2019 advanced track webinars - immucor.com program handouts/jolly_slides.pdf · u n enda enev jenu...
TRANSCRIPT
2 All Content © Immucor, Inc.
Handouts
http://www.immucor.com/en-us/Pages/Educational-Program-Handouts.aspx
3 All Content © Immucor, Inc.
2019 Advanced Track Webinars
Link to register: https://immucor.webinato.com/register
4 All Content © Immucor, Inc.
2019 Advanced Track Webinars
Link to register: https://immucor.webinato.com/register
5 All Content © Immucor, Inc.
6 All Content © Immucor, Inc.
Link to register: https://immucor.webinato.com/register
7 All Content © Immucor, Inc.
learn.immucor.com
8 All Content © Immucor, Inc.
Continuing Education
• PACE, Florida and California DHS
• 1.0 Contact Hours
• Each attendee must register to receive CE at: https://www.surveymonkey.com/r/TheJollyBloodBanker
• Registration deadline is April 5, 2019
• Certificates will be sent via email only to those
who have registered April 19, 2019
9 All Content © Immucor, Inc.
Questions?
• You are all muted
• Q&A following session - Type in questions
10 All Content © Immucor, Inc.
• Course content is for information and
illustration purposes only. Immucor makes
no representation or warranties about the
accuracy or reliability of the information
presented, and this information is not to be
used for clinical or maintenance evaluations.
• The opinions contained in this presentation
are those of the presenter and do not
necessarily reflect those of Immucor.
The Jolly Blood Banker and “Other” Blood Groups
Jill R. Storry, PhD FIBMS
Associate Professor, Lund University
Technical Director, Immunohematology
Clinical Immunology and Transfusion Medicine, Lund
Blood systems covered in this talk:
• MNS
• Kell
• Lewis
• Duffy
• Kidd
ABO P1PK
LewisFORSGLOB
HI
LWXg
DuffyLutheranIndian Scianna
RaphJMHOka
36 blood group systems are carried on functional molecules
Host defence/innate immunity
(Glyco)proteins of structural orunknown function
Complement regulation
Adhesion molecules
Transporters and channels
Enzymes
The MNS Blood Group System (ISBT 002)
• MNS antigens are carried on:GPA
GPB
Hybrids of GPA & GPB
• Specific to red blood cells
• Highly polymorphic system – 49 antigens
• Function of GPA and GPB not completely understood:Chaperone proteins?
Protection by sialic acid?
Antigens of the MNS blood group system
Prevalence n Antigens
Variable 4 M N S s
High 10 Ena ENKT ENEP ENEH ENAV
U ‘N’ ENDA ENEV JENU
Low 35 He Mia Mc Vw Mur Mg Vr Me
Mta Sta Ria Cla Nya Hut Hil Mv
Far sD Mit Dantu Hop Nob Or
DANE TSEN MINY MUT SAT ERIK
Osa HAG MARS MNTD SARA KIPP
Numbering:
Counted from initiatingMethionine (19aa leadersequence included)
MNS antigens are carried on GPA and GPB
RBC lipid bilayer
N-linked sugarO-linked sugar
15091
20’N’
20 M/N
48 S/s
α-chymotrypsinsite at aa 51Papain site ~aa 54
Trypsin sites at aa 50 & 58Papain site at aa 78/80
6
31 2 4 5 6
31 2 4 5 7
GYPB
GYPA
31 2 5 6
GYPE
Low nucleotide identityHigh nucleotide identity
GYPA
Chromosome 4q31.21
4
GYPEGYPB
The GYPA gene family
Molecular Basis of MNS Antigens
Mechanisms for generating diversity:
• Single nucleotide polymorphisms (SNPs)
• Deletions/insertions
• Gene recombination events
All of the above are reported for the MNS system
MNS SNPs
GYPB exon 4GA GAA ATG GGA CAA CTT GTC CAT CGT TTC ACT GTA CCA G S
E M G Q L V H R F T V P
GA GAA ACG GGA CAA CTT GTC CAT CGT TTC ACT GTA CCA G s
E T G Q L V H R F T V P
Single nucleotide polymorphisms are an effectivemethod of creating diversity, e.g. S/s antigens
