B Zellen und Antigene - University Institute of Immunology

Immunologie II für NaturwissenschaftlerEffector Mechanisms ofHumoral ImmunityBeda M. StadlerInstitute of ImmunologyInselspitalBern, Switzerlandhttp://www.immunology.unibe.ch/teaching/imm2/immuno2.htm1

Learning Goals• Repetition• Effector functions of antibodies• Pathways of complement activation• MAC• Functions of complement• Mucosal Immunity2

Repetition• Antibodies are produced by B lymphocytes and plasma cells inthe lymphoid organs and bone marrow, but antibodies performtheir effector functions at sites distant from their production.• The antibodies that mediate protective immunity may be derivedfrom short-lived or long-lived antibody-producing plasma cellsfollowing the activation of naive or memory B cells• Many of the effector functions of antibodies are mediated by theheavy chain constant regions of Ig molecules, and different Igheavy chain isotypes serve distinct effector functions• Although many effector functions of antibodies are mediated bythe Ig heavy chain constant regions, all these functions aretriggered by the binding of antigens to the variable regions3

Effector Functions of Antibodies4

Human Antibody IsotypesIsotype ofantibodySubtypes H chain Serumconcentr.(mg/mL)Serum half-life(days)IgA IgA1,2 α(1 or 2) 3.5 6IgD None δ Trace 3IgE None ε 0.05 2IgG IgG1-4 γ(1,2,3 or 4) 13.5 23IgM None μ 1.5 55

Functions of Antibody IsotypesAntibody Isotype-specific effector functionsIsotopeIgG• Opsonization of antigens for phagocytosis by macrophages andneutrophils• Activation of the classical pathway of complement• Antibody-dependent cell-mediated cytotoxicity mediated by naturalkiller cells• Neonatal immunity: transfer of maternal antibody across theplacenta and gut• Feedback inhibition of B cell activationIgM• Activation of the classical pathway of complement• Antigen receptor of naive B lymphocytes*IgA• Mucosal immunity: secretion of IgA into the lumens of thegastrointestinal and respiratory tracts• Activation of complement by the lectin pathway or by the alternativepathwayIgE• Mast cell degranulation (immediate hypersensitivity reactions)IgD• Antigen receptor of naive B lymphocytes**These functions are mediated by membrane-bound and not secreted antibodies6

Neutralization of microbes and toxinsby antibodies7

Vaccine-Induced Humoral ImmunityInfectiousdiseasePolioTetanus,diphtheriaHepatitis, A or BPneumococcalpneumonia,HaemophilusVaccineOral attenuated poliovirusToxoidsRecombinant viralenvelope proteinsConjugate vaccinescomposed of bacterialcapsular polysaccarideand proteinMechanism of protectiveimmunityNeutralization of virus bymucosal IgA antibodyNeutralization of toxin bysystemic IgG antibodyNeutralization of virus bysystemic IgG antibodyOpsonization andphagocytosis mediated byIgM and IgG antibodies,directly or secondary tocomplement activation8

Durch Impfungen verhütbare Krankheiten:WHO-Ziele und aktuelle Lage in der SchweizKrankheit WHO-Ziel (Jahr) Aktuelle Lage in der Schweiz (1998–2001)Diphtherie Inzidenz 20 Jahren keine neonatalenFälle, gemeldete Tetanusfälle:2–4/Jahr (0,03–0,06/105/J.)Pertussis Inzidenz

Antibody-mediated opsonization andphagocytosis of microbes10

Antibody-dependent cell-mediatedcytotoxicity11

Fc Receptors12

The early steps of complement activation bythe alternative and classical pathways13

The alternative pathway ofcomplement activation14

The classical pathwayof complement activation15

C1 binding tothe Fc portions of IgM and IgG16

Late steps of complement activationand formation of the MAC17

Structure of the MAC in cellmembranes18

Functions of complement19

Mucosal ImmunologyZilien Mucus MucusLungeSäure• Talg• pH• Schweiss• Lysozym• Magensaft• TransferrinDarmFettsäurenHautNorm. bakt. FloraHaarFollikel

Transport of IgA across epithelial cells21

IgA• Struktur– Serum - Monomer– Sekretion (sIgA)• Dimer (11S)• J chain• SekretorischeKomponenteEine B Zelle sekretiertentweder monomeres ordimeres IgA.22

IgA• Eigenschaften– 2. höchst im Serum– häufigstes Ig imKörper– bindet keinKomplement(ausser aggregiert)23

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IgA and Antiviral Defence25

IgA and Antibacterial DefenceIgA 2 is more proteaseresistant than IgA 1 .26

Learning Goals• Repetition• Effector functions of antibodies• Pathways of complement activation• MAC• Functions of complement• Mucosal Immunity27