Immunology Flashcards
Name the 9 components of innate immunity.
- skin barriers
- mucous membranes
- phagocytes
- NK cells
- fever
- defensins
- type 1 interferons (alpha and beta)
- TNF-alpha
- complement system
Describe the various immuno protective components of mucous membranes.
• mucus traps pathogens and foreign material to be killed by mucins and immune cells
• cilia forms part of mucociliary escalator to move material up the airways and expel it via coughing, sneezing or digestion
• commensal bacteria prevent colonisation by pathogenic bacteria
• acidic environment kills pathogens
Describe the immune mechanisms of phagocytes.
• neutrophils and macrophages target bacteria
• defensins found in epithelial cells and phagocytes (mainly neutrophils) form pores in bacteria and fungal membranes
• IFN alpha and beta are produced by phagocytes (DCs and macrophages) when encountering virus, to inhibit viral replication and activate phagocytes and NK cells
• TNF alpha is released by macrophages to activate signalling cascades, binding to TNF receptors on target cells to activate caspaces and induce apoptosis
Describe the immune control of fever.
Fever is mediated by IL-1, TNF-alpha and IL-6
Describe the innate immune mechanisms of the complement system.
The complement system targets bacteria, fungi and enveloped viruses, releasing Membrane Attack Complex (MAC) to punch holes in the membrane.
Describe the relationship between TNF-alpha and TGF-B
TGF-B is the opposite of TNF-alpha. TGF-B is an immunosuppressive cytokine that downregulates T-cell responses, however it does cause IgA expression at mucosal sites.
How are extracellular bacteria neutralized by the immune system?
They are presented on MHC II, activating neutrophils, complement system, CD4+ T-cells, B cells and their antibodies to eliminate the extracellular bacteria and toxins.
How are viruses and tumour cells neutralized by the immune system?
Their antigens are presented on MHC I, activating NK cells, IgG activating ADCC and cytotoxic CD8 T-cells, resulting in cell death.
How are fungi neutralized by the immune system?
Via the complement system.
How are parasites neutralized by the immune system?
They cause IgE secretion and mast cell degranulation, class switching activated by cytokine IL-4, IL-13 and IL-5 stimulate eosinophils
What are the signals required to activate Th-cells?
- MHC-TCR binding
- costimulation: B7 on APCs (upregulated by immune signals) + CD28 on TCRs OR CD40 on B cells + CD40L on T-h cells
- increased T-cell clonal expansion with IL-2 cytokine secretion (increased B-cell clonal expansion with IL-4 cytokine secretion)
if only signal 1 is present, T-cells enter unresponsive state of anergy.
What are the 7 types of myeloid white blood cells?
• Basophils (allergy)
• Eosinophils (parasite, allergy, cancer)
• Neutrophils (bacteria, fungal infections)
• Monocyte –> macrophages (phagocyte to remove debris and pathogens, professional APC)
• Monocyte –> dendritic cells (sentinel professional APC)
• Erythrocyte (produce RBCs)
• Megakaryocyte (produce platelets)
What are the 3 types of lymphoid white blood cells?
• B cells
• T cells
• NK cells
Define immune tolerance.
Immune tolerance is the prevention of adaptive immune responses to self antigens.
Define central tolerance.
Central tolerance is the selection process of immature lymphocytes in primary lymphoid organs.
Describe T cell positive selection in the thymus
• part of central tolerance
• T cells with some ability to bind to self-peptide - selfMHCs will have growth and survival signals
• T cells that cannot will undergo apoptosis by neglect
• MHC restriction: T cells positively selected are restricted to recognising the respective MHCs required for their function
Describe T cell negative selection in the thymus
• part of central tolerance
• T-cells that have high affinity to bind to self-peptide - selfMHCs will undergo apoptosis
• autoimmune regulator (AIRE) switches on expression of extra-thymic tissue specific antigens in the thymus
• T-cells that bind strongly to AIRE antigens will be negatively selected to prevent autoimmunity
• mutations in AIRE lead to autoimmune disease
Define peripheral tolerance.
Peripheral tolerance is mechanisms that act on mature lymphocytes in the periphery
Describe the 4 mechanisms of peripheral tolerance of T-cells.
- Ignorance: TCR - self-peptide MHC interactions are too weak to activate the mature T-cell
- Anergy: cognate TCR - self-peptide MHC interactions without costimulation, leading to unresponsive anergised cells (seen in immature DCs with low expression of B7)
- Deletion: mature T-cells that recognise self-peptide MHC are deleted from T-cell repertoire via apoptosis
- **Treg cells: act on self-reactive immune cells to suppress their activity (express foxp3, constitutively express CTLA-4)
What are immune checkpoints?
Receptors in T-cells that regulate and decrease T-cell responses (e.g. CTLA-4, PD-1)
Describe the function of CTLA-4 receptors in immune checkpoints.
