Discontinuation of fucose therapy in LADII causes rapid loss of selectin ligands and rise of leukocyte counts

Blood ◽  
2001 ◽  
Vol 97 (1) ◽  
pp. 330-332 ◽  
Author(s):  
Kerstin Lühn ◽  
Thorsten Marquardt ◽  
Erik Harms ◽  
Dietmar Vestweber
Keyword(s):  
Leukocyte Adhesion ◽  
Leukocyte Adhesion Deficiency ◽  
Rapid Loss ◽  
Selectin Ligands ◽  
Ligand Expression ◽  
Selectin Ligand ◽  
Carbohydrate Ligands ◽  
Leukocyte Counts ◽  
Deficiency Type ◽  
Peripheral Neutrophil

Abstract Leukocyte adhesion deficiency type II (LADII) is a rare inherited disorder of fucose metabolism. Patients with LADII lack fucosylated glycoconjugates, including the carbohydrate ligands of the selectins, leading to an immunodeficiency caused by the lack of selectin-mediated leukocyte-endothelial interactions. A simple and effective therapy has recently been described for LADII, based on the administration of oral fucose. Parallel to this treatment the lack of E- and P-selectin ligands on neutrophils was corrected, and high peripheral neutrophil counts were reduced to normal levels. This study reports that discontinuation of this therapy leads to the complete loss of E-selectin ligands within 3 days and of P-selectin ligands within 7 days. Peripheral neutrophil counts increased parallel to the decrease of selectin ligands. Selectin ligands reappeared promptly after resumption of the fucose therapy, demonstrating a causal relationship between fucose treatment and selectin ligand expression and peripheral neutrophil counts.

Correction of Leukocyte Adhesion Deficiency Type II With Oral Fucose

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 3976-3985 ◽  
Author(s):  
Thorsten Marquardt ◽  
Kerstin Lühn ◽  
Geetha Srikrishna ◽  
Hudson H. Freeze ◽  
Erik Harms ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Culture Medium ◽  
Leukocyte Adhesion ◽  
Effective Therapy ◽  
Type Ii ◽  
Leukocyte Adhesion Deficiency ◽  
Oral Supplementation ◽  
Selectin Ligands ◽  
Deficiency Type ◽  
Core Fucosylation

Abstract We describe a simple, noninvasive, and effective therapy for leukocyte adhesion deficiency type II (LAD II), a rare inherited disorder of fucose metabolism. This disorder leads to an immunodeficiency caused by the absence of carbohydrate-based selectin ligands on the surface of neutrophils as well as to severe psychomotor and mental retardation. The fucosylation defect in LAD II fibroblasts can be corrected by addition of L-fucose to the culture medium. This prompted us to initiate dietary fucose therapy on a patient with LAD II. Oral supplementation of fucose in this patient induced the expression of fucosylated selectin ligands on neutrophils and core fucosylation of serum glycoproteins. During 9 months of treatment, infections and fever disappeared, elevated neutrophil counts returned to normal, and psychomotor capabilities improved.

scholarly journals CD44 is a physiological E-selectin ligand on neutrophils

2005 ◽  
Vol 201 (8) ◽  
pp. 1183-1189 ◽  
Author(s):  
Yoshio Katayama ◽  
Andrés Hidalgo ◽  
Jungshan Chang ◽  
Anna Peired ◽  
Paul S. Frenette
Keyword(s):  
Posttranslational Modifications ◽  
Leukocyte Adhesion ◽  
Binding Activity ◽  
Polymorphonuclear Neutrophil ◽  
Selectin Ligands ◽  
Selectin Family ◽  
Selectin Ligand ◽  
Human Pmns ◽  
Deficiency Type

The selectin family of adhesion molecules and their glycoconjugated ligands are essential for blood polymorphonuclear neutrophil (PMN) extravasation into inflammatory and infectious sites. However, E-selectin ligands on PMNs are not well characterized. We show here that CD44 immunopurified from G-CSF–differentiated 32D cells or from peripheral blood PMNs binds specifically to E-selectin. In contrast, CD44 extracted from bone marrow stromal or brain endothelial cell lines does not interact with E-selectin, suggesting cell-specific posttranslational modifications of CD44. PMN-derived CD44 binding activity is mediated by sialylated, α(1,3) fucosylated, N-linked glycans. CD44 enables slow leukocyte rolling on E-selectin expressed on inflamed endothelium in vivo and cooperates with P-selectin glycoprotein ligand–1 to recruit neutrophils into thioglycollate-induced peritonitis and staphylococcal enterotoxin A–injected skin pouch. CD44 extracted from human PMNs also binds to E-selectin. Moreover, we demonstrate that CD44 is hypofucosylated in PMNs from a patient with leukocyte adhesion deficiency type II, suggesting that it contributes to the syndrome. These findings thus suggest broader roles for CD44 in the innate immune response and uncover a potential new target for diseases in which selectins play a prominent role.

