IMMUNO IMMUNO--HEMATOLOGY. HEMATOLOGY. IMMUNO IMMUNO HEMATOLOGY. HEMATOLOGY. P f Adi K A S PK(KH) P f Adi K A S PK(KH) Prof. Adi Koesoema Aman SpPK(KH) Prof. Adi Koesoema Aman SpPK(KH) Dr. Zulfikar Lubis SpPK(K) Dr. Zulfikar Lubis SpPK(K) DIVISI HEMATOLOGI DEPARTEMENT PATOLOGY KLINIK DIVISI HEMATOLOGI DEPARTEMENT PATOLOGY KLINIK FK USU/RSUP.H.ADAM MALIK MEDAN . FK USU/RSUP.H.ADAM MALIK MEDAN .
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P f Adi K A S PK(KH)P f Adi K A S PK(KH)Prof. Adi Koesoema Aman SpPK(KH)Prof. Adi Koesoema Aman SpPK(KH)Dr. Zulfikar Lubis SpPK(K)Dr. Zulfikar Lubis SpPK(K)
DIVISI HEMATOLOGI DEPARTEMENT PATOLOGY KLINIK DIVISI HEMATOLOGI DEPARTEMENT PATOLOGY KLINIK FK USU/RSUP.H.ADAM MALIK MEDAN .FK USU/RSUP.H.ADAM MALIK MEDAN .
IMMUNO IMMUNO –– HEMATOLOGI .HEMATOLOGI .
Mengandung arti reaksi Mengandung arti reaksi i l ik b k iti l ik b k itimmunologik yg berkaitanimmunologik yg berkaitandengan sel darah merah .dengan sel darah merah .Tidak saja mencakup Tidak saja mencakup Immunologi , hematologiImmunologi , hematologig gg gtapi juga genetika &tapi juga genetika &biokimia biokimia biokimia biokimia
The ABO SystemThe ABO SystemThe ABO SystemThe ABO System
Discovered in 1901 by Dr. KarlDiscovered in 1901 by Dr. KarlDiscovered in 1901 by Dr. Karl Discovered in 1901 by Dr. Karl LandsteinerLandsteiner4 Main Phenotypes (A, B, AB, O)4 Main Phenotypes (A, B, AB, O)yp ( , , , )yp ( , , , )ABOABO gene located on long arm of gene located on long arm of chromosome 9chromosome 9
The ABO AntigensThe ABO AntigensThe ABO AntigensThe ABO Antigens
Added to Proteins or Lipids in Red CellsAdded to Proteins or Lipids in Red CellsSubstrate Molecule is H (fucose)Substrate Molecule is H (fucose)Substrate Molecule is H (fucose)Substrate Molecule is H (fucose)A antigen is NA antigen is N--acetylacetyl--galactosamine galactosamine (GalNAc)(GalNAc)(GalNAc)(GalNAc)B antigen is Galactose (Gal)B antigen is Galactose (Gal)A and B genes code for transferase A and B genes code for transferase enzymesenzymesenzymesenzymes
A and B substances very commonA and B substances very commonA and B substances very commonA and B substances very commonAntibodies produced to “nonAntibodies produced to “non--self”self”P d d ft fi t f th f lifP d d ft fi t f th f lifProduced after first few months of lifeProduced after first few months of lifeA & B people have mainly IgMA & B people have mainly IgMO people have IgGO people have IgGMay fade in old ageMay fade in old ageMay fade in old ageMay fade in old age
May be life threateningMay be life threatening–– May be life threateningMay be life threatening–– Can be caused by technical or clerical errorCan be caused by technical or clerical error
Intra asc lar haemol sisIntra asc lar haemol sis–– Intravascular haemolysisIntravascular haemolysis–– More severe in group O patientsMore severe in group O patients
Universal Donor and RecipientUniversal Donor and RecipientUniversal Donor and RecipientUniversal Donor and Recipient
Universal DonorUniversal Donor Universal RecipientUniversal RecipientUniversal DonorUniversal DonorGroup OGroup O–– Carries no A or BCarries no A or B
Universal RecipientUniversal RecipientGroup ABGroup AB–– Patient has no antiPatient has no anti--AACarries no A or B Carries no A or B
antigensantigens–– Packed and processed Packed and processed
it h littlit h littl
Patient has no antiPatient has no anti A A or antior anti--B presentB present
–– Cannot lyse any Cannot lyse any t f d llt f d llunits have little units have little
antibodyantibodytransfused cellstransfused cells
–– Beware: otherBeware: otherantibodies may beantibodies may be–– antibodies may be antibodies may be presentpresent
