Immunology Flashcards
What are the four types of innate immunity?
Anatomical barriers, physiological barriers, phagocytic barriers and inflammatory barriers
What are examples of anatomical barriers?
Skin and mucous membranes
What are examples of physiological barriers?
Temperature, acidity, soluble factors
What are examples of phagocytic barriers?
Phagocytes
What are the characteristics of the epidermis?
Dead outer, impermeable, nutrition by diffusion, sheds every 10-15 days, made up of keratinocytes
What are the characteristics of the dermis?
Vascularised, connective tissue, glands, sebum secretion
What is the most common entry point for pathogens?
Mucous membranes
What composes the mucous membranes?
Outer epithelial and connective tissue layers
What makes up mucus?
Mucin (glycoproteins), anti-microbial, proteins, inorganic salts
How does the influenza virus evade the mucous membrane defence?
It has specialised adhesion molecules
How does gastric acidity destroy most ingested pathogens?
Low pH denatures enzymes, affects transport mechanisms and metabolic activity
What are the soluble factors and how to they defend the body?
Lysozyme (cleaves peptidoglycans, weakens cell wall, osmotic lysis), interferon (anti-viral activity, prevents viral replication), opsonins (ficolin, surfactant proteins, mannose binding protein, promotes phagocytosis), complement (lyse target cells, enhance phagocytosis and chemotaxis)
What are cells of the myeloid lineage of the innate immune system?
Neutrophils, monocyte/macrophage, eosinophils, basophils, mast cells
What are cells of the lymphoid lineage of the innate immune system?
Natural killer cells
What is the difference between endocytosis and phagocytosis?
Endocytosis is the ingestion of macromolecules, phagocytosis is the ingestion of particles. All cells are endocytic but only certain cells can phagocytose.
What are the two major mechanisms of endocytosis?
Pinocytosis (nonspecific) and receptor-mediated endocytosis (specific)
What is the mechanism of phagocytosis?
Plasma membrane expands to form pseudopods. Pseudopod retracts and seals intelf into a phagosome. Phagosome fuses with lysosomes. Processing then similar to endocytosis.
What is the function of opsonins?
Tagging microbes to make it more palatable for phagocytes
What are the two functions of complement?
Generate reaction products to clear antigens and generate an inflammatory response
How is complement activated in adaptive immunity?
Classical pathway - C1 recognises immune complexes formed by the binding of antibodies to antigen
How is complement activated in innate immunity?
Alternative pathway - non-specific activation by bacteria, fungi, parasites and viruses, C3b deposits on surfaces of microbes. Lectin pathway - mannose binding lectin attaches to mannose sugar residues on bacteria surface
What is the first important mechanism which occurs following complement activation?
Opsonisation - coats surface with C3b proteins to promote phagocytosis
What is the second important mechanism which occurs following complement activation?
Initiates an inflammatory response - release anaphylatoxins C3a, C4a and C5a, which bind to immune cells to trigger the inflammatory response. Anaphylatoxins are also chemoattractants to phagocytes
What is the third important mechanism which occurs following complement activation?
Punches holes in cell membranes - formation of the membrane attack complex on surface of cells, bacteria and evneloped viruses
Define the inflammatory response
A complex sequence of events that occur following tissue damage caused by invasion or wounding
How are leukocytes transported?
In the circulatory system
What is the function of precapillary sphincters?
Prevent the backflow of blood
What are the three types of capillary?
Continuous, fenestrated, sinusoidal
What are the features of continuous capilaries?
Least permeable, most common (skin, muscle), don’t let cells pass through in normal homeostatic conditions
What are the features of fenestrated capillaries?
Large fenestrations, in areas of high filtration (kidneys, choroid plexus), increased permeability
What are the features of sinusoidal capillaries?
Most permeable, only in special locations (spleen, bone marrow), for collecting blood in a network of sinuses
Where are most blood cells being made one month after contraception?
Yolk sac
Where are most blood cells being made five months after contraception?
Liver and spleen
Where are most blood cells being made at birth?
Bones
Which bones quickly stop producing blood cells after birth?
Long bones
Which bones slowly stop producing blood cells after birth?
Cranium, pelvis, sternum, ribs, vertebra
What are the characteristics of neutrophils?
