RARE DISEASE
Leukocyte adhesion deficiency type II
Leukocyte adhesion deficiency type II
Leukocyte adhesion deficiency type II
Synonyms: CDG syndrome type IIc, CDG-IIc, CDG2C, LAD-II, Rambam-Hasharon syndrome, SLC35C1-CDG
Synonyms: CDG syndrome type IIc, CDG-IIc, CDG2C, LAD-II, Rambam-Hasharon syndrome, SLC35C1-CDG
Synonyms: CDG syndrome type IIc, CDG-IIc, CDG2C, LAD-II, Rambam-Hasharon syndrome, SLC35C1-CDG
Drug discovery
1
drug
With orphan designation
Overview
Leukocyte adhesion deficiency type II (LAD II) is a rare autosomal recessive immunodeficiency caused by SLC35C1 gene mutations, leading to defective GDP-fucose transport and impaired fucosylation of glycoconjugates. This disrupts selectin ligand synthesis, resulting in neutrophilia, recurrent bacterial infections (e.g., pneumonia, periodontitis), Bombay blood phenotype, severe growth retardation, and intellectual disability [2][4][10]. Infections typically decrease after age 3, but developmental and growth deficits persist [2][11]. Diagnosis involves flow cytometry (CD15 deficiency), blood typing, and genetic testing [4][10].
Burden
Chronic infections and periodontal disease impair quality of life; developmental delays require lifelong multidisciplinary care [2][10].
Economic burden from recurrent hospitalizations and specialized care [10].
Mortality is lower than in LAD I/III, with survival into adulthood possible with infection management [10][14].
Therapies
Antibiotics: Prophylactic or acute use to manage infections [11][14].
Oral fucose supplementation: Restores neutrophil fucosylation and reduces infections in some patients, though efficacy varies [3][8][14].
Hematopoietic stem cell transplantation (HSCT): Curative but limited data; reserved for severe cases due to variable outcomes [11][14].
Categories: rare genetic diseases, rare immunological diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
47 drug discovery papers about Leukocyte adhesion deficiency type II, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
47 drug discovery papers about Leukocyte adhesion deficiency type II, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2022-06-14 | Defining the mild variant of leukocyte adhesion deficiency type II (SLC35C1-congenital disorder of glycosylation) and response to l-fucose therapy: Insights from two new families and review of the literature.
Leukocyte adhesion deficiency type II (LAD II, also known as SLC35C1-congenital disorder of glycosylation) is an autosomal recessive disorder characterized by growth and cognitive impairment, peripheral neutrophilia, recurrent infections, and the Bombay blood phenotype. A subset of patients with a milder presentation has been described with short stature and developmental delay but minimal immune and hematologic features. Some patients with LAD II benefit from oral fucose therapy, though this has not been previously studied in patients with milder disease. In this study, we describe two new patients from separate families with the milder variant of LAD II and review the published literature on this rare disorder. We demonstrate improvement in speech and cognition, CD15 expression, and core fucosylation of serum glycoproteins after 27 months of oral fucose supplementation in one patient. These patients further support the stratification of this disorder into distinct subtypes, a classical severe and an attenuated variant, and provide preliminary evidence of benefit of fucose therapy in the latter group.
2005-04-11 | CD44 is a physiological E-selectin ligand on neutrophils
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.
1995-09-01 | A central role for microvillous receptor presentation in leukocyte adhesion under flow
Leukocyte adhesion to endothelium requires specialized mechanisms for contact initiation under flow. L-selectin (CD62L), an efficient initiator of adhesion, is clustered on the tips of leukocyte microvilli. To test whether microvillous presentation is critical for contact formation ("tethering"), we transfected lymphoid cells with chimeras of L-selectin and CD44, an adhesion molecule that is excluded from microvilli. CD44 transmembrane and intracellular (TM-IC) domains targeted the L-selectin ectodomain to the planar body, whereas L-selectin TM-IC segments conferred CD44 ectodomain clustering on microvilli. Wild-type and chimeric transfectants bound similarly to anti-ectodomain MAbs in static assays, but MAb binding under flow was much more efficient in the context of microvillous presentation. Similarly, wild-type and chimeric L-selectin possessed equivalent lectin activity, but microvillous presentation dramatically enhanced contact initiation on a native ligand. These findings demonstrate a critical role for receptor topography in leukocyte adhesion and suggest a novel regulatory mechanism of leukocyte trafficking.
small molecules
2023-07-07 | Activation of ryanodine-sensitive calcium store drives pseudo-allergic dermatitis via Mas-related G protein-coupled receptor X2 in mast cells.
Mast cell (MC) activation is implicated in the pathogenesis of multiple immunodysregulatory skin disorders. Activation of an IgE-independent pseudo-allergic route has been recently found to be mainly mediated via Mas-Related