Using the patient’s own group ASAP will conserve resources
The Rh(D) AntigenThe Rh(D) AntigenThe Rh(D) AntigenThe Rh(D) Antigen
RH is the most complex system, withRH is the most complex system, withRH is the most complex system, with RH is the most complex system, with over 45 antigens over 45 antigens Discovered in 1940 after work on Discovered in 1940 after work on Rhesus monkeysRhesus monkeysSubsequently discovered to be Subsequently discovered to be q yq yunrelated to monkeysunrelated to monkeysRHRH gene located on short arm of gene located on short arm of chromosome 1chromosome 1
Simple Genetics of Rh(D)Simple Genetics of Rh(D)Simple Genetics of Rh(D)Simple Genetics of Rh(D)
86% of caucasians are Rh(D) pos86% of caucasians are Rh(D) pos86% of caucasians are Rh(D) pos86% of caucasians are Rh(D) posThe antithetical antigen d has not been The antithetical antigen d has not been foundfoundfoundfoundThe The dd gene is recessive:gene is recessive:–– Dd, dD, DDDd, dD, DD, persons are Rh(D) pos, persons are Rh(D) pos–– Only Only dd dd persons are Rh(D) negpersons are Rh(D) neg
Distribution of Rh(D) TypesDistribution of Rh(D) TypesDistribution of Rh(D) TypesDistribution of Rh(D) Types
Significance of Rh(D)Significance of Rh(D)Significance of Rh(D)Significance of Rh(D)
80% of Rh(D) neg persons exposed to Rh(D)80% of Rh(D) neg persons exposed to Rh(D)80% of Rh(D) neg persons exposed to Rh(D) 80% of Rh(D) neg persons exposed to Rh(D) pos blood will develop antipos blood will develop anti--DDAntiAnti--D can also be stimulated by pregnancy with D can also be stimulated by pregnancy with y p g yy p g yan Rh(D) positive babyan Rh(D) positive baby–– Sensitisation can be prevented by the use of antiSensitisation can be prevented by the use of anti--D D
immunoglobulin, antenatally and post natallyimmunoglobulin, antenatally and post natallyRh(D) neg females of childbearing potential Rh(D) neg females of childbearing potential h ld b i Rh(D) iti bl dh ld b i Rh(D) iti bl dshould never be given Rh(D) positive blood should never be given Rh(D) positive blood
productsproducts
Significance of Rh(D)Significance of Rh(D)Significance of Rh(D)Significance of Rh(D)
80% of Rh(D) neg persons exposed to Rh(D)80% of Rh(D) neg persons exposed to Rh(D)80% of Rh(D) neg persons exposed to Rh(D) 80% of Rh(D) neg persons exposed to Rh(D) pos blood will develop antipos blood will develop anti--DDAntiAnti--D can also be stimulated by pregnancy with D can also be stimulated by pregnancy with y p g yy p g yan Rh(D) positive babyan Rh(D) positive baby–– Sensitisation can be prevented by the use of antiSensitisation can be prevented by the use of anti--D D
immunoglobulin, antenatally and post natallyimmunoglobulin, antenatally and post natallyRh(D) neg females of childbearing potential Rh(D) neg females of childbearing potential h ld b i Rh(D) iti bl dh ld b i Rh(D) iti bl dshould never be given Rh(D) positive blood should never be given Rh(D) positive blood
productsproducts
InheritanceInheritanceInheritanceInheritance
ABOABO && RHRH genes are not linkedgenes are not linkedABOABO & & RHRH genes are not linkedgenes are not linkedABO & Rh(D) type are inherited ABO & Rh(D) type are inherited independentlyindependentlyindependentlyindependentlyFor example:For example:An A Rh(D) pos mother An A Rh(D) pos mother and a B Rh(D) pos father and a B Rh(D) pos father could have an O Rh(D) neg childcould have an O Rh(D) neg child
Inheritance of ABO and Rh(D)Inheritance of ABO and Rh(D)Inheritance of ABO and Rh(D)Inheritance of ABO and Rh(D)
Mother FatherGroup A AO
Rh(D) pos Dd
Group B BO