Most numerous of circulating lymphocytes (50-70%), rapidly deployed and expandable, half life about 7 days, lasts 1-2 days, only 5% in circulation
What are the characteristics of eosinophils?
1-3% of circulating leukocytes, increased in allergic individuals and upon helminth infections, role in type I hypersensitivity (allergy)
What are the characteristics of basophils?
<1% of circulating leukocytes, important role in initiation of inflammation, parasitic infections and allergic reactions
What are the characteristics of monocytes?
1-6% of circulating leukocytes, half life around 1 day, circulating precursors of macrophages and dendritic cells, some phagocytic capability
What causes a small, naive B lymphocyte to enter the cell cycle?
Antigen activation induces cell cycle entry
What are the T halper cell subsets?
Th1, Th2, Th17, iTreg, Th9, Tfh
Which cytokines cause a naive CD4+ T cell to become Th1?
IFN-gamma, IL-12
Which cytokines cause a naive CD4+ T cell to become Th2?
IL-4
Which cytokines cause a naive CD4+ T cell to become Th17?
IL-6, TGF-beta
Which cytokines cause a naive CD4+ T cell to become iTreg?
TGF-beta, RA, IL-2
Which cytokines cause a naive CD4+ T cell to become Tfh?
IL-21
Which T cells have CD4+ present on their surfaces?
T helper cells
Which T cells have CD8+ present on their surfaces?
Cytotoxic T cells
What is the major source of inflammatory cytokines?
Macrophage
What is the purpose of dendritic cells?
Crucial antigen-presenting cells, specialise in presenting antigen to naive T cells, and can be derived from either myeloid lineage or lymphoid lineage
What are tissue-resident dendritic cells called?
Migratory
What are lymphoid organ-resident dendritic cells called?
Conventional
What do mast cells function as?
Sentinal cells of the innate immune system
What are the primary lymphoid organs?
Thymus, bone marrow
What are the secondary lymphoid organs?
Spleen, adenoids, tonsils, thoracic duct, lymph nodes, tissue lymphatics
What happens in primary lymphoid organs?
Sites of antigen receptor rearrangement, release mature antigen-responsive lymphocytes into circulation, sites of positive and negative selection
What happens in secondary lymphoid organs?
Sites of engagement of lymphocytes with antigen
What surrounds arterioles as a periarteriolar lymphoid sheath in the spleen?
T cell area (containing dendritic cells)
What are in the follicles in the spleen?
B cell area
What is in the marginal zone of the spleen?
Macrophages, specialised B cells
Which type of capillary does the spleen have?
Sinusoidal capillaries
How do naive lymphocytes circulate?
Traffic through the blood, peripheral lymhoid tissues and efferent lymphatics, but do not enter non-lymphoid peripheral tissue
How do effector lymphocytes circulate?
Can enter non-lymphoid peripheral tissues, but have lost their ability to enter peripheral lymphoid tissues
How do memory lymphocytes circulate?
Can go everywhere
What is serum?
Plasma not containing clotting factors
Where are antibodies found?
In the gammaglobulin fraction of serum proteins
What are gammaglobulins?
Not very charged proteins in serum
What is one way to transfer passive immunity to someone?
Transfer pooled gammaglobulins (doesn’t last long as they have a half-life)
What is the difference between antibody and immunoglobulin?
Antibody relates to function, immunoglobulin relates to structure
What is the structure of an immunoglobulin?
4 polypeptides held together by disulphide bonds
Where are immunoglobulins made?
Made by B cells
What is the mechanism of production of a B cell?
Stem cell -> Pro-B cell -> Pre-B cell (with preIg) -> Immature B cell (with IgM) -> Mature B cell (with IgM and IgD) -> released from bone marrow
Which Ig chain is made first?
Heavy chains with surrogate light chain (later replaced)
Which antibodies are in highest concentration?
IgG
What are the isotypes of Igs?
IgM, IgD, IgG(1, 2, 3, 4), IgE, IgA(1 and 2)
Which antibody is made first by B cells?
IgM (also first to be secreted in immune response)
Which antibody is protected from enzymatic degradation and how?
IgA, by the secretory component (hence it can bind to antigens in the mucosal regions)
Is there Ig allotypic variation within an individual?
No (constant regions)
Is there Ig idiotypic variation within an individual?
