplasms
melanoma and mesothelioma also malignant
What are the different aetiologies of cancer?
Transformation of germline cells: inheritable cancers (<10%, Rb, BRCA1, 2)
Transformation of somatic cells: noninheritable cancers (>90%)
Environmental factors
What are some hallmarks of cancer?
Growth self-sufficiency
Evade apoptosis
Ignore anti-proliferative signals
Limitless replication potential
Sustained angiogenesis
Invade tissues
Escape immune surveillance
What is cancer immunosurveillance?
Immune system can recognize and destroy nascent transformed cells, normal control
What is cancer immunoediting?
Tumours tend to be genetically unstable; thus immune system can kill and also induce changes in the tumour resulting in tumour escape and recurrence
What are tumour specific antigens?
Are only found on tumours
As a result of point mutations or gene rearrangement
Derive from viral antigens
What are tumour associated antigens?
Found on both normal and tumour cells, but are overexpressed on cancer cells
Developmental antigens which become derepressed. (CEA)
Differentiation antigens are tissue specific
Altered modification of a protein could be an antigen
What is the main purpose of the immune system?
Discriminate between self and non self
What are the different types of immunity?
Innate
Adaptive
both made up of cells and soluble factors
What is innate immunity?
Instinctive
non-specific
does not depend on lymphocytes
present from birth
What is adaptive immunity?
Specific ‘Acquired/learned’ immunity
requires lymphocytes
antibodies
What is haematopoesis?
The commitment and differentiation processes that leads to the formation of all blood cells from pluripotent haematopoietic stem cells
starts in bone marrow
What are the polymorphonuclear leukocytes?
Neutrophils
Eosinophil
Basophil
What are the mononuclear leukocytes?
Monocytes
B cells
T cells
Mast cells
Natural killer cells (type of T)
Dendritic cells (kupffer in liver, langerhans in skin)
What are the different T cells?
T-regs
T-helpers (CD4,Th1,Th2)
Cytotoxic (CD8)
What do B cells become when they differentiate?
Plasma cells
What are the soluble factors of the immune system?
Complement
Antibodies
Cytokines
Chemokines
What is complement?
in the immune system
Group of 20 serum proteins secreted by teh liver that need to be activated to be functional
Activated as part of the immune response
What are the main modes of action for complement?
Direct lysis
Attract more Leukocytes to site of infection
Coat invading organisms
What do antibodies do?
can also be called immunoglobulins
Bind specifically to antigens
soluble
secreted
bound to B cells as part of B-cell antigen receptor
glycoproteins
What are the 5 distinct classes of immunoglobulins?
IgG (IgG1-4)
IgA (IgA1 & 2)
IgM
IgD
IgE
Which parts of IgG bind to what?
Fc binds to receptors
Fab bind to non self
Y shape, fab at top, fc at bottom
What does IgM do?
Responsible for primary immune response
Initial contact with the antigen
What is the structure of IgM?
Pentamer
J chain
Mainly found in blood
10% of serum Igs
What is the structure of IgA?
Monomer or dimer
15% of Igs in serum
Held together with J chain
What is the structure of IgD?
Accounts for 1% of Ig in serum
A transmembrane monomeric form (mIgD) is present on mature B cells
What is the structure of antibodies?
Y shape
Fab region at top with antigen binding site
Antigen binding site binds to specific epitope
Fc region and receptor at bottome
What is IgE associated with?
Associated with hypersensitivity allergic response and defence against parasitic infections
What does IgE bind to?
Receptors on basophils and mast cells triggering histamine release
What are cytokines?
Proteins secreted by immune and non-immune cells
What are the different cytokines?
Interferons
Interleukins
Colony stimulating factors
Tumour necrosis factors
What do interferons do?
(cytokines)
induce a state of antiviral resistance in uninfected cells & limit he spread of viral infection
What are chemokines?
Group of approx 40 proteins that direct movement of leukocytes (and other cells) from the bloodstream into the tissues or lymph organs by binding to specific receptors on cells
What do interleukins do?