Rh(D) pos Dd
Group A AO
Rh(D) pos Dd
Group B BO
Rh(D) pos Dd
Group O OO
Rh(D) neg dd
Clinical significance of Rh Clinical significance of Rh –– antigenantigeng f fg f f gg11-- Blood transfusionBlood transfusion::
If Rh If Rh ––ve person is transfused with Rh + ve blood, anti ve person is transfused with Rh + ve blood, anti –– Rh antibodies will develop in his Rh antibodies will develop in his If Rh If Rh ve person is transfused with Rh ve blood, anti ve person is transfused with Rh ve blood, anti Rh antibodies will develop in his Rh antibodies will develop in his plasma.plasma.Latter on if he needs a second blood transfusion and is given Rh +ve blood, agglutination Latter on if he needs a second blood transfusion and is given Rh +ve blood, agglutination of donor's R.B.Cs would occur inside the blood vessels of the recipient haemolysis.of donor's R.B.Cs would occur inside the blood vessels of the recipient haemolysis.of donor s R.B.Cs would occur inside the blood vessels of the recipient haemolysis.of donor s R.B.Cs would occur inside the blood vessels of the recipient haemolysis.
22-- In marriage : ( erythroblastosis foetalis )In marriage : ( erythroblastosis foetalis )If Rh + ve male person married Rh If Rh + ve male person married Rh –– ve female, the fetus will be Rh + ve in most cases.ve female, the fetus will be Rh + ve in most cases.During delivery ( i.e. separation of the placenta ), some fetal blood containing Rh During delivery ( i.e. separation of the placenta ), some fetal blood containing Rh agglutinogen may cross the placenta and reach the mother's blood.agglutinogen may cross the placenta and reach the mother's blood.So, sensitization of mother's blood will occur with formation of antibodies (So, sensitization of mother's blood will occur with formation of antibodies (anti anti –– RhRh. Or . Or , f f f (, f f f ( RRanti anti –– DD) in her plasma, (usually first baby saved).) in her plasma, (usually first baby saved).In the second pregnancy with Rh + ve fetus, antibodies already present cross the placenta In the second pregnancy with Rh + ve fetus, antibodies already present cross the placenta to the foetus and cause haemolysis of his R.B.Cs (to the foetus and cause haemolysis of his R.B.Cs (erythroblastosisFoetaliserythroblastosisFoetalis). ). f y f R (f y f R ( yy ))
LEWIS SYSTEMLEWIS SYSTEM
A serum antigen secondarily absorbed to th d llthe red cellsLe gene produces Lea
Secretors change the Lea to Leb
Le may also modify the A antigenLe may also modify the A antigen review the relationship to ABO precursors
Lewis Red Cell PhenotypesLewis Red Cell Phenotypes
Genes Lewis Red Cell Phenotype
Le Se Lea- Leb+Le Se Lea Leb+
Le se Lea+ Leb-
lele Lea- Leb-
le se Lea- Leb- Lec+
le Se Lea- Leb- Lec- Led+
Development of AntigensDevelopment of Antigens
Newborns born Le a-b-Newborns born Le If Le and Se
2 k t 6 th L a+– 2 weeks to 6 months Le a+
– then Le a+b+
b– then Le a-b+
During pregnancy antigens become weakerDuring pregnancy, antigens become weaker
Phenotype FrequenciesPhenotype Frequencies
Phenotype White Black yp
Le a+b- 22% ---
Le a-b+ 72% ----
Le a-b- 6% 20%
Lewis AntibodiesLewis Antibodies
Anti-Le a, Anti-Le b, Anti-Lex
Most react at room temperature or below -Most react at room temperature or below Often fix complementS i it h l iSome in vitro hemolysisLe a may cause HTR
I Blood GroupI Blood Group
Two antigens I and iI antigen present on almost all healthy g p yadults Rare adults that are I negative - spectrumRare adults that are I negative spectrum on page 175I antigen varies in strength on adult cellsI antigen varies in strength on adult cells
I Blood GroupI Blood Group
