Immunology Flashcards
What is the role of the immune system?
Detect and respond to threat
Minimising collateral damage
Retaining memory in case of future infection
What does an immunodeficiency lead to?
INC infection/cancer susceptibility
Abnormal regulation/function leading to autoimmune disease
What is involved in the normal function of immune system?
To identify and eliminate harmful microorganisms/subs by distinguishing self from non-self and abnormal-self (cancer) as well as identifying danger signals e.g. Tissue damage
Compare generation times of bacteria vs viruses
Bacteria replicate in mins
Viruses replicate in hrs
What are the 2 strategies for recognising danger?
#1 Germ-line encoded #2 Random recombination
What is involved in the germ-line encoded strategy for recognising danger
Genes code for 100s of specific, non-changing receptor proteins for molecular patterns; many cells have same receptors so v rapid and effective response, yet limited diversity so some pathogens not recognised
What is involved in the random recombination strategy for recognising danger
Mills of receptors to recognise specific structs using rand recomb of gene segments; few cells express each receptor, so must replicate for effective response, massive diversity allows for recognition of all structures
Pattern Recognition Receptors (PRRs) use either……
PAMPs (pathogen associated molecular patterns) OR DAMPs (damage AMPs)
What does PAMP stand for
Eg.s of PAMPs
Pathogen-Associated Molecular Patterns
eg. Bacteria, Virus, Fungus, Parasite
What does DAMP stand for
Eg.s of DAMPs
Damage-Associated Molecular Patterns
Cell (inv. Necrosis) Extracell Matrix (inv. Injury- fragments from aggrecan, fibronectin, collagens etc)
What do PAMPs do?
Manipulate differences in human and pathogenic cells
What do DAMPs do?
Recognise damage through ECM fragments from damage or proteins released after Necrosis
What do B cells do?
Bind to intact antigens w surface receptor antibody
What do T cells do>
Have T-cell receptors w a/B chains which bind to processed antigen fragments called epitopes that have been presented on cell surfaces
What is innate immunity?
Uses PPRs so independent to antigen exposure; fast and depends on rapidly synthesised components that have a limited specificity
- destroys invading nucleic acids in cytoplasm, activates inflammatory pathways and elicits type 1 interferons for anti-viral defence (buys time for adaptive immunity and promotes appropriate immune response)
What is adaptive immunity?
Adaptation to exposure that depends on clonal selection so is slower yet highly specific to foreign antigens
Differences between innate and adaptive immuntiy
Innate uses PPRs, independent to antigen exposure, fast, limited specificity
Adaptive depends on clonal selection, slower, highly specific to foreign antigens
Innate immune response is ______ specific
Adaptive immune response is ______ specific
INN- Pattern
ADAP- Antigen
What 3 cell types are linked to both innate and adaptive immunity types
Basophils/mast cells
Dendritic cells
Natural Killer (NK) cells
Define clonal diversity
During B / T cell development random genetic recombination occurs within each cell w multiple copies of immunoglobulin gene segments to prod. single, unique antigen receptors
Define clonal response
Mills of diff lymphocytes in body expressing Mills of receptors that will lead to proliferation if they bind to their complimentary antigens
Where are the T cells distributed
2% T cells in blood,
98% in lymph/organs
Define clonal selection
Activation of naïve lymphocyte leads to replication of only this one (antigens typically recognised by 1 in 105 naïve T cells
What is/happens at the primary lymphoid organ?
Lymphocytes are prod. by lymphopoiesis (lymphoid stem cells differentiate to mature funct. lymphocytes - thymus and bone marrow)
What is/happens at the secondary lymphoid organ?
Lymphocytes interact w antigens and each other eg. Spleen, lymph nodes and mucosal associated lymphoid tissues (MALT)
What does MALT stand for
Mucosal Associated Lymphoid Tissues
All lymphocytes are derived from…..
Precursor bone marrow stem cells
The Thymus -
Septum divides ____ to lobules and Hassall’s _____ have ______ cells that are involved in the formation of _________; dark staining regions around outside of lobule = cortex; light staining region in middle = medulla (full of maturing/proliferating T-lymphocytes)
lobes lobules corpuscles fibroblast regulatory T-cells
How does the thymic output change?
Declines w age
fewer T-cells prod.
Total no. does NOT change as highly regulated
What is the bone marrow the site of>
Haematopoiesis
& INC white cell prod. during infection
(visible change)
How do the organs involved in Harmatopoiesis change from foetus to adults?
