W1P2 Flashcards
What are the main effectors of adaptive immunity
B lymphocytes
- B cell receptors (BCR)
- Antibodies
T-lymphocytes
- T cell receptors (TCR)
Compare innate vs adaptive immune cells ability to recognize invaders
Adaptive, T and B cells:
recognize pathogens via specific receptors that recognize peptides present in the structure of the invader
VS
Innate cells: recognition of patterns rather than specific peptides
How does the adaptive cellular immune response get initiated
cellular immune response = T cell
A virus, bacteria, fungus or allergen crosses the epithelial barrier
This is a protein that is given in its native form
T cell receptors DO NOT recognize complex proteins
They can only recognize peptides
- They are presented by APCs
What are the types of APCs
- Monocyte
- Macrophage
- Dendritic cell (DC)
- B-cell
APC process proteins into peptides that can be presented and recognized by T cells
What are Antigen Presenting Cells (APCs)
- there are two types
All nucleated cells express Major Histocompatibility Complex (MHC) class I and can present antigen usually only when infected Only CD8+ T-cells can recognize class I
Professional APCs express MHC Class II and can pick up antigens, process them and present to CD4+ T cells
Professional APCs express Class II and include: monocytes/macrophages, B cells, dendritic cells, Langerhans cells, Kupfer cells, and astrocytes.
What type of cells are langerhans, kupfer and astrocytes
Langerhans: resident macrophages of the SKIN
Kupfer: Resident macrophages of the Liver
Astrocytes: are the most numerous cell type within the central nervous system (CNS) and perform a variety of tasks, from axon guidance and synaptic support, to the control of the blood brain barrier and blood flow.
All of these are further examples of PROFESSIONAL APCs. Thus they all have MHCII receptors
Dendritic cells: what receptors do they have, what can they recognize
Dendritic cells have a large number of innate immune receptors
- eg Toll-like receptors (TLRs 1-11)
- Can also recognize antibody coated antigens
- Complement coated antigens
Dendritic Cells, what are their functions?
- Engulf and process Ag, and process them for T cell by digestion into peptides on MCHII
- Releases cytokines (IL-12)
- Migrate to areas that have large T cell populations e.g. lymph nodes
- Express co-stimulatory molecules
T lymphocytes
- where can they be found
- where were they developed
Found: Circulating cells that populate the blood and lymph nodes, make up 70-85% of peripheral lymphocytes in normal individuals
- Develop in the Thymus
- We are all born with a limited ‘repertoire’ of antigens that our T cells do or do not recognize
Exposure helps mature and refine the responses!!
How do T cells work?
- What must it have to recognize an antigen
For recognition, T cell must have:
- a receptor that can recognize a specific peptide (TCR) which would interact with the MCH2
- a signaling complex (CD3)
- a CD4 or 8 molecule
How does a T cell know they are meeting the right APC?
The immune system has developed a system to ensure that T cells only respond to cells from the “Self”
These are known as Major Histocompatibility antigens
Biometrics!
What are the 3 roles for T cells?
- Fight intracellular infections
- CD8 cytotoxic T-cells - Assist other cells by activating them and helping them multiply or differentiate
- CD4+ effector T-cells: Th1, Th2, Th9, Th17 - Provide signals that inhibit or slow down inflammatory responses
- Regulatory T-cells (CD4+Foxp3+)
Which are the effector T cells?
Effector T cells are CD4+ and have various functions:
- Supply cytokines to monocytes to help them fight intracellular organisms. These are designated T helper 1 (Th1).
- They also can supply cytokines to B cells to direct specific antibody responses. These are designated T helper 2 or Th2.
- Supply cytokines that activate phagocytes and other innate immune cells; designated T-helper 17 (Th17)
- Regulate all cell activites via IL-10, TGF-b or cell-cell contact: Regulatory T-cells (Treg)
T cell Activation
Once a naïve T cell is stimulated,
it’s surface architecture changes
When a T cell recognizes a peptide, its surface changes, it up-regulates:
- cytokine receptors eg IL2R
- adhesion molecules eg CD28
- chemokine receptors eg CCR3,4,5
These help amplify the T cell multiplication
the cytokines;
- help T cell multiply
- tell other cell in the environment, what to do
T cell proliferation depends on…
If T cells are not able to produce or recognize cytokines
- They cannot grow or multiply
- eg IL-2 receptor common gamma chain deficiency
- IL-7Ra deficiency
They cannot defend against specific pathogens
- IFN-γ or IL-12 and severe mycobacterial infection
What are the clones of T cells and what are their functions
Effector T cells: cells that will stimulate or attack other cells in the environment (CD4 derivatives: Th1, Th2, Th17, Treg)
- This will magnify the response.
