Immunology Flashcards
Describe ‘Recognition of foreign molecules (non-self)’
- Resistance to infection
- Resistance to tumour
- Recognition of non-infectious foreign molecules
Describe ‘Tolerance = specific inability to recognise antigens’
Means immune system does attack certain antigens (e.g. mother’s immune system tolerates antigen of foetus)
Describe innate immunity
Occurs immediately with its response being non-specific. It provides immediate protection against infection and is stereotypical in response. It occurs in the same fashion every time.
- Cellular barriers (Epithelium and antibacterial chemicals)
- Cells (neutrophils,macrophages, dendritic cells, and NK cells)
- Plasma proteins
- Cytokines
Describe ‘Adaptive immunity’
Develops over days to weeks, the adaptive immune system improves with repeated exposure. It also improves with exposure to wider range of antigens, as B and T memory cells will confer an improved repertoire of immune responses to different substances
- Cells (B cells and T cells)
- Plasma proteins (antibodies)
Describe Haemopoietic stem cells
- Undifferentiated cells that differentiate to blood cells and immune cells
- In bone marrow
- Self renewing
Describe macrophages (two types of phagocytic cells)
- Neutrophils: Grainy, multi-lobed nucleus
- Monocytes: bean-shaped nucleus
List and describe the types of lymphocytes
T lymphocyte
- Mediate cell-mediated immunity
- CD4 and CD8 T cells
B lymphocyte
- mediate antibody immunity
Describe natural killer cells
- large granular lymphocytes
- Part of innate immune response
- lack antigen specific receptor
Describe dendritic cells
- Potent antigen presenting cells (APC)
- uptake antigen in peripheral sites and present to T-lymphocytes
Describe eosinophils
- Bilobed nucleus with cytoplasmic granules
- defence against parasites
Describe basophils
Heavily granulated
Describe mast cells:
- Round nucleus
- involved in allergic reactions
- not usually in circulation; just beneath epithelia in blood vessel
What are the functions of the primary lymphoid organs?
- Develop mature lymphocytes
- Generate receptor diversity
- Eliminates self-reactive cells
- MHC restriction for T cells
What are the primary lymphoid organs?
- Bone Marrow
- Thymus
Bone marrow is the site of:
- site of generation of all circulating blood cells
- site of B lymphocytes maturation
The thymus is the site of:
- T lymphocytes maturation
Describe functions of secondary lymphoid organs:
- Site for the generation of immune response
- Trap antigens
- Present antigens for T cell and B cell activation
List the secondary lymphoid organs (3 of them)
- Lymph nodes
- Spleen
- Tonsils
Describe differences between innate and adaptive immunity
Innate immunity:
- rapid response
- Independent of prior exposure. Same influence every time despite prior exposure
- Limited number of antigen-binding receptor
- General specificity for classes
- No self-reactivity
Adaptive immunity:
- Slow response
- Prior exposure causes retention of memory B cells and T cells makes subsequent responses faster and more potent
- Large number of antigen-binding receptor
- Very specific
- Self reactive cells are destroyed
Name all the innate immunity components
- Cellular barriers: epithelium, anti-bacterial chemicals
- Cells: phagocytes (neutrophils and macrophages), NK cells, dendritic cells
- Plasma proteins
- Cytokines
What are pathogen recognition receptors (PRR)
- PRRs recognise common structures shared by different pathogen but not structures found in host cells
- Receptors can be on cell surface or in cytotoxic endosomes
- E.g. toll-like receptors and NOD-like receptors
Outline the properties of Pathogen associated molecular patterns (PAMP)
- Molecular structures on pathogen which are recognised and bound by the PRR
- E.g. lipopolysaccharides, mannose, dsRNA
What is function of innate immunity?
- Early protection
- Activating and enhancing adaptive immunity
What are toll-like receptors?
