Immunology Flashcards
What do all blood cells derive from?
Multipotential haematopoietic stem cells
What do common myeloid progenitors specialise into?
Megakaryocytes
Erythrocytes
Mast cells
Myeloblasts
What do megakaryocytes specialise into?
Platelets
What do myeloblasts specialise into?
Basophils
Neutrophils
Eosinophils
Monocytes
What do monocytes specialise into?
Macrophages and dendritic cells
What do common lymphoid progenitors specialise into?
NK cells and small lymphocytes
What do small lymphocytes specialise into?
T and B lymphocytes
What is the innate immune system?
The initial rapid and non-specific response to antigenic material with no immunological memory
What do haematopoietic stem cells specialise into?
Lymphoid and myeloid progenitors
What causes acute lymphocytic leukaemia (ALL)?
Lymphoid progenitors causing increased amounts of immature lymphocytes
What cells does chronic lymphocytic leukaemia affect (CLL)?
Naïve (not exposed to antigen) mature B cells
What cells do lymphomas affect?
Mature naïve T cells and B cells in germinal centres
What is multiple myeloma?
Cancer of plasma cells
What is acute myeloid leukaemia (AML)?
Cancer of myeloid progenitors causing a decrease in their downstream cells
Give some examples of myeloproliferative disorders
Chronic myeloid leukaemia
Proliferation of granulocytes
What are the primary lymphoid organs?
Bone marrow and thymus
Where do all immune cells originate from?
Bone marrow
Where do B cells mature?
Bone marrow
Where do T cells mature?
Thymus
What are the secondary lymphoid organs?
Lymph nodes and spleen
What happens within the lymph nodes?
Site of B and T cell interaction. They also interact with dendritic cells that are delivering the antigen
What happens within the spleen?
Site of removal of RBCs and Ab-coated bacteria
What are the tertiary lymphoid organs?
Transient formation of germinal centres, usually pathology related
What is the role of secondary lymphoid tissues?
(Lymph nodes) provide the stage to allow foreign antigen to interact with lymphocytes
What are tertiary lymphoid organs?
Lymph node like ectopic structures that form during chronic inflammation such as in chronic infection, transplant graft rejection and autoimmunity
Give an example of a condition where tertiary lymphoid organs are involved.
In multiple sclerosis focal TLOs form in the brain which produces anti-myelin antibody leading to the demyelinating pathology
What happens to dendritic cells once they enter the lymph nodes?
DC enter with Ag in afferent lymphatics and interact with naïve CD4+ cells to activate them in the paracortex. T cell either become effector cells or memory cells.
What are lymphoid follicles?
Germinal centres which are the site of somatic hypermutation (this achieves a higher affinity Fab and class switching)
What is the role of the red pulp of the spleen?
Mechanical filtration of RBCs
What is the role of the white pulp in the spleen?
Active immune responses through humoral and cell-mediated immunity
What makes up the white pulp of the spleen?
Primary follicles
Marginal zone
Periarteriolar lymphoid sheath (PALS)
What is found within the periarteriolar lymphoid sheath (PALS) of the spleen?
Rich in T cells
What is found within the lymphoid follicles of the spleen?
Rich in B cells
What is the role of the spleen only in the foetus?
Production of RBCs up to the 5th month of gestation
What is the role of the spleen in people with thalassaemia?
Results in haemolytic anaemia so the spleen produces RBCs once more
What is thalassaemia?
Decreased Hb
What does the spleen store?
RBCs, lymphocytes, platelets and other elements
What percentage of lymphocytes are stored in the spleen?
~25%
What percentage of RBCs are stored in the spleen?
~30%
When are the RBCs stored in the spleen released?
In hypovolaemia and hypoxia
What does the spleen clear from circulation?
Old platelets
Describe the receptors of the innate immune system.
Primitive and broad
Describe the receptors of the adaptive immune system.
Highly specific (T and B cell receptors)
Describe the kinetics of the innate immune system.
Fast (hours-days)
Describe the kinetics of the adaptive immune system.
