Simona Kaftanová
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Transcript of Simona Kaftanová
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)
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
The structure of immunoglobulins
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)neutralizationcomplement 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- pentamer- monomer (BCR)
0,9-2,5 6 serum, membrane of B lymfo
complement activation (classic.)primary immune response (the first and main Ig)produced by fetus during IU infectionreceptor for Ag (BCR)
IgD-monomer
0,1 3 serum, membrane of B lymfo
receptor for Ag (BCR)
IgE-monomer
3x10-4 2 serum, interst.liquidmastocyte and basophils surface
anti-helminth defenseimmediate type allergic reactions
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
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)
H chain recombination:
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
• 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
Primary immune response (reaction against primary infection):
Humoral 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 period of primary immune response :
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
b/ postnatalB 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
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)