Download Primary immune response

Immunoglobulins - structure.
Immunoglobulins - function.
Genetic background of immunoglobulin production.
Biological and chemical characteristics of immunoglobulin
classes IgG and IgA.
Biological and chemical characteristics of immunoglobulin
classes IgM, IgD and IgE.
Isotype switching. Idiotypes and anti-idiotypes - their role.
Immunological memory.
Ontogenesis of the immune response.
Primary immune response.
Secondary immune response .
Effector functions of immunoglobulins.
Simona Kaftanová
The structure of immunoglobulins
• 4 polypeptid chains:
2 identical heavy chains (H)
2 identical light chains (L)
H chains: μ, δ, γ, α, ε
L chains: κ, λ
Izotypys = classes of antibodies :
IgM (μ)
IgD (δ)
IgG (γ)
IgA (α)
IgE (ε)
The structure of immunoglobulins
Ig fragments produced by proteolytic digestion (papain):
• Fab fragments (portions) contain the antigen binding
sites of the antibody
• Fc fragment binds to cells through Fc-receptor
Domains:
• domains of V regions form a recognizing unit for Ag
• domains of C regions determine secondary biological
functions of antibody
The structure of immunoglobulins
Paratop - the binding site for Ag (for it’s epitop )
= part of Ig made of hypervariable regions of VH and VL (hypervariable
region – spike of variable region with hypervariable loops of amino acid
(AA) sequences; the binding site specificity is determined by AA
sequences and both by morphology and shape of the loop)
Idiotop – individual and rarely structures localized in the variable region;
some of them are identical with the binding site, some lie except of the
paratop
Idiotyp - the sum of idiotopes of an Ig molecule
Anti-idiotypic antibodies
• antibodies of the 2nd generation (idiotyp of the 1st gen. of antibodies looks like an
antigen, idiotyp can start production of Abb against itself – antiidiotypic antibodies)
• in principle reflect the antigen
• other new antibodies (3rd generation) are produced against them → antiantiidiotypic
antibodies → idiotypic net
• regulatory function
idiotyp of the 1st generat. of
antibodies
epitops
antibodies of the 2nd
generation
antibodies of the 3rd
generation
Function of Igg
– antibodies – solubil Igg
– antigen receptor (BCR) – (IgM a IgD on the surface of B cells)
• differences in H chain structure (Fc ftagment) determine secondary
biological function of antibodies: biological half life, distribution in
the body, passing through the placenta, complement activation,
binding to cells through Fc-receptor – opsonization, IgE binding on
mastocytes etc.
Izotyp
Serum
conc.(g/l)
Biolog.
half life
(days)
Tělesné tekutiny
Funkction
IgG
(subclass IgG1-4 )
-monomer
8-18
21
serum, intersticial
liquid
opsonization (the main Ig)
neutralization
complement activation (classic.)
passing through the placenta (the
only Ig)
secondary immune response (the
main Ig)
IgA
- serum
- mucose (dimer)
0,9-3,5
6
serum,
seromucinous
secretions
defense of mucosa (neutralizace)
opsonization
IgM
0,9-2,5 6
- pentamer
- monomer (BCR)
serum, membrane
of B lymfo
complement activation (classic.)
