Immunology Flashcards
Parent, undifferentiated cells
Self-renew, “immortal” - can outlive 6x, daughter cells have function
Totipotent
All cells have stem cell properties
Erythrocytes
No nucleus or ER and live for 120 days, only have a sac of gas
Neutrophils
Migrate towards infection (chemotaxis) half life is hours
Lymphocytes
Are cytotoxic T cell - target cell instructed to die by T cell as T cell has specific antigen recognition which generates immune response (target molecule)
Macrophages
Ingest my phagocytosis
Humoral immunity
Anything soluble - immunoglobulin or antibody
Cytokines
Low Mr and are secreted - proteins that stimulate or inhabit cell differentiation and proliferation - communicate with haematopoetic cells
Interleukins
A group of cytokines that enable communication between leukocytes
Chemokines
Structurally related substance that induce chemotaxis in neutrophils and activation of leukocytes, much smaller
Interferons
Soluble glycoproteins of cytokines, interfere with viral inections
Antibodies
Multi-chain glycoproteins that are produced by beta-lymphocytes and contain a very variable antigen binding site and a functional/constant region
Complement
Soluble proteins that “complement” the action of antibodies, can also kill pathogens directly and are mainly produced by the liver
Innate immune response
No learning or memory. Can identify foreign things, no capacity to earn, pattern recognition receptor, react to generalities - evolutionary immunity to infection NK cells macrophages Neutrophils Complement cells Dendritic cells
Pattern recognition receptors
Toll-like receptors
Receptors conserved in evolution
TLR and PRR play a key role in signalling DANGER to immune system
PRRs also play a role in several physiological states
Adaptive or required immune response
All learned and memory - takes a while to produced enough cells to fight infection Learning Memory Specific antigen receptors T and B cells
Lymphocytes
T cells, B cells, NK cells
Cause specificity of immune system, large nuclei but whole barely bigger than RBC. Found in blood, tissue and lymph
Very stable - 20% of circulating leukocytes
Differentiate from common precursor - must undergo maturation to be functional
T cell
Precursor in bone marrow but must migrate to thymus to mature, express specific antigen receptor (TCR), different functional subclasses. Important in activating B cell responses, phagocyte killing of intracellular bacteria by innate system, kill virally infected cells
Helper T cells
CD4
Function to produce cytokines that support the immune response
Cytotoxic killer T cells
CD8
Function to kill virally infected cells - instruct target cell to die by clubbing membrane and chromatin collapses
What if you have no T cells?
DiGeorge syndrome - thymus does not develop, so not mature T cells produced. Immunoglobulin levels disturbed, causing candidiasis, pneumonia etc. Can survive to adulthood on innate system but virus fighting is poor, no antibodies.
B cells
Only cells producing antibodies (immunoglobulin), produced and mature in bone marrow (self/non-self testing) and express immunoglobulin (antibody) as surface antigen receptor complex. B cells and product are central to attacking extracellular pathogens e.g. bacteria. Found in peripheral blood and part of adaptive humeral response. Activate complements and opsonising (coating) bacteria in antibodies so that it can be recognised and undergo phagocytosis. Intermediate stage between introduction dn infection.
No B cells
X-linked infantile hypogammaglobulinaemia and show recurrent bacterial infection,but can be treated. IGMO initially taken from mother. B cells must learn to make own IGMO - no B cells from mother in bloodstream, so declines over time
Transient hypogammaglobulinameia - full IMGO at 6 months, but mother’s has a half life of 3 months
Can be treated with pofaltic antibiotics, blood transfusion or gene therapy to address fundamental genetic defect
Natural killer cells
Large granular lymphocytes - Innate lymphoid cells (ILCs). Detect virus infected cells by changes in cell surface molecules, kill using apoptosis and rare in blood. Express MHC molecules, exploits humeral immune system, have receptors identifying IMGO. Undergo editing - your own MHC is good, not bad -> self. Therefore, ability to infect virally infected cells and kill them is unique to you, looks like learning, but just ensures they are the right receptors for you.
