2 volume setThesis (M.D.) -- University of Adelaide, Dept. of Obstetrics and Gynaecology, 197

Need, Jillian Ann

English

Adelaide Research &amp; Scholarship

THE  ROLE  OF  IMMUNOGENETIC  FACTORS  IN  TH E AETIOLOGY 	 OF  PRE-ECLAMPTIC  TOXAEMIA  OF HUMAN  PREGNANCY Vo1 ume  I by JILLIAN  ANN  NEED,  M.B.,  B.S.  ( Adelaide) Being  a  Thesis presented  for  the Degree  of DOCTOR  OF  MEDICINE at  the University  of  Adelnide Department  of  Obstetrics  and  Gynaecology, University  of  Leeds,  England. March,  1978. .. Paqe CONTENTS  - VOLUME  I  and  VOLUME  I I. VOLUME  I SUMMARY  1 7 DE CLARA  TI  ON 9 CONTRIBUTION  OF  THIS  THESIS  TO  MEDICAL  KNOWLEDGE  10 SECTION  I ACKNOWLEDGEMENTS INTRODUCTION  AND  LITERATURE  REVIEW Chapter  1.  Definition,  Incidence  and  Clinical  12 Importance  of  pre-eclamptic  toxaemia in  human  reproduction. Chapter  2. 	 Aetiological  theories  of  pre-eclamptic  17 toxaemia. , . Chapter  3. 	 Immunogenetic  aetiological  theories  of  21 pre-eclampsia  and  human  vascular  disease. Chapter  4. 	 Maternal  and  fetal  imunological  42 responsiveness  during  nOTlal  human pregnancy. SECTION  II  EXPERIMENTAL  STUDIES Chapter  5.  Aims  and  design  of  the  study.  53 Patient  profile.  60 PART  I  GENET! C  FACTORS 70 Chapter  6. 	 Blood  group  antigens  ( ABO  and  Rhesus ) . 75 Chapter  7. 	 Human  leucocyte  antigens. Page PART  II  - IMMUNOLOGI  CAL  ASPECTS Ila  - HUMORAL  IMMUNE  RESPONSE Chapter Chapter Chapter 8. 9. 10. Specific  humoral  imune  resporrse:­Anti-HLA  cytotoxic  antibodies. Serum  Immunoglobulins  A,  t ,  G,  D. Non-specific  humoral  immune  response. Serum  seromucoid. 4 91 109 lIb  - CELLULAR  IMMUNE  RESPONSE Chapter  11.  Non-specific  cellular  immune  response:­The  effect  of  pregnancy  and  pre-eclampsia  on the  materna 1  and  cord  leucocyte  response  to phytohaemaggl utinin  and  the  effect  of autologous  serum  on  thi   response. 113 Chapter  12.  Specific  cellular  immune  response:­The  effect  of  pregnancy  and  pre-ec1 amps  i  a  on the  maternal-paternal,  maternal-fetal  and fetal-ma tena 1  leucocyte  response  and  the effect  of  autologous  serum  on  this  response. 133 SECTION  II  I  - CONCLUSIONS  158 Chapter SECTION  IV 13.  Concl  us ions. - B13LlOGRAPHY  - Volume  I  166 , VOLUME  II --.----SECTION  V  - APPENDIX  See Vo 1.  II - SECTION  VI  RESULTS SECTION  VII  - BIBLlOGRAP Y  - Volume  II VOLUME  I CONTENTS  - VOLUME  I  and  VOLUME  II. SUMMARY DE  CLARA  TI ON ACKNOWLEDGEMENTS CONTRIBUTION  OF  THIS  THESIS  TO  MEDICAL  KNOWLEDGE SECTION  I  - INTRODUCTION  AND  LITERATURE  REVIEW Chapter  1.  Definition,  Incidence  and  Clinical Importance  of  pre-eclamptic  toxaemia in  human  reproduction. Chapter  2.  Aetiological  theories  of  pre-eclamptic toxaemi  a. Chapter  3.  Immunogenetic  aetiological  theories  of pre-eclampsia  and  human  vascular  disease. Chapter  4. 	 Maternal  and  fetal  immunological responsiveness  during  normal  human pregnancy. SECTION  II  - EXPERIMENTAL  STUDIES Chapter  5.  Aims  and  design  of  the  study. Patient  profile. PART  I  - GENETIC  FACTOPS Chapter  6.  Blood  group  antigens  (ABO  and  Rhesus ) . Chapter  7.  Human  leucocyte  antigens. PART  II  - IMMUllOLOGICAL  ASPECTS Ila  - HUMORAL  IMMUNE  RESPONSE Chapter  8. 	 