What are the 3 parts of the traditional innate immune system?
1) Barrier and chemical mechanisms - complement system
2) PRR - pattern recognition receptors
3) Cellular component
What are the 5 major components of the innate immune system?
1) Pattern recognition receptors
2) Antimicrobial peptides
3) Cells
4) Complement components
5) Cytokines
What are the 2 parts to the adaptive immune system?
1) Humoral - Ab
2) Cellular - B and T lymphocytes
What are the 5 PRRs?
1) Toll-like receptors
2) NOD-like receptors
3) Rigl-like receptors
4) C-type lectins
5) Scavenger receptors
What are the 8 types of cell of the innate immune system?
1) Macrohpages
2) Dendritic cells
3) NK cells
4) Neutrophils
5) Eosinophils
6) Mast cells
7) Basophils
8) Epithelial cells
What is meant by pattern recognition receptors?
Its an inclusive term for antigen recognition receptors in the innate immune system
What are 2 things that PRRs commonly recognise?
Pathogen associated molecular patterns (PAMPs)
Danger associated molecular patterns (DAMPs)
Is there diversity of type in PRRs?
Yes, but each immune cell carries identical receptor of a given type
What are the 2 broad groups of PRRs?
1) Cell surface (transmembrane) and intracellular receptors - TLRs, NLRs, RLRs, CLRs
2) Fluid-phase soluble molecules
Which 2 PRRs recognise LPS?
TLR4
CD14
Which 2 PRRs recognise Triacylated lipopeptides?
1) TLR 1
2) TLR 2
Which 2 PRRs recognise diacylated lipopetides?
1) TLR 2
2) TLR 6
Which PRR recognises flagellin?
TLR 5
Which cytokine is the first produced in response to infection?
IL1
Which intracellular PRR recognises single stranded DNA released by viruses when they begin to multiply in a cell?
TLR 9
What is the name of the fluid phase recognition molecules?
Collectins
Give 2 examples of collectins (fluid phase recognition molecules)?
1) Mannan-binding lectin
2) Surfactant protein A&D
What do collectins recognise?
Microbial complex carbohydrates
How do collectins bind to their substrate?
Bind via carbohydrate recognition domains (CRDs)
What 2 roles do collectins have once they’ve bound to their substrate?
1) Neutralisation of a pathogen
2) Recruitment of adaptive response
What do PRRs do once they have bound to their substrate?
Starts a cascade and cytokines are released to signal to the adaptive immune and innate immune system
IL1 is a cytokine released from what cells (3) and what are its 3 targets and thus effects?
Released from
macrophages, endothelia and epithelia
Effects
Endothelia - increased coagulation and inflammation
Hepatocytes - leads to increased acute phase proteins
Hypothalamus - increased fever
TNF is released from what cells 2, has what targets and thus what effects 4?
Released from
Macrophages and T lymphocytes
Targets and effects
Endothelia - increased coagulation and inflammation
Hepatocytes - increased acute phase proteins
Neutrophils - increased activation
Hypothalamus- increased fever
IL6 is released from what cells 3, has what targets and what effects 2?
Released from
Macrophages and T lymphocytes and endothelia
Targets and effects
Hepatocytes - increased acute phase proteins
B lymphocytes - increased proliferation
IL23 is released from what cells 2, has what targets and thus what effects 1?
Released from
macrophages, dendritic cells
Targets and effects
T lymphocytes - increased production IL17
What is the major role of macrophages in innate immunity? 4
1) Phagocytose and kill bacteria
2) Produce antimicrobial peptides
3) Bind LPS
4) Produce inflammatory cytokines
What is the major role of plasmacytoid dendritic cells in innate immunity? 1
1) Produce large amounts of interferon which has antitumour and antiviral activity
What is the major role of myeloid dendritic cells in innate immunity? 1
1) Strong producers of IL 12 and IL 10
Where are plasmacytoid dendritic cells found in the body? 2
T cell zones of lymphoid organs
Circulate in the blood
Where are myeloid dendritic cells found in the body? 4
T cell zones of lymphoid organs
Interstices of lung heart and kidney
Skin epithelia and thymic medulla
Circulate in blood
What is the major role of natural killer cells in innate immunity?