Foetus: bone marrow very cellular, and liver/spleen involved in haematopoiesis
Adults: large, flat bones involved in haematopoiesis - NO LIVER/SPLEEN
Lymphatic system: fluid drained from ________ are absorbed into lymph with ____ litres returned to blood each day via duct to SVC
Btwn tissue cells
2-3
What does the lymph node do?
Filters antigens in lymph
Afferent/Efferent lymphatic vessels bring lymph fluid into/out of node
FLuid collected is filtered thru lymphocytes so can react if antigens = present
Lymphoid cells on outside of lymph nodes tend to be…
B cell aggregates in follicles
If ongoing immune response, B cells in lymph node will proliferate & prod. _____ in ________
Antibodies
Germinal centres
What is a high endothelial venule
Specialised area of artery w much thicker endothelium causing T/B-cells to leave circulation & enter the lymph node
B-cells go to follicles on outside whilst T-cells move closer to centre following chem signals (Chemokines)
What is a germinal centre seen as?
Distinct spheres of proliferating B-cells
What does the spleen do?
Filters antigens in the blood (while lymph nodes do same for antigens in lymph)
In the spleen there is white pulp where _________ and red pulp where ___________
(what colour do red/white stain)
WHITE - Lymphocytes reside (stains dark purple)
RED - Erythrocytes present (stains lighter purple)
What does the PALS (Periarterial lymphatic sheath) within the spleen do?
Immediately surrounds arteries (in white pulp) w predominantly T-cells
What is the first line of bodily defence against infection?
Mucosae and skin (physical barrier) w a large SA & single layer of cells
Gut: _______ lymphocytes reside on villus
Intraepithelial
Villi of the gut has lymphatic drains to _________
Mesenteric Lymph nodes
What are Peyer’s patches
Large aggregates of lymphocytes/follicles espec B-cells that drain to lymph nodes
Specialised mucosal epithelium over Peyer’s patches contain…..
Microfold cells which sample antigens in gut to pass to present to lymphocytes in patches to allow for surveillance
WHat does the cutaneous immune system do?
Lymphatic vessels drain from skin & intraepidermal lymphocytes present; epidermal langerhans (specialised dendritic cells) - capture & present antigens, migrating through lymphatic vessels to lymph nodes
Define immune system recirculation
Primary lymphoid tissues prod. naive lymphocytes that enter blood & circulate btwn blood and secondary/peripheral lymphoid tissues till react or die
WHat happens during extravasation of naive T-cells into lymph nodes:
Lymphocytes roll along cell surf & bind to Selectin and CD34, and chemokine receptors on T-cells bind to chemokines on cell surface membrane to change the conformation of integrin
What are the steps involved in extravasation (3 steps involved)
1) Naive T-Cell roll along endothelium until they reach the HEV
2) Selectin binds weakly to endothelial CD34
3) Chemokines present on surface of HEV bind strongly to receptors on T-Cell, causing integrins to have a higher affinity, allowing movement over endothelium into lymphoid tissue
Define lymphocytes
Small cells w a granular cytoplasm & large nucleus
- divided into 2 groups depending on where produced (b=bone marrow, t=thymus) - CANNOT be differentially stained
T-lymphocytes all express _____
90% have ……
10% have ……
ALL = CD3
2/3 have CD4
1/3 have CD8
90% have an alpha beta T cell receptor
10% have gamma delta T cell receptor
Describe what occurs during T-cell antigen recognition
T-cells recognise processed antigens presented @ cell surface using a TCR presented by a major histocompatibility complex (MHC)
What type of receptors do B-lymphocytes have?
IG like surface receptors expressing CD19 and CD20 (NOT 3/4/8 as in T),
express MHC Class II so can present to TH cells & prod. antbodies; recognise intact antigens in body fluids not on cell surfaces using a B cell receptor
What do antigen presenting cells do?
Present processed antigens to T-Cells to initiate adaptive immune response including B-Cells, dendrite cells and activated macrophages
Define innate immunity
Rapid cellular/soluble component immune response present from birth, using PAMPs/DAMPs to detect microbial structures and damage
What are the anatomical defensive barriers?
Skin (mechanical barrier, acidic environment) and Mucous membranes (secretions trap microbes and cilia expel)
What are the physiological defensive barriers?
