Deze Engelse samenvatting bevat een ruim overzicht van onderwerpen besproken in Parham et al. 2012 'The immune System'. Onder andere: immuunlichaam productie, diversiteit en recombinatie.
Het bevat alle belangrijken concepten en definities van Hoofdstuk 4 en het gebruikt afbeeldingen om het te ve...
Antibodies
In adaptive immunity, extracellular pathogens and their toxins are cleared by antibodies or immunoglobulins, a
secreted form of the B-cell receptor. They are specific; they can bind only one or several antigens.
The total antibody repertoire that the body can produce is 1016.
Clonal selection =
Antigen binds BCR " differentiation into plasma cell " proliferation " many of the same antigen-specific Ig’s
Agammaglobulinemia is an inability to make Ig’s; patients are highly susceptible to certain infections.
Structural basis of antibody diversity
Heavy chains = H chains (50 kDa)
Light chains = L chains (25 kDa)
Variable region = antigen-binding site; 1 L and 1 H-chain
Constant region = very little vibration between antibodies
Differences in the C – constant – region define 5 isotypes or classes:
IgG gamma γ * monomers
IgM mu μ pentamers
IgD delta δ monomers
IgA alpha α mono-/dimers
IgE epsilon ε monomers
* corresponding heavy chains.
Two classes of light chain: kappa and lambda.
There is no functional difference and they pair with all H chain
isotypes.
The hinge region provides flexibility to the antibody.
It can be cleaved by proteases:
- 2 Fab fragments (Fragment Antigen Binding)
- 1 Fc fragment (Fragment Crystallizable)
The immunoglobulin superfamily
1. Immunoglobulin domain = motif of 100+ amino acids folded into a compact domain.
V region consists of one variable domain: VH and VL
C region consists of constant domains and varies per isotype:
IgG – IgD – IgA 8 C domains
IgM – IgE 10 C domains
2. Immunoglobulin-like domains are found in other areas,
3. mainly in cells and proteins of the immune system.
Variability and antigen-binding
There are three hypervariable regions (HV) per V domain.
= also called complementary determining regions: CDR1, CDR2, CD3
The Beta-sheets in between are made up by less variable framework regions.
Antibody binds to the antigenic determinant or epitope on a pathogen.
- Multivalent antigen = antigen with several (different) epitopes.
- Two categories: linear epitopes and discontinuous epitopes.
, - Non-covalent binding: van der Waals, hydrophobic interactions, H-bonds, electrostatic force. The affinity or
binding strength determines which antibody binds to the epitope.
Monoclonal antibodies
There are several clinical methods for getting antibodies of a desired specificity.
I. Antisera
You immunize mice with the appropriate antigen and prepare antisera from their blood.
For this, you need purified antigen.
II. Hybridoma
You isolate B-cells from immunized animals and fuse them with tumor cells to form hybridoma cell lines.
Then, you decide which of the antibody-producing cell line you will select.
One hybridoma cell line produces the same antibodies = monoclonal antibodies.
III. Flow cytometry
Measures the reaction between antibodies and cells.
- Used in medicine to study the cell populations in peripheral blood.
For example, by using fluorescent antibodies you can distinguish between B- and T-cells.
Intravenous immunoglobulin = IgG antibodies from 10.000+ healthy blood donors.
For example, in B-cell deficient children who are highly susceptible to encapsulated bacteria.
Monoclonal antibodies are used in therapy:
To prevent a host-response to the animal-part of the antibodies we can use two types…
Chimeric monoclonal antibodies specific for CD3 on human T-cells to inhibit the T-cell mediated graft rejection.
Chimeric means ‘formed with parts of animals’, since the V region is from a mouse.
Rituximab is used to treat non-Hodgkin B-cell lymphoma. It binds to CD20 present on malignant and healthy B-
cells and signals NK cells to kill them. Patients still make antibodies since plasma cells do not have CD20.
Humanized antibodies are created by humanizing the mouse antibodies by genetic engineering.
CDR regions in the human Ig are replaced by the CDR sequences from mice.
Omalizumab binds IgE and is used to treat severe allergic asthma.
Human antibodies: antibodies are made by mice but the genes are replaced with human counterparts.
Adalimumab binds TNF-α and is used in Rheumatoid arthritis.
Gene rearrangement of the antibody
Ig genes are fragmented in gene segments. This arrangement is called the germline form/configuration.
The segments must be rearranged to form a functional gene.
This occurs in development from B-cell precursors in the bone marrow.
When a functional heavy and light chain are produced, it appears at the B-cell surface.
V region rearrangement
L Leader peptides
C C-region
V V-region
For the V-region:
There are two types of segments that
encode the light-chain locus:
Variable (V) gene segments Light chain:
Joining (J) gene segments CDR1 and CDR2 diversity comes from differences in the sequence of V gene segments.
The heavy chain locus also contains: CDR3 diversity results from differences in sequence diversity at the V-J junction.
Heavy chain:
CDR1 and CDR2 diversity comes from differences in the sequence of V gene segments.
CDR3 diversity results from differences in the D segments and their junction with V and J.
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