Memory T cells: small clone of antigen recognizing cells for future recognition of the same antigen
Th1
- which cytokines
Intracellular organisms
IFN-γ, IL-12, IL-18
Supply cytokines to monocytes to help them fight intracellular organisms. These are designated T helper 1 (Th1).
Th2
- Which cytokines
Antibody production, parasite defense, allergy
IL-4, IL-5, IL-13
They also can supply cytokines to B cells to direct specific antibody responses. These are designated T helper 2 or Th2.
Th17
- which cytokines
Supply cytokines that activate phagocytes and other innate immune cells; designated T-helper 17 (Th17)
Antibacterial, antifungal
IL-17, IL-22
T reg
- which cytokines
Immune response regulation: IL-10, TGF-β
Regulate all cell activites via IL-10, TGF-b or cell-cell contact: Regulatory T-cells (Treg)
CD8 T cells, roles?
T lymphocytes directly fight viral and fungal infections. These are cytotoxic T cells (designated by the molecule CD8
- Recognition of infected cells Viral immunity - Production of Pro-apoptotic Proteins Perforin and Granzyme - Can produce pro-inflammatory cytokines e.g. IFN−γ
and has a T reg: Immune response regulation: IL-10, TGF-β
Cytotoxicity
Mediated by CD8
CD8+ cells recognize antigen presented on MHC I by infected or diseased cell
Induces apoptosis by
- FAS-FASL interaction
- production of TNF
- injection of toxic substances
- Peforins and granzyme.
What happens if T cells do not work?
- Cell mediated immunity
- Severe viral infections
- Severe bacterial infections - Humoral Immunity
- B cells can’t make antibodies - Other cells can’t get activated
- Monocytes, macrophages, eosinophils - Congenital
- Severe Combined Immune Deficiency
- Defective cytokine receptor (X-linked SCID)
- Defective receptor signaling (JAK3, ZAP70 deficiencies)
- Absent T cells (Adenosine deaminase deficiency)
- Many others - Acquired
- HIV disease
How do you measure if T-Cells have memory for a virus like SARS-COV2
B-Cells
- what percentage of circulating lymphocytes do they make up
What are their primary functions
- The producers of antibody
- So named because they come from “bone marrow” or, in chickens, from the “Bursa of Fabricus”
- They make up 5-15% of circulating lymphocytes.
- Each progenitor B cell is capable of coding for a distinct antigen.
Primary Functions:
- Recognize foreign substances (antigens) via B-cell receptors (BCR) on their surface that look like antibody molecules (surface Ig or sIg)
- Present Antigens to T-cells (they are professional APCs)
- Secrete Antibodies!!
- Produce Cytokines
What is the basic structure of a B cell
B cell receptor (BCR)
MCH class II [professional APC]
CD19, CD20
B cell maturation
- B cells arise in bone marrow from stem cells
- They are released into circulation after several maturation steps
- Immature or naïve B cells are released into circulation at a stage when most cells can secrete IgM and have a BCR on their surface
- B cells home to areas of antigen dependent maturation (e.g.) lymph nodes, spleen, to interact with T cells and specialized Follicular Dendritic Cells
How do B cells recognize antigens
- B cells recognize three dimensional structures of antigens
- Because they are antigen presenting cells, they internalize antigens and process them into peptides
- B cells trap antigen in a different form than they present them
- T-cells are presented these peptides via MHC II to the TCR
When a B cell presents an antigen to a T cell, what does it lead to?
It leads to production of Ig/ antibodies
co stimulus: CD80/86 on B cell stimulated CD28 on T cell
then MHC2 on B cell with CD3/CD4/8 on T cell
Key Messages,
relationship between antibodies, antigens, B cells, the isotopes…
One antigen, many potential antibodies
BUT: One B-cell, one antibody
One antibody, multiple isotypes
How to make a better antibody?
- In lymph nodes, antigen specific B cells undergo affinity maturation
- Antibodies of increased affinity for better immune responses are produced through mutation of their BCR genetic program (somatic mutation)
- Only those able to interact strongly with antigen will mature (many are called, few are chosen!)