Fever (doesn’t favour replication by microbes), Low pH in stomach (kills many ingested microorganisms), Chemical mediators (lysozymes, interferons, complement)
Define neutrophils
Phagocytes w multi-lobed nucleus (polymorphonuclear granulocytes) - relatively short lived cells that circulate in blood then migrate to tissues - first cells to be recruited to a site of tissue damage
What are the first cells to be recruited to a site of tissue damage?
Neutrophils
Define Eosinophils
Phagocytic, releasing granules & defend against parasitic infection; stain w eosin and help w B cell responses in producing IgA
Define Basophils
Release granules, may act as antigen presenting cells for “type 2” immunity - antibody mediated
Define Monocytes/macrophages
Important for phagocytosis, and release cytokines as mediators when do; also present fragments of antigens on surface to T-cells
Define what Mast cells do
Release granules containing histamine (pro-inflammatory)
Define what Dendritic cells do
Capture antigens and present these to T-cells
Define what Natural Killer cells do
Lyse infected cells
Neutrophils: exit circulation & enter tissues to bind to pathogens, phagocytose AND kill them:
1) Roll along surface of blood vessels, ____ weakly binds to lining
2) Macrophages release_____ if ingesting microorganisms that bind to surface of endothelium, allowing rolling neutrophil to bind tightly with______ and migrate thru the endothelium
3) More ______ near site of infection, so moves along gradient toward site of infection
selectin
chemokines
integrins
chemokine molecules
What happens during Opsonisation?
Micro-organisms coated w proteins to facilitate phagocytosis - antibody and complement both function as opsonins
What are opsonins?
Molecules that bind to antigens and phagocytes
What is the oxygen independent neutrophil killing mechanism?
Enzymes (lysozymes, hydrolytic etc.) and antimicrobial peptides
What is the oxygen dependent neutrophil killing mechanism?
free radicals, nitric oxide, nitrogen intermediates, singlet oxygen, hydroxyl radicals, hydrogen peroxide and superoxide anion
What are neutrophil extracellular traps?
Activated neutrophils which release granule net-like materials that form extracellular fibres to trap microbes, in turn killing the neutrophils but allowing phagocytosis
Macrophages
_________ in blood
_________ in tissue
monocytes
macrophages
-> Granules fuse w phagosomes to digest ingested material
What is the function of Macrophages?
Receptors for microbes, upon binding & ingesting, release soluble cytokine mediators to recruit further cells
What do mast cells secrete?
Histamine and other inflammatory mediators eg. cytokines
Where are mast cells found?
Near mucosa and near connective tissue
What type of receptors do mast cells have?
Pattern recognition receptors to recognise bacteria for subsequent phagocytosis (can be activated by complement products - anaphylatoxins)
Describe what NK cells do?
- No antigen-specific receptors
- Lyse cells
- Secrete interferon-y
- Activatory & Inhibitory receptors
- Binds Antibody coated cells
Target cell recognition: under viral stress, cell upregulates ______ that activate ____ cells and downregulate ___________ so ____ cells are not inhibited to kill cell
stress-induced molecules
NK
inhibitory molecules
NK
What are cytokines?
Small proteins
Secreted for local, short-lived cell-to-cell communication
What 5 forms of cytokines?
- Interleukins: btwn leukocytes
- Interferons: anti-viral effects - interfere with replication
- Chemokines: chemotaxis (cell movement)
- Growth factors: help stem cells to differentiate and proliferate
- Cytotoxic tumour necrosis factors: induce programmed cell death in target cells
Steps in cytokine prod:
- Stimulus in cytokine prod. cell causes…
- Cytokines bind to specific receptors on other cells, affecting….. and causing biological effects
Production & granule fusion w the memb
Gene expression in target cell (up/downregulate 100s of genes)
Define autocrine
Cytokines act on self
Define paracrine
Works on nearby cells
Define endocrine
Travel via circulation to distant cell
Dendritic cells produce cytokines and are a network of cells located near __________(eg. skin and mucosal surfaces); they have ________ receptors and will capture ________
likely Sites of infection
pattern recognition
pathogens before migrating to lymph nodes to present antigens
WHat does the complementary system have a major role in complementing?
The activity of specific antibody in bacteria
The complementary system is a complex series of around 30 proteins and glycoproteins that leads to _____________ in a rapid response
Components are present as __________ by ____, but part of peptide must be cleaved to activate; substrate is next enzyme in pathway, so will cleave and activate, leading to sequential activation of subsequent enzymes to amplify number of activated molecules
Cleavage waste is __________ so signals to nearby cells - causes mast cells to degranulate
triggered enzyme cascade system
inactive enzyme precursors
liver
proinflammatory molecule
What are the 3x activation methods of the complementary system?
