Neonatal Intracranial Hemorrhage with a Dramatic Outcome Due to Maternal Anti CD36 Antibodies

Fetal/neonatal allo-immune thrombocytopenia (FNAIT) results from maternal immunization against fetal platelet-specific antigens (HPA) inherited from the father. Most cases involve HPA located on glycoproteins (GP) IbIX, IaIIa and IIbIIIa. Iso-immunizations can also occur in the absence of expression of membrane proteins, such as GPIIb or GPIIIa in Glanzmann patients. CD36 (also called glycoprotein GPIV) deficiency is observed in 3 to 5% of Asian and African populations. We report here the case of a 41-year-old Canadian woman originated from Africa, who delivered a male dead new-born at 39 weeks of gestation. A massive intracranial haemorrhage was identified as being the obvious cause of death. No platelet antibody against GPIbIX, IaIIa, and IIbIIIa was identified by the gold-standard Monoclonal Antibody-specific Immobilization of Platelet Antigens (MAIPA) assay. Surprisingly, anti CD36 iso-antibodies were identified in the maternal serum with a new bead-based multiplex assay. The CD36 gene was sequenced for both parents, and a mutation was identified on Exon 10 of the mother’s CD36 gene, which was absent for the father: NM_000072.3:c.975T>G inducing a STOP codon at position 325 of the mature protein. The absence of CD36 expression on the mother’s platelets was confirmed by flow cytometry.

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Alloimmune neonatal neutropenia due to an antibody to the neutrophil Fc- gamma receptor III with maternal deficiency of CD16 antigen

Blood ◽

10.1182/blood.v77.7.1572.1572 ◽

1991 ◽

Vol 77 (7) ◽

pp. 1572-1580 ◽

Cited By ~ 38

Author(s):

DF Stroncek ◽

KM Skubitz ◽

LB Plachta ◽

RA Shankar ◽

ME Clay ◽

...

Keyword(s):

Healthy Person ◽

Maternal Serum ◽

Maternal Antibody ◽

Fc Gamma Receptor ◽

Glycosyl Phosphatidylinositol ◽

Gamma Receptor ◽

Rabbit Polyclonal Antibody ◽

Specific Antigens ◽

Neonatal Neutropenia ◽

Cd16 Antigen

Abstract Antibodies to the neutrophil-specific antigens NA1 and NA2 are associated with alloimmune neonatal neutropenia (ANN), autoimmune neutropenia of childhood, and acute pulmonary transfusion reactions. These antigens have been found to be located on the neutrophil Fc-gamma receptor III (FcRIII). The mother of a child with ANN was found to lack both NA antigens and to produce an antibody that reacted with all normal neutrophils tested. We used maternal antibody and a CD16 monoclonal antibody (MoAb) that has specificity for FcRIII to immunoblot and immunoprecipitate neutrophil membranes of various NA phenotypes. Both antibodies immunoblotted an approximately 40- to 70-Kd glycoprotein (GP) on NA1, NA2-positive membrane, an approximately 40- to 55-Kd GP on NA1-homozygous membranes, and an approximately 55- to 70- Kd GP on NA2-homozygous membranes. Both antibodies also immunoprecipitated a 50- to 80-Kd GP from NA1, NA2-positive cells, a 50- to 60-Kd GP from NA1-homozygous cells, and a 55- to 80-Kd GP from NA2- homozygous cells. To further examine the specificity of the maternal antibody, sequential immunoprecipitation studies were performed using maternal antisera and a CD16 MoAb. After extracts of 125I surface- labeled neutrophils were precleared with maternal serum, CD16 MoAbs no longer immunoprecipitated any GP. Neither the CD16 MoAb nor a rabbit polyclonal antibody specific for FcRIII detected any GP in maternal neutrophil membranes by immunoblotting. Neutrophil FcRIII is a glycosyl- phosphatidylinositol anchored membrane GP as is decay accelerating factor and both are absent from neutrophils of patients with paroxysmal nocturnal hemoglobinuria (PNH). Maternal neutrophil membranes were probed with antibody specific for DAF and an 80-Kd GP was detected. This woman also has had no clinical evidence of PNH. These studies provide further evidence that the NA1 and NA2 antigens are on FcRIII and identify a healthy person whose neutrophils lack not only the neutrophil specific antigens NA1 and NA2 but multiple other epitopes of FcRIII and, therefore, likely lack FcRIII entirely.