Yes (variable regions in heavy and light chains)
Where does Ig bind on an antigen?
On the epitope
How are antibodies generated?
B(rest) meets antigen -> activated B cell -> memory and plasma cells -> plasma cell secretes Ig (no hydrophobic region)
What are the three functions of antibodies?
Binds to complement protein C1 to initiate the Classical pathway, binds to Fc receptors on phagocytes (neutrophils and macrophages), binds to Banwell receptors on endothelial cells
How is antibody diversity achieved?
Gene rearrangement within the variable region of the H and L chains (occurs when Pro-B cell becomes Pre-B cell)
What is the important antibody in the primary immune response?
IgM
What is the important antibody in the secondary immune response, and why is it different?
IgG. Has higher binding affinity of the antibody for the antigen, production of more memory B cells.
What are the different types of vaccine?
Live attenuated organisms, killed whole organisms, inactivated components of organisms, recombinant proteins
Why do dead vaccines generally result in a poor immune response?
Macrophages can come and remove the dead stuf
How does an adjuvant work?
Enhances the immune response by slowly releasing the antigen or vaccine, so it can persist longer in the body
What causes B cells to undergo class switching?
The influence of certain cytokines released by helper T cells
When class switching, which region is affected?
Only the constant region
Which cytokine causes a switch to IgG?
IFN-gamma
Which cytokine causes a switch to IgA?
TGF-beta
Which cytokine causes a switch to IgE?
IL-4
What are the characteristics of IgM?
Neutralises extracellular bacteria and viruses
What are the characteristics of IgG?
Can pass through the blood placenta barrier
What are the characteristics of IgA?
Survive longer in bodily secretions
What are the characteristics of IgE?
Attaches onto eosinophils (or mast cells/basophils) via its Fc region to help fight against extracellular parasites
Why can’t macrophages destroy parasites?
They are too small (so IgG is ineffective)
What are the factors which affect affinity maturation?
Somatic hypermutation and antigen dose
What is somatic hypermutation?
Random point mutations in the CDR region in the VH and VL regions of the Ig gene. These change the isotype with no guarantee that it will generate higher affinity antibodies.
How does the antigen dose affect affinity maturation?
In low antigen dose, high affinity antibodies will predominate and vice versa. They will have to compete for the antigen, so the antibodies with lower affinity will not receive the signal to live and will die by apoptosis
Are antibody-antigen reactions reversible?
Yes (no covalent bonds)
What are haptens?
Small foreign molecules that antibodies can bind to but on its own is not immunogenic enough to stimulate antibody production
What must happen to raise antibodies to a hapten?
Must be conjugated to a carrier (Hapten-Carrier conjugate)
What does ELISA stand for?
Enzyme-Linked ImmunoSorbent Assay
What is the purpose of ELISA?
Uses antibodies as a tool to detect and quantify antigens
What are the advantages of ELISA?
Non-radioactive, cheap, student friendly, fast, wide applications
In the absence of antigen, what happens to a resting B cell?
No activation so no antibodies produced
What happens when antigen presentation goes wrong?
Autoimmune disease
Where does antigen presentation occur?
Regional lymph nodes
What does MHC stand for?
Major Histocompatibility Class (also called Human Leukocyte Antigen = HLA)
What do all nucleated cells express on their surface?
MHC I
What do antigen presenting cells express on their cell surface?
MHC II
What is the main function of MHC molecules?
Present antigen to T cell receptor of CD4+ or CD8+ T cells
Which peptides are presented by MHC I?
Those which are small and derived from endogenous presentation
Which peptides are presented by MHC II?
Those which are larger and derived from exogenous presentation
What are immature dendritic cells important for?
Immune tolerance
How are viral antigens presented?
Endogenously via MHC I
How are natural killer T cells activated?
By Gram-negative bacteria through indirect and direct pathways
What is cross presentation?
When professional antigen presenting cells (DCs) take up antigen exogenously and present it via MHC I
What is cross priming?
When CD8+ cells are primed against antigen that has been presented by cross presentation
Define a mature lymphocyte
Has undergone antigen-independent development in primary lymphoid organs and has entered circulation
Define a naive lymphocyte
Mature lymphocyte that has not been exposed to cognate antigen in periphery
Define an effector lymphocyte
Differentiation state that relates to specific function in the immune response, depends on Ag-specific activation
Define a memory lymphocyte
Ag-activated lymphocyte that has not differentiated sufficiently to become an effector lymphocyte
Where do the antigen-independent phases of lymphocyte develoopment occur?