SNPs Encode Low Incidence Antigens
‘N’
M/N
GPA GPB
20
24
150
23 Mg
50 Or
66 Vr73 Osa76 Ria77 Mta78 ERIK82 MARS84 HAG
20
24
22 MV
54 Mit
58 sD
48 S/s
Numbering:
Counted from initiatingMethionine (19aa sequence included
46 Nya47 Vw/Hut
36 MNTD
91
SARA 80
Homology Between Genes Creates Diversity
31 2 4 5 6
31 2 4 5 76
t
Low nucleotide identityHigh nucleotide identity
Recombinationhotspot
GYPB
GYPA
Creation of MNS hybrid genes
GP.SchSt(a+)
GP.Hil (MINY+, Hil+)GP.JL (MINY+, TSEN+)GP.TK (SAT+)
Novel antigens are created at crossover points
GYPA GYPB
GYPB GYPAGYPA GYPB
Unequal crossover
DNA exchange by double strand break repair (DSBR) mechanism leaves one chromosome unaltered
New antigens are encoded by the novel hybrid sequence
GYPA GYPB
GYPB -A -BGYPA
Gene conversion
GP.HilGenerated by unequal crossover
GP.MurGenerated by gene conversion
GPB
GPB
GPA
Hil
GPB
AHil
GP.Hil GPMurGP.BunGP.HF
Different mechanisms can produce the same antigen
PEEETGETGDL
MNS Antigens Produced by Hybrids
• Mia, Hut, Mur, MUT, Hil, TSEN, MINY, Hop, Nob, DANE,
Sta, Dantu, SAT
• Antibodies can cause HDN
• The GP.Mur (Mi.III) phenotype is ~15% in Chinese
populations
• HDN due to ”anti-Mia” is a concern
• Anti-Mur +/- MUT
• One of the most common antibodies in Asian populations
High Prevalence MNS antigens
‘N’
20
24
91
81 ENEV82 ENAV/MARS84 ENEP/HAG
20
68&71 ENKT
150
EnaFR
EnaFS
U
59
48
GPA GPB
Ena
JENU: encoded by GYPB, absent from GP.Mur hybrid
47 ENEH/Vw/Hut
ENDA: encoded by GYPA absent from GP.Dane hybrid
Null Phenotypes in the MNS System
• En(a−): absence or alteration of GPA
• S−s− : absence or alteration of GPB
• MkMk phenotype: absence of GPA and GPB
Clinical significance of MNS antibodies
Anti- Ig class HTR HFDN Comments
M IgM/IgG Rarely Rarely Worth monitoring in pregnancy
N IgM>IgG No No
S IgG Yes Yes
s IgG Rarely Rarely
U IgG Yes Yes
Ena IgG Rarely Rarely Can be an autoantibody
’N’ IgG Yes Yes
’Lows’ IgM>IgG No Yes Mabye naturallyoccurring
Many low prevalence MNS antigens have been detected as a consequenceof HDFN in women with negative antibody screens. Disease can range from mild to severe.
The Kell Blood Group System (ISBT 006)
• 1st antibody – anti-K, identified in 1946 in a report of HDFN
• 36 antigens
• Kell is expressed on:• RBCs, erythropoietic tissues, testes
• Lower expression in brain, lymphoid organs, muscle (heart and skeletal)
Kell blood group system antigens
001 002 003 004 005 006
K k Kpa Kpb Ku Jsa
007 008 009 010 011 012
Jsb --- --- Ula K11 K12
013 014 015 016 017 018
K13 K14 --- K16 K17 K18
019 020 021 022 023 024
K19 Km Kpc K22 K23 K24
025 026 027 028 029 030
VLAN TOU RAZ VONG KALT KITM
031 032 033 034 035 036
KYO KUCI KANT KASH KELP KETI
037 038 039
KHUL KYOR KEAL Low High
Geographic variation in expression oflow prevalence antigens
Antigen Ethnic group Occurrence Others
K Whites Arabs
9%25%
<2%
Jsa Blacks (USA) 20% <0.01%
Ula Finns 2.6% <0.01%
Kpc Japanese 0.32% <0.01%
The KEL gene is located on chromosome 7
Chromosome 7q33 - KEL
19 exons 21,5 kb
exonsintrons
Exons contain coding nucleotides Introns contain non-coding nucleotides:
High percentage of the gene is noncoding but it contains important regulatory sequences
..ccccctctctctcctttaaag CTT GGA GGC TGG CGC ATC
TCT GGT AAA TGG ACT TCC TTA AAC TTT AAC CGA ACG
CTG AGA CTT CTG ATG AGT CAG TAT GGC CAT TTC CCT
TTC TTC AGA GCC TAC CTA GGA CCT CAT CCT GCC TCT
CCA CAC ACA CCA GTC ATC CAG gtgagggatg......
