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1.
Hematol Oncol Clin North Am ; 29(3): 495-507, 2015 Jun.
Article in English | MEDLINE | ID: mdl-26043388

ABSTRACT

The severe clinical symptoms of inherited CD59 deficiency confirm the importance of CD59 as essential complement regulatory protein for protection of cells against complement attack, in particular protection of hematopoietic cells and human neuronal tissue. Targeted complement inhibition might become a treatment option as suggested by a case report. The easy diagnostic approach by flow cytometry and the advent of a new treatment option should increase the awareness of this rare differential diagnosis and lead to further studies on their pathophysiology.


Subject(s)
Anemia, Hemolytic/immunology , CD59 Antigens/immunology , Complement System Proteins/immunology , Hemoglobinuria/immunology , Mutation/immunology , Anemia, Hemolytic/diagnosis , Anemia, Hemolytic/prevention & control , Animals , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , CD59 Antigens/genetics , CD59 Antigens/metabolism , Complement System Proteins/metabolism , Flow Cytometry , Hemoglobinuria/diagnosis , Hemoglobinuria/prevention & control , Humans , Models, Immunological , Mutation/genetics , Protein Binding/drug effects , Protein Binding/immunology
2.
Infez Med ; 23(1): 74-8, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25819056

ABSTRACT

A 25-year-old man developed macroscopic haemoglobinuria after a persistent dry cough. Although chest radiograph findings were normal, since the serum antibody for Mycoplasma pneumoniae was significantly elevated, a diagnosis infection with this organism was made. Despite the absence of apparent anaemia, a marked increase in serum haemolytic markers and positive result for urine haemoglobin indicated the haemolysis of red blood cells, which was likely to have occurred secondarily to M. pneumoniae infection. Shortly after the initiation of a macrolide antibiotic, clarithromycin, the patient's haemoglobinuria completely disappeared together with a complete resolution of his respiratory symptoms. In this case, due to the lymphocyte-stimulatory nature of M. pneumoniae, an enhanced immune response, such as the production of cold agglutinins, was likely to be involved in the pathogenesis of erythrocyte haemolysis. The immunomodulatory property of clarithromycin was thought to repress the increased immunological reaction and thus enable the resolution of the urine abnormality.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Clarithromycin/therapeutic use , Hemoglobinuria/etiology , Immunosuppressive Agents/therapeutic use , Mycoplasma Infections/complications , Mycoplasma Infections/drug therapy , Mycoplasma pneumoniae/drug effects , Adult , Biomarkers/blood , Cryoglobulins/metabolism , Hemoglobinuria/immunology , Hemoglobinuria/microbiology , Humans , Male , Mycoplasma Infections/immunology , Mycoplasma pneumoniae/immunology , Treatment Outcome
3.
Mol Immunol ; 67(1): 51-5, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25818314

ABSTRACT

CD59 encodes a 77 amino acid glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein that inhibits the final step of membrane attack complex (MAC) formation. CD59 deficiency is a common finding in adult patients with paroxysmal nocturnal hemoglobinuria (PNH). In this condition, there is a clonal expansion of hematopoietic stem cells that have acquired a mutation in the PIGA gene (phosphatidylinositol glycan anchor biosynthesis, class A). PIGA encodes a GPI biosynthesis protein, phosphatidylinositol N-acetylglucosaminyltransferase subunit A, and erythrocytes deficient in GPI-anchored membrane proteins, including CD59, undergo complement-mediated hemolysis. We have recently described a primary homozygous Cys89Tyr CD59 deficiency in humans that resulted in the amino acid substitution p.Cys89Tyr with resulting failure of proper localization of the CD59 protein to the cell surface. The Cys89Tyr mutation in CD59 was clinically manifested in infancy, and associated with chronic hemolysis and relapsing peripheral demyelinating disease resembling recurrent Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP). In this review we describe differences and similarities in the pathogenesis and clinical manifestations of PNH and primary CD59 Cys89Tyr mutation with the aim of tracking the contribution of CD59 deficiency to the pathophysiology and perhaps deepening our understanding of both diseases.