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Comparison of a Multiplexed Herpes Simplex Virus Type-Specific Immunoglobulin G Serology Assay to Immunoblot, Western Blot, and Enzyme-Linked Immunosorbent Assays

Clinical and Vaccine Immunology ◽

10.1128/cvi.00351-08 ◽

2008 ◽

Vol 16 (1) ◽

pp. 55-60 ◽

Cited By ~ 12

Author(s):

Thomas B. Martins ◽

Ryan J. Welch ◽

Harry R. Hill ◽

Christine M. Litwin

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Western Blot ◽

Immunoglobulin G ◽

Multiplex Assay ◽

Specific Alternative ◽

Specific Antigens ◽

Immunosorbent Assays ◽

Simplex Virus ◽

Hsv 1

ABSTRACT The human herpes simplex virus (HSV) is highly pathogenic, with infections caused by two distinct antigenic types, HSV-1 and HSV-2. Differentiation of antibodies to these specific antigens can provide useful information for the diagnosis of subclinical or undiagnosed HSV-2 infections, as well as for reducing the risk of maternal transfer of HSV to the neonate. In this study, a multiplex assay capable of concurrent detection of HSV-1 and -2 immunoglobulin G (IgG) antibodies was compared to immunoblot, Western blot, and enzyme-linked immunosorbent assays. Agreement of the multiplex assay was 95% or greater (n = 332) for both HSV-1 and -2 compared to the three assays. Sensitivities for HSV-1 ranged from 94.9 to 97.9%, with specificities of 93 to 97%. For HSV-2, the sensitivity and specificity ranges were 92.6 to 98.9% and 98.3 to 98.7%, respectively. Our studies show that the multiplexed microsphere-based assay offers a sensitive and specific alternative method for the detection HSV-1 and -2 type-specific antibodies. Advantages of the multiplex assay include multiple results per assay, the inclusion of internal controls for each specimen, and higher throughput of results.

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Family Studies of Type II CD36 Deficient Subjects: Linkage of a CD36 Allele to a Platelet-Specific mRNA Expression Defect(s) Causing Type II CD36 Deficiency

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649809 ◽

1995 ◽

Vol 74 (02) ◽

pp. 758-763 ◽

Cited By ~ 20

Author(s):

Hirokazu Kashiwagi ◽

Yoshiaki Tomiyama ◽

Satoru Kosugi ◽

Masamichi Shiraga ◽

Robert H Lipsky ◽

...

Keyword(s):

Mrna Expression ◽

Family Studies ◽

Positive Control ◽

Type Ii ◽

Cd36 Deficiency ◽

Cd36 Expression ◽

Silent Allele ◽

Compound Heterozygotes ◽

Cd36 Gene ◽

Specific Mrna

SummaryWe performed family studies with type II CD36 deficiency. In the Mi.Y family, the proband (YII.1) and his brother (YII.2) displayed a type II deficient phenotype. In the mother(YI.2), binding of the anti CD36 monoclonal antibody, 0KM5, to both platelets and monocytes was reduced as compared to CD36 positive control cells. In the father (YI.1), while 0KM5 binding to his platelets was reduced, that of his monocytes was almost the same as normal control monocytes. Analysis of genomic DNA showed that YI.2, YII.1 and YII.2 were heterozygous for a proline90→serine mutation, and showed that both alleles of YI.1 did not have the mutation. Analysis of CD36 cDNA showed that the Pro90 form of CD36 cDNA could be detected in monocytes, but not in platelets from YII.1 and YII.2. These data indicated that YII.1 and YII.2 could be compound heterozygotes; an allele having a platelet-specific mRNA expression defect(s), which was responsible for the different CD36 expression between their platelets and monocytes, and the Ser90 allele. YI.1 was suggested to be a carrier of the platelet-specific silent allele. The platelet-specific silent allele was linked to a specific genotype of a polymorphic microsatellite sequence in the CD36 gene, supporting our hypothesis that mRNA expression defect(s) occurred at or near the CD36 gene. In a second type IICD36 deficient family, we also obtained results consistent with this hypothesis.