Correction of Leukocyte Adhesion Deficiency Type II With Oral Fucose

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 3976-3985 ◽  
Author(s):  
Thorsten Marquardt ◽  
Kerstin Lühn ◽  
Geetha Srikrishna ◽  
Hudson H. Freeze ◽  
Erik Harms ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Culture Medium ◽  
Leukocyte Adhesion ◽  
Effective Therapy ◽  
Type Ii ◽  
Leukocyte Adhesion Deficiency ◽  
Oral Supplementation ◽  
Selectin Ligands ◽  
Deficiency Type ◽  
Core Fucosylation

We describe a simple, noninvasive, and effective therapy for leukocyte adhesion deficiency type II (LAD II), a rare inherited disorder of fucose metabolism. This disorder leads to an immunodeficiency caused by the absence of carbohydrate-based selectin ligands on the surface of neutrophils as well as to severe psychomotor and mental retardation. The fucosylation defect in LAD II fibroblasts can be corrected by addition of L-fucose to the culture medium. This prompted us to initiate dietary fucose therapy on a patient with LAD II. Oral supplementation of fucose in this patient induced the expression of fucosylated selectin ligands on neutrophils and core fucosylation of serum glycoproteins. During 9 months of treatment, infections and fever disappeared, elevated neutrophil counts returned to normal, and psychomotor capabilities improved.

scholarly journals A crucial role for T-bet in selectin ligand expression in T helper 1 (Th1) cells

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3867-3873 ◽  
Author(s):  
Greg H. Underhill ◽  
Dimitrios G. Zisoulis ◽  
K. Pallav Kolli ◽  
Lesley G. Ellies ◽  
Jamey D. Marth ◽  
...  
Keyword(s):  
Interleukin 12 ◽  
Th1 Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Th1 Cell ◽  
Selectin Ligands ◽  
Ligand Expression ◽  
Selectin Ligand ◽  
Carbohydrate Ligands ◽  
Transcriptional Pathway

Proinflammatory T helper 1 (Th1) cells express high levels of carbohydrate ligands for the endothelial selectins, but the molecular basis for this phenotype is incompletely understood. We document here a significant role in selectin ligand formation for the recently described Th1 transcription factor T-bet. Th1 cells generated from T-bet-/- mice showed significantly lower levels of ligands for both E-selectin and P-selectin, compared with wild-type (WT) Th1 cells. Enforced expression of T-bet in WT Th0 cells only modestly up-regulated P-selectin ligands and had no effect on E-selectin ligands. To define a mechanism for the defects observed in T-bet-/- mice, we examined expression of glycosyltransferases involved in selectin ligand biosynthesis. T-bet-/- Th1 cells expressed significantly lower levels of core 2 β1,6 N-acetylglucosaminyltransferase I (C2GlcNAcT-I), but no differences in levels of α 2,3-sialyltransferase IV (ST3Gal-IV). Further, we show that T-bet is responsible for the signal transducer and activator of transcription 4 (Stat4)–independent increase in Th1 cells of fucosyltransferase VII (FucT-VII). We also identify ST3Gal-VI, which is thought to play an important role in E- and P-selectin ligand formation, as an interleukin 12 (IL-12)–regulated, T-bet–dependent gene. These data show that T-bet controls selectin ligand formation in Th1 cells via control of expression of multiple key enzymes in response to IL-12 signaling and establishes an independent transcriptional pathway for control of Th1 cell traffic.