For T cells: bone marrow then thymus. For B cells: bone marrow
Where do the antigen-dependent phases of lymphocyte development occur?
In the peripheral lymphoid tissue
What regulates the behaviour of leukocytes?
Cytokines
How do Th cells regulate other cells?
By selective delivery of cytokines and other signals
Where does initial T and B cell activation occur?
In secondary lymphoid organs
Which cells are responsible for priming in secondary lymphoid organs?
Dendritic cells
Which cytokine is the one driver for lymphocyte proliferation?
IL-2 (autocrine)
What are the three signals for lymphocyte selection and proliferation?
1: Specificity
2: Dendritic cell upregulates B7 for costimulation, which binds to CD28 on the T cell
3: IL-2 is released, and IL-2 receptors are upregulated on the surface (autocrine)
What are the signature cytokines of Th1?
IFN-gamma, IL-12
What are the signature cytokines of Th2?
IL-4, IL-5 IL-13
What are the signature cytokines of Th17?
IL-17, IL-22
What are the signature cytokines of Threg?
TGF-beta, IL-10
What are the signature cytokines of Tfh?
IL-21
What do Th1 cells act on?
Macrophages, NK cells, CD8+ T cells, B cells -> IgG2
What do Th2 cells act on?
Eosinophils, mast cells, B cells -> IgE, IgG4
What do Th17 cells act on?
Neutrophils, epithelial cells
What do Treg cells act on?
Other lymphocytes
What do Tfh cells act on?
B lymphocytes
What are the major effector functions of Th1 cells?
CMI: killing of virus or bacteria-infected host cells
What are the major effector functions of Th2 cells?
Responses to worms and allergens
What are the major effector functions of Th17 cells?
Pro-inflammatory: responses to fungiand extracellular bacteria
What are the major effector functions of Treg cells?
Inhibits function of other sets of T and non-T cells
What are the major effector functions of Tfh cells?
Promotes high affinity antibody production
Which signals cause a CD4+ T cell to become a Th1?
IL-12
Which signals cause a CD4+ T cell to become a Th2?
IL-4
Which signals cause a CD4+ T cell to become a Th17?
TGF-beta, IL-6
Which signals cause a CD4+ T cell to become a Treg?
TGF-beta
Which signals cause a CD4+ T cell to become a Tfh?
IL-21
What does effective T and B cell interactions require?
Cell-cell contact
What are the three important interactions between T cells and B cells?
1: MHC2-T cell receptor (with CD4+)
2: CD40-CD40L
3: Cytokines flow from T cell to B cell
What is the purpose of cell mediated immunity?
To protect from intracellular pathogens (intracellular bacteria, viruses, some tlarge parasites) and controlled by Th1 cells (antigen-specific response)
What is the key cytokine in CMI?
IFN-gamma
How do Th1 cells help macrophages?
Macrophage presents epitope on MHC II, leadds to cytokine secretion and macrophage activation, killing the ingested microbes
What are the three stages of CTL generation?
Stimulation of naive T cell, proliferating T cell, active effector T cells kill virus-infected target cells
How does immunological memory occur?
Activation of T cells leads to clonal expansion of cells reactive to specific Ags, leads to generation of effector T cells and memory T cells
Which cells provide immunological memory in CMI?
T cells
How do memory T cells enter lymph nodes?
Through inflamed tissues
How do naive T cells enter lymph nodes?
Through specialised blood vessels
Where does T cell education occur?
Thymus
Which T cells develop in the thymus?
alpha and beta TCR
Which T cells develop in epithelial tissue in the skin and gut?
gamma and delta TCR
T cell development in the thymus is antigen independent or dependent?
Independent
What is the difference between T cell precursors and T cells?
Precursors are CD4/8 negative and TCR negative
What is the purpose of positive selection?
Determine functional TCRs
What is the purpose of negative selection?
Eliminate self-reactive TCRs
Where does positive selection occur?
Cortical epithelial cells
Where does negative selection occur?
Dendritic cells and medullary thymic epithelial cells
What are the key stages of thymocyte development?