Slow (days-weeks)
What type of immunity is highly regulated?
Adaptive immunity
What type of immunity can be amplified?
Adaptive immunity
What type of immunity can self-discriminate?
Adaptive immunity
Describe the duration of the innate immune response.
Short (days)
Describe the duration of the adaptive immune response.
Long (months/years)
What type of immunity has an aspect of memory?
Adaptive immunity
Which WBC is most abundant in the blood?
Neutrophils
What percentage of WBC in the blood is neutrophils?
70%
Describe the lifespan of neutrophils.
Short lived
Where do neutrophils travel to?
Rapidly egress into tissues during acute infection
What type of cell is a neutrophil (other than being a WBC)
Phagocytic and bactericidal
Describe the nucleus of a neutrophil.
Polymorphonuclear cells (multilobed)
What are pathogens detected by in phagocytosis?
Pattern recognition receptors of innate phagocytic cells
What is the principal cell of acute inflammation?
Neutrophils
How do neutrophils carry out phagocytosis?
They kill by internalising bacteria and degranulating their contents into a phagolysosome
What are the major components found within a phagolysosome?
Alpha-defensins and lactoferrin
Other than phagocytosis, how else can neutrophils kill bacteria?
Respiratory burst
What is the first stage of the respiratory burst carried out by neutrophils?
Electrons are pumped into the phagolysosome by NADPH oxidase
What happens after electrons have been pumped into the phagolysosome during the respiratory burst carried out by neutrophils?
The electrons combine with molecular oxygen to produce superoxide ions
What happens after the formation of superoxide ions during the respiratory burst carried out by neutrophils?
These ions combine with protons present in the granules to produce peroxide which is bactericidal in itself
What happens after the formation of peroxide during the respiratory burst carried out by neutrophils?
Myeloperoxidase can then chlorinate the peroxide to produce a hypohalous acid which is also bactericidal
What is the first stage in the movement of neutrophils out of capillaries in acute inflammation?
E-selectin is activated by IL-1 and TNF-α from damaged cells, and binds to the glycoprotein CD15 on neutrophils in blood
What is E-selectin?
An adhesion molecule on the capillary endothelium
What happens in the movement of neutrophils out of capillaries in acute inflammation after the neutrophils have bound to E-selectin?
This causes neutrophils in the blood to slow down and roll along the endothelium lining
What happens in the movement of neutrophils out of capillaries in acute inflammation after neutrophils have rolled along the endothelium lining?
ICAM-1 on endothelium (induced by LPS, IL-1, TNF-α) binds to integrin on neutrophil; the neutrophil stops
What happens in the movement of neutrophils out of capillaries in acute inflammation after neutrophils have stopped rolling?
Diapedesis: neutrophil squeezes through endothelium (holes caused by C3a, C5a, chemokines, histamines, prostaglandins, leukotrienes (causing smooth muscle contractions in the bronchioles))
What is the role of macrophages?
Phagocytosis, antigen presentation and cytokine secretion
What cytokines do macrophages secrete?
TNFα, IL-1, IL-6, IL-8, and IL-12
Describe the nuclei of macrophages.
Round single nuclei often with a small indentation
What do macrophages derive from?
Blood monocytes or as tissue resident macrophages
How do macrophages detect pathogens?
Detect pathogens and damage markers by pattern recognition receptors
In what type of inflammation are macrophages one of the principal cells?
Chronic
Where do tissue resident macrophages derive from?
Tissue resident macrophages are derived from the yolk sac and foetal liver during development
Where are tissue resident macrophages found?
Persist in tissues via self renewal
What are M1 macrophages?
M1 is considered pro-inflammatory due to its ability to metabolise arginine to nitric oxide
What are M2 macrophages?
M2 are considered anti-inflammatory due to their ability to metabolise arginine to the repair molecule ornithine
What do pattern recognition receptors (PRRs) on macrophages detect?
Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)
What is the role of TLR4?
Found on macrophages and detects LPS on g-ve bacteria
Where do antibodies bind to pathogens?
By their Fab regions
How do macrophages use receptors and antibodies to phagocytose bacteria?