(cytokines)
produced by many cells, over 30 types
Can be pro-inflammatory (IL1) or anti-inflammatory (IL-10)
Can cause cells to divide, to differentiate and to secrete factors
What do colony stimulating factors do?
(cytokines)
Involved in directing the division and differentiation on bone marrow stem cells – precursors of leukocytes
What do Tumour Necrosis Factors do?
(cytokines)
Mediate inflammation and cytotoxic reactions
Features of the innate immune response
1st line of defence
Provides barrier to antigen
Instinctive
Present from birth
Slow response
No memory
Features of the adaptive immune response
Response specific to antigen
Learnt behaviour
Memory to specific antigen
Quicker response
What are some physical barriers in the innate immune response?
Skin
Lysozyme in tears
Mucus and cilia
Acid in the gut
commensals
What is the process of inflammatory response to tissue damage?
Stop bleeding (coagulation)
Acute inflammation (leukocyte recruitment)
Kill pathogens, neutralise toxins, limit pathogen spread
Clear pathogens/dead cells (phagocytosis)
Proliferation of cells to repair damage
Remove blood clot – remodel extracellular matrix
Re-establish normal structure/function of tissue
What are the main chemokines?
CXCL – mainly neutrophils
CCL –monocytes, lymphocytes, eosinophils, basophils
CX3CL – mainly T lymphocytes & NK Cells
XCL – mainly T lymphocytes
chemokine - attracted cell
Where are pathogen-associated molecular patterns?
On surface of bacteria/microbe
Bind to PRR
What receptors are on cells in our body that bind to PAMPs?
Pattern recognition receptors
Where are the cells that sense microbes?
In blood – Monocytes, Neutrophils
In tissues – Macrophages, Dendritic cells
What are C-type lectin receptors?
Expressed by Macrophages and DC
bind to carbohydrates in a Ca2+-dependent manner
The receptors have a carbohydrate-recognition domain/s (CRD)
bind to foreign carbs
What do scavenger receptords bind to?
Bind to a variety of ligands including endogenous lipids and lipoproteins
in particular bacterial cell wall components of both Gram-negative and Gram-positive bacteria.
they are membrane bound
What do toll-like receptors do?
Bind to different foreign molecules
What is the function of scavenger receptors in homeostasis?
bind and internalize lipid containing molecules such as modified low-density lipoprotein (LDL) and oxidised LDL (oxLDL) from the plasma
when this is dysregulated it can lead to atherosclerosis
What different receptors are there in the immune response?
CLR
TLR
Scavenger
What are the different activation pathways for complement?
Classical - Ab bound to microbe
Alternative – C’ binds to microbe
Lectin – activated by mannose binding lectin bound to microbe
What is phagocytosis?
What are the stages of phagocytosis?
Binding
Engulfment
Phagosome formation
Phagolysosome
Membrane disruption/fusion
antigen presentation
What mediates phagocytosis?
opsonic receptors
What are the 2 mechanisms of microbial killing?
oxygen dependent
oxygen independent
How does O2 dependent killing pathway work?
Reactive Oxygen Intermediates (ROI)
Superoxides (O2-) are converted to H2O2 then ·OH (free radical)
Nitric Oxide (NO) – vasodilation (Viagra) increase extravasation but also anti-microbial
What is involved in the O2 independent killing pathway?
Enzymes: (eg lysozyme)
Proteins: defensins (insert into membranes), TNF
pH
How does the neutrophil get from circulation to the site of infection?
extravasation
Neutrophil moving very fast in circulation
Rolls and tethers onto endothelium
Remains static (adhesion) and passes through gaps in endothelium walls
Travels through chemokine gradient (transmigration)
Reaches site of infection
What cells are in adaptive immunity?
T cells
B cells
Anitgen presenting cells
Where are T cells?
Start in thymus
Circulation
Lymphoid tissues (spleen, lymph nodes, MALT)
Where do adaptive immune cells gather?
Secondary lymphoid tissues
(spleen, lymph nodes, MALT)
Where do B cells and APCs start?
Bone marrow
Why does cell-mediated immunity require cell to cell contact?
to control Ab responses via contact with B cells
to directly recognise and kill viral infected cells
What is T cell selection?