Newborns do not have much I antigenNewborns do not have much I antigen Newborns have i antigen At about 18 months the i is replaced with ISome transitional antigens
I Blood GroupI Blood Group
Antibodies Anti-I anti-i– Anti-I
usually reacts at room temperature, saline or belowft tt h l toften attaches complement
doesn’t cause hemolysis unless it reacts at 37oC37 C Can be found in almost all sera in low titers and titers increase during some diseases (viral infections - syphilis - atypical pneumonia)COLD AUTOAGGLUTIN
I Blood GroupI Blood Group
Antibodies Anti-I anti-i– Anti-i
rare antibody occurs in patients with infectious mononucleosis, cirrhosis, myeloid leukemia,
ti l ireticulosis
P Blood GroupP Blood Group
Discovered in 1927 by LandsteinerAntigens P1 P p pk Luke g 1– Luke antigen and disease association
- page 173
P Blood GroupP Blood Group
Antibodies Anti-P1 Anti-P Anti-pk
Anti- P + P1 + pk
– Anti-P11Usually IgM reacts at room temperature and salineMay attach complementrarely a problem with transfusioneasily inhibited with P substanceeasily inhibited with P1 substance
P Blood GroupP Blood Group
Antibodies Anti-P1 Anti-P Anti-pk
Anti- P + P1 + pk
– Anti-Pfound in sera from pk individuals - an IgM hemolytic antibody that is clinically significant also found as an IgG biphasic antibody in parozysmal cold hemoglobinuria called Donath-Landsteiner antibody y
P Blood GroupP Blood Group
Antibodies Anti-P1 Anti-P Anti-pk
Anti- P + P1 + pk
– Anti-pk and Anti P + P1 + pk
Anti-pk has only been found as part of other antibodiesantibodiesAnti-P + P1 + pk found in p individuals -formerly called Anti-Tja and very hemolytic
Duffy Blood GroupDuffy Blood Group
Discovered in early 1950’s Fy antigen locus on chromosome 1 withFy antigen locus on chromosome 1 with Rh locusAntigensAntigens codominant inheritance– Fya Fyb Fyx
– Others Fy3 Fy 4 Fy5 Fy6 Fs - (page 185)
Kell Blood GroupKell Blood Group
Many antigens in this system and hasMany antigens in this system and has been given a numerical nomenclature Refer to table 8 8Refer to table 8-8Six most important
Numeric Alpha Name IncidenceKEL 1 K Kell 10%KEL 2 k Cellano 99 8%KEL 2 k Cellano 99.8%KEL 3 Kpa Penny 2%KEL 4 Kpb Rautenberg 99.9KEL 6 Jsa Sutter Rare (19% Blacks)KEL 6 Jsa Sutter Rare (19% Blacks)KEL 7 Jsb Matthews 99.9%(99.8% Blacks
Kell Blood Gro pKell Blood Group
Most common gene complexes
MNSs Blood GroupMNSs Blood Group
M ti i thi t dMany antigens in this system and some are alleles to the four common antigensM N S s
Association with GPA and GPB Four gene complexes
MS Ms NS NsMS Ms NS Ns Other alleles Mg, Mk, Mc, Mr, Mz, Mv, Na, T1m, Sj, S2, some quantitative differences j, 2, q
MNSs Blood GroupMNSs Blood Group
Ph tPhenotypes
MNSs Blood GroupMNSs Blood Group
A tib diAntibodiesAnti-M and Anti-N– Usually room temperature– IgM saline reaction– Dosage (antibodies react better with
homozygous cells)– Destroyed by enzymes – Possible HDN and HTR if reaction at AHG– Anti-Nf found in dialysis patients
MNSs Blood GroupMNSs Blood Group
AntibodiesAnti-SAnti S– Usually igM and room temperature although
some at AHG– destroyed by enzymes– Rare HTR and HDNRare HTR and HDN
MNSs Blood GroupMNSs Blood Group
A tib diAntibodiesAnti-s and anti-U – Usually IgG and AHG– Not destroyed by enzymes– HTR and HDN– Anti-U found as warm autoantibody and y
does not react well with Rh null cells– Other antibodies rarely detected but not
uncommon (ex. anti-Mg common antibody)
Kidd Blood GroupKidd Blood Group
Di d i th 1950Discovered in the 1950sTwo antigens Jka Jkb
Kidd Blood GroupKidd Blood Group
Antibodies - Anti-Jka and Anti-Jkb
Usually IgG and require AHG– Usually IgG and require AHG– bind complement
