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Transfer of Immunity

Transfer of Immunity. D. I. Stott. Introduction. Fetus as allograft . Rejection avoided by:- Separation of fetal & maternal circulation No MHC Class I & II on trophoblast Placental hormones (progesterone, prostaglandin) & cytokines (IL-4, IL-10) suppress Th1 (but not Th2) response

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Transfer of Immunity

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  1. Transfer of Immunity D. I. Stott

  2. Introduction • Fetus as allograft. Rejection avoided by:- • Separation of fetal & maternal circulation • No MHC Class I & II on trophoblast • Placental hormones (progesterone, prostaglandin) & cytokines (IL-4, IL-10) suppress Th1 (but not Th2) response B. Newborn very susceptible to infection Immature defences:- • Barrier function (skin & mucosal surfaces) • Innate I.S. • Specific adaptive I.S. (no memory)

  3. Protection provided by mother:- • Prenatal (placenta or yolk sac) • Postnatal (colostrum & milk) Route & mechanism of transport differ between species.

  4. Route of Transmission of Abs. from Mother to Infant’s Blood

  5. Prenatal Transfer of Immunity Evidence:- Rodents & rabbits • ligation of yolk sac prevents tf. of Abs Man & primates • Gm allotype on maternal Ab  fetus via placenta

  6. Transfer of IgG from mother to fetus is via FcRn Evidence:- • Expressed on yolk sac & gut epithelium (rodents) and trophoblast (man) • FcRn K.O. mice – no transfer of Ig to fetus (yolk sac) or neonate (colostrum)

  7. Properties of FcRn • Homology with MHC Class I •  chain + 2--globulin • Binds IgG at pH 6.0 • Released at pH 7.4 • X-ray Xlly suggests 2 FcRns bind 1 IgG

  8. Structure of FcRn

  9. Mechanism of Transfer (1) Rodent yolk sac & Human Placenta • Neutral pH both sides,  uptake of fluid-phase IgG by pinocytosis • Endosome  acidic • IgG binds FcRn & transcytosis • Release into blood (pH 7.4) From Rojas & Apodaca (2002)

  10. Mechanism of Transfer (2) • In rodent gut lumen, acidic pH, IgG binds FcRn on apical surface of gut epithelial cell. • Pinocytosis & transcytosis • Release into blood (pH 7.4)

  11. Immunoglobulin Levels in Prenatal & Newborn Infants IgG levels of newborn infants are low from c.3 – 6 months after birth

  12. FcRn also regulates serum IgG level in adult Evidence:- • FcRn expressed on vascular endothelial cells. • FcRn K.O. mice: IgG has faster turnover • SDM of IgG Fc to lower K for FcRn  lowerserum IgG level • SDM of IgG Fc to higher K. for FcRn  slower turnover and higher serum IgG level • Implications for Ab therapy?

  13. Homœostasis of IgG in Blood • High plasma concn.: unbound IgG degraded in endosomes of endothelial cells • Low concn. FcRn- bound IgG protected & recycled

  14. Maternal Abs can be harmful1. Autoimmunity • Mother with autoimmune disease • IgG autoantibodies transported across placenta • Baby born with symptoms of mother’s autoimmune disease • Resolve when maternal IgG degraded

  15. Maternal Abs can be harmful: Graves’ Disease • Mother produces IgG anti-TSHR Abs • Anti-TSHR Abs cross placenta to fetus • Stimulate fetal thyroid gland • Baby born with same symptoms as mother

  16. Maternal Abs can be harmful: Neonatal Lupus Erythematosus Cutaneous NLE Annular erythematous plaques on the head of an infant. All manifestations of NLE eventually resolved. Lee, L.A. (2005) Autoimmunity Revs. 4, 207 – 213.

  17. Maternal Abs can be harmful: Haemolytic Disease of Newborn (HDNB) • Rh- mother & Rh+ father  Rh+/- fetus • 1st birth = Sensitisation  IgG anti-RhD • 2nd pregnancy: IgG anti-RhD crosses placenta • Ab-coated fetal RBC phagocytosed in liver  HDNB • Prophylaxis: Anti-RhD i.v. immediately after delivery.

  18. Haemolytic Disease of the Newborn

  19. A Baby with HDNB

  20. Reduction in Child Mortality due to Anti-RhD Prophylaxis

  21. Postnatal Transfer of Immunity from Colostrum and Milk • Rodents & Ungulates: IgG uptake across gut epithelium via FcRn. • Man: Very little or no IgG uptake; • IgA stays in gut, protects mucosal surface. Also synthesised locally.

  22. Ig Concns. in Human Colostrum & Milk

  23. Antibodies in Human Milk • P.C.s & activated B & T-L.s from Peyer’s patches migrate to mammary gland • Also activated. L.s from systemic I.S.  broad range of Abs. • Abs v. many bact. & viral ags. in milk • IgA transport via polyIg rec. (secretory piece), as into gut

  24. Other Components of Human Colostrum & Milk • Complex oligosaccharides – inhibit adherence of bact. to cells • Lactoferrin – binds Fe • Lysozyme – degrades bact. cell wall

  25. Protective Effects of Breast v. Bottle Feeding *Risk ratio =  of disease bottle fed/  breast fed

  26. Human Breast Milk Substitutes

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