1、Australia Antigen and the Biology of Hepatitis BBaruch S Blumberg,MD,PhDThe Nobel Prize in Physiology or Medicine 1976Learning Objectives To learn about polymorphisms and diseases associated with them To learn about the steps that lead to discovery of relationship between Australia antigen and Hepat
2、itis B To learn the virology of Hepatitis B and its modes of transmission To explore ethical implications of this discoveryPolymorphism “.The occurrence together in the same habitat of two or more(inherited)discontinous forms of a species,in such proportions,that the rarest of them cannot be maintai
3、ned merely by recurrent mutation”E.B.Ford,Oxford zoologist Sickle cell hemoglobin system:another example of polymorphismNormal red blood cellSickled cellOliver SmithiesDevelopment of the ingenious starch-gel electrophoresis method that allowed the separation of serum protein on the basis of complex
4、characteristics of their size and shape 1960Hypothesis:Patients who received large number of transfusions might develop antibodies against one or more of the polymorphic serum proteins(either known or unknown)which they themselves had not inherited,but which the blood donors had.1963Study of serums
5、of a group of hemophilia patients from Mt.Sinai Hospital in New YorkWhy did precipitin band has developed between the serum of a hemophilia patient in New York and that of an aborigine from Australia?Worldwide distribution of AuPopulationPercentage of positive serumsUS0.1%Filipino from Cebu6%Japanes
6、e1%Pacific Ocean populations5-15%June 28,1966 Association between Au and hepatitis was hypothesized “SGOT slightly elevated!Prothrombin time low!We may have an indication of the reason for his conversion to Au+.”Alton Sutnick(from patients chart)Late 1966:Association between Au and acute viral hepat
7、itis was found“The discovery of the frequent occurrence of Au(1)in patients with virus hepatitis raises the possibility that the agent present in some cases of this disease may be Australia antigen or be responsible for its presence.The presence of Australia antigen in the thalassemia and hemophilia
8、 patients could be due to virus introduced by transfusions.”(Ann.Int.Med.66:924-931,1967)Practical Applications of this Finding1969-routine screening of all donor blood and exclusion of all Au positive DonorsFrequency of post-transfusion hepatitis reduced from 18 percent to 6 percentAnnual healthcar
9、e saving of half a billion dollars(as of 1977)Fig.1.Electron micrograph showingthe several kinds of particles associatedwith hepatitis B virus(see Figure 2).Magnification=90,000X.Electron micrograph prepared by E.Halpern and L.K.Weng.VirologyFig.2.Diagram showing appearance of particles associated w
10、ith hepatitis B virus,the large or Dane particle(top),small surface antigen particle and the sausage shaped particle(middle),and the core of the Dane particle(bottom).(Adapted from E.Lycke,Lkartidningen 73,1976.)Structure of the DNA extracted from Dane particlesproposed by Summers et al.The position
11、 of the gapsin the single strands.an d the location of the 5 and 3 endsare shown.Vaccine Against Hepatitis BIn 1968 we were informed by the Federal government,who provided most of the funds for our work,that they would like to see applications of the basic research they had funded for many years.It
12、occurred to us that the existence of the carrier state provided an unusual method for the production of a vaccine.Variations in Response to Infection with Hepatitis B1)Development of acute hepatitis proceeding to complete recovery.Transient appearance of HBsAg and anti-HBc.Subsequent appearance of a
13、nti-HBs which may be persistent.2)Development of acute hepatitis proceeding to chronic hepatitis.HBsAg and associated anti-HBc are usually persistent.3)Chronic hepatitis with symptoms and findings of chronic liver disease not preceeded by an episode of acute hepatitis.HBsAg and anti-HBc are persiste
14、nt.4)Carrier state.Persistent HBsAg and anti-HBc.Carrier is asymptomatic but may have slight biochemical abnormalities of the liver.Variations in Response to Infection with Hepatitis B5)Development of persistent anti-HBs without detectable HBsAg or symptoms.6)Persistent HBsAg in patients with an und
15、erlying disease often associated with immune abnormalities,i.e.Downs syndrome,lepromatous leprosy,chronic renal disease,leukemia,primary hepatic carcinoma.Usually associated with anicteric hepatitis.7)Formation of complexes of antigen and antibody.These may be associated with certain“immune”diseases
16、 such as periarteritis nodosa.Family StudiesFamily-essential human social unit that is of major importance in the dissemination of disease Family clustering of Au in a Samaritan family from Israel We suggested that hepatitis virus may have several modes of transmission:Horizontally Sputum Fecal-oral
17、 route Hematophagous insects Computer cardsHost Responses to Human Antigens and HBV:Kidney TransplantationsProbability of rejecting a kidney graft by renal dialysis patients who received kidneysfrom malt donors.There is a significant difference in rejection rate between patients who were carriers an
18、d those who developed anti-HBsSex of Offspring and Fertility of Infected Parents In many areas of the world,including many tropical regions(i.e.the Mediterranean,Africa,southeast Asia,and Oceania)the frequency of HBsAg carriers is very high.In these regions most of the inhabitants will eventually be
19、come infected with HBV and respond in one of the several ways already described.Primary Hepatic Carcinoma*Add evidence of infection with HBVTransmission by InsectsAu antigen was found in-Mosquitoes(including mosquito eggs)-North American bedbug-Tropical bedbugHepatitis B as a PolymorphismThe origina
20、l discovery of hepatitis B resulted from the study of serum antigen polymorphisms.Its identification as an infectious agent does not diminish the value of this concept.It is useful to view infection with HBV not only as a“conventional”infection but also as a transfusion or transplantation reaction;a
21、nd our studies on renal transplantation are an example of this.Bioethics and the Carrier State Transmission by contact,fecal oral spread,and the like Conflict between public health and individual liberty Denial of the right to donate blood What is the extent to which biological knowledge about individuals should impinge on daily lives?Impact of this Research:Discovery of Hepatitis B Vaccine 1982 Hepatitis B vaccine becomes availableUniversal childhood vaccination for hepatitis B has now been adopted by more than 85 countries
