1. HIV – FIV - LCMV Immune system + viruses Tricks of pers. V: T deletion / escape nAb delay / escape Re-encountered / persistent antigen maintains nAb (successful vaccines) and act. T (infection immunity: no vaccine) for protection

4. LCMV-viremia control or nAb escape Ciurea, Hunziker et al.

8. Prevent penetration IgA systemic neutr.-opson.IgM/G adoptive transferable IgG IgM 1-2d, regulated by Ag-dose and structure (no negative selection) Control-elim. intracell parasites also in solid organs regulate longterm IgG cause imunopathology (negative selection) T B Ab

9. glycoprotein: LCMV-GPglycoprotein:IND-G rLCMV/INDGrVSV/LCMV-GP reverse genetic glycoprotein exchange between LCMV and VSV Pinschewer, de la Torre et al. LCMVVSV-IND glycoprotein: LCMV-GPglycoprotein:IND-G

10. Only VSVG expressing viruses induce a neutralizing antibody response

11. Neutralising Ab: GP structure early:T H independent IgM, germline high affinity / avidity late:immunosuppression ? affinity maturation?

13. HypergammaglobulinemiaNeutralising antibodies Hypergammaglobulinemia vs. neutralizing antibodies Recher, Lang, Hunziker 2004

14. Conclusion: Many nAb "specificities" control V, if "one" too slow/low: V-escape! Hypergammaglobulinemia and polyclonal B cell activation compete with nAb responses and seem to depend upon amount of virus-specific CD4 T cells. Mechanisms of B cell competition? (Cytokine receptor competition? Anatomic competition in germinal centers? Competition for anti-apoptotic cytokines?).

15. Why autoimmune disease in humans mostly via antibodies? Why>> ! Why all vaccines that function protect via neutr. antibodies? First infection kills host: no memory needed Host survives first infection: memory not necessary Memory vs. Protection

16. No protection by Memory B cells but protection by immune serum in IFN-aBR _ / _ against VSV VSV IND immune spleen cells T+B LCMV immune spleen cells VSV IND Ab Anti-VSV neutr. AB < 1 : 40 < 1 : 2500 % Survivors 0 100

17. Maintenance of protection 1. Agent persists: TB, leprosy, HIV, HCV, LCMV Herpes viruses crippled: measles? 2. Repetitive inf.: polio, bact. toxins 3. Antibody-antigen complex depots in lymph nodes and spleens

18. persistent virus from mother

19. Poliomyelitis – age distribution in Massachusetts 1912 – 1952

21. Memory / Pregnant Female Academic: earlier + higher (AG –) Immune against cytopathic infections otherwise abortions / malformations MHC-incompatibility – offspring / mother Maternal antibodies attenuate acute infections physiological vaccinations (incl. malaria, eggs) Non-cytophatic infections transferred via placenta / at birth / after birth (LCMV, HCV, Herpes) Resistance via T cells: HIV, HTV, TB Lepr. slow "Emerging" infections

22. Conclusions: Persistent infections numbers / variability T cell control – immunopathology – "tolerance" nAb essential (affinity maturation?) or escape antigen maintains nAb titers and act. T cells (but immunopathology!) All successful vaccines: nAb not successful: should (also) maintain act.T (not achieved yet)

23. H. Hengartner E.Battegay A.Ciurea L.Hunziker M. Recher U.Steinhoff B.Odermatt Th.Leist K.Lang D.Pinschewer J.de la Torre

26. IMMUNITY “innate resistance“ > 95 % Ab in eggs protective memory via Ab (vaccines) TB: no vaccine autoimmunity > 30 y, female > male 5:1