Subject(s)
Anemia, Hemolytic/pathology , CD59 Antigens/immunology , Hemoglobinuria, Paroxysmal/pathology , Hemoglobinuria/pathology , Membrane Proteins/immunology , Anemia, Hemolytic/diagnosis , Anemia, Hemolytic/genetics , Anemia, Hemolytic/immunology , CD59 Antigens/genetics , Cell Proliferation , Clone Cells , Diagnosis, Differential , Erythrocytes/chemistry , Erythrocytes/immunology , Erythrocytes/pathology , Gene Expression , Hematopoietic Stem Cells/immunology , Hematopoietic Stem Cells/pathology , Hemoglobinuria/diagnosis , Hemoglobinuria/genetics , Hemoglobinuria/immunology , Hemoglobinuria, Paroxysmal/diagnosis , Hemoglobinuria, Paroxysmal/genetics , Hemoglobinuria, Paroxysmal/immunology , Hemolysis/immunology , Homozygote , Humans , Membrane Proteins/genetics , Mutation
4.
J Autoimmun ; 53: 67-77, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24698947

ABSTRACT

Spinal cord pathology with inflammatory, demyelinating lesions spanning three or more vertebral segments is a characteristic feature of neuromyelitis optica (NMO). NMO pathogenesis is thought to involve binding of immunoglobulin G anti-aquaporin-4 autoantibodies (NMO-IgG) to astrocytes, causing complement-dependent cytotoxicity (CDC) and secondary inflammation, demyelination and neuron loss. We investigated the involvement of CD59, a glycophosphoinositol (GPI)-anchored membrane protein on astrocytes that inhibits formation of the terminal C5b-9 membrane attack complex. CD59 inhibition by a neutralizing monoclonal antibody greatly increased NMO-IgG-dependent CDC in murine astrocyte cultures and ex vivo spinal cord slice cultures. Greatly increased NMO pathology was also found in spinal cord slice cultures from CD59 knockout mice, and in vivo following intracerebral injection of NMO-IgG and human complement. Intrathecal injection (at L5-L6) of small amounts of NMO-IgG and human complement in CD59-deficient mice produced robust, longitudinally extensive white matter lesions in lumbar spinal cord. Pathology was most severe at day 2 after injection, showing loss of AQP4 and GFAP, C5b-9 deposition, microglial activation, granulocyte infiltration, and demyelination. Hind limb motor function was remarkably impaired as well. There was partial remyelination and recovery of motor function by day 5. Our results implicate CD59 as an important modulator of the immune response in NMO, and provide a novel animal model of NMO that closely recapitulates human NMO pathology. Up-regulation of CD59 on astrocytes may have therapeutic benefit in NMO.


Subject(s)
Anemia, Hemolytic/immunology , CD59 Antigens/immunology , Hemoglobinuria/immunology , Immunoglobulin G/toxicity , Neuromyelitis Optica/immunology , Spinal Cord/immunology , Anemia, Hemolytic/genetics , Anemia, Hemolytic/pathology , Animals , Aquaporin 4/genetics , Aquaporin 4/immunology , Astrocytes/immunology , Astrocytes/pathology , CD59 Antigens/genetics , Cells, Cultured , Complement Membrane Attack Complex/genetics , Complement Membrane Attack Complex/immunology , Disease Models, Animal , Glial Fibrillary Acidic Protein , Hemoglobinuria/genetics , Hemoglobinuria/pathology , Humans , Immunoglobulin G/immunology , Mice , Mice, Knockout , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/immunology , Neuromyelitis Optica/chemically induced , Neuromyelitis Optica/genetics , Neuromyelitis Optica/pathology , Spinal Cord/pathology
6.
Transfusion ; 54(7): 1817-22, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24383981