Kill foreign and host cells that have low levels of MHC+self peptides
They express NK receptors that inhibit NK function in the presence of high expression of self-MHC
What is the major role of neutrophils in innate immunity?
Phagocytose and kill bacteria and produce antimicrobial peptides
What is the major role of eosinophil’s in innate immunity?
Kill invading parasites
What is the major role of mast cells and basophils in innate immunity?
Release TNF, IL 6 and IFN in response to a variety of PAMPs
What is the major role of epithelial cells in innate immunity?
Produce antimicrobial peptides
Tissue specific epithelia produce mediator of local innate immunity eg. lung epithelia cells produce surfactant proteins that bind and promote the clearance of lung invading pathogens
What are the 2 primary lymphoid organs and what takes place there?
1) Bone marrow
2) Thymus
Lymphocyte development and selection - bone marrow for B cells and thymus for T cells
What are the 3 secondary lymphoid organs and what takes place there?
Immune response takes place there
1) Spleen (white pulp)
2) Lymph nodes
3) Mucosal surfaces
There arent enough genes to code for every kind of B or T cell receptor, how is such great variability achieved?
VDJ recombination
Which region of the Ab binds to immune cells?
Fc region
Which region of Ab binds to Ag?
Fab region
Which kind of T cell do APCs present Ag to? And then what happens?
Present to helper T cells CD4
If Ag is foreign then they are recognised by T helper cells which are then activated and produce various cytokines which are needed by B cells, T cells etc.
How do different components of the immune system communicate? Why is this clinically relevant?
Communicate through the production of cytokines
Relevant to therapeutics as new drugs being created are Ab which knock out certain cytokines thus preventing certain parts of the immune response
What are human leucocyte antigens?
6 families of proteins coded for by genes in MHC 2 classes, class 1 and class 2 (HLAs are the same thing as MHC proteins!)
What are the 3 HLAs in Class 1, where are they found?
1) HLA-A
2) HLA-B
3) HLA-C
MHC/HLA class 1 are found on all body cells
What type of T cells to HLA class 1 present peptides to?
cytotoxic T cells
What are the 3 HLAs in class 2, where are they found?
1) HLA-DP
2) HLA-DQ
3) HLA-DR
MCH/HLA class 2 are found only on APCs
What type of T cells do HLA class 2 present peptides to?
Helper T cells
Binding of Ab to Ag inactivates Ag by what 4 methods and leads to what 2 things which damage the pathogen?
1) Neutralization (blocks viral binding sites/coats bacteria)
2) Agglutination of microbes (sticks them together)
3) Precipitation of dissolved Ag (clumps them together causing them to precipitate out)
Above 3 lead to enhancement of phagocytosis
4) Activation of complement system
Above leads to cell lysis
Dendritic cells activating a Th1 CD4+ T cell leads to what kind of response?
Cytotoxic T cells and macrophages are activated
B cells produced IgG antibody
Inhibition of Th2 responses
Dendritic cells activating Th2 CD4+ T cells leads to what kind of response?
Causes eosinophils to kill invading parasites
Activates mast cell and basophils
Causes B cells to make IgM, IgG, IgA and IgE Ab
Inhibition of the Th1 responses
What are the cytokines of adaptive immunity? ie. those produced by T cells? 7
1) Lymphotoxin
2) IL-2
3) IL-4
4) IL-5
5) IL-13
6) IL-17
7) IFN-gamma
What are the 3 uses of immunosuppression?
1) To prevent transplant rejection
2) Autoimmune disease
3) Lymphoproliferative diseases
What 2 diseases are patients with immunodeficiency related to poorly functioning PRRs prone to?
1) Pneumococcus
2) HSV
What 3 diseases are patients with immunodeficiency related to poorly functioning phagocytes (macrophages and neutrophils) prone to?
1) CGD
2) Staphylococcus
3) Aspergillus
What diseases are patients with immunodeficiency relating to poorly functioning B cells prone to?
1) Recurrent sino pulmonary infections
What disease are patients with immunodeficiency relating to poorly functioning complement proteins prone to?