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Reversible Metaphyseal Dysplasia, a Novel Bone Phenotype, in Two Unrelated Children with Autoimmunepolyendocrinopathy-Candidiasis-Ectodermal Dystrophy: Clinical and Molecular Studies

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-030089 ◽

2003 ◽

Vol 88 (10) ◽

pp. 4576-4585 ◽

Cited By ~ 11

Author(s):

Mark Harris ◽

Ouafae Kecha ◽

Cheri Deal ◽

C. Rolfe Howlett ◽

Dorothee Deiss ◽

...

Keyword(s):

Endochondral Ossification ◽

Potential Role ◽

Frameshift Mutation ◽

Stop Codon ◽

Growth Failure ◽

Growth Plates ◽

Metaphyseal Dysplasia ◽

Aire Gene ◽

Calcified Cartilage ◽

Exon 10

Abstract We report the association of an undescribed, reversible metaphyseal dysplasia (RMD) with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in two patients, one homozygous and one heterozygous for a 13-bp deletion in exon 8 of the autoimmune regulator (AIRE) gene. One patient also had a novel deletion in exon 6, resulting in a frameshift mutation and introduction of a STOP codon in exon 10. Their APECED phenotypes differed, but both patients developed progressive skeletal deformities and growth failure from early childhood. Radiological examination suggested a generalized abnormality of endochondral ossification, with irregular, flared, radioopaque regions in the metaphyses, subjacent to the growth plates. Histopathology in patient 1 showed islands of calcified cartilage within bone, consistent with impaired coupling of cartilage resorption with vascular invasion and ossification. Despite discordance for puberty, both patients experienced radiological resolution of their bone disease in their mid-teens, with improvement in histopathology in patient 1. RMD may constitute a rare phenotypic variation of APECED, possibly resulting from autoimmunity directed against skeletal proteins. We also demonstrated AIRE expression in chondrocytes derived from human fetal growth plates, primary culture of human chondrocytes, and two chondrosarcoma cell lines, suggesting a potential role for abnormal AIRE expression in the development of RMD.

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Characterization of a cDNA Encoding Murine Coagulation Factor VII

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650301 ◽

1996 ◽

Vol 75 (03) ◽

pp. 481-487 ◽

Cited By ~ 13

Author(s):

Esohe Idusogie ◽

Elliot Rosen ◽

Jie-Ping Geng ◽

Peter Carmeliet ◽

Desirá Collen ◽

...

Keyword(s):

Stop Codon ◽

Coagulation Factor ◽

Factor Vii ◽

Mature Protein ◽

Reading Frame ◽

Coagulation Factor Vii ◽

Murine Liver ◽

Translation Initiation Codon ◽

Amino Acid Signal

SummaryThe cDNA encoding murine coagulation factor VII (mfVII) was isolated and reconstructed from a Λ Zap cDNA library generated from murine liver mRNA. The cDNA contains 1903 nucleotides spanning 15 bases upstream of the 5’-translation initiation codon, an open reading frame of 1338 nucleotides, 550 nucleotides downstream of the first stop codon and a 3’ poly(A) tail. The translation product is composed of a 41-amino acid signal/propeptide region followed by a 405-residue mature protein. The latter is highly homologous to that of human, rabbit, bovine, Rhesus monkey, and canine fVII. All protein domains of hfVII are strictly conserved in mfVII.