WHat is the same about all of the 3x different activation methods?
ALL converge to activated C3b which opsonises antigens/pathogens
Classical Pathway
- AB bound to antigen forming immune complex
Lectin Pathway
- Lectin proteins that bind to carbs on bacteria to trigger complementary system
Alternative Pathway
- Bacteria directly trigger complementary system
What is the final common pathway?
When C3b is activated, the membrane attack complex forms holes in bacterial cell membrane
-> Causes loss of integrity
What are the functions of the complementary system?
- Cell lysis
- Opsonisation
- Pro-inflamm effects
- Clearing of immune complexes
What is the system “acute-phase” response?
After 1-2 days
fever, INC prod. WBCs and acute phase liver proteins induced by cytokines
Define antibody
Protein prod. in response to foreign antigen, specifically binds to antigens
Define Immunoglobulins
Protein class Soluble glycoproteins
What are Fab fragments?
Bind to antigens
Not variable as did not crystallise
What are Fc fragments?
Will crystallise therefore homogenous sequence (constant region)
What does the hinge region of the antibody allow?
Flexible binding to antigens, so Fab regions can move to bind to more widely spaced surface proteins/determinants
Where are Fab/Fc fragments located on antibody?
Fab= antigen binding site Fc= heavy chain
Both light and heavy chains have constant regions but then variable regions are where ……
Where antigens bind
-> allows specificity
Explain the hypervariable regions of antibodies?
Complementarity determining regions which interact w antigen
-> Ensures specificity, aligned to loops @ end of variable domains; disulfide bridges exist btwn B-pleated sheets
What forces are involved in antigen binding?
All forces = non-covalent
eg. Hydrogen, ionic, hydrophobic, VDW
Define antibody affinity?
Strength of total non-covalent interactions btwn single AB binding site and single epitope on antigen
WHat is the association constant K for antibodies?
K = [Ab-Ag] / [Free Ab] [Free Ag]
What is antibody avidity?
Overall strength of multiple interactions btwn an AB w multiple epitopes -
eg. Monovalent = low
Bivalent = High
Polyvalent = V High
What is an epitope?
Part of antibody which binds to the antigen
WHat is antibody cross-reactivity?
AB which can recognise different similar antigens
How do different classes of antibodies differ from each other?
Differ in constant region of heavy chains IgG/A/M/E/D with gamma/alpha/upsilon/sigma/epsilon heavy chains and kappa or gamma light chain
What are the subclasses of antibodies?
IgG has IgG1-4
with gamma 1-4
IgA has IgA1-2
with alpha 1-2
What is the most abundant class of antibody?
IgG - gamma heavy chain
Describe the IgG class of antibodies:
- Variability btwn subgroups usually in hinge region
- Actively transported over placenta to give baby passive immunity
- Found mainly in blood and ECF
- Major activator of classical complement pathway
What is the 2nd most abundant class of antibody?
IgA - alpha heavy chain
Describe the IgA class of antibodies:
- Occurs in monomer in blood & dimer in secretions
- Major secretory immunoglobulin to protect mucosal surfaces
- J chain forms!!!
- Binds to basolateral surface of epithelial cells (onto Poly-Ig receptor), allowing endocytosis to vesicle where receptor is cleaved, yet part remains that forms a dimer secretory IgA with a longer half life to neutralise pathogens in lumen upon release
Describe the IgA class of antibodies:
- Forms pentamers: 5 monomers joined by J chains
- Mainly in blood
- 1st Ig synthesised after exposure
- Multiple binding sites compensate for low affinity
- Efficient for agglutination and activating complement
Describe the IgD class of antibodies:
- Extremely low serum concentrations
- Surface IgD expressed in early B cell development
- Involved in development and activation
Describe the IgE class of antibodies:
- Present at low levels
- Prod. against parasites and in allergy
- Binds to high affinity Fc receptors of mast cells and basophils
- Cross-linking by antigen triggers mast cell activation and histamine release (hence allergic reaction)
- When IgEs linked by allergen causes degranulation
What type of heavy chain do the following classes of antibodies have: IgG IgA IgM IgE IgD
Gamma Alpha Upsilon Epsilon Sigma
Where are the immunoglobulins (Igs) distributed?
IgG and IgM in blood
IgG in ECF
Dimeric IgA in epithelia & breast milk
What are 5 consequences of antibody binding to antigen
Neutralisation Agglutination Opsonisation Complement activation Bound by cells w Fc receptors
What is the main driver of adaptive/memory immune response
Lymphocytes
What are SCID babies?