enhanced by enzymes– enhanced by enzymes– implicated in HDN and HTR
S ld t t d d t i t idl– Seldom potent and deteriorate rapidly– Classic delayed HTR
Kidd Blood GroupKidd Blood Group
Antibodies Anti Jk3Anti-Jk3
– found in some Jka-b- individualsi h Jk d Jkb– reacts with Jka and Jkb
Lutheran Blood GroupLutheran Blood Group
T ti L a (8%) L b (99%)Two antigens Lua (8%) Lub (99%)– Other antigens Table 8-12
Important blood group that demonstratesImportant blood group that demonstrates multiple methods for inheritance of the null cell typetypeLu a-b- inheritance– InLu dominate inhibitor geneInLu dominate inhibitor gene– lulu recessive lack of Lu gene– sex linked inhibitor gene
Lutheran Blood GroupLutheran Blood Group
AntibodiesAntibodies– Anti-Lua - not common - reacts in saline but
can be IgG and require AHG gives a (mf)can be IgG and require AHG - gives a (mf) agglutination - unclear about HTR & HDN
– Anti-Lub - rare - mostly IgG and requires– Anti-Lu - rare - mostly IgG and requires AHG - probable HTR and HDN
– Anti-Luab (Anti-Lu3 ) - reacts with all butAnti Lu (Anti Lu ) reacts with all but Lu a-b- of the recessive type
– Other antibodies react with rare Lu– Other antibodies react with rare Lu phenotypes found on Lua-b- (page 192/3)
Other Blood GroupsOther Blood Groups
Diego - Dia Dib Wra Wrb 3 othersDiego Di Di Wr Wr 3 others– Dia found in Chippawah Native Americans
and Japanese and Chineseand Japanese and Chinese– uncommon antibodies - AHG reaction and
important in HTR and HDNimportant in HTR and HDN– Wra is a low incidence antigen and Wrb is
a high incidence antigeng g– anti-Wra is a fairly common antibody - IgM
or IgGg
Other Blood GroupsOther Blood Groups
Chido/Rogers– Nine antigens - all normal individuals are g
either Rg + or Ch +– HTLA - use plasma inhibition– Determinants on C4 molecule and linked to
HLA -
Other Blood GroupsOther Blood Groups
Gerbich– system with at least 3 high incidence y g
antigens and 4 low incidence antigens– Antibodies usually IgG which require AHG
and clinically significantScianna– Sc:1 - 100% Sc:2 - 0.3% Sc:3 - 100%– Antibodies are rare
Other Blood GroupsOther Blood Groups
ColtonColton– antigens: Coa -99.7% Cob -10.7% Co3 -100%
the null phenotype has been found and– the null phenotype has been found and associated with genetic abnormality and anemiaanemia
– antibodies IgG and clinically significantCromerCromer– consists of 7 high incidence antigens and
I id d b t tb k Fi 14 3 97 K bImages provided by textbook: Figure 14.3, page 97, KubyImmunology, 4th Edition, W.H. Freeman and Company
Immune ResponseImmune ResponseDefinition: Physiological mechanism to fight Definition: Physiological mechanism to fight
Immune ResponseImmune Responsey g gy g g
disease or clear foreign substances.disease or clear foreign substances.Primary immune response: First exposure of a Primary immune response: First exposure of a f i I M i h d i ib df i I M i h d i ib dforeign agent. IgM is the predominant antibody foreign agent. IgM is the predominant antibody produced that attaches to and fights the foreign produced that attaches to and fights the foreign agent In our case a foreign red blood cellagent In our case a foreign red blood cellagent. In our case a foreign red blood cell agent. In our case a foreign red blood cell antigen.antigen.Secondary immune response: Subsequent Secondary immune response: Subsequent exposure of the same foreign agent. Rapid exposure of the same foreign agent. Rapid response in which IgG is the predominant response in which IgG is the predominant antibody producedantibody producedantibody produced.antibody produced.