T cells that recognise self are killed in the foetal thymus as they mature
What does cell-mediated immunity require?
Major Histocompatibility Complex (MHC)
Intrinsic/Endogenous (intracellular) antigens
Extrinsic/Exogenous (extracellular) antigens
Cell to cell contact
What is the purpose of cell mediated immunity?
Recognise self or non-self
Interlay between APCs and T cells
What does a major histocompatibility complex do?
Displays peptides from self or non-self proteins
MHC 1 glycoproteins on all nucleated cells
MHC 2 glycoproteins only on APCs
What do T cells do?
recognise antigen in association with MHC
DO NOT respond to soluble antigens only intracellular presented antigens
How do T cells become functional?
inactive naive T cell
activated, e.g. into CD4 or CD8
CD4: IL-12lo —> ab production, IL-12hi —> IFNy helps kill pathogens intracellularly
CD8: kill intracellular pathogens directly
How are B cells activated?
th2 cells are primed and bind to specific B cell
Th2 secretes cytokines
B cells divide (clonal expansion) and differentiate into plasma cells and memory B cells
Make 1 antibody that bind to 1 specific receptor
What are the primary lymphoid organs?
thymus
bone marrow
What are the secondary lymphoid organs and tissues?
tonsils and adenoids
bronchus associated lymphoid tissue
lymph nodes
bone marrow
spleen
peyers patach
How do B cells activate and differentiate?
Binds antigen and becomes activated
Activated B cells go to lymph nodes where they proliferate (clonal expansion)
differentiate into plasma cells.
These plasma cells secrete antibodies of same specificity but are generally IgM – these later turn into IgG but still have same specificity to the same antigen (class switching)
Some B cells recalculate for years (Memory B cells)
What is the restimulation of memory B cells?
Very quick secondary response
What can specific secreted antibodies do?
Neutralise toxin by binding to it
Increase opsonisation – phagocytosis
Activate complement
What are damage associated molecular patterns?
Endogenous molecules created to alert the host to tissue injury and initiate repair
What are secreted and circulating PRRs?
Antimicrobial peptides secreted into lining fluids (from epithelia and phagocytes)
What are pentraxins?
Proteins like CRP
react with the C-polysaccharide of pneumococci, some antimicrobial actions
activates complement, promotes phagocytosis
e.g. of secreted and circulating PRR
Examples of secreted and circulating PRRs
Pentraxins
Lectins and collectins
What are lectins and collectins?
carbohydrate-containing proteins that bind carbohydrates or lipids in microbe walls.
Activate complement, improve phagocytosis.
Mannose binding lectin
Surfactant proteins A and D
What are cell-associated PRRs?
Receptors that are present on the cell membrane or on organelles within the cytosol of cells
TLRs are the main family
Recognise a broad range of molecular patterns
What do TLR2 and 4 bind to?
bacteria, viruses and self
What does TLR5 bind to?
Bacteria flagellin
What are some examples of membrane bound PRRs?
Mannose receptor - on macrophages (fungi)
Dectin-1 - widespread on phagocytes (beta glucans in fungal walls)
Scavenger receptors - on macrophages (wide variety of lipid-related ligands from pathogens or from host cells that are damaged, apoptotic or senescent)
What are nod-like receptors involved in?
sensing cytoplasmic bacterial pathogens and DAMPS
regulation of inflammatory & cell death responses
What characterised NOD like receptors?
presence of a conserved nucleotide-binding and oligomerisation domain
What does NOD1 do?
recognizesmeso-diaminopimelic acid (meso-DAP)-containing PGN fragments (mainly Gram-negative) in the periplasmic space
What does NOD2 do?
senses muramyl dipeptide (MDP) a breakdown product of PG in the cell wall, found in the PGN of nearly all Gram-positive and Gram-negative organisms
What is type 1 hypersensitivity?
an immediate reaction to
environmental antigens mediated via IgE
What is atopy?
an inherited trait for Type I hypersensitivity
What are allergens?
antigens that trigger allergic
reactions
What diseases are associated with ageing?
Cardiovascular
Neurodegenerative
Cancer
COVID-19
Autoimmune