Meningococcus
What kind of pathogens are patients with immunodeficiency relating to cytokines more vulnerable to?
Mycobacterium
What 2 diseases are patients with immunodeficiency related to effector T cells prone to?
1) SCID
2) Opportunistic infections
What are the 4 types of hypersensitivity reactions?
1) Type I - IgE mediated reaction
2) Type II - Cytotoxic reaction (Ab dependent cell mediated cytotoxicity)
3) Type III - Immune complex reaction
4) Type IV - Cell mediated reaction
Which type of hypersensitivity reaction is anaphylactic?
Type I
What are the 3 clinical features of a Type I hypersensitivity reaction?
1) fast onset - 15-30 mins
2) Weal and flare
3) Can have 2nd phase (late) reaction
Hay fever and allergic asthma are examples of what kind of hypersensitivity reaction?
Type I
What are the main players in the early phase and late phase reactions of a type I hypersensitivity reaction?
Early - mast cells and IgE
Late - CD4 T cells
How does sensitisation and the early phase reaction of a Type I hypersensitivity reaction work?
1) Exposed to an allergen
2) B cell has a receptor that recognises this allergen and presents allergen to CD4 cells
3) CD4 cells release IL 4 causing IgE Ab to be produced by plasma cells aswell as the formation of some memory cells
4) The IgE Ab binds to the IgE Fc receptor on the mast cell - cross linking the FcR1 (IgE receptor)
The above process is sensitisation
5) On re-exposure to the same allergen, it binds to the IgE receptors on the now-sensitised mast cell inducing degranulation of pre-formed mediators and synthesis of lipid mediators leading to allergic response
What are the 3 pre-formed mediators released from mast cells on degranulation and what is their major role?
1) histamine - stimulation of irritant nerve receptors, smooth muscle contraction, increase in vascular permeability
2) Kallikrein - activates bradykinin - similar actions to histamine
3) Tryptase. -role unclear
The substances released from a mast cell in degranulation in a type I hypersensitivity reactions act on what 6 things?
1) Smooth muscle
2) Blood vessels
3) Mucous glands
4) Platelets
5) Sensory nerve endings
6) Eosinophils
What are the lipid mediators synthesised in the early phase reaction of a type 1 hypersensitivity reaction?
1) Leukotrienes
2) Prostaglandins
Synthesised from arachidonic acid
What is typical of the binding of IgE?
Permits stable binding (ie. to mast cell) over long periods
What 3 types of cell are involved in the late phase response of a type I hypersensitivity reaction and what is their role?
1) Basophils - similar properties to mast cells over a long time scale
2) Eosinophils - granules contain cytotoxic proteins, attracted to sites of allergic inflammation by chemokines, in tissues they release the contents of their granules which is a major source of tissue damage in allergic response
3) T cells (do have a role in early phase) - in late phase it is the cytokine production by T cells which is critical in ongoing response
Asthma, rhinitis, dermatitis and food allergies are examples of what kind of hypersensitivity reactions?
type I
What is the process of a hypersensitivity type II reaction?
1) Binding of an Ab to target Ag on cell membrane results in:
2) Activation of the complement cascade resulting in cell lysis
3) Aggregation of Fc portions of immunoglobulin/C3b resulting in opsonisation, phagocytosis and destruction
Which kind of hypersensitivity reaction has an early and a late phase response?
Type I hypersensitivity
What kind of immunoglobulin is involved in Type II hypersensitivity reactions?
Initiated by IgM or complement binding IgG, IgM is most efficient as its pentavalent (has 5 bits), but IgG requires multiple binding
What kind of cells are normally effected by Type II hypersensitivity reactions?
Haematopoietic cells
Name 4 examples of hypersensitivity reactions?
1) Blood group incompatibility
2) Autoimmune haemolytic anaemias
3) Those affecting neutrophils
4) Those affecting platelets
What is the basic process of a type III hypersensitivity reaction?
Ab becomes attached to Ag but doesnt activate T cells
They stay attached as a complex, go round the body and deposit in various places causing a local inflammatory response - if in large enough quantities this can activate the complement system leading to tissue damage
What are the 6 steps involved in type III hypersensitivity reactions (complicated version)?