Speci  fi c  hmora 1  imune  response :.­Anti-HLA  cytotoxic  antibodies. Chapter  9. 	 Serum  Immunoglobulins  A,  M,  G,  O. Chapter  10. 	 Non-specific  humoral  imune  response. Serum  seromucoid. lIb  - CELLULAR  IMMUNE  RESPONSE Chapter  11.  Non-specific  cellular  imune  response:-The  effect  of  pregnancy  and  pre-eclampsia  on the  maternal  and  cord  leucocyte  response  to ph ytohaemagglutinin  and  the  effect  of autologous  serum  on  this  response. Chapter  12.  Specific  cellular  imune  response:-The  effect  of  pregnancy  and  pre-eclampsia  on the  maternal-patel-nal,  maternal-fetal  and fetal-matena 1  1 eucocyte  response  and  the effect  of  autologous  serum  on  this  response. SECTION  III  - CONCLUSIONS Chapter  13.  Conclusions. SECTION  IV  - BIBLIOGRAPHY  - Volume  I VOLUME  II SECTION  V  - APPENDIX SECTION  VI  - RESULTS SECTION  VII  - BIBLIOGRAPHY  - Volume  II 1. The  present  study  examined  the  role  of  some  imunogenetic  factors in  the  aetiology  of  pre-eclamptic  toxaemia. A  normal  pregnant  population  was  used  as  a  reference  population for  a  compatative  study  of  a  group  of  women  who  developed  severe pre-eclampsia/eclampsia. Rigid  diagnostic  criteria  were  employed  in  an  attelnpt  to  make  the clinical  diagnosis  as  unequivocal  as  possible.  This  made  the number  of  cases  available  for  study  quite  small,  but  was  necessary to  avoid  the  inclusion  of  such  mild  cases  of  pre-eclampsia  that the  diagnosis  must  be  seriously  in  doubt. The  genetic  marker  studies  revealed  no  linkage  association between  susceptibility  to  the  disease  and  any  particular  leucocyte antigen.  However,  there  appeared  to  be  a  higher  degree  of  HLA antigen  matching  between  the  pre-eclamptic  women  and  their  husbands than  between  the  normal  pregnant  women  and  their  husbands.  This has  some  similarity  to  the  Oxford  data  ( Redman  1975,  personal comunication )  which  shows  a  high  degree  of  parental  HLA homozygosity  in  severe  pre-eclampsia. This  matching  would  provide  for  less  histoincompatibility  between mother  and  fetus  and  thereby  the  fetus  would  fail  to  induce  a sufficiently  strong  maternal  immunological  recognition  of  itself, necessary  for  the  maintenance  of  normal  pregnancy. <, Such  an  hypothesis  is  supported  by  the  fail  ure  of  women   Iith severe  pre-eclampsia  in  this  study  to  develop  anti-HLA  cytotoxic an  ti bodi  es, The  immunological  studies  examined  both  the  cellular  and  humoral immune  response  of  the  mothers. The  PHA-induced  responsiveness  of  the  maternal  lymphocytes  was reduced  in  women  with  severe  pre-eclamptic  toxaemia.  While other  studies  have  shown  a  reduced  response  to  PHA  of  lymphocytes from  normal  pregnant  women,  this  seems  to  be  a  purely  serum  mediated inhibition  - the  intrinsic  function  of  the  lymphocytes  being  normal in  the  absence  of  maternal  serum.  The  results  of  the  present study  were  consistent  with  this  also.  However,  the  women  with severe  pre-eclampsia  had  a  greater  reduced  responsiveness  to  PHA and  the  suppressing  effect  of  maternal  serum  was  not  as  great  as in  normal  pregnancy, This  raises  two  possibilities.  