Lecture 1 Flashcards
What are the sources of infection?
Pathogens
What are pathogens?
Organisms that cause disease • Bacteria • Viruses • Fungi • Parasites (Worms, Protozoa)
What must the immune system be able to do for an effective immune response?
Be able to recognise & respond to any invading organism
Not over react to benign or self
Be able to direct different effector mechanisms against different pathogens
What is the difference between innate & adaptive immunity?
Innate is activated very quickly
Adaptive takes over if innate doesn’t completely control the pathogen
What is specific/adaptive immunity
Induced by exposure to a particular infection
Shows a high degree of specificity
Exhibits memory
Features of specific immunity
Clonally distributed receptors
Large repertoire
Response takes time to develop
Memory cells produced
Clonal selection
- Removal of potentially self-reactive immature lymphocytes by clonal deletion
- Pool of mature naïve lymphocytes
- Proliferation & differentiation of activated specific lymphocytes to form a clone of effector cells
Followed by clonal expansion
What are the 2 lymphocyte receptors for antigens?
B lymphocytes
T lymphocytes
B lymphocytes
BCR expressed by B cells
Membrane anchored protein on the surface of B cell
Binds free antigen
Is subsequently secreted with B cell is activated = an antibody
T lymphocytes
TCR expressed by T cells
Membrane form only - stays on the surface where it functions
Recognises a peptide fragment of antigen bound to MHC expressed by APCs
What do antibodies do?
Activation of complement
Activation of effector cells
What are antibodies made of
Formed of 4 polypeptides
• 2 heavy chains & 2 light chains
Formed by domains - variable & constant
Held together by covalent & non-covalent bonds
Pathogens that may infect mammals can include fungi, bacteria, viruses as well as large, multi-cellular organisms such as …
parasites - worms, protozoa
The first phase of an immune response is known as the innate response with the second phase called the …
Adaptive immunity
The acquired phase is specific and relies on the detection of infectious agents using …
antibodies/cytokines specific for that pathogen
Why is the secondary immune response more effective than the primary response?
The memory cells recognise the pathogen, and the antibodies can respond much faster.
Antibody structure:
- immunoglobulin
- basic 4-chain structure
- 2 identical heavy chains & 2 identical light chains, held together by covalent and non-covalent bonds
- 2 types of L chain (λ & κ)
- each chain has a variable (V) and a constant (C) region
- antigen-binding sites (variable region) consist of VH and VL
- different CH regions interact with complement and the Fc region binds to different FcRs expressed by effector cells (macrophages, neutrophils, NK cells)
What do the variable & constant regions do?
Variable regions form the antigen-binding sites - specific for a given Ab
Constant regions are responsible for antibody structure & interacting with other molecules
What are the 2 types of light chain?
Lambda and Kappa
5 antibody classes - what are they?
IgM, D, A, G and E
Isotype is determined by the heavy chain (C region)
Isotypes differ in their structure and functions
Antibody domains
Analysis of amino acid sequences of H and L chains reveals homology regions (domains)
each domain ~ 110 amino acids
each domain comprises two b sheets,
linked by a disulphide bridge (S-S, C)
domains are paired –> folded units within the protein
Immunoglobulin-like domains
present in a range of other proteins:
Immunoglobulin superfamily
includes:
TCR, MHC class I and II, various other molecules
(e.g. CD4, CD8, CD80, CD86, CTLA-4, KIR, IL-6R)
Antibody – antigen interaction:
- variable region (heavy and light chains)
- V regions are specific for a given Ab
- concentrated region of variability
- hypervariable regions (3 in VH & VL)
- HV1-3
- 6 hypervariable loops-> Ag binding site
- complementary-determining regions (CDR1-3)
- both heavy and light chains contribute
- Ag binds to aa in CDRs
- size/shape of Ag affects binding
Antigen recognition:
- epitopes recognised by antibodies may be continuous or conformational (discontinuous)
- Ag can be almost any molecule (protein, polysaccharide even nucleic acids), along with non-biological molecules e.g. chemicals, metals
- antibody and Ag form non-covalent interactions
- Ag sequence may be manipulated in vaccine design
- Ag may be folded
- CDRs present in antibody V regions determine the specificity and the affinity of an antibody for Ag
What are the 2 chains of an antibody called?