Severe Combined ImmunoDeficient kids
- cannot fight infections as no T and B cells §die
Define innate immunity
Generic & early response
- CONTROLS INFECTION
Define adaptive immunity
Improves efficacy of innate immune response, focussing on site and organism, has memory and needs time to develop
- CLEARS INFECTION
2ndary response, stronger and faster
Define antigens
Proteins/mols that induce adaptive immune response
Difference btwn linear and structural epitopes?
Linear = recognised by T-cells; recognise sequence
Structural = recognised by antibodies; recognise structure
What 2 cell types are involved in a humoral response
B-cells and antibodies
What cells are involved in cell-mediated response
T-cells w cytokines and killing
Define what B-lymphocytes are
WBCs derived from haematopoietic stem cells that are effector cells of humoral immune system, secreting ABs & becoming memory cells
Describe the 4 steps of clonal selection
#1 Each lymphocyte bears single, unique receptor #2 Develop panel of T/B-cells when growing #3 Interaction btwn foreign antigen & receptor on naïve cell leads to activation #4 Activation leads to transition to effector state (and later memory state) & clonal selection
In natural recombination to prod. lymphocytes, some will be produced against self antigens that would lead to an autoimmune response. How is this controlled?
Selection pathway destroys those reacting w self
B-cell receptors are ______ and have unique binding sites where ___________
They are attached to _________ that can transduce signals to cascade mols
ABs
Antigenic determinant/epitope can bind
Transmembrane domains
B-cell receptors are a transmembrane protein complex composed of ….
Monomeric immunoglobulin and di-sulfate linked heterodimers of IgA and IgB on either side for signalling
B-Cell Receptors-
Cytoplasmic tails of IgA and IgB contain_______ that allow for intracellular signalling
ITAM domains
On B-cell receptor binding to antigen, structural changes occurs that leads to …..
IgA and IgB signalling into cytoplasm
Each BCR chain (kappa, lambda and heavy chains) encoded by separate multigene families on _______, and these are rearranged during maturation to form unique BCRs
different chromosomes
WHat do T-cells do?
Detect and combat INTRACELLULAR pathogens - as antigens can only destroy extracellular pathogens
What is the only sub able to destroy extracellular pathogens
Antigens
T-cell receptor is used to detect infected cells.
How do they do this>
Antigen presented on MHC molecule of host infected cell
analogous in struct to Fab region of antigen
What allows for association w CD3 polypeptides (expressed by all T-cells) for signalling
Charged residues in membrane
What is a CD4 receptor
Co-receptor that recognises antigens on MHC Class II molecules (class II restricted)
WHat is a CD8 receptor
Co-receptor that recognises antigens on MHC Class I molecules (class I restricted)
What do co-receptors bind to? What effect does this have?
Bind to invariant region of MHC;
INC avidity of T cell-target interaction and for signalling
CD4 cells (Th cells) secrete….
Cytokines to recruit effector cells and activate macrophages
CD8 cells (Tc cells) are cytotoxic and there function is to…
Kill target cells by secreting cytokines to induce apoptosis
What does the Major Histocompatibility Complex do?
Displays sample of internal cell contents @ cell surface for immune cell recognition
-> Markers of self/health & continuously present peptides even when not infected
MHC are a group of tightly linked genes for immune responses, molecules present antigens to….
T-CELLS
MHC Class I has ____ transmembrane and ____ cytoplasmic region. They also have immunoglobulin-like regions with…..
one
one
a single beta chain that is non-covalently bonded
MHC Class II has ____ transmembrane and ____ cytoplasmic region. Both polypeptides are same size, larger than the ones in MHC I with peptides spanning length of whole MHC being ___ AAs
Two
Two
>13
Where are the two types of MHC genes expressed?
- MHC Class I: all nucleated cells, though levels may be altered during infection or by cytokines
- MHC Class II: normally only on professional antigen presenting cells and may be regulated by cytokines - activated naïve T-Cells
What do antigen presenting cells do?
Present processed antigens to T-cells to initiate adaptive immune response, including dendritic cells, B cells and macrophages
Where do endogenous antigens come from?
Inside cells
eg. virus infected cells- use CD8 Class I restricted T-cells
Where do exogenous antigens come from?
Outside cells
eg. phagocytic and antigens captured and presented on B-cells- use CD4 Class II restricted T-cells