The Kell glycoprotein
• Type 2 membrane protein732aa; Mr 93 kDa
15 cysteine residues: predicts a heavily folded protein
Glycosylated 5 (4) N-linked branched oligosaccharides
• One of M13 family of neutral zinc endopeptidases
• Specifically cleaves big endothelin-3 to ET-3ET-3 is a powerful vasoconstrictor
• Biological role on RBCs is still unknown
3
2
1
4
5
6
7
8
9
1012
13
14
15
16
17
18
19
11
KEL
K18+/K18–388C>T; 389G>A
K/k 578T/CK14/K24 538G/C
KTIM+/KYIM– 913G>AK11/K17 905T/CKHUL/KEAL 877C>TKYOR/KYO 875G/AKpb/Kpc 842G/AKpa/Kpb 841T/C KELP+/KELP– 780G>TKASH+/KASH– 758A>GRAZ+/RAZ– 745G>AVLAN–/VLAN+ 743G>AVONG–/VONG+ 742C>T
K13+/K13– 986T>CK22+/K22– 965C>T
K23–/K23+ 1145A>G TOU+/TOU– 1217G>AKUCI+/KUCI– 1271C>TKANT+/KANT– 1283G>T
K19+/K19– 1475G>AUl(a–)/Ul(a+) 1481A>T
K12+/K12– 1523A>G
Reid, Lomas-Francis & Olsson
The blood group antigen factsbook, 3rd ed.
Slide modified from ES Wester et al.
Transfusion 2005,45:545
KELP+/KELP– 2024G>A
Jsa/Jsb 1790C/T
Kell antigens are created by missense SNPs
KETI+/KETI– 1391C>T
KALT+/KALT– 1868G>A
Kell glycoprotein interacts with XK
COOH
15
NH2
H
E
L
L
H
158
16
3
2
1
4
5
6
7
KEL
17
18
19
9
1012
13
14
11
Exons 1-19
Cys347=Cys72N-glycans
XK
Kell
Preferential processing of big ET-3 by wild-type s-Kell
Lee S et al. Blood 1999;94:1440-1450
©1999 by American Society of Hematology
S-Kell: His-tagged extracellular domain of Kell gp
The K0 phenotype
• Null phenotype of the Kell system All Kell antigens are absent
Expression of Kx is elevated
Amount of XK protein is reduced
• No apparent physiological defect
• Reported in all populations
• May produce anti-Ku (KEL5)
• Many molecular backgrounds Missense mutations
Nonsense mutations
Altered splicing due to intron mutations
Preferential processing of big ET-3 by RBCs of common Kell phenotype: comparison with K0 phenotype
Lee S et al. Blood 1999;94:1440-1450
©1999 by American Society of Hematology
Reference allele KEL*02 encodes KEL2, KEL4, KEL5, KEL7, KEL11, KEL12, KEL14, KEL18, KEL19, KEL22, KEL26,
KEL27, KEL29, KEL30, KEL32, KEL33, KEL34, KEL35, KEL36, KEL37, KEL38
Phenotype Allele Name Nucleotide change† Intron/
Exon
Amino acid change
K0 KEL*01N.01 c.1678C>G 15 p.Pro560Ala
K0 KEL*01N.02 c.244T>C 4 p.Cys82Arg
K0 KEL*02N.01 c.223+1g>c Intron 3 Alternative splicing:
p.Arg75fs
K0 KEL*02N.02 c.382C>T
c.1790C
4
(17)
p.Arg128Ter
K0 KEL*02N.03 C246T>A 4 p.Cys82Ter
K0 KEL*02N.04 c.1042C>T 9 p.Gln348Ter
K0 KEL*02N.05 c.2027G>A 18 p.Ser676Asn
K0 KEL*02N.06 c.223+1g>a Intron 3 Alternative splicing:
p.Arg75fs
K0 KEL*02N.07 c.574C>T 6 p.Arg192Ter
K0 KEL*02N.08 c.526−2a>g Intron 5 Alternative splicing
Mod phenotypes
Classification of a mod phenotype may depend on the reagents used.