Cell surface receptors which bind proteins and lipoproteins
What does cell surface TLR bind to and name examples of this
- They bind to bacteria lipoproteins and proteins
TLR4 binds lipopolysaccharides (LPS)
TLR2 binds lipotechoic aic
TLR5 binds bacteria flagellum
What does cytotoxic endosome TLR bind to and name some examples
Bacterial and viral DNA and RNA
- TLR3 binds dsRNA
- TLR7 binds ssRNA
- TLR9 binds unmethylated DNA
List some common examples of C-type lectins, and their corresponding ligand and sources
C-type Lectins - cell surface protein that binds carbohydrates
- NOD binds peptidoglycan
- RIG binds RNA
Describe the cellular effects of activating TLR
- Cytokines production (inflammation)
- Chemokine production (cell recruitment)
- Activate bacterial killing mechanisms
- Activate dendritic cells
Describe the steps of Interleukin-1 and toll-like receptor pathways and their shared signalling pathway
- TLR ligand binds to surface receptor
- Adaptor molecule recruited (MyD88)
- Enzymes activated (MAP kinase)
- Transcription factors activated (NFkB)
Describe the difference between anti-specific and antigen non-specific immune responses
Antigen non-specific immune responses —> communication between cells
- Requires binding of general class of antigen
- Cytokines
- Chemokines
- Complement system
Antigen specific immune response —> long distance adaptive immunity
- Requires binding of a specific antigen
- Antibodies
Define cytokines, outline their properties and list common examples
Cytokines
- Antigen non-specific effector molecules
- Secreted by macrophages, T and B cells, and dendritic cells
- E.g. Interleukins (IL) and interferons (IFN)
Properties of cytokines:
- Potent in small quantities
- only produced when signal present
- mRNA rapidly degrades
- Bind to specific cell surface receptors
- Act locally
Describe the difference in function between cytokines and chemokines
Chemokines:
- “Chemoattractant cytokines” (type of cytokines)
- Attract cells to site of inflammation or lymph node
Describe the role of the innate vs the adaptive immune system in clearing an infection
Innate immune system mechanism of clearing infection
- Opsonization: proteins which bind to cover and increase phagocytic activity
- Complement system coats bacteria
- Neutrophils recruited to the site of infection to phagocytise the bacteria
- APC activate adaptive immune system
Adaptive immune system mechanism of clearing infection
- Adaptive immunity uses and amplifies innate immunity processes
- Antibodies coat the bacteria and enhance phagocytosis
- Antibodies activate the complement pathway
- Antibodies activate killing mechanisms in phagocytes
Describe the phagocytic role of neutrophils and macrophages in inflammation and bacterial killing
- Complement system and cytokines allow leukocytes to adhere to blood vessels walls
- Leukocytes leak through endothelium to inflammation site
- Neutrophils and macrophages engulf microbes
- Kill microbes: via lysosomal enzymes, via reactive oxygen species and nitrous oxide
Describe Clonal selection theory
Burnet’s clonal selection theory
- Lymphocytes acquire a unique, antigen receptor via gene recombination
- Foreign antigens select for specific receptor-bearing cell leading to clonal expansion of that specific cell
- Re-exposure to the same antigen induces a rapid ‘memory’ response due to the previously clonal-expanded population of cells that can bind that antigen
- Self-binding receptors are destroyed in the primary lymphoid organs during development
Describe clonal expansion
- Antigen binds one B cell
- Selected B cell proliferates
- Plasma cells and memory cells differentiate
Describe the phases of adaptive immune responses
- Antigen recognition
- lymphocyte activation
- Antigen elimination
- Contraction
- Memory
Describe the properties of dendritic cells and their role in linking innate and adaptive immunity
Immature dendritic cells
- surveillance cells in peripheral locations (e.g. skin, lungs, mucosa)
- Specialized in antigen uptake
- mature to be better antigen presenter
Mature dendritic cells
- mature dendritic cells up-regulate expression of MHC1 and MHC2 —> better presenters
- produce cytokines
- migrate to lymph nodes to activate T cells —> links innate immune with adaptive immune by bringing antigen from periphery to lymph node
Describe the function of dendritic cells as antigen presenting cells
Dendritic cells
- Antigen presenting cells
- phagocytise antigen and present antigen-peptide fragment on their MHC class 2 receptors: able to present pathogens that are inside host cells (e.g. viruses and intracellular bacteria
- MHC class 2 genetic makeup is unique to each person
- Must have antigen bound to the MHC peptide to present the antigen to the T-cell.
- Reside in tissues as immature cells and can regulate their MHC surface receptors
Describe the function of T cells as antigen presenting cells
T-cells:
- antigen receptors stay on the T-cell after activation
- secrete cytokines to recruit cells to the area where antigen binds T-cell receptors
- Only recognise presented antigen presented on self-MHC complex on the antigen-presenting cell
Explain the structure and function of the human leukocyte antigens (HLA) or ‘MHC’ complex 1
Structure of MHC class 1 - Two chains (heterodimer) —> alpha chain and beta chain Beta chain: 1 domain, constant domain for binding CD8 of T cell Alpha chain: 3 domains, alpha1 and alpha2 domains (variable) for antigen binding, alpha3 domain (constant) for binding CD8 of T cell.