Concentration of Ag and Ab also affects agglutination reactions both also affects agglutination reactions, both the first and second stages.
1.1. Menyesuaikan donor dan resipien utk Menyesuaikan donor dan resipien utk y py ptransfusi dn trasnplantasi organ .transfusi dn trasnplantasi organ .
2.2. Identifikasi dan pencegahan thd Identifikasi dan pencegahan thd ll i i i it h il l h ti ll i i i it h il l h ti alloimmunisasi wanita hamil oleh antigen alloimmunisasi wanita hamil oleh antigen
Rh .Rh .3.3. Menentukan diagnosis , prognosis , terapi Menentukan diagnosis , prognosis , terapi g , p g , pg , p g , p
HDN .HDN .4.4. Diagnosis dan pemeriksaan destruksi Diagnosis dan pemeriksaan destruksi
it it di b bk t tib di t it it di b bk t tib di t eritrosit yg disebabkan autoantibodi atau eritrosit yg disebabkan autoantibodi atau alloantibodi . alloantibodi .
1.1. ANTIGEN H ANTIGEN H 1.1. ANTIGEN H ANTIGEN H Komponen dasar Ag eritrosit , Komponen dasar Ag eritrosit , Diatur oleh gen H , ada pada semua eritrosit , Diatur oleh gen H , ada pada semua eritrosit , K d dit t k l h A &B K d dit t k l h A &B Kadarnya ditentukan oleh gen A &B Kadarnya ditentukan oleh gen A &B Subtansi H oleh gen A & gen B → antigen A dan B Subtansi H oleh gen A & gen B → antigen A dan B Gen O tdk merubah substansi H → substansi H >>>Gen O tdk merubah substansi H → substansi H >>>
ABO BLOOD GROUP SYSTEMABO BLOOD GROUP SYSTEMABO BLOOD GROUP SYSTEMABO BLOOD GROUP SYSTEM
GOLONGAN DARAH O BAMBAYGOLONGAN DARAH O BAMBAYGOLONGAN DARAH O BAMBAYGOLONGAN DARAH O BAMBAY
Orang gol O tanpa gen H ( genotype hh ) → Orang gol O tanpa gen H ( genotype hh ) → g g p g ( g yp )g g p g ( g yp )tidak mampu membentuk Antigen A dan B tidak mampu membentuk Antigen A dan B walau gen A & B normal → tidak memiliki anti walau gen A & B normal → tidak memiliki anti gen A B dan H pada eritrisit tapi anti bodi A gen A B dan H pada eritrisit tapi anti bodi A gen A , B dan H pada eritrisit tapi anti bodi A , gen A , B dan H pada eritrisit tapi anti bodi A , B, H dalam serumnya sangat kuat → fenotipe B, H dalam serumnya sangat kuat → fenotipe Bombay ( Oh ) .Bombay ( Oh ) .