Naive T cels
Haven’t encountered cognate antigen so continue to do so, respire and go back to resting state
Memory T cells
Have been activated - lots of lamellae which pumps out soluble protein antibodies (many ER and golgi)
Dendritic cells
Amplify immune response - vaccination
Antigen presenting cells
Have dendrites and are derived from lyphoic or myeloid lineages. Langerhans cells (skin), interdigitating cells (lymph node), follicular dendritic cells (B cell follicle), link innovative to adaptive immunity, present engulfed antigens to B and T cells
Mononuclear phagocyte system
Has cell types involved in phagocytosis of particles, part of the myeloid linage - 10% of circulating leukocytes are monocytes. Provoke inflammatory responses. Respond to TH1 helper cells and can intervene by blocking specific actions of the TNF alpha, allowing developments of TH2 responses. Deficiency of inflammatory responses can lead to TB.
Macrophages
Process bacteria onto cell surface - present to T cells which can recognise antigens - TH1 or TH2 response. TH1 can now provide help to be better at ingesting and killing - no learning but interacts with adaptive immune system.
Mononuclear phagocytes
Sensitive to T cell cytokines - part of effector part of immune response and phagocytised bacteria and bacteria living in macrophages are killed more efficiently when macrophages activated by cytokines. Uptake of antibody-opsonised particles and recruit inflammatory cells to sites of infection, especially neutrophils.
Granulocytes
Eosinophils Basophils Mast cells Neutrophils Are granular and innate
Neutrophils
Phagocytes and granulocytes and make up about 70% circulating leukocytes. Have a single, multi-lobed nuclei (multi-lobistic). Fine blue granules (stained with neutro dyes) contain proteases and microbial effector molecules such as defensins. Migrate to site of infection by chemotaxis migrate towards agar plug. If unable to phagocytose they for a granuloma to wall it off in which nuclei help migrate through cells (multi-lobed). Chronic granulodadu disease if can ingest pathogens but can’t kill (treat with gene therapy. Bone marrow transplant or antibiotics). Produce an oxidative burst following phagocytosis of a pathogen. reactive oxygen species (O2-) which are highly destructive radicals and kill anything they bump into. More effective if activated by T cells. No neutrophils = death half life of about 12 hours. ½ million every second of life to continue.
Eosinophils
Stain with red eosin dye. Mainly responsible for killing parasites that cannot be digested by binding to antibody-coated parasites, degraunlating and dissolving the sell surface. 1-2% circling leukocytes. Snail like structure with proteases in granules which are released when it comes into contact with thick protein coagulant into the synapse (cell and parasite), eroding away protein dense layers of parasites so macrophages and antibodies can get in and do damage.
Basophils
Circulatory and mast cells inhabit mucous and connective tissue. They are involved in the acute inflammatory response (important in allergy and hypersensitivity). Allergies mean mast cells are degranulatng in response to allergen to expel parasites. Basophils have big granules and play a role in regulation of immune response
Lymphoid stem cells
T, B, NK cells, lost potency to make any other cells
Myeloid stem cells
All other haematopoietic cells
Bone marrow
Occupies space within structural bone.
Produce all progenitors of haematopoietic system and primary repository of these stem cells
Primary site of lymphoid generation and B cell maturation
Gaps in marrow which become larger (more fatty) as we age - red haematopoeitic cells to yellow fatty marrow (adipose).
Initial phases of B cell selection take place. Partly mature B cells exported and pre-T cells -> thymus
Heterogenous - many cell types produces in haematopoietcs marrow
Homogenous has very little fat - leukaemia clones occupy marrow meaning there is inefficient haematopoiesis so not enough RBC, platelets, effector cells etc.
Thymus location and size (change in time)
Underneath sternum, skeletal bone protects the pharageal pouch
Relative size greatest at births and absolute size greatest at puberty. Relative size then declines over time. Also shows structural changes in nuclear density, inner components, area of dense nuclei conc smaller, involution to fatty tissues
Body and mass grows with thymus, maintain eduction of T cell immuity
Efficiency of T cell conversion to memory and effector cells
High - can take out thymus and very long time before T cell deficient occurs as T cell memory have effective adaptive T cell response for at least 3 decades.
Naive educated T cells
Out to fight infection, very dense nuclei in cortex and low in medulla, only 5% progress to medulla as extraordinary levels of cell death.
Thymocyctes
Actively migrate through thymus. Most die (selection) to ensure self-reactive T cells are eliminated.
T cell selection
Involves TCR and takes place within thymic epithelium. T cells with a TCR with a strong affinity for self die by apoptosis.
T cells with a TCR that has a weak affinity for self MHC do survive.
MHC regulated immune identity
Positive and negative selection in thymus - negative selection = bind strongly to MHC
Secondary lymphoid tissues
Sample environment and initiate immune response to make more effective (lymph nodes, mucosal associated lymphoid tissue and spleen)
Spleen function
Acts as a filter and samples blood, capable of increasing in size to become haematopoeitic organ if no bone marrow, high asteroid.