- Domains held together with disulfide bonds
- Found in all uncleared cells
- Function = presents to CD8+ T cells
Explain the structure and function of the HLA or MHC Class 2
- Two chains (heterodimer) —> alpha chain and beta chain
- Both chains have a constant and variable domain
- Both chains bind with the antigen peptide
- Found in immune cells, mostly dendritic cells
- Function = Presents to CD4+ T cells
Explain how protein antigens are processed by the endogenous and exogenous antigen pathways to be presented by HLA class 1 molecules to CD8 and CD4 T cells
Presentation on MHC Class 1 molecules (Cytoplasmic antigen processing pathway):
1) Virus is IN cytoplasm of cell or virus phagocytised
2) Viral protein moved to cytoplasm where it’s ubiquitinated
3) Viral protein broken down to peptides
4) peptide binds with MHC class 1 in ER
5) MHC class 1 complex exported to surface from Golgi
Explain how protein antigens are processed by the endogenous and exogenous antigen pathways to be presented by the HLA class 2 molecules to CD8 and CD4 T cells
Presentation on MHC Class 2 molecules (Endogenous antigen processing pathway)
- protein uptake from the outside of the cell via endocytosis forms vesicles. Antigen protein never enters cytoplasm
1. Protein antigen endocytosed in vesicles
2. Lysosome fuses and digest antigen protein
3. Exocytotic vesicle containing MHC class 2 fuses with antigen peptide vesicle; complex forms
4. MHC Class 2 complex exported to surface
Explain how T lymphocytes are activated by antigen presenting cells
Activation of T-lymphocytes
- CD4 T cells are activated when an MHC Class 2 presents the corresponding antigen peptide for the TcR
- CD8 T cells are activated when an MHC Class 1 presents the corresponding antigen peptide for the TcR
Explain how T lymphocytes recognise an “infinite” variety of protein antigens from microbes
- T cells are developed in the thymus
- Rearrangement of TcR genes allow for 10^10 possible TcR combinations
- Positive selection = T cells that bind with self MHC and any peptide are kept
- Negative selection = T cell that bind with self peptides are deleted
Explain how the activation of T cells is regulated
CD4 T cells:
There are 2 signals required from APC for T-cell activation:
- Signal 1–> MHC complex and peptide must bind to TcR (I.e. same MHC gene content and matching antigen peptide fragment)
- Signal 2–> B7 on APC must bind with CD28 on T cell. B7 produced in presence of pathogens.
No activation if either signal is not present
CD8 T cells:
- Cross priming of CD8 T cells by dendritic cells
- Expansion of CD8 T cells requires CD4 T cell help
Explain the different processes of activation
CD4 T-cell activation - requires two signals from APC
CD8 T-cell activation - requires cross-pricing from APC and help from CD4 T cells
Summarise classes of antibodies and how they develop
5 classes: IgM, IgG, IgA, IgE, IgD
Development:
- B cells bind antigen at unique membrane receptors (B- cell receptors)
- Clonal expansion occurs
- B cells differentiate into plasma cells or memory B cells: Plasma cells release antigen-specific antibodies, memory cells remain in body to detect reinfection.
Describe structure of antibodies
Antibody structure contains heavy chain, light chain, hinge region, Fc region
Heavy chain:
- 3 constant regions and 1 variable region
- C- terminus inserts into membrane; N terminus responsible for antigen binding (variable region)
Light chain:
- 1 constant region and 1 variable region
- on N terminus on responsible for antigen binding
Hinge region: holds heavy chains together
Fc region:
- Region with only heavy chain
- Bind with effector cells and proteins to confer function: C1q to activate complement pathway, Opsonize phagocytosis - macrophages, recognition killing - Natural killer cells, sensitisation cell activation - mast cells.