Kmod; KEL:1weak KEL*01M.01 c.578C>G 6 p.Thr193Arg
Kmod KEL*02M.01 c.1088G>A 10 p.Ser363Asn
Kmod KEL*02M.02 c.2030A>G 18 p.Tyr677Cys
Kmod KEL:−13 KEL*02M.03 c.986T>C 9 p.Leu329Pro
Kmod KEL*02M.04 c.2107G>A 19 p.Gly703Arg
Kmod KEL*02M.05 c.1719C>T 16 p.Gly573Gly
Kmod KEL*0M2.06 c.306C>A, c.1298C>T 4, 11 p.Asp102Glu,
p.Pro433Leu
http://www.isbtweb.org/nc/working-parties/red-cell-immunogenetics-and-blood-group-terminology/
Alloantibodies to Kell Antigens
• Usually IgG1
• Clinically important antibodies: Cause of HTR
Mild to severe HDFN
• Anti-K is the most common alloantibody specificityoutside ABO & Rh systems
• Anti-K often found in sera containing antibodies tohigh incidence Kell antigens
Anti-K and HDFN
• Kell antigens are well developed on fetal RBCs
• Clinical presentation is very different than HDFN due to other non-Kell antibodies
• Prediction of disease severity based on antibody titre or amniotic bilirubin is unreliable
• Antibodies inhibit erythropoeisis
• Post-delivery: Hyperbilirubinaemia is lower than expected Reduced reticulocytosis Reduced erythroblastosis Very anaemic babies
Why is the HDFN so severe?
Southcott MJG, et al. The expression of human blood group antigens during erythropoiesis in a cell culture system. Blood 1999;93:4425-35
”… may have an important role in the early stages of hematopoiesis or cell lineage determination.”
Time in culture (days)
Onset of RBC proteins in cultured cord blood
The Lewis blood group system (ISBT 007)• 6 antigens recognized by ISBT: Lea, Leb, LebH,
ALeb, BLeb, Leab
• Adsorbed onto RBCs from the plasma
• ”Histo-blood” group antigens: Glycoproteins in saliva and blody fluids
Lymphocytes, platelets
Epithelia of various tissues
• Synthesized by α(1,3/4) fucosyltransferaseencoded by FUT3
Blood group
Le(a+b−)Le(a−b+)Le(a−b−)
RBC Antigens
Lea
Leb
Neither
Secretor?
NoYesYes or No
Lewis antigens and Secretor Status
• FUT2 encodes α2FucT2, which synthesizes H antigen on soluble glycoproteins
Genes
FUT3FUT2, FUT3(FUT2)
Structure of Lewis Antigens on RBCs
Type 1 chain
Lea and Leb are not synthesized on RBCs, but adsorbed from plasma
Leb
Lea
Rβ1-4β1-3
α1-4
β1-3 β1-1
Rβ1-3β1-3
α1-4α1-2
β1-4 β1-1
R = Core structureGlucose
Fucose
Galactose
GlcNAc
Function of Lewis Antigens
• Receptors for various pathogens
• Leb identified as the receptor for Helicobacter
pylori
• Sialyl-Lea is a tumour marker
– diagnostic marker in carcinomas such as colorectal,
pancreatic and gastric cancers
• The related sialyl-Lex is not found on RBCs but
expressed on endothelium
– Ligand for selectins
H. pylori BabA adhesinrecognizes Leb ongastric epitheliumresulting in binding
Mahdavi et al. Science 297:573-578, 2002Slide courtesy of S. Spitalnik
Helicobacter pylori and Gastritis
Helicobacter pylori and Gastritis
Inflammation increases SLex expression on gastric epithelium,which is recognized by H. pylori SabA adhesin
Mahdavi et al. Science 297:573-578, 2002Slide courtesy of S. Spitalnik
Helicobacter pylori and Gastritis
Neutrophils, which expresshigh levels of SLex, infiltrateepithelium. Phase variationin H. pylori leads to decreasedSabA expression and evasionof phagocytosis