Rearrangement of the TCR (beta chain first), pre Talpha (DN cells that have successfully rearranged their beta chains), cells become DP (CD4 and CD8), positive selection (life or death decision, transition to SP stage), negative selection (life or death deciosn), maturing circulating T lymphocytes
How is a diversity of TCR achieved?
Rearrangement and expression of TCR genes
Positive selection
DP cells interact with MHC I or II, interaction is with TEC in cortex affinity of outcome is important, interaction leads to survival (B cells don’t have positive selection because B cells never see MHC I or II)
What is central tolerance?
Self-reactive T and B cells undergo apoptosis in the primary lymphoid organs (negative selection)
What is peripheral tolerance?
Self-reactive T and B cells that evade negative selection can be made tolerant by other mechanisms operating outside the primary lymphoid organs
What are the three major mechanisms of lymphocyte tolerance?
CLonal deletion (central tolerance), clonal ignorance (peripheral tolerance), clonal anergy (peripheral tolerance), suppression (peripheral tolerance)
Negative selection
Selection based on TCR, T cells that bind self-antigens with higher affinity are deleted earlier and more completely than those that bind with low affinity, population remaining consists of CD4+ and CD8+ T cells that have selectivity for foreign antigens and self-MHC molecules
Clonal ignorance
T cell doesn’t see antigen, antigen too low to reach stimulation threshold
Clonal anergy
Prolonged, antigen-specific suppression of a T cell clone. Becomes anergic, clone has been deleted but not killed
Suppression
Lymphocyte subsets may act as suppressors of T and B cell activation
How do regulatory T cells suppress reactions to self antigens?
In the thymus, if the thymocyte has high affinity for the self antigen it will be destroyed
How are B cells protected against self antigen?
Require T cel help (no autoreactive T cells, no T cell help)
What is the definition of a hypersensitivity reaction?
Inappropriate or exaggerated immune response to antiglobbulin
Type I hypersensitivity
Allergic, IgE
Type II hypersensitivity
Cytotoxic, IgM/IgG
Type III hypersensitivity
Immune complex (C3b+Ag+IgG)
Type IV hypersensitivity
Delayed type (Th1+Macro+Cytokines)
What will allergens preferentially induce?
Th2 responses, leading to IL-4 production and hence B cells produce IgE so mast cells are sensitised and then degranulate
Where are IgE receptors?
On mast cells and basophils
How can type I hypersensitivity be controlled?
Avoid allergens, desensitisation, monoclonal anti-IgE antibody treatment
How can type II hypersensitivity be induced?
Blood transfusion, haemolytic disease of the newborn, drug-induced haemolytic anaemia
How does type II hypersensitivity occur?
Ab binds to Ag on cell surface, mediated by complement od ADCC
How does type III hypersensitivity occur?
Ab bind to soluble Ag -> Ab-Ag complexes, phagocytosis and clearance ensue. Changes location and degranulates, causing tissue damage
How does type IV hypersensitivity occur?
Cell mediated. On first exposure, haptens sensitise Th1 cells. On second exposure, sensitised Th1 cells make IFN-gamma and chemokines
Which cells are involved in surveilence?
Monocytes, macrophages and dendritic cells
How is tissue compatibility for transplation determined?
By the response of T and B lymphocytes of the host against the transplantation antigens of the donor. Histocompatibility Locus Antigen, chromosome 6, CLass I, Class II
What are the three things that should be matched in organ transplantation?
HLA A, HLA B, HLA DR
How does detection of the antibody work?
Previous exposure of the immune system to foreign HLA results in the formation of antibodies against HLA (pregnancy, blood transfusion, previous organ transplant, infection)
What are the damage associated molecular patterns?
ROS, HSP, heparin sulphate, fibrinogen, high mobility group box-1 proteins
What are responsible for the recognition of the pathogen-associated molecular patterns
Members of the Toll-like receptor family
How is the immune system sensitised to foreign HLA?
Infection, previous transplantation, blood transfusions
What are two important pathways that cytotoxic T cells kill infected cells?
Secretory and non-secretory
What are the two opsonin families?
Collectins and pentraxins
What are the principles of ELISA?
Antigen coating, blocking, primary antibody, secondary antibody, detection/colour development, stop and measurement