ABSTRACT

BACKGROUND: CD59 is a cell surface glycoprotein of approximately 20 kDa limiting the lytic activity of the terminal complement complex C5b-9. Although CD59 is known as a red blood cell (RBC) antigen defined by monoclonal antibodies, it so far has not been identified as a blood group antigen, since the description of a human alloantibody was missing. In this study we show the presence of an anti-CD59 in a patient affected by a homozygous CD59 deficiency. STUDY DESIGN AND METHODS: RBC CD59 and CD55 were determined by flow cytometry or by the column agglutination technique using monoclonal antisera. Commercially available His-tagged recombinant soluble CD59 protein was used to inhibit anti-CD59. RESULTS: Seven cases of an isolated CD59 deficiency due to three distinct null alleles of the CD59 gene have been published so far. Recently we described the CD59-null allele c.146delA in a young child of heterozygous parents. Her plasma contained an alloantibody directed against the high-prevalence RBC antigen CD59. The antibody specificity was identified using soluble recombinant human CD59 protein, which blocked the reactivity of the patient's antibody and of monoclonal anti-CD59 but not of monoclonal anti-CD55. In addition, RBC alloantibodies such as anti-K, anti-C, anti-c, or anti-Fy(a) remained unaffected. Therefore, inhibition by recombinant CD59 is a useful diagnostic tool to detect alloantibodies in the presence of anti-CD59. CONCLUSION: This is the first demonstration of a human anti-CD59 alloantibody, which defines CD59 as an RBC blood group antigen. CD59 represents a candidate for a new blood group system.


Subject(s)
Anemia, Hemolytic/immunology , Blood Group Antigens/immunology , CD59 Antigens/immunology , Hemoglobinuria/immunology , Isoantibodies/blood , Anemia, Hemolytic/genetics , Blood Group Antigens/genetics , CD59 Antigens/genetics , Child, Preschool , Female , Frameshift Mutation , Hemoglobinuria/genetics , Humans
7.
J Immunol ; 189(11): 5434-41, 2012 Dec 01.
Article in English | MEDLINE | ID: mdl-23109726

ABSTRACT

CD59 is a GPI-anchored membrane regulator of complement expressed on blood cells as well as peripheral tissues. It protects host cells from complement injury by inhibiting formation of the membrane attack complex. Recent studies in mice have suggested also a role of CD59 in T cell immune response that was mechanistically independent of complement. In the present study, we investigated the function of CD59 in the MRL/lpr model of murine lupus. We backcrossed the Cd59a knockout (Cd59a(-/-)) mouse onto the MRL/lpr background and compared Cd59a(+/+)-MRL/lpr and Cd59a(-/-)-MRL/lpr littermates for the development of systemic autoimmunity. We found that CD59a deficiency significantly exacerbated the skin disease and lymphoproliferation characteristic of MRL/lpr mice. It also increased autoantibody titers and caused a higher level of proteinuria in male MRL/lpr mice. Bone marrow transfer experiments indicated that CD59a expression on both bone marrow-derived cells and peripheral tissues played a role in lymphoproliferation, whereas the skin disease phenotype is determined mainly by local CD59a expression. Importantly, C3 gene deletion or C5 neutralization with a blocking mAb in Cd59a(-/-)-MRL/lpr mice did not rescue the proautoimmune phenotype associated with CD59a deficiency. These results together suggest that CD59a inhibits systemic autoimmunity in MRL/lpr mice through a complement-independent mechanism.


Subject(s)
Autoantibodies/biosynthesis , Autoimmunity , CD59 Antigens/immunology , Lupus Erythematosus, Systemic/immunology , Anemia, Hemolytic/genetics , Anemia, Hemolytic/immunology , Animals , Antibodies/pharmacology , CD59 Antigens/genetics , Complement C3/deficiency , Complement C3/genetics , Complement C3/immunology , Complement C5/antagonists & inhibitors , Complement C5/genetics , Complement C5/immunology , Dermatitis/genetics , Dermatitis/immunology , Dermatitis/pathology , Female , Gene Expression , Hemoglobinuria/genetics , Hemoglobinuria/immunology , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/pathology , Male , Mice , Mice, Inbred MRL lpr , Mice, Knockout , Proteinuria/genetics , Proteinuria/immunology , Proteinuria/pathology , Sex Factors , Skin/immunology , Skin/pathology , T-Lymphocytes/immunology , T-Lymphocytes/pathology
8.
Immunohematology ; 27(3): 83-8, 2011.
Article in English | MEDLINE | ID: mdl-22462101