Heavy and light chains.
Which part of an antibody interacts with the epitope of an antigen?
The variable domains of the heavy and light chains (VH and VL)
Define the Fab and the Fc regions of an antibody?
The Fc region is constant. The Fab region binds to antigens and consist of VH and VL
The antigen binding site of an antibody is made up of …
VH and VL
The Lamda and Kappa chains form the L chain of an antibody?
Light
How many hypervariable regions are involved with antigen binding in a single antibody molecule?
3 in VH and 3 in VL – 12 in total
Antibodies only recognise peptide antigens?
False, antigens can be almost any molecule (protein, polysaccharide, nucleic acids, chemicals, metals)
Lymphocyte receptors for antigen:
• TCR expressed by T lymphocytes:
membrane form only
recognizes peptide fragment of antigen bound to MHC expressed by APC
What does a TCR do?
- unlike antibody, it doesn’t bind free antigen
- binds/recognizes processed antigen (peptides)
- “presented” in the cleft/binding “groove” of MHC class I or class II molecules
TCR:
- membrane bound receptor (and unlike BCR is not secreted)
- smaller than BCR/antibody (only 4 Ig-like domains)
- recognizes short peptide fragments (of Ags) bound to MHC molecules on other cells (i.e. not free/ “native” antigens)
- heterodimer of a and b chain (sometimes g and d)
- each chain has a V and a C region
- domains (x4) are Ig-like
- V domains interact with antigen = peptide bound to MHC molecule
- each chain contributes 3 CDRs to Ag binding
Major histocompatibility complex (MHC) molecules
chromosome 6, 7 x106 bp MHC class I (expressed by nearly all cell types in body) MHC class II (expression restricted to a specialized group of immune cells)
MHC class I and II
- related, but different structures
- different expression patterns
- present peptides from different sources
- many alleles (polymorphic)
- first identified due to role in transplant rejection
MHC class I
• expressed on all nucleated cells
• heterodimer: a chain (43 kD)
b2- microglobulin (12 kD)
• in humans three different MHC class I molecules: HLA-A, HLA-B and HLA-C
• HLA-A, B and C molecules are encoded by separate a chain genes. A single (non-MHC located) gene encodes b2-microglobulin which associates with HLA-A, HLA-B and HLA-C
• a1 and a2 domains fold to form b-sheet structure known as peptide binding site (“groove, cleft”)
• DNA encoding encoding a1 and a2 domains is very polymorphic (many alleles differ here)
• a3 domain/b2-microglobulin fold into “Ig-like” domains
MHC class II
• expression limited to APC (and cytokine-activated cells)
• heterodimers, a and b chains similar size (34 and 29 kD) and both transmembrane
In humans three different MHC class II molecules: HLA-DP, HLA-DQ and HLA-DR
• a and b chains encoded by separate genes encoded within MHC
• both a2 and b2 domains are Ig-like
• similar structure to MHC class I molecules
• polymorphic a1 and b1 domains form peptide-binding site
• more open than “groove” seen in MHC class I molecules, and binds longer peptides)
TCR, CD8 and CD4
The TCR expressed by a T cell that co-expresses CD8 can bind MHC class I molecules (that expressed on most cells) The TCR expressed on a T cell that co-expresses CD4 will bind MHC class II molecules expressed on APC
Summary Antibody
H2L2, expressed on B cells, also secreted
Binds free antigens
Highly variable, clonally distributed
Summary TCR
alpha beta on T cells
Binds peptide-MHC complex: dual specificity
Highly variable, clonally distributed
Summary MHC class I
alpha chain plus beta2-microglobulin, expressed on all nucleated cells
Binds peptide 8-10 amino acids to present to TCR
Highly polymorphic, limited variation in one individual
Summary MHC class II
alpha beta chain heterodimers, expressed on APC
Binds peptide 13+ amino acids to present to TCR
Highly polymorphic, limited variation in one individual