1) IgG and Ag = Ag/Ab complex - this deposits in parts of the body, if they accumulate in large enough quantities you get activation of the complement system and the following occurs
2) FcR in complex bind C1q
3) Complement activation leads to generation of activated complement fragments
4) C5a - attractant for neutrophils
and C3b is involved in opsonisation (opsonin)
5) Attempted phagocytosis of complexes - release of enzymes, oxygen radicals
6) Consequence is tissue damage
Which type of immunoglobulin is involved in Type III hypersensitivity reactions?
IgG
What is the main consequence of a type III hypersensitivity reaction?
Tissue damage
What is the resulting disease from a type III hypersensitivity reaction when immune complexes are deposited in blood vessel walls?
Vasculitis
What is the resulting disease from a type III hypersensitivity reaction when immune complexes are deposited in renal glomeruli?
glomerular nephritis
What is the resulting disease from a type III hypersensitivity reaction when immune complexes are deposited in joint spaces?
arthritis
What is the resulting disease from a type III hypersensitivity reaction when immune complexes are deposited in the perivascular area?
Arthus reaction
What is the resulting disease from a type III hypersensitivity reaction when immune complexes are deposited in the alveolar/capillary interface?
Farmer’s lung
Is a type IV hypersensitivity reaction Ab or cell mediated?
Cell mediated
Why is Type IV sensitivity often called the delayed type?
The reaction takes 2 to 3 days to develop
What is the basic process of a type IV hypersensitivity reaction?
1) Type 4 reactions are mediated by T lymphocytes which react with an Ag and release IL2 INF-gamma and other Th1 cytokines
2) Once the T lymphocytes have been sensitised 2nd challenge is followed by a delayed type hypersensitivity reaction
3) This a localised inflammatory response which takes 2-3 days to develop
4) Histologically these reactions consist of infiltrating T lymphocytes, macrophages and occasional eosinophils - no Ab are involved!
‘Inactivation’ is another antibody-mediated immunopathology and is sometimes referred to as Type V hypersensitivity, give 3 different types of inactivation and an example for each?
1) Direct - eg. inactivation of intrinsic factor - pernicious anaemia
2) Indirect - binding to, eg. hormone results in clearance of AgAb complex
3) Receptor blockade eg. To AChR in myasthenia gravis
What type of hypersensitivity is contact dermatitis?
Type 4
The tuberculin skin reaction is which type of hypersensitivity reaction?
Type 4
How does the tuberculin skin reaction work?
1) Small amount of mycobacterium tuberculosis is injected intradermally (Mantoux test)
2) In individuals with no immunity there is no effect
3) In individuals with previous exposure as a result of TB infection of BCG vaccine you get a local inflammatory response as T cells have already been sensitied
4) Langerhan’s cells present Ag to T cells which produce cytokines
5) Get infiltration of lymphocytes and macrophages around the small blood vessels and the activated macrophages cause tissue damage
What happens in contact dermatitis?
1) Small amounts of Ag (eg. nickel or poison ivy) bind to covalently to tissue or skin proteins - the sensitising agent is known as a hapten and the protein as a carrier
2) The hapten-carrier complex is presented as an Ag by Langerhan’s cells in conjunction with MHC II to CD4+ cells
3) Induction of T cells normally occurs after months of exposure to an Ag
4) Re-exposure to that Ag triggers the elicitation phase where effector T cells migrate to the epidermis to meet the Langerhans cells presenting the complex and release cytokines leading to skin inflammation
Which type of T cells are involved in granulomatous reactions and what do they release?
Th1 type - release IL2 and IFN gamma
Release of what cytokine by macrophages is critical in initiating a granulomatous reaction?
IL-12
Granulomatous reactions can be caused by what 3 mycobacterium infections?
1) Tuberculosis
2) Atypical mycobacterium
3) Leprosy
^Tuberculoid Th1 - Protective
^Lepromatous Th2 - Non Protective
Name 3 granulomatous diseases with unknown aetiology?
1) Sarcoidosis
2) Wegener’s Granulomatosis
3) Crohn’s disease
