Immunologie II für Naturwissenschaftler Effector Mechanisms of Humoral Immunity Beda M. Stadler Institute of Immunology Inselspital Bern, Switzerland http://www.immunology.unibe.ch/teaching/imm2/immuno2.htm 1
Learning Goals Repetition Effector functions of antibodies Pathways of complement activation MAC Functions of complement Mucosal Immunity 2
Repetition Antibodies are produced by B lymphocytes and plasma cells in the lymphoid organs and bone marrow, but antibodies perform their effector functions at sites distant from their production. The antibodies that mediate protective immunity may be derived from short-lived or long-lived antibody-producing plasma cells following the activation of naive or memory B cells Many of the effector functions of antibodies are mediated by the heavy chain constant regions of Ig molecules, and different Ig heavy chain isotypes serve distinct effector functions Although many effector functions of antibodies are mediated by the Ig heavy chain constant regions, all these functions are triggered by the binding of antigens to the variable regions 3
Effector Functions of Antibodies 4
Human Antibody Isotypes Isotype of antibody Subtypes H chain Serum concentr. (mg/ml) Serum half-life (days) IgA IgA1,2 α(1 or 2) 3.5 6 IgD None δ Trace 3 IgE None ε 0.05 2 IgG IgG1-4 γ(1,2,3 or 4) 13.5 23 IgM None μ 1.5 5 5
Functions of Antibody Isotypes Antibody Isotype-specific effector functions Isotope IgG Opsonization of antigens for phagocytosis by macrophages and neutrophils Activation of the classical pathway of complement Antibody-dependent cell-mediated cytotoxicity mediated by natural killer cells Neonatal immunity: transfer of maternal antibody across the placenta and gut Feedback inhibition of B cell activation IgM Activation of the classical pathway of complement Antigen receptor of naive B lymphocytes* IgA Mucosal immunity: secretion of IgA into the lumens of the gastrointestinal and respiratory tracts Activation of complement by the lectin pathway or by the alternative pathway IgE Mast cell degranulation (immediate hypersensitivity reactions) IgD Antigen receptor of naive B lymphocytes* *These functions are mediated by membrane-bound and not secreted antibodies 6
Neutralization of microbes and toxins by antibodies 7
Vaccine-Induced Humoral Immunity Infectious disease Polio Tetanus, diphtheria Hepatitis, A or B Pneumococcal pneumonia, Haemophilus Vaccine Oral attenuated polio virus Toxoids Recombinant viral envelope proteins Conjugate vaccines composed of bacterial capsular polysaccaride and protein Mechanism of protective immunity Neutralization of virus by mucosal IgA antibody Neutralization of toxin by systemic IgG antibody Neutralization of virus by systemic IgG antibody Opsonization and phagocytosis mediated by IgM and IgG antibodies, directly or secondary to complement activation 8
Durch Impfungen verhütbare Krankheiten: WHO-Ziele und aktuelle Lage in der Schweiz Krankheit WHO-Ziel (Jahr) Aktuelle Lage in der Schweiz (1998 2001) Diphtherie Inzidenz <0,1/105 (2010) Letzter Fall 1983 Tetanus, neonatal Elimination (2005) Seit >20 Jahren keine neonatalen Fälle, gemeldete Tetanusfälle: 2 4/Jahr (0,03 0,06/105/J.) Pertussis Inzidenz <1/105 (2010) 80 180/105/Jahr Poliomyelitis Elimination (2000) Letzter Fall 1982 (Wildvirus, indigen) Hib, invasiv Inzidenz <1/105 (2010) Bei 0 15-Jährigen um 1/105/Jahr Masern Elimination (2007) 8 28/105/Jahr Mumps Inzidenz <1/105 (2010) 113 390/105/Jahr Röteln, kongenital Inzidenz <1/105 (2010) Kongenitale Röteln: Um 0,6/105 Neugeborene/Jahr, Rötelnfälle: 16 25/105/Jahr Hepatitis B Neue Träger um 80% (2010) Etwa 30 160 neue Träger/Jahr (200 300 akute Erkrankungen) 9
Antibody-mediated opsonization and phagocytosis of microbes 10
Antibody-dependent cell-mediated cytotoxicity 11
Fc Receptors 12
The early steps of complement activation by the alternative and classical pathways 13
The alternative pathway of complement activation 14
The classical pathway of complement activation 15
C1 binding to the Fc portions of IgM and IgG 16
Late steps of complement activation and formation of the MAC 17
Structure of the MAC in cell membranes 18
Functions of complement 19
Mucosal Immunology Zilien Mucus Mucus Lunge Säure Talg ph Schweiss Lysozym Magensaft Transferrin Darm Fett säuren Haut Norm. bakt. Flora Haar Follikel
Transport of IgA across epithelial cells 21
IgA Struktur Serum - Monomer Sekretion (siga) Dimer (11S) J chain Sekretorische Komponente Eine B Zelle sekretiert entweder monomeres or dimeres IgA. 22
IgA Eigenschaften 2. höchst im Serum häufigstes Ig im Körper bindet kein Komplement (ausser aggregiert) 23
1 2 24
IgA and Antiviral Defence 25
IgA and Antibacterial Defence IgA 2 is more protease resistant than IgA 1. 26
Learning Goals Repetition Effector functions of antibodies Pathways of complement activation MAC Functions of complement Mucosal Immunity 27