Firstly,  that  the  lymphocytes  of women  with  severe  pre-eclampsia  are  depressed  by  a  non-serum factor.  Secondly,  that  there  is  a  reduced  ability  of  the  women with  severe  pre-eclampsia  to  produce  serum  blocking  or  inhibitory factors, The  specific  imunological  response  of  the  pre-eclamptic  mothers against  paternal  antigens  was  similar  to  that  of  normal  pregnant· o. women  and  little  or  no  serum  effect  was  noted.  Where  cord leucocyte  antigens  were  stimulatory  in  the  mixed  leucocyte  culture. however,  there  was  less  maternal  response  noted  in  pre-eclamptic pregnancies.  Again.  there  was  a  suggestion  that  the  inhibitory effect  of  maternal  serum  on  this  response  was  less  in  pre-eclamptic pregnancies  than  in  normal  pregnancies. The  role  of  the  fetus  in  the  development  of  pre-eclamptic  toxaemia has  generally  been  ignored.  The  fetus  is  imunologically  competent at  an  early  stage  of  its  development  (Jones  1976)  so  that  it  may well  take  an  active  role  in  its  survival  as  an  allograft.  Cord lymphocyte  responses  to  PHA  were  studied  and  noted  to  be  higher than  that  of  their  mothers,  but  similar  to  that  of  non-pregnant adults.  Cord  serum  had  no  effect  on  the  autologous  leucocyte response  to  PH/,. Cord  leucocyte  response  to  maternal  antigens  was  also  similar  in the  wo  groups  studied  and  the  effect  of  cord  serum  on  this  response was  interesting.  Where  the  pregnancy  was  normal,  there  was  no effect  but  in  severe  pre-eclamptic  pregnancies  the  serum  was immunosuppressive. The  difference  is  difficult  to  explain.  It  may  be  due  to  the fact  that  maternal  serum  seromucoid  is  elevated  in  severe  pre­eclampsia  and  was  also  elevated  in  cord  serum  and  that  this  non­specific  immunosuppressive  substance  may  be  responsible.  Such effect,  however,  was  not  noted  in  the  cord  responses  to  PHA  as would  be  expected. There  is  no  evidence,  from  this  study,  therefore,  that  the  fetus has  an  active  role  to  play  in  the  immunological  aetio1ogica1 mechanisms  of  severe  pre-eclamptic  toxaemia. The  serum  imunoglobulins  were  also  examined.  IgA  levels  were similar  in  the  control  and  study  groups,  but  IgM  and  IgG  levels were  reduced  in  the  women  with  severe  pre-eclampsia.  While  IgG is  lost  in  large  quantities  in  the  urine,  this  is  not  so  of  IgM. Furthermore,  in  severe  pre-eclampsia  where  there  is  a  loss  of fluid  from  the  intravascular  space  so  that  the  blood  is  haemo­concentrated  (Williams  1966)  these  low  levels  of  immunoglobulins are  even  more  significant. While  loss  of  IgG  in  the  urine  must  be  accepted  as  the  most  likely explanation,  an  immunological  explanation  is  possible  also ( Benster  and  Wood  1970).  Accordingly,  the  following  possibility exists.  IgM  is  the  immunoglobulin  produced  in  the  initial immunological  response  with  IgG  produced  later  in  the  immunological response  ( Rowe  1975).  The  initial  challenge  of  a  first  pregnancy may,  therefore,  induce  first  IgM  and  then  IgG  later.  