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Characterization of molecular defects of Fitzgerald trait and another novel high-molecular-weight kininogen-deficient patient: insights into structural requirements for kininogen expression

Blood ◽

10.1182/blood-2002-11-3329 ◽

2003 ◽

Vol 101 (11) ◽

pp. 4430-4436 ◽

Cited By ~ 13

Author(s):

Yelena Krijanovski ◽

Valerie Proulle ◽

Fakhri Mahdi ◽

Marie Dreyfus ◽

Werner Müller-Esterl ◽

...

Keyword(s):

Molecular Weight ◽

Amino Acid ◽

High Molecular Weight ◽

Stop Codon ◽

Premature Stop Codon ◽

Amino Acid Residues ◽

High Molecular Weight Kininogen ◽

Basilar Artery Thrombosis ◽

Domain 3 ◽

Exon 10

Abstract A 6-year-old male with vertebral-basilar artery thrombosis was recognized to have high-molecular-weight kininogen (HK) deficiency. The propositus had no HK procoagulant activity and antigen (< 1%). Using monoclonal antibodies (Mabs) to kininogen domain 3, the propositus, family members, and Fitzgerald plasma were determined to have detectable low-molecular-weight kininogen. Mabs to HK domains 5 and 6 do not detect HK antigen in the propositus' plasma. The propositus has a single base pair (bp) deletion in cDNA position 1492 of exon 10 affecting amino acid 480 of the mature protein and resulting in a frameshift and a premature stop codon at position 1597 (amino acid 532). Unexpectedly, Mabs to the heavy chain and domain 5 of HK detect a 92-kDa form of HK in Fitzgerald plasma, the first HK-deficient plasma. The 92-kDa Fitzgerald HK has amino acid residues through 502, corresponding to domains 1 through 5, but lacks epitopes of domain 6 (positions 543 to 595). Fitzgerald DNA has a normal exon 10, but a 17-bp mutation in intron 9. These combined results indicate that mutations in the kininogen gene may differentially affect biosynthesis, processing, and/or secretion of HK.

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Five new mutations in the uroporphyrinogen decarboxylase gene identified in families with cutaneous porphyria

Blood ◽

10.1182/blood.v88.9.3589.bloodjournal8893589 ◽

1996 ◽

Vol 88 (9) ◽

pp. 3589-3600 ◽

Cited By ~ 26

Author(s):

JF McManus ◽

CG Begley ◽

S Sassa ◽

S Ratnaike

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Stop Codon ◽

Porphyria Cutanea Tarda ◽

Premature Stop Codon ◽

Amino Acid Position ◽

Uroporphyrinogen Decarboxylase ◽

The Impact ◽

Exon 10 ◽

New Mutations

We describe five new mutations in the uroporphyrinogen decarboxylase (UROD) gene. All mutations were observed in conjunction with decreased erythrocyte UROD and clinical familial porphyria cutanea tarda (fPCT), (four families) or hepatoerythropoietic porphyria (HEP), (one family). The fPCT mutations included three point mutations that resulted in amino acid substitutions: a lysine to glutamine at amino acid position 253 (exon 7); a glycine to arginine at position 318 (exon 10); an isoleucine to threonine at position 334 (exon 10). The lysine to glutamine at amino acid position 253 was found in conjunction with a single C nucleotide deletion in exon 8 on the same allele of the UROD gene in the same family. This deletion resulted in a shift in the reading frame and the introduction of a premature stop codon 8 amino acids downstream. In the fourth family, a 31-bp deletion (nucleotides 828–858: exon 8) of the coding region, resulted in a frameshift and the introduction of a stop codon 19 amino acids downstream. A point mutation was observed in an individual diagnosed with HEP, resulting in an alanine to glycine change at amino acid position 80 and was present on both alleles. All mutations were confirmed in at least one other family member. The impact of these mutations on the function of the UROD protein was examined using in vitro protein expression and with activity assessed using pentacarboxylic acid porphyrinogen I as a substrate for UROD. Although three mutations reduced UROD activity to < 15% of normal, one resulted in a UROD protein with 50% functional activity and the other had near normal activity. These results indicate that many different genetic lesions of the UROD gene are associated with fPCT.