primary immune response (the
first and main Ig)
produced by fetus during IU
infection
receptor for Ag (BCR)
IgD
-monomer
0,1
3
serum, membrane
of B lymfo
receptor for Ag (BCR)
IgE
-monomer
3x10-4
2
serum, interst.liquid anti-helminth defense
mastocyte and
immediate type allergic reactions
basophils surface
Genetic basis of Ig production
H chains genes (chromosome 14)
• genes are structured in V, D, J, C segments (segments contain more
regions compared with L chains)
– V („variability“, several hundred)
– D (cca 50)
– J (9)
– C (encoding izotypes - Cμ, Cγ, Cα, Cδ, Cε)
L chains genes (κ – chromosome 2, λ – chromosome 22)
• less complicated
• V, J, C segments
H chain recombination:
a) D-J rearrangement - accidental
D-J joining
b) V-D rearrangement – V-D-J
joining
c) transcription if V-D-J product is
readable, then splicing (V-D-J-C
joining)
d) translation in protein (H chain)
L chain recombination :
V-J rearrangement
transcription
splicing –VJC rearrangement
Mechanisms contributing to antibody diversity:
• chance recombinations
• imprecise joining of V, D, J genes
• extensive mutations involving variable-region
genes after antigen exposure
Isotype switching
• during the immune response, plasma cells switch from producing
IgM to IgG or to another Ig class (IgA, IgE)
• mechanism: segment Cμ is excluded and replaced by other next
segment f.e. Cγ (IgG production)
• regulation – mainly IL-4
• change only in the H-chain constant domains (CH); no change in
antigen-binding specificity
Humoral immune response
Primary immune response (reaction against primary infection):
• 2 periods: primary, secondary
• characteristic: memory cells, production antibodies with the increasing
affinity to Ag
Primary period of primary immune response:
• the first Ag exposure (secondary lymf. org.) → …see Th2 based immune
reaction…
• clonal expansion of B cell with identical or similar specifity to Ag →
diferenciation to plasmocytes and memory cells
• some of plasmocytes back to circulation (bone marrow,...)
• in 3-4 days secretion plenty of IgM with low affinity to Ag
• imunokomplexes are displayed by FDC (folicular dendritic cells in
secondary lymf. org.)
Exception: T-independent Ag– antibody production is induced directly,
without the involvement of T helper cells; typically polysaccharides, lipids
Secondary period of primary immune response :
a) affinity maturation : the antigen displayed by FDC is
recognized by B cells → other proliferation a
diferenciation of B lymfo → their Ig V genes undergo
extensive somatic mutations → changes of Ig binding
sites (hypervariability parts) → competition about lower
amount of Ag → B cells that recognize the antigen with
the highest affinity are selected to survive
b) isotype switching: start of production other Ig which is
on (mainly IgG, others IgA, IgE, IgD))
After primary immune response Abb circulate in organism for a
certain time; they stop reinfection for a certain time.
Secondary immune response (reaction against repeatedly infection):
• activation of memory cells
• increasing of the affinity maturation (production of antibodies with
increased affinity to Ag)
• continuation of isotype switching (higher amount of antibodies is
produced; start of Ig production is faster (faster and higher amount of
IgG)
• suppression of infection is quicker and more effectively
Effector functions of immunoglobulins
• neutralization – Igg bind a blocade critical epitops of toxins, virus and
other microorganisms
• inhibition of patogen adherence – IgA blocade adherence of
microorganisms on the mucose surface
• opsonization – Ig is binded on Ag; fagocytes are more able to swallow up
Ag (FcR on the fagocytes surface)
• ADCC (antibody-dependent cell-mediated cytotoxicity) – IgG is binded
on Ag; FcR for IgG on the NK cells surface; binding IgG and FcR is a stimul
for NK degranulation on Ag (cytotoxic products)
• complement activation via classical pathway → products of
complement...
Ontogenesis of immune response
a/ prenatal
• Hematopoesis – extraembryonaly (start in the week 2-3 of
gestation) → then in liver (whole prenatal period) → postnataly
bone marrow (the main organ of hematopoesis)
• T-cells - precursors to thymus → diferenciation in lymfoid cells,
selection.
• B-cells – synthesis interauter. IgM unable to detection (detectable
concentration IgM = information about IU infection) x IgG
production starts after the birth
• monocytes-makrophages – mature already in foetus
• neutrophils – smaller amount
Ontogenesis of immune response
b/ postnatal
B lymfo:
• mainly IgM production immediately after the birth (adult conc.
between the year 1.- 3.)
• IgG production increases slow (and decrease of mothernal IgG) →
the most decrease between the month 3. – 6.
• humoral response to polysacharide antigen (f.e. Haemophilus) arises
by the age of 2 yr.
T lymfo :
• lower activity after the birth
Innate imunity:
• lower ability of the function
Ontogenesis of immune response
c/ old age
• decreased cytotoxicity of NK-cells and macrophages
• decreased resistance against viral infections,
decreased anti-tumour immunity
• switching from Th1 to Th2 (weaker humoral response
under new stimuli but increased production of
autoantibodies)