If  this immunological  response  is  inadequate,  then  the  production  of  both these  immunoglobulins  would  be  reduced. It  is  possible.  then,  that  the  lower  levels  of  IgM  and  JgG observed  in  the  women  with  severe  pre-eclampsia  may  be  compatible with  the  overall  hypothesis  that  women  who  develop  severe  pre­eclampsia  are  imunologically  hypo-responsive  to  the  fetal  antigenic challenge.  This  is  further  supported  by  the  findings  of  this study  in  relation  to  the  specific  anti-HLA  antibody  formation. Women  with  severe  pre-eclampsia  failed  to  produce  detectable anti-HLA  antibodies,  unlike  the  women  whose  pregnancies  were  normal. The  non-specific  serum  factor  studied  was  serum  seromucoid.  This was  significantly  elevated  in  the  women  with  severe  pre-eclampsia and  confirms  other  studies.  It  has  ueen  suggested  that  the production  of  seromucoid  is  a  compensation  by  the  maternal  organism for  her  inability  to  mount  an  adequate  specific  immunological response  ( Good  1975). That  the  maternal  host  with  severe  pre-eclampsia  is  unable  to mount  an  adequate  i nunological  response  is  further  supported  by the  lower  response  to  phytohaemagglutinin  and  the  reduced blocking  activity  of  matemal  serum. The  results  of  this  study,  therefore,  suggest  that  women  who  develop severe  pre-eclampsia  make  an  inadequate  immunological  adaptation  to the  antigenic  challenge  of their  pregnancy.  The  possible  mechanism proposed  is  that  the  recognition  phase  of  blocking  antibody  prod­uction  is  impaired.  This  results  in  "inadequate  enhancing antibodies  for  the  maintenance  of  normal  pregnancy  so  that  pre­eclamptic  toxamia  develops. 4; ';  >, LYI{'f?> ;   \"\  "  ,C ,"/ 'j  'I"  /,j .: sli:i ..\  .. ·,7 ,    ;',7 , .; -,: I  "  ) -    . ... THE  ROLE  OF  It MUNOGENETI C  FACTORS  n  THE AETIOLOGY 	 OF  PRE-ECLAMPTIC  TOXAE HA  OF HU lAN  PREGNANCY Vo lume  JJ by JILLIMI  ANN  NEED,   1.B.,  B.S.  ( Adelaide) Being  a  Thesis presen  ted  for  the Degree  of DOCTOR  OF  MEDICINE at  the University  of  Adelaide Department  of  Obstetrics  and  Gynaecology, University  of  Leeds,  England. t arch,  1978. Page   1 50 90 SECTION  V CONTENTS  VOLUME  II _......  _  ..  .  ,-APPENDIX  A  {'lETHO OOLOGY  OF  LEUCOCYTE  CULTURES SECTION  VI  - RESULTS APPE  01 X  B  NON-SPECIFIC  CELLULAR  IMMUNE  RESPONSE APPENDIX  C  SPEC! FI C  CELLULAR  IMr UNE  RESPONSE  - 58  1I XED  LEUCOCYTE  CULTURES r PPENDIX  D  BLOOD  GROUP  ANTI GENS  - ABO  and  RHESUS  73 APPENDIX  E  HUrW1  LEUCOCYTE  ANTI  GEN  TYPES  77 APPENDIX  F  ANTI  HL-A  ANTIBODIES  -,.  CYTOTOXIC CROSS- 1A TCHES APPENDIX  G  S  ERU l  rr·l lUNOGLOBULI  NS APPE:W I  X  H  SERUM  SEROHUCOI  D  113 SECTION  VII  BIBLIOGRAPHY  - VOLUME  I I  120 , 94 

The role of immunogenetic factors in the aetiology of pre-eclamptic toxaemia of human pregnancy

Abstract

Similar works

Full text

Available Versions

Adelaide Research & Scholarship

The role of immunogenetic factors in the aetiology of pre-eclamptic toxaemia of human pregnancy

Abstract

Similar works

Full text

Available Versions

Adelaide Research &amp; Scholarship

Adelaide Research & Scholarship