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Neonatal Alloimmune Thrombocytopenia (NATP) Associated with Maternal-Fetal Incompatibility for Blood Group B.

Blood ◽

10.1182/blood.v106.11.955.955 ◽

2005 ◽

Vol 106 (11) ◽

pp. 955-955

Author(s):

Brian R. Curtis ◽

Janice G. McFarland ◽

Andrea Fick ◽

Andrew J. Lochowicz ◽

Robert H. Ball ◽

...

Keyword(s):

Flow Cytometry ◽

Blood Group ◽

Maternal Serum ◽

Blood Group Antigens ◽

Igg Antibodies ◽

Abo Incompatibility ◽

Specific Antigens ◽

Group B ◽

Positive Direct ◽

Rbc Transfusion

Abstract In most individuals, A and B blood group antigens are weakly expressed on platelets, allowing ABO incompatible platelets to be tolerated when transfused. However, in a minority of normal subjects (high expressers, H-Exp), platelets carry 10–20 times the usual number of A or B epitopes (up to 20,000/platelet, Blood2000;96:1574). Post-transfusion survival of incompatible H-Exp platelets has not been systematically studied. We recently encountered a family in which NATP in two infants appears to have been caused by maternal anti-B reacting with H-Exp fetal platelets inherited from a father with the group B H-Exp trait. The first two children (C1 and C2) born to a G4P2 group O mother and A2B father were positive for blood group B, and had neonatal thrombocytopenia (TP) (C1 = 33K/μL, C2 = 61K/μL), anemia, positive direct antiglobulin test, elevated reticuloytes and hyperbilirubinemia requiring phototherapy. C1 required 3 platelet transfusions and RBC transfusion, and C2 required RBC transfusion. Both recovered in the immediate neonatal period. A third child (C3) inherited blood group A2 from the father and was born with a normal platelet count. The parents were incompatible for HPA-2b and -3b, but no platelet-specific antibodies were detected in maternal serum. High titer IgG antibodies were detected in maternal serum against father’s platelets in both flow cytometry and modified antigen capture ELISA. This activity was completely removed by absorption with normal, washed group B RBCs. When tested by flow cytometry with monoclonal anti-B and anti-A, the father’s platelets were shown to carry 17 times the normal level of B antigen, and only trace amounts of A antigen. We previously showed that the potent glycosyltransferase activity associated with the H-Exp trait causes essentially all H antigen on platelets and RBCs to be converted to A and/or B antigen. Consistent with this, father’s platelets and RBCs were found to express no detectable H. Quantitation of B and H antigens on platelets and RBCs from C1 and C2 is pending receipt of samples. Findings made in this family indicate that maternal anti-B (and presumably anti-A) IgG antibodies can cause NATP in infants with the ABO “high expresser” trait. Maternal-fetal ABO incompatibility should be considered as a cause of NATP when maternal antibodies against platelet-specific antigens cannot be demonstrated. The possibility that ABO incompatibility can aggravate thrombocytopenia caused by antibodies against recognized platelet-specific antigens also deserves consideration.

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Alloimmune neonatal neutropenia due to an antibody to the neutrophil Fc- gamma receptor III with maternal deficiency of CD16 antigen

Blood ◽

10.1182/blood.v77.7.1572.bloodjournal7771572 ◽

1991 ◽

Vol 77 (7) ◽

pp. 1572-1580 ◽

Cited By ~ 1

Author(s):

DF Stroncek ◽

KM Skubitz ◽

LB Plachta ◽

RA Shankar ◽

ME Clay ◽

...