Unique CD18 mutations involving a deletion in the extracellular stalk region and a major truncation of the cytoplasmic domain in a patient with leukocyte adhesion deficiency type 1

Blood ◽  
2004 ◽  
Vol 103 (3) ◽  
pp. 1105-1113 ◽  
Author(s):  
Patricia Hixson ◽  
C. Wayne Smith ◽  
Susan B. Shurin ◽  
Michael F. Tosi
Keyword(s):  
Leukocyte Adhesion ◽  
Cytoplasmic Domain ◽  
Lymphocyte Function ◽  
Wild Type ◽  
Leukocyte Adhesion Deficiency ◽  
Binding Function ◽  
Domain Truncation ◽  
Low Levels ◽  
Deficiency Type

AbstractTwo novel CD18 mutations were identified in a patient who was a compound heterozygote with type 1 leukocyte adhesion deficiency and whose phenotype was typical except that he exhibited hypertrophic scarring. A deletion of 36 nucleotides in exon 12 (1622del36) predicted the net loss of 12 amino acid (aa) residues in the third cysteine-rich repeat of the extracellular stalk region (mut-1). A nonsense mutation in exon 15 (2200G>T), predicted a 36-aa truncation of the cytoplasmic domain (mut-2). Lymphocyte function-associated antigen 1 (LFA-1) and macrophage antigen-1 (Mac-1) containing the mut-1 β2 subunit were expressed at very low levels compared with wild-type (wt) β2. Mac-1 and LFA-1 expression with the mut-2 β2 subunit were equivalent to results with wt β2. Binding function of Mac-1 with mut-2 β2 was equivalent to that with wt β2. However, binding function of LFA-1 with the mut-2 β2 subunit was reduced by 50% versus wt β2. It was concluded that (1) the portion of the CD18 stalk region deleted in mut-1 is critical for β2 integrin heterodimer expression but the portion of the cytoplasmic domain truncated in mut-2 is not; and (2) the mut-2 cytoplasmic domain truncation impairs binding function of LFA-1 but not of Mac-1. Studies with the patient's neutrophils (PMNs) were consistent with functional impairment of LFA-1 but not of Mac-1. (Blood. 2004;103:1105-1113)

scholarly journals Case Report: A Case of Leukocyte Adhesion Deficiency, Type III Presenting With Impaired Platelet Function, Lymphocytosis and Granulocytosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Amal M. Yahya ◽  
Asia A. AlMulla ◽  
Haydar J. AlRufaye ◽  
Ahmed Al Dhaheri ◽  
Abdulghani S. Elomami ◽  
...  
Keyword(s):  
Platelet Function ◽  
Leukocyte Adhesion ◽  
Compound Heterozygous ◽  
Type I ◽  
Leukocyte Adhesion Deficiency ◽  
Persistent Lymphocytosis ◽  
Type Iii ◽  
Fibrinogen Receptor ◽  
Primary Hemostasis ◽  
Deficiency Type

Fermitin family homolog 3 (FERMT3), alternatively kindlin-3 (KIND3), is an integrin binding protein (of 667 residues) encoded by the FERMT3 gene. The molecule is essential for activating integrin αIIbβ3 (the fibrinogen receptor) on platelets and for the integrin-mediated hematopoietic cell (including platelets, T lymphocytes, B lymphocytes, and granulocytes) adhesion. Its defects are associated with impaired primary hemostasis, described as “Glanzmann's thrombasthenia (MIM#273800)-like bleeding problem.” The defects are also associated with infections, designated as “LAD1 (leukocyte adhesion deficiency, type I; MIM#116920)-like immune deficiency.” The entity that joins the impaired primary hemostasis with the leukocyte malfunction has been termed “leukocyte adhesion deficiency, type III” (LAD3, autosomal recessive, MIM#612840), representing a defective activation of the integrins β1, β2, and β3 on leukocytes and platelets. Here, we report a male toddler with novel compound heterozygous variants, NM_178443.2(FERMT3):c.1800G>A, p.Trp600* (a non-sense variant) and NM_178443.2(FERMT3):c.2001del p.*668Glufs*106 (a non-stop variant). His umbilical cord separated at about 3 weeks of age. A skin rash (mainly petechiae and purpura) and recurrent episodes of severe epistaxis required blood transfusions in early infancy. His hemostatic work-up was remarkable for a normal platelet count, but abnormal platelet function screen with markedly prolonged collagen-epinephrine and collagen-ADP closure times. The impaired platelet function was associated with reduced platelet aggregation with all agonists. The expression of platelet receptors was normal. Other remarkable findings were persistent lymphocytosis and granulocytosis, representing defects in diapedesis due to the integrin dysfunction. The natural history of his condition, structure and sequence analysis of the variations, and comparison with other LAD3 cases reported in the literature are presented.

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