Describe “Antigen binding region”
- N terminus binds antigen
- Composed of 3 loops of variable region of HC and LC
- Each monomer of antibody has 2 antigen-binding regions
Describe antibody IgM
- heavy chain ‘mu’
- 5 monomers
- Functions in primary response
- has C1q complement system
Describe Antibody IgG
- Heavy chain gamma
- 1 monomer
- secondary response
- has C1q complement system
- It does opsonize
Describe antibody IgA
- Heavy chain alpha
- it has two monomers
- functions in mucosal response
Describe antibody IgE
- Heavy chain epsilon
- 1 monomer
- For helminth parasites
Describe Antibody IgD
- heavy chain delta
- 1 monomer
- Naive B cell antigen receptor
Describe B-cell receptors
- Basically antibodies that are embedded in the cell membrane: light and heavy chain, variable regions bind antigen
- Signal transduction molecules next to BcR
- BcR binds to antigens
- Have CD19 proteins
Describe T-cell receptors
- Two chains, each with 1 constant domain and 1 variable domain
- CD3 proteins are next to TcR (all T-cells have CD3, then either CD4 or CD8)
- TcR binds to antigen-peptide fragments that are presented by antigen-presenting cells (I.e. dendritic cells): antigen-peptide fragment is bound to HLA (MHC)
Describe development of B-cell Receptor and T-cell receptor
- Variable regions of heavy and light chain are encoded by separate gene fragments that recombine to form a unique DNA sequence for the functional region
- There are multiple genes for the three domains (variable, diversity and junctions) that are combined together
- Bases are added and removed from the junctions between genes during RNA processing
Describe surface receptors on T-lymphocytes (4 of them)
T-cell receptor - generated from VDJ recombination, specific to one antigenic sequence
CD3 - complex or proteins that signals activation of T-cell from antigen specific TcR to nucleus
CD4+ - CD4+ is on T-helper cells and binds to MHC class 2 molecules to recognise antigen
CD8+ - CD8+ is on cytotoxic T cells and binds to MHC class 1 molecules to recognise antigen
CD4+ and CD8+ are like the specific Velcro that holds a T-cell to the antigen-presenting cell. T-cells can only have either CD4+ and CD8+ (mutually exclusive)
Describe T cell activation, including the role of co-stimulation and responses to activation
T-cells require two signals:
- Signal 1: TcR binds antigenic peptide-bound to MHC
- Signal 2: T-cell binds co-stimulator (B7 on APC)
Proliferation factors:
- cytokines (IL-2) must be present for proliferation
- IL-2 is released by activated dendritic cell and activated T-cell (autocrine stimulation)
Explain how the activation of T cells is regulated
T-cell activation is highly regulated because generated cytokines can be harmful to the host.
1) Stimulation via Co-stimulator from APC: binding of co-stimulator (B7) to CD28 receptor STIMULATES T-cell activation response
2) Inhibition via Co-stimulator from APC:
- B7 binds with greater affinity to another receptor termed CTLA4
- Binding to CTLA4 INHIBITS T-cell activation
- Expression of CTLA4 leads to cessation of signal to activate T-cells (no more binding to CD28)
3) Antibody Regulation
- Antibodies bind to receptors (CD28 or CTLA4) to block either inhibitory or activating signals
Summarise T-cell differentiation into effector and memory T-cells
Expansion and contraction of T-cells:
1) T-cells bind to APC via binding MHC molecules bound to peptide
2) In infection and pathogenic products, APC express B7 which binds to CD28 receptors on T-cells. Co-stimulation activates T-cell and IL-2 is secreted.
3) Activated T-cells are generated
4) T-cells bind interleukin-2 (IL-2) and promote cell proliferation
5) Cell death of expanding T-cell clones occurs due to lack of IL-2 growth factor, induced apoptosis via Fas-Fas ligand, or elimination of antigen
Describe the properties of cytokines and chemokines and the role of cytokines receptor expression in immune responses
T-cell activities are highly regulated by cytokines
- Cytokines are very short-lived and are only expressed for a few days
- Receptors for cytokines are also very short-lived and are also only expressed for a few days
- Different levels of different cytokines mediate the action of the T-cell
- The type of T-cell produced are dependent on the type of cytokines present around the T-cell
- E.g. IL-12 will cause differentiation into Th1 cells, IL-4 will cause differentiation into Th2 cells.
Summarise the migration of T-cells to sites of activation and infection or inflammation
Circulatory Path
- Heart pumps blood with T-lymphocytes in circulation: Blood —> interstitial fluid —> lymph vessels —> Thoracic duct —> Jugulosubclavian junction —> blood
- T cells exit the arteries in lymph nodes at the high endothelial venue (HEV)
- Afferent lymph vessels enter the lymph node and brings antigen presenting cells bound to antigen and activate T -cells
- Naive T-cells migrate to different lymph nodes until APC activates th T-cell
- Activation of the Naive T-cell will result in expression of L-selection which binds T-cell to lymph node
- Once sufficient T-cell clones are produced, they are released to the circulatory system to go to infection
- Once T-cells are activated, they need to migrate back to tissues where the antigen was originated
- Down-regulation of L-selection and production of VCAM-1 which binds activate T-cells to inflamed tissue
List the 4 functional types of CD4 T-cells
- Th1 T-cells
- Th2 T-cells
- Th17 T-cells
- Treg T-cells
What does Th1 T-cell respond to?
Intracellular pathogens
What does Th2 T-cells respond to?
Parasites and supports B-cells for production of antibodies