Keyword(s):

Healthy Person ◽

Maternal Serum ◽

Maternal Antibody ◽

Fc Gamma Receptor ◽

Glycosyl Phosphatidylinositol ◽

Gamma Receptor ◽

Rabbit Polyclonal Antibody ◽

Specific Antigens ◽

Neonatal Neutropenia ◽

Cd16 Antigen

Antibodies to the neutrophil-specific antigens NA1 and NA2 are associated with alloimmune neonatal neutropenia (ANN), autoimmune neutropenia of childhood, and acute pulmonary transfusion reactions. These antigens have been found to be located on the neutrophil Fc-gamma receptor III (FcRIII). The mother of a child with ANN was found to lack both NA antigens and to produce an antibody that reacted with all normal neutrophils tested. We used maternal antibody and a CD16 monoclonal antibody (MoAb) that has specificity for FcRIII to immunoblot and immunoprecipitate neutrophil membranes of various NA phenotypes. Both antibodies immunoblotted an approximately 40- to 70-Kd glycoprotein (GP) on NA1, NA2-positive membrane, an approximately 40- to 55-Kd GP on NA1-homozygous membranes, and an approximately 55- to 70- Kd GP on NA2-homozygous membranes. Both antibodies also immunoprecipitated a 50- to 80-Kd GP from NA1, NA2-positive cells, a 50- to 60-Kd GP from NA1-homozygous cells, and a 55- to 80-Kd GP from NA2- homozygous cells. To further examine the specificity of the maternal antibody, sequential immunoprecipitation studies were performed using maternal antisera and a CD16 MoAb. After extracts of 125I surface- labeled neutrophils were precleared with maternal serum, CD16 MoAbs no longer immunoprecipitated any GP. Neither the CD16 MoAb nor a rabbit polyclonal antibody specific for FcRIII detected any GP in maternal neutrophil membranes by immunoblotting. Neutrophil FcRIII is a glycosyl- phosphatidylinositol anchored membrane GP as is decay accelerating factor and both are absent from neutrophils of patients with paroxysmal nocturnal hemoglobinuria (PNH). Maternal neutrophil membranes were probed with antibody specific for DAF and an 80-Kd GP was detected. This woman also has had no clinical evidence of PNH. These studies provide further evidence that the NA1 and NA2 antigens are on FcRIII and identify a healthy person whose neutrophils lack not only the neutrophil specific antigens NA1 and NA2 but multiple other epitopes of FcRIII and, therefore, likely lack FcRIII entirely.

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Transcriptome and metabolome analysis of crGART, a novel cell model of de novo purine synthesis deficiency: Alterations in CD36 expression and activity

10.1101/2020.06.23.167924 ◽

2020 ◽

Cited By ~ 1

Author(s):

Randall C Mazzarino ◽

Veronika Baresova ◽

Marie Zikánová ◽

Nathan Duval ◽

Terry G. Wilkinson ◽

...

Keyword(s):

Cell Line ◽

De Novo ◽

Cell Model ◽

Growth Conditions ◽

Second Step ◽

Metabolome Analysis ◽

Purine Synthesis ◽

Cd36 Expression ◽

Cluster Of Differentiation ◽

Cd36 Gene

ABSTRACTIn humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). 5-PRA is extremely unstable under physiological conditions and is unlikely to accumulate in the absence of GART activity. Recently, a HeLa cell line null mutant for GART was constructed via CRISPR-Cas9 mutagenesis. This cell line, crGART, is an important cellular model of DNPS inactivation that does not accumulate DNPS pathway intermediates. In the current study, we characterized the crGART versus HeLa transcriptomes in purine-supplemented and purine-depleted growth conditions. We observed multiple transcriptome changes and discuss pathways and ontologies particularly relevant to Alzheimer disease and Down syndrome. We also report initial analysis of the Cluster of Differentiation (CD36) gene, which is highly expressed in crGART versus HeLa.

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