Mahdavi et al. Science 297:573-578, 2002Slide courtesy of S. Spitalnik
Antibodies to Lewis antigens
• Mostly IgM
• Oftern naturally occurring
• More often found in plasma from pregnant women
• Readily neutralised by saliva
• Anti-Leb is not clinically significant
• Most anti-Lea are not clinically significant
Blood group
Le(a+b−)Le(a−b+)Le(a−b−)
Anti- Lea
NoVery rarelyOccasionally
Anti- Leb
Very rarelyNoOccasionally
The Duffy blood group system (ISBT 008)• Consists of 5 antigens:
Polymorphic: Fya, Fyb
High prevalence: Fy3, Fy5, Fy6
• Carried by Atypical Chemokine receptor 1 (ACKR1) on RBCs
• Also found on endothelial cells i capillaries, epithelia of the kidneys, lungs and in brain
(Fya is a high prevalence antigen in South East Asia)
(Fy6 is defined by a monoclonal antibody only)
N-glycans
Fy3
Fya/Fyb
Fy6
Atypical Chemokine receptor 1 (ACKR1)
RBC membrane
• Major isoform of glycoprotein is 336 aa
• Fya/Fyb at position 42 (Gly42Asp)
• Susceptible to papain/ficin treatment of RBCs
Genetic basis of Duffy phenotypes
• Polymorphism at −67 (t>c) interrupts a GATA-1 binding site and the gene is not transcribed
• No protein on the RBC
• Fy(a−b−) phenotype Found in >90% West Africans, ~60% of African Americans (FY*B) Also found in Papua New Guinea (FY*A)
Exon 1
−67 265 298
A/GFya/Fyb
C/T”Fyx”
t/c
125
G/A
Exon 2
Function of ACKR1• Binds different chemokines – RBC chemokine ”sink”
• Associated with hematopoeisis: neutropenia in healthyFy(a−b−) individuals of African ancestry has been associatedwith absence of ACKR1
Nature Immunology 2017
ACKR1 is a receptor for Plasmodium spp.
• Major receptor for P. vivax and P. knowlesi
• Individuals with Fy(a−b−) phenotype areprotected from infection
• BUT… evidence that ACKR1 protein helps PF4 from platelets kill P. falciparum
Platelet Factor 4 and Duffy Antigen Required for Platelet Killing of Plasmodium falciparum
McMorran et al. Science 2012;338:1348-51.
McMorran et al. Science 2012;338:1348-51.
Fig. 4
Antibodies to Duffy blood groupantigens• Readily formed following transfusion
• IgG antibodies
• Anti-Fya and anti-Fyb can cause both transfusion reactions and HDFN
• Anti-Fy3 is generally weak and not clinicallyimportant but… Anti-Fy3 produced by true Fynull individuals (mutations in FY
gene) can be clinically important
• Anti-Fy5 is very rare
• Anti-Fy6 only described as a monoclonal antibodyreactive with a papain-sensitive epitope on ACKR1
Properties of SLC14A1389 amino acidsMultipass membrane protein
Null phenotypeJk(a−b−)Reduced urine concentrationAnti-Jk3
AntigensJka, Jkb and Jk3
AntibodiesDelayed HTRHDFN
Gene SLC14A1(HUT11A), UT-B Chromosome 18, 10 exons
Jka/Jkb
3
21
5
6
4
7 89
10
11
SLC14A1
Jka/Jkb
3
21
5
6
4
7 89
10
11
SLC14A1
Olives, Lucien, Sidoux-Walter et alInstitute National de la Transfusion Sanguine, Paris
The Kidd blood group system (ISBT 009)
Function
Urea transporterFound on RBCs, kidney, colon
JK alleles
838G
JK*01
588A
838A
JK*02
588G
-46 a/g
3 st Single Nucleotide Polymorphisms (SNPs)
Asp280Asn
Jka Jkb
Olives et al., J. Biol. Chem. 1994.
