Simona Kaftanov

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  • 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 Kaftanov

  • The structure of immunoglobulins 4 polypeptid chains:2 identical heavy chains (H)2 identical light chains (L)

    H chains: , , , , L chains: ,

    Izotypys = classes of antibodies :IgM ()IgD ()IgG ()IgA ()IgE ()

  • Ig fragments produced by proteolytic digestion (papain):Fab fragments (portions) contain the antigen binding sites of the antibodyFc fragment binds to cells through Fc-receptor

    Domains:domains of V regions form a recognizing unit for Agdomains of C regions determine secondary biological functions of antibody

    The structure of immunoglobulins

  • Paratop - the binding site for Ag (for its 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 moleculeThe 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 functionidiotyp of the 1st generat. of antibodiesepitopsantibodies of the 2nd generation antibodies of the 3rd generation

  • Function of Iggantibodies 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.

  • IzotypSerum conc.(g/l)Biolog. half life (days)Tlesn tekutinyFunkctionIgG(subclass IgG1-4 )-monomer8-1821serum, intersticial liquidopsonization (the main Ig)neutralizationcomplement activation (classic.)passing through the placenta (the only Ig)secondary immune response (the main Ig)IgA- serum - mucose (dimer) 0,9-3,56 serum, seromucinous secretionsdefense of mucosa (neutralizace)opsonizationIgM- pentamer- monomer (BCR) 0,9-2,56 serum, membrane of B lymfocomplement activation (classic.)primary immune response (the first and main Ig)produced by fetus during IU infectionreceptor for Ag (BCR)IgD-monomer0,13 serum, membrane of B lymforeceptor for Ag (BCR)

    IgE-monomer3x10-42 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 - C, C, C, C, C)

    L chains genes ( chromosome 2, chromosome 22) less complicatedV, 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 rearrangementtranscriptionsplicing 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 C is excluded and replaced by other next segment f.e. C (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 cellssome of plasmocytes back to circulation (bone marrow,...)in 3-4 days secretion plenty of IgM with low affinity to Agimunokomplexes 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, lipidsPrimary immune response (reaction against primary infection):Humoral immune response

  • 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 cellsincreasing 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 immunoglobulinsneutralization 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 responsea/ prenatalHematopoesis 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 foetusneutrophils 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 agedecreased cytotoxicity of NK-cells and macrophagesdecreased resistance against viral infections, decreased anti-tumour immunityswitching from Th1 to Th2 (weaker humoral response under new stimuli but increased production of autoantibodies)