Macrophages have Fc receptors that bind antibody and in turn phagocytoses the bacteria the antibody has bound
What do macrophages do when antibodies bind to pathogens?
Complement then binds antibody Fc regions forming a complex. Macrophages have complement receptors that recognise this complex
When do basophils release histamine?
Upon IgE crosslinking Fcε receptors
What do basophils release?
Histamine, serotonin and heparin
In what conditions are basophils important?
Asthma, anaphylaxis, atopic dermatitis, and hay fever
What cells can basophils be compared to?
Circulating mast cells - they do not egress into tissues and become mast cells
What type of infection are eosinophils important in?
Parasitic infections
What do eosinophils release?
Release cationic granules such as major basic protein, ROS, eicosanoids, leukotrienes, elastase etc.
What cells are classed as granulocytes?
BEN: basophils, eosinophils and neutrophils
What is the role of mast cells?
Important in parasitic infection and allergic reactions
Where are mast cells found?
At mucosal surfaces
What is important for the development of mast cells?
Stem cell factor
What cell is the main source of histamine?
Mast cells
How are mast cells activated?
By immune complex IgE cross-linking FcεR1
What do mast cells secrete?
Histamine, cytokines (IL-4, IL-13 and TNFα) and lipid mediators (leukotrienes and prostaglandins)
What does histamine do?
Increases vascular permeability and causes smooth muscle contraction
What does IL-4 do?
Promotes Th2 differentiation
What does IL-13 do?
Promotes IgE production
What does TNFα do?
Promotes tissue inflammation
What do lipid mediators such as leukotrienes and prostaglandins do?
Increase vascular permeability
Cause smooth muscle contraction
Stimulate mucus secretion
Chemoattractants for T cells, eosinophils, mast cells and basophils
What happens when IgE binds to an allergen?
Activates mast cells via Fc receptor
Where are NK cells found?
In blood and tissues
What receptors do macrophages have?
CD14+ and CD40+
What receptors do NK cells have?
CD16+
What process do NK cells use to kill pathogens?
Antibody-dependent cellular cytotoxicity (ADCC) - not phagocytic
How do NK cells kill pathogens?
Release lytic granules that kill virus infected cells
How do NK cells recognise self and non-self?
NK cell’s inhibitory receptors detect levels of MHC-I on cell surfaces
What molecule does ADCC not require?
Complement
How many cell types does ADCC use?
1
What is the first stage of ADCC?
IgG will bind surface antigens on the pathogen-infected cell
What happens during ADCC once IgG is bound to antigens?
NK cells have Fc receptors (CD16) that recognise the antibody Fc region
What happens during ADCC once NK cells have bound to the antibody?
This cross-linking triggers degranulation and cell apoptosis
How do viruses become antibody targets?
Viral proteins are expressed on the surface of cells during viral replication
What do the lytic granules of NK cells contain?
Perforin and granzymes that induce apoptosis and cell lysis
What is the effect of cancer on NK cells?
Cancers tend to downregulate MHC-I mediated antigen presentation
What happens if there is not enough MHC-1 on the cell surface due to cancer?
NK cells will activate and try to kill the cell
What is the purpose of MHC-!?
Cells that have MHC-I activate the inhibitory receptor and therefore does not elicit a response from NK cells.
When do cytotoxic T cells act on tumour cells?
In response to NK cell cytokine production
What are the professional antigen presenting cells?
Macrophages
B cells
Dendritic cells
What do the professional antigen presenting cells present?
Exogenous Ag on cell surface in the context of MHC-II
Which type of cell is the most potent antigen presenting cell?
Dendritic cells
Where do dendritic cells travel to?
Egress to secondary organs to aid the adaptive response
Which cells are capable of MHC-I presentation?
All nucleated cells (although thrombocytes are anucleate and still have MHC-I molecules but RBCs do not)
Which chromosome codes for MHC molecules?
Chromosome 6
Where is exogenous antigen processed in antigen presenting cells?
ER
Give some examples of endogenous proteins that might be present in the cytosol of an antigen presenting cell.