Monitoring of circulatory systems for pathogenic insult, development of immune response to circulatory pathogens, organisation of T cells, B cells and phagocytes promote effective development of immune response. Fe+ ions will kill if released into blood cells, so haemolysis occurs in extravascular space, recycling haemoglobin. Liver can substitute this function.
Spleen organisation
Consists of organised islands of white pulp on arterioles, surrounded by red pulp (RBC cycling) - 1 million RBC made/sec must also be removed
Germinal centre is a clone of B cells expanding for response to infection. T cells help B cells expand in germinal centre
What happens if the spleen bursts?
Cardiac output is released without restraint, but if removed before = ok
What happens if you are born without a spleen?
Severe consequences, but if removed in 20s, very minimal damage due to effector or memory T cells and cant acquire memory, allowing living without a spleen.
Lymphatic system
Small blind-ended vessels draining from tissues into lymph nodes into efferent vessels. Skin, GI and DU tracts very well supplied with lymphatic. Drains into circulatory system via thoracic duct, good system from sampling antigenic exposure of tissues, especially skin. Plasma fluid leaks from capillaries through gap junctions into extravascular fluid, every tissue has lymphatic draining into lymph nodes. Closed loop, 1 direction system back into blood.
Schematic lymph node
Afferent in
Sponge assembled of cells in immune system, allowing it to raise an immune response, should that be necessatu.
White cells
Full of leukocytes, lymphocytes etc.
Cortex of medulla
contains B and T cells
Contains activated effector cells with IMGO producing B cels.
Follicles present when lymph activated.
Medulla is where effector cells transiting and pump out IMGO
Germinal centres
Lots of cytoplasm and small nuclis
Lymph node follicle structure
Stain with monoclonal antibodies
Naive T cells come out of HEV and into lymph node - anything to interrogate? - leaves of stays
Addressins
Use selections to roll along surface, making and breaking weak adhesion forces. Finds something that activates it to stop rolling -> strong adhesions.
Binding addressing cause T cells entering lymph nodes
Associated secondary lymphoid tissues
Almost all mucosal tissues have - Peyer’s patch, appendix, tonsils and lung
Mucosal associated lymphatic tissue
Tertiary lymphoid tissue
Temporal and transitory
Sites of effector responses and skin and sites of inflammation
Lymphocyte trafficking
T cells migrate out of lymph nodes mainly memory T cells, naive T cells retained. Memory mainly in gut and naive mainly in lymph nodes. Move out of skin to lymphatic system where infection is. Naive T cells out of blood, if they discover TCR binds to antigens from skin = activated
Functions of Immunoglobulin
Bacterial toxins -> neutralisation -> ingestion by macrophage
Bacteria in extracellular space -> opsonisation -> ingestion by macrophage
Bacteria in plasma -> complement activation -> lysis and ingestion
How structure of IMGO relates to function
Variability in V region is not randomly distributes - heavy and light chains
V region invariability is clustered around the antigen binding site - CDR (complementary determining region)
IMGO antigen binding site shows tremendous variety. A single B cell will produce an antibody with a single specific. Random generation of variable regions by recombination of genomic elements, editing process ensures only one specificity is determined for each B cell. But the antibody in the secondary response is qualitatively better at fighting infection
Hyper-IgM syndrome
Lymph node biopsy shows the absence of germinal centres
Isotypes of IMGO
5 different - some can form multimers
Isotopes present in different parts of the body e.g. IgG can get into tissues and transfer to babies by the placenta. Each different isotype has a different function. IgM (monomers) and IgD can act as receptors on naive B cells as IMGO can have transmembrane regions and act as receptors or can be secreted as soluble proteins in the absence of TM regions. IgM is good at complement activation. Also good at activating NK cells. IgA good for mucosal surfaces
Eosinophils utilise…
IgG and IgA bound to Fc receptors to attack parasites.
IgE
Good at activating mast cells
Histocompatability
e.g. skin grafts are a measure of tissue matching
Minor histocompatibility loci
Some genetic loci found to influence skin graft acceptance, but not dominant - scattered all over the genome
Major histocompatibility complex
Genetic loci which have a significant effect on tissue graft acceptance found to be clustered together in the genome.. This complex of loci has different names in different species. Humans = HLA, mouse = H-2
Differences in MHC control tissue graft acceptance
MHC loci to be highly polymorphic
Allogenic
Differences at various loci result in graft rejection, however may be trained to accept if they saw the tissue through development
Syngenic
If alleles of the MHC are matched between individuals, graft is usually accepted (identical twin)
Autologous
Self-graft
Why are MHC molecules vital?
Presentation of antigen to T cells. T cells recognise antigens as peptides - antigenic peptides have to be resented to T cell receptors by MHC molecules, B cells do not need MHC molecules to “see” antigen. IMG can be recognised 3D structures with CDR. MHC has at least 2 independent functions - immune identity and presenting peptides to T cells
MHC class I molecules
1 heavy chain (very polymorphic), 1 beta-microglobulin chain which is not very polymorphic or encoded within MHC.
90 AA long and intra-sulphide bond in heavy chain
To get crystal structure, must provide MHC. Impossible to crystallise MHC without having string - cant get MHC Class I on surface of cell in absence of peptide.
Peptide intimately bound non-covalently to structure of class I heavy chain. Thousands of peptides in peptide groove. The MHC class I peptide binding groove can only bind one peptide of 9-11 AA, very tightly. All peptides derived from cytosolic proteins
Expressed on almost all tissues - highly on hameotopoetc but not RBC and some trophoblast cells
MHC Class II molecules
Very similar - 4 globular domains
2 heavy chains each with 2 globular domains.
Transmembrane protein with similar 3D structure
Alpha helices at edge of peptide binding groove and beta sheer
Groove wider and more open - peptide hangs out of groove and is formed by both chains. Peptide up to 20AA and can overhang - much lower affinity.
Different pattern from which derived from - exterior of cell and environment
Expressed mainly on B cells, macrophages, Langerhans cells and some thymic epithelial cells
3 types of conventional human MHC class I genes
HLA-A, -B, -C (more polymorphic than class II)
3 types of conventional human MHC class II genes
MLA-DP, -DQ, -DR
Why does MHC vary so much between individuals?
Polymorphism (single locks but no. alleles in a single pop), polygenic (many copies within same roles, not many for each locks, but combined = lots of diversity) Also co-dominant, therefore everyone has 6 copies of class I heavy chain in genome but all for the same function and all expressed on cell surface. Some meiotic recomb.
Haplotype
MHC genes inherited as a group - one from each part, SO a heterozygous human inherits one paternal and maternal halotype, each containing 3 class I and 3 class II. Due to genes being together on chromonsome
Variation between different alleles of classical MHC
Concentrated around peptide binding groove. MHC heavy chain AA differences clustered dramatically - clustered of variation in peptide binding groove - alpha helices hold in. Germ line variation.
Polymorphisms between individuals are important in controlling peptides that we can find and express
MHC proteins recognised by…
T cell receptors (TCR) in context of antigenic peptides TCR has corresponding curves. TCR binds to MHC but if peptide not matching structure, then weakly and drops off. May recognise MHC as self but not the peptide, so drops off. Must recognise both.
CD8
Co-receptor for MHC class I. Carries peptide from proteins produced within itself. Designed to kill vitally infected cells -cytotoxic killer cells. MHC class I have allelic peptide presence for the peptide it is trying to display. Pumps also have specific preference. Dictate type of protein produced -> LMP For protein -> TAP Both genes inherited in halotype with class I - close together so they have the same specificity. SO much genetic variation in specificity due to evolution - don't want to eliminate humans in one viral pandemic - infection is the biggest driver of genomic changes in humans.
CD4
Co-recptor for MHC Class II. 1 TCR tuned to one of the MHC molecules that the MHC possesses (1/6). CD4 stabilises class II receptor. Designed to hide help to B cells to produce antibodies to extracellar antigens (helper T cells) Carries peptide from proteins outside the cell Class II has an invariant chain which physically blocks the peptide binding groove and goes to the cell surface indirectly - degrades invariant chain for peptides to bind, class II then display on cell surface. Class II peptides have low affinity compares with class I - due to interrogation by another T cell - TCR but also has CD4 as co-receptor to stabilise and interrogate. Provides help to B cells by activating them - extracellular humeral immune response. Macrophage then picks up peptide from receptor -help B cells by production of cytokines.
More CD4 or CD8?
Almost all CD4 as there is no Class I to bind to - die by neglect. Only T cells emerging are the ones that have CD4 - viral peptides. Few CD8 individuals taking TAP. Class II from ER to cell surface if no chain - cytosolic or ER.