ABSTRACT

AnWj is a high-incidence antigen present on the red blood cells (RBCs) of greater than 99 percent of the general population. A 58-year-old man underwent autologous hematopoietic stem cell transplantation (HSCT) for stage IVa mantle cell lymphoma. This procedure was complicated by failure to engraft, necessitating ongoing support with blood components. After a 2-month period of uneventful transfusion support, the patient experienced increasingly severe reactions with fever and evidence of intravascular hemolysis, including hemoglobinuria. Testing revealed a complement-dependent anti-AnWj. Phenotyping confirmed the AnWj- phenotype. Anti-AnWj was persistent despite immunosuppression, including treatment with allogeneic HSCT. Of interest, the pathogenesis of the downregulation of the graft AnWj in this patient is unclear.


Subject(s)
Blood Group Antigens/immunology , Complement System Proteins/immunology , Erythrocytes/immunology , Graft Rejection/immunology , Hematopoietic Stem Cell Transplantation , Lymphoma, Mantle-Cell/therapy , Antibodies/metabolism , Antibody-Dependent Cell Cytotoxicity , Erythrocyte Transfusion , Hemoglobinuria/immunology , Hemolysis/immunology , Humans , Immunosuppression Therapy , Male , Middle Aged , Postoperative Complications/immunology
10.
Blood ; 95(8): 2523-9, 2000 Apr 15.
Article in English | MEDLINE | ID: mdl-10753830

ABSTRACT

Rh(o)(D) immune globulin intravenous (anti-D IGIV) was licensed by the United States Food and Drug Administration (FDA) in March 1995 to treat patients with immune thrombocytopenic purpura (ITP). Anti-D IGIV induces extravascular hemolysis, an expected adverse reaction that is consistent with the presumed mechanism of action. Between licensure and April 1999, the FDA received 15 reports of hemoglobinemia and/or hemoglobinuria following anti-D IGIV administration that met the case definition for this review. The mechanism responsible for hemoglobinemia and/or hemoglobinuria is unexplained. Review of these reports was prompted by the seriousness and the unexpectedness of treatment-associated sequelae experienced by 11 patients. Of these patients, 7 developed sufficient onset or exacerbation of anemia that orders were written for packed red blood cell transfusions, although only 6 patients were transfused. Eight patients experienced the onset or exacerbation of renal insufficiency, and 2 patients underwent dialysis. One patient died due to complications of exacerbated anemia. Six patients experienced 2 to 3 sequelae. Absent validated incidence data, a 1.5% estimated incidence rate from published clinical trial data and a 0.1% estimated reporting rate from FDA and drug utilization data were calculated for reported cases of hemoglobinemia and/or hemoglobinuria. This review presents the first case series of anti-D-IGIV-associated hemoglobinemia and/or hemoglobinuria and provides pretreatment and posttreatment clinical and laboratory findings of the case series patients. The primary purpose of this review is to increase awareness of this potentially serious occurrence among physicians and health care professionals who manage ITP patients treated with anti-D IGIV, thereby enabling prompt recognition and treatment of sequelae. (Blood. 2000;95:2523-2529)


Subject(s)
Hemoglobins/deficiency , Hemoglobinuria/chemically induced , Immunoglobulins, Intravenous/adverse effects , Isoantibodies/administration & dosage , Isoantibodies/adverse effects , Purpura, Thrombocytopenic/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Hemoglobinuria/immunology , Humans , Male , Purpura, Thrombocytopenic/blood , Purpura, Thrombocytopenic/immunology , Rho(D) Immune Globulin
12.
Monatsschr Kinderheilkd ; 137(12): 785-6, 1989 Dec.
Article in German | MEDLINE | ID: mdl-2628748

ABSTRACT

We report the case of a two-year-old boy, who presented with two episodes of severe abdominal pain and consecutive macrohematuria after he had been outside the house at very low temperatures. The cause of this was found to be acute hemolytic anemia with hemoglobinuria, induced by a cold reacting Donath-Landsteiner autoantibody. After a few days parameters of hemolysis had normalized, hemoglobin levels were within the normal range after 4 weeks. Eight months later the Donath-Landsteiner autoantibody could not be detected any more, the boy is healthy since then.