Primary vs Secondary Follicle
Primary Follicle: Naïve B-cells who had not seen antigen; cells can mature to Memory B-cells or Plasma Cells
Secondary Follicle: Memory B-cells already present, more rapid response, more memory cells, more plasma cells
B cell facial features of a Memory Cell
- Memory cells: responds rapidly to antigens, matures rapidly
BCR: same structure as an antibody molecule; it recognizes presented antigens. Short signal transduction chain, coupled to two intracellular signaling molecules Igα and Igβ
CD19,CD20: common B cell surface adhesion molecules; important in allowing a cell to be activated.
MHC class II means that B cells can be professional antigen presenting cells to T cells.
Fc receptors: many cells have receptors for the “constant region” of antibody molecules. B cells have a subclass called FcγRIIb - unique because it inhibits or diminishes cell activation when it is occupied.
CD40: strengthens T cell - B cell interaction.
CD28/B7.1: strengthens T cell - B cell interaction.
B cell facial features of Plasma Cells
Plasma Cells: most mature subtype of B cell, produces and stores copious amount of Ig and cytokines
- CD38
- CD138
Antibodies
- made by
- where are they found
- types
- regions
- Made by B cells
- Circulates
- Recognizes specific substances on its “variable region”
- Taken up by phagocytic cells via its “constant region”
- IgG, IgA, IgM, IgE and their subclasses
Antibody structure
- Made up of proteins known as immunoglobulins.
- Two pairs of chains: heavy chain and light chain, linked together by different bonds.
constant region: heavy chain (legs), Fc fragment
variable region: light chain (arms), antigen binding site
What are the types of Heavy and Light Chains
5 different heavy chains µ makes IgM, α makes IgA, γ makes IgG, ε makes IgE, δ makes IgD.
2 different light chains:
Kappa κ
Lambda λ
Fc portion vs antigen binding cite
Fc:
The COOH ends of the heavy chains, plus a small part of the light chain, pairs up into the constant region. All molecules of a particular Isotype have similar constant regions.
Antigen binding site:
The NH2 ends heavy and light chains pair up to form the variable region of an antibody molecule. In this area is the specific antigen binding region - the unique portion of the molecule.
Consequences of B cell dysfunction
- No antibodies
- Moderate to severe bacterial infections
- Encapsulated organisms (pnemococcus,
- moraxella, hemophilus influenza)
- Mycoplasma and species
- Pneumonia, sinusitis, sepsis, meningitis,
- Osteomyelitis
Humoral Immune Disorders
No B cells
- X linked agammaglobulinemia
Missing cell communication adhesion molecules
- Hyper IgM syndrome (non functioning CD40L on T cells)
Other poor B or T cell function
- combined immune deficiency
- common variable immune deficiency
IgM
- 10% of circulating Ig’s
- Circulates as a pentamer, linked by disulphide
- bonds and a J-chain
- 1st antibody made (“defaut setting for B cells”)
- Excellent at complement fixation
- No Fcµ receptors so poor at opsonization
- Good at neutralization
This is the PRIMARY response antibody
- Primary response is IgM, think M for mother
- Subsequent antigen challenges leads to switch
- from IgM to IgG, A or E via gene rearrangement
cytokine and environment dependent
IgG
- percentage of circulating ABs
- what are the 4 subclasses
- unique feature
- 75% of all circulating antibodies
- Main Ig produced in secondary antibody responses
- 4 subclasses IgG1 (70%), IgG2 (15-20%), IgG3 (5-10%), IgG4 (1-5%)
- Only antibody that crosses the placenta
- Most pass actively in 3rd trimester
IgG properties
- half life
- other downstream functions
- which surfaces are they found on?
- ½ life app. 21 days: produced after age 3-4 months
- Good at fixing complement (IgG3 > IgG1 > IgG2»_space; IgG4
- Excellent opsonization (Fcγ receptors)
- Some IgG at mucosal surfaces
IgA
- 15-20% of circulating Ig
- Lines mucosal surface : excellent 1st line of defense
- Exists as a dimer (2 molecules + J chain)
- Secretory piece added: protection from proteolysis
- Excellent at neutralization, but fair at complement activation
- Fair at opsonization
- Most common immune deficiency (1:700)
IgE
- Very low amounts in serum
- Most IgE is bound to mast cells + basophils (FcεR)
- Key Ig in parasite defence
- Responsible for allergy and anaphylaxis
- Some complement activation (alternate pathway)
- More in later lectures
IgD
Little circulating
No clear role in host defense
Important marker of B cell maturation
What is necessary to elicit a strong antibody response
- Antigen
- T cells for direct contact (usually TH2 cells)
- Soluble cytokines (eg) IL4 + IL13, INF-γ or IL10)
- Certain adhesion molecules esp CD40