Jk(a+)
Jk(b+)
JK alleles that encode weak antigen expressionReference allele JK*01 encodes JK1, JK3
Phenotype Allele name Nucleotide change Exon Predicted amino acid change
JK:1 or Jk(a+) JK*01 or
JK*A
c.838A>G 8 p.Asn280Asp
JK:2 or Jk(b+) JK*02 or
JK*B
Weak phenotypes
Jk(a+W) JK*01W.01 c.130G>A 3 p.Glu44Lys
Jk(a+W) JK*01W.02 c.511T>C 6 p.Trp171Arg
Jk(a+W) JK*01W.03 c.28G>A 3 p.Val10Met
Jk(a+W) JK*01W.04 c.226G>A 4 p.Val76Ile
Jk(a+W) JK*01W.05 c.742G>A 7 p.Ala248Thr
Jk(b+W) JK*02W.01 c.548C>T 6 p.Ala183Val
Jk(b+W) JK*02W.02 c.718T>A 7 p.Trp240Arg
The common Jka+w phenotype is due to an intracellular amino acid change
2030
50
60
40
70
100
90
120
130150
170
180
230
240
270
360
80
110
140
160
190
200
210
220
370
380
Asp280Asn
Jka/Jkb
340
350
300
290
310
320
330
Glu44Lys
Pro196
10
Function of Jk (SLC14A1)
• Major urea transporter on RBCs and kidneys
• Absence of SLC14A1 has no clinical symptoms but individuals have reduced urine concentratingability
• Since SLC14A1 is an important functional protein in kidneys, Jka/Jkb are minor histocompatibilityantigens in transplantation
The Jk(a−b−) phenotype
• Rare phenotype but up to 1% in Polynesians
• RBCs are resistant to hemolysis by 2M Urea
Phenotype Urea transport Hemolysis
Jknull Passive 30 min
Jka/Jkb Passive/Active 1 min
Jk(a+b-) Jk(a-b-) Jk(a-b-)
Read after 2 min
JK alleles that silence antigen expressionNull phenotypes JK*02
JK:–3 or Jk(a–b–) JK*02N.01 c.342-1G>A Intron 4 p.Arg114_Thr156del; Alternative
splicing
JK:–3 or Jk(a–b–) JK*02N.02 c.342-1G>C Intron 4 p.Arg114_Thr156del; Alternative
splicing
JK:–3 or Jk(a–b–) JK*02N.03 c.222C>A 4 p.Asn74Lys
JK:–3 or Jk(a–b–) JK*02N.04 c.663+1G>T Intron 6 p.Leu223fs*?; Alternative splicing
JK:–3 or Jk(a–b–) JK*02N.05 c.723delA 7 p.Gly243Alafs*20
Identical to JK*01N07? (c.838A>G is
located past termination)
JK:–3 or Jk(a–b–) JK*02N.06 c.871T>C 8 p.Ser291Pro
JK:–3 or Jk(a–b–) JK*02N.07 c.896G>A 8 p.Gly299Glu
JK:–3 or Jk(a–b–) JK*02N.08 c.956C>T 9 p.Thr319Met
JK:–3 or Jk(a–b–) JK*02N.09 c.191G>A 4 p.Arg64Gln
JK:–3 or Jk(a–b–) JK*02N.10 c.194G>A 4 p.Gly65Asp
JK:–3 or Jk(a–b–) JK*02N.11 c.499A>G; c.512G>A 6 p.Met167Val; p.Trp171Ter
JK:–3 or Jk(a–b–) JK*02N.12 c.437T>C; c.499A>G 5; 6 p.Leu146Pro; p.Met167Val
JK:–3 or Jk(a–b–) JK*02N.13 c.499A>G; c.536C>G 6 p.Met167Val; p.Pro179Arg
Antibodies to Kidd blood groupantigens
• Readily formed following transfusion
• IgG antibodies
• Anti-Jka, -Jkb and anti-Jk3 can cause severehemolytic immediate/delayed transfusion reactions
• HDFN is mild to moderate
• Anti-Jka and anti-Jkb may disappear rapidly butare readily boosted by transfusion of antigen-positive blood
For more information on blood group alleles….
www.erythrogene.com
Thank you for yourattention!
Questions?
67 All Content © Immucor, Inc.
Questions?
• You are all muted
• Q&A following session - Type in questions
68 All Content © Immucor, Inc.
69 All Content © Immucor, Inc.
Questions?
• You are all muted
• Q&A following session - Type in questions
70 All Content © Immucor, Inc.
Continuing Education
• PACE, Florida and California DHS
• 1.0 Contact Hours
• Each attendee must register to receive CE at: https://www.surveymonkey.com/r/TheJollyBloodBanker
• Registration deadline is April 5, 2019
• Certificates will be sent via email only to those
who have registered April 19, 2019
71 All Content © Immucor, Inc.
We like you!
Like us on social media!
72 All Content © Immucor, Inc.
Thank you!