Subject(s)
Anemia, Hemolytic, Autoimmune/immunology , Autoantibodies/analysis , Cold Temperature/adverse effects , Erythrocytes/immunology , Hemoglobinuria/immunology , Anemia, Hemolytic, Autoimmune/diagnosis , Child, Preschool , Humans , Male
14.
Rev. chil. pediatr ; 58(3): 241-3, mayo-jun. 1987. tab
Article in Spanish | LILACS | ID: lil-58701

ABSTRACT

Diez días después del comienzo de molestias sugerentes de infección respiratoria alta viral, un paciente de 11 meses tuvo síntomas, signos y evidencia de laboratorio, de anemia hemolítica y hemoglobinuria que pudieron relacionarse con la exposición al frío. El estudio inmunológico demostró que en su sangre había anticuerpos de Donath-Landsteiner con actividad contra antígeno P. La hemólisis pudo ser controlada manteniendo al paciente en un ambiente calefaccionado


Subject(s)
Infant , Humans , Male , Cold Temperature/adverse effects , Hemoglobinuria/etiology , Autoantibodies/analysis , Coombs Test , Hemoglobinuria/immunology , Hemolysin Proteins/analysis , Hemolysis
17.
Rev Fr Transfus Immunohematol ; 29(1): 5-12, 1986 Feb.
Article in French | MEDLINE | ID: mdl-3715313

ABSTRACT

90 serum samples from patients with cold agglutinin syndrome were tested for the presence of complement dependent hemolysins, against normal donor red cells versus red cells from patients with paroxysmal nocturnal hemoglobinuria. Hemolysins could be found only in 50% of samples in the first but in up to 95% of samples in the second test configuration. The difference in sensitivity was still more pronounced when protease untreated red cells were used: 1 weak versus 64 strong reactions. The high performance of PNH red cells in detecting hemolysins is specifically observable in any patient with this disease, and should be utilized as a useful diagnostic tool to reveal hemolysins otherwise undetectable by conventional immunohematologic methods.


Subject(s)
Erythrocytes/immunology , Hemoglobinuria, Paroxysmal/blood , Hemolysin Proteins/analysis , Complement System Proteins/immunology , Hemoglobinuria/immunology , Humans , Reference Values
19.
CRC Crit Rev Clin Lab Sci ; 9(1): 49-83, 1978.
Article in English | MEDLINE | ID: mdl-401365

ABSTRACT

The clinical and hematological features of a rare autoimmune disorder, PCH, are reviewed. Based on the case reports of 24 patients suffering from this disease, the presence of cold hemolysins in the sera of these patients as the main cause for the red cell destruction following exposure to cold is further discussed. However, recent electron microscope and biochemical studies suggest, in addition, that alterations of the red cells, and especially of their membranes, may play a role in the hemolytic process. The role of other factors, such as thermal range, specificity, and the immunological properties of the Donath-Landsteiner antibodies, as well as the role of the complement in the cold and warm phase of the Donath-Landsteiner reaction, is discussed. The differential diagnosis between PCH and the closely related CHD is outlined. While most of the reports deal with the mechanism of red cell destruction, relatively little attention is given to the treatment of the disease. It appears that the oldest remedy, i.e., warming of the patient and prevention of his exposure to cold, remains the best.


Subject(s)
Cold Temperature/adverse effects , Hemoglobinuria/etiology , Adult , Aged , Anemia, Hemolytic, Autoimmune/etiology , Anemia, Hemolytic, Autoimmune/immunology , Autoimmune Diseases/etiology , Autoimmune Diseases/immunology , Child , Erythrocytes/immunology , Erythrocytes/ultrastructure , Hemoglobinuria/immunology , Hemoglobinuria/pathology , Hemolysin Proteins/immunology , Humans
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