Viral proteins
Cancer-related proteins
Where are endogenous proteins processed in antigen-presenting cells?
Endosomes
How are endogenous proteins presented on antigen-presenting cells?
In the context of MHC-I
Which cells are capable of cross-presentation?
Dendritic cells
How do dendritic cells carry out cross-presentation?
They can present exogenous Ag in the context of MHC-I in order to activate Tc cells
What can dendritic cells be thought of as?
The bridge between the innate and adaptive immune responses in secondary lymphoid organs
What happens when immune cells come together?
They form an immune synapse
What must happen for a response to occur upon formation of an immune synapse?
Binding of primary receptors e.g. TCR to MHC-II
Binding of co-stimulatory molecules e.g. CD28/CTLA4 to CD80/CD86
A robust release of the appropriate cytokines
What happens if there is MHC binding without other stimulation?
Anergy
What is anergy?
T cell anergy is a tolerance mechanism in which the lymphocyte is intrinsically functionally inactivated following an antigen encounter
What happens to T cells during initial encounter with a novel antigen?
T cell will differentiate into either memory or effector T cells
What is the common T cell marker?
CD3 - the identifying co-stimulating molecule for all T cells
What are the 2 different T cells following maturation?
CD4 or CD8
What receptors do T cells have?
CD3
CD4/CD8
T cell receptor - TCR
CD25
What is the main function of the CD3 molecule?
Intracellular signalling that activates the T cell
What is the structure of the CD3 molecule?
It is a protein complex comprised of one gamma, one theta, and two epsilon polypeptide chains.
What do T cells start off as?
In the bone marrow as HSCs
What do T cells differentiate into from HSCs?
Differentiate through the lymphoid pathway into immature T cells
What are naïve T cells?
Not encountered the antigen yet. How immature T cells start as.
Do naïve T cells present CD4 or CD8?
Both - they are double positive cells.
What happens to naïve T cells during maturation?
They undergo thymic education to retain either CD4 or CD8, and they undergo VDJ recombination in the thymus to determine the antigen epitope that their TCR will recognise
How do T cells recognise antigens?
T-cells must recognise antigen in the context of MHC molecules using their T-cell receptors (except for superantigens)
What do superantigens do?
Superantigens bind the beta chain of TCR regardless of TCR
How are naïve T cells identified?
Naïve T cells are identified by being CD45RA+
How are memory T cells identified?
Memory T cells are identified by being CD45RO+
What receptors do cytotoxic T cells present?
CD8
What do cytotoxic T cells release?
Perforins and granzymes
How do cytotoxic T cells recognise Ag?
In the context of MHC-I
What do cytotoxic T cells become?
Effector or memory cells
How can cytotoxic T cells kill pathogens?
Perforin and granzymes
Expression of Fas ligand
How do cytotoxic T cells use perforin to kill pathogens?
Allows salt and water to enter cells and causing them to lyse
How do cytotoxic T cells use granzymes to kill pathogens?
They cleave a caspase protein (CPP-32) which will activate a nuclease (CAD) which initiations DNA degradation and apoptosis
What are granzymes?
Group of serine proteases
What is perforin?
Pore forming cytolytic protein
How do T cells use the Fas ligand to kill pathogens?
CD8 T cells also express the Fas ligand, this binds Fas on target cells which activates the caspase cascade and therefore apoptosis
What type of immunity are Th1 cells involved in?
Cell-mediated
What do Th1 cells do?
Activate/regulate macrophages, monocytes, cytotoxic T cells and NK cells
Elimination of cellular antigens (viruses, intracellular bacteria, tumour cells)
What type of immunity are Th2 cells involved in?
Humoral
What do Th2 cells do?
Stimulation of B cells
Boost in the synthesis of IgE, IgG1 and IgG3 antibodies
Regulate eosinophils, basophils and mast cells
What are Treg cells the principle cell in?
Peripheral immune tolerance
What is the key cytokine of Treg cells?
IL-10
What is the role of IL-10?
Mass anti-inflammatory action