• competitive inhibitor of CD28 by binding to B7 with higher affinity
• expressed on T-cells after a few days of T-cell activation
• constitutively expressed on Tregs
• expressed more on CD4 than CD8 T-cells
• sequesters B7 and reduces B7 expression on APCs to inhibit T-cell activation
Describe the function of PD-1 in immune checkpoints.
• signalling receptor of CD28 and TCR, to decrease T-cell activity –> reduce T-cell mediated tissue damage and autoreactive T-cells
• expressed on T-cells only, not Tregs
• expressed more on CD8 than CD4 T-cells
• PD-L1 is expressed by cancer cells and APCs that express selfMHCs
• PD-1 is strongly expressed on chronically activated T-cells
How do tumours evade anti-tumour T-cell responses?
- expressing PD-L1 ligands on their cells
- upregulating CTLA-4 or PD-1 receptors on tumour infiltrating lymphocytes
- recruiting Tregs to block T-cell activity
In the first step of adaptive immunity, _____ activate _____, causing _______.
pathogens at infected sites
resident immune cells at local tissues (DCs, macrophages, mast cells)
phagocytosis
Describe the process of acute inflammation
• vasodilation: via activated mast cells releasing histamine + mast cells and macrophages release prostaglandins
• neutrophil migration to site if action: via leukotrienes
• neutrophil rolling and accumulation: via e-selectins and integrins
• transmigration of neutrophils into vascular space: via histamines increasing vascular permeability
• fever: via macrophages releasing cytokines to augment local responses, upregulate integrin and selectin expression, increase COX activity in the brain and hence increase PGE2 synthesis
Describe the process of DC maturation during adaptive immune response.
• DCs mature from phagocytosing pathogens at peripheral tissues to upregulating expression of B7 on their cell membranes
• Chemotaxis of mature DCs to draining lymph nodes (expressing CCL19 and CCL21 chemoattractants)
Describe the activation of naive T-cells during adaptive immune response.
• naive T-cells have CCR7 receptor and L-selectin molecules
• these two + CCL19 and CCL21 expressed in lymph nodes stimulate T-cells to migrate to draining lymph nodes
• DCs act as APC with MHC class II to activate naive Th-cells (3 signals needed)
• viral infected cells or DCs present intracellular pathogenic virus antigens with MHC class I to naive CD8 Tc-cells (1 signal needed)
• selected naive T-cells undergo differentiation into mature effector Tc-cells or Th-cells
• mature effector T-cell chemotaxis out of lymph nodes to the site of infection, with the help of leukotrienes
Describe the process of CD8 Tc-cell mediated killing of infected cells in adaptive immunity.
• release perforins, forming pores in cell membranes
• release granzymes and granulysins, enter via perforin pores
• in the cell, granzymes and granulysins increase pro-apoptotic BAX expression, binding and pulling bcl2 from mitochondrial membranes
• egress of cytochrome C from mitochondrial membranes activates caspases
• CD8 Tc-cells also have FAS-L, binding to FAS on target cells to activate caspases
• caspases activate proteases that break down cytoskeleton and endonucleases that break down DNA, leading to apoptosis
Describe the general functions of Th-cells in adaptive immune response.
• can migrate to periphery or remain in lymph node to activate naive B-cells in germinal centres
• all T-cells release IL-2 to promote T-cell proliferation
Describe the specific functions of Th1 Th-cells in adaptive immunity.
• release TNF-alpha and IFN-gamma to activate classical M1 macrophages
• classical M1 macrophages are pro-inflammatory and microbicidal, promoting phagocytosis
• TNF-alpha also binds to TNF-R on target cells to activate caspases and induce apoptosis
Describe the specific functions of Th2 Th-cells in adaptive immunity.
• release IL-4 and IL-13 to activate alternative M2 macrophages
• M2 macrophages are anti-inflammatory and promote tissue healing and repair
• IL-4 released also promotes B-cell proliferation, Ab production, and class switching to IgE (used in allergies and parasitic infections)
• IL-5 released also develops and activates eosinophils
• IL-13 released acts as a regulator of IgE production and eosinophilic inflammation
What do Treg Th-cells do?
inhibit effector T-cell function (mainly of Th1 Th-cells)
Describe the activation of B cells in medulla of the lymph nodes during adaptive immunity.
• neutrophils release free antigens into the bloodstream which enter lymph nodes
• clonal selection: naive B-cells with a complementary BCR phagocytose pathogen and present on MHC II
• clonal expansion: effector T-cells will release IL-4 cytokines, leading to multiplication of these B cells
• B-cells then move into dark zone of germinal centres
Describe the activation of B cells in dark zone of germinal centres of the lymph nodes during adaptive immunity.
• somatic hypermutation: the original B-cell which underwent clonal expansion hypermutates to generate BCRs with different Fab regions
• this creates antibody diversity
Describe the activation of B cells in light zone of germinal centre of the lymph nodes during adaptive immunity.
• hypermutated B cells compete to bind to iccosomes presented by follicular dendritic cells
• B-cells with higher affinity receptors can outcompete other B-cells to rip the iccosomes of the DC, and are conferred survival signals
• unsuccessful B-cells undergo apoptosis due to neglect
• this process is affinity maturation
• successful B-cells move into the mantle zone of the germinal centre
Describe the activation of B cells in mantle zone of germinal centre of the lymph nodes during adaptive immunity.
• B-cells present the antigens on MHC II (provided by neutrophils at the start of B-cell activation) to T-cells
• B-cells require 3 signals for activation
1. MHC II bind to Th2 TCR
2. costimulation: B-cell CD40 bind to Th2 cell CD40-L
3. release of IL-4, IL-5, IL-13 from Th2 cells promotes B-cell differentiation and expansion + class switching to become either plasma or memory B-cells
• plasma B-cells then release immunoglobins targeting pathogen
Where are memory cells located?
• Central memory T-cells remain in lymphoid tissues
• Peripheral effector memory T-cells and B-cells reside in peripheral tissues
Why are memory cells formed in adaptive immunity?
Activated Th cells promotes memory B-cell and T-cell formation, which enables faster and stronger adaptive immune response to future infections of similar pathogens, leading to long term immunologic memory
Define specificity.
Ability to distinguish small differences in 3D structure of ligands/antigens
Define epitope.
specific part of antigen that antibody binds
Contrast affinity and avidity.
Affinity is the strength of monovalent antibody binding, while avidity is total binding strength of antibody after accounting for all binding sites
What is valency?
The number of binding sites on an antibody
Where do B-cells develop?
Initial B cells development takes place in the bone marrow. Later stages of maturation and differentiation take place in secondary lymphoid organs such as lymph nodes and spleen.
What are the parts of an antibody?
• 2 heavy chains and 2 light chains
• Fab variable region formed by heavy and light chains to bind antigens
• Fc constant region formed by only heavy chain to interact with cell surface receptors of other immune cells
When and why does somatic recombination of B-cells take place?
When: during initial B-cell development in the bone marrow
Why: to generate primary antibody repetoire
Distinguish combinatorial diversity and junctional diversity in B-cell somatic recombination.
Combinatorial diversity: random selection and ligation of V and J segments to form light chain and V, D and J segments to form heavy chain
Junctional diversity: insertion of random nucleotides at joining sites between gene fragments
Both processes generate different Fab regions to increase primary antibody repetoire.
When does positive and negative selection of B-cells take place?
Before antigen exposure during B-cell initial development in the bone marrow
What is B-cell positive selection?
• successful expression of pre-BCR (functional heavy chain) confers growth and survival signals to B-cell
• B-cells which fail to express pre-BCRs undergo apoptosis by neglect
• Positively selected B-cells will go on to express IgM
What is B-cell negative selection?
• B-cells with IgM that bind to self-antigens will undergo apoptosis or anergy
• This prevents autoreactivity
• B-cells that don’t bind self-antigens can exit the bone marrow into blood
Describe the process of B-cell class switching.
• activated Th2 cells release IL-4, IL-5 and IL-13 to induce IgG and IgE class switch response
• this induces heterochromatin DNA to open up, allowing switch recombinase complex to access the DNA
• genes are deleted, hence class switching is non-reversible
• class switching changes the antibody produced by mature B-cell from initial IgM to other classes
What are the 6 functions of antibodies?
- neutralisation: bind and block pathogens and toxins from binding to host cell receptors
- opsonization: Fc region recruits macrophages and neutrophils and enhances phagocytosis of pathogens
- agglutination and formation of immune complexes: use multi-valebt binding sites to bind and trap pathogens into large complexes which are phagocytosed
- activation of complement system: classical pathway where Fc region binds to complement proteins, induce MAC which leads to osmotic lysis
- antibody dependent cellular cytotoxicity: antibodies bind to tumour cells and virus infected cells, recruiting NK cells to kill pathogens with perforins and granzymes
- mast cell degranulation: IgE uses Fc region to bind to Fc€RI on mast cells, causing mast cells to release toxic granules with histamines, lipid mediators and prostaglandins (allergies, type I hypersensitivity, parasites)
What are the functions of the IgM antibody class?
• agglutination and formation of immune complex
• activate complement system C1q classical pathway (for MAC)
• important in bacterial infections
What are the functions of the IgG antibody class?
• neutralisation
• ADCC, which is important for cancers and virus
• opsonization
• agglutination and forming of immune complex
What are the functions of the IgE antibody class?
• mast cell degranulation
• important for parasitic infections and allergens
What are the functions of the IgA antibody class?
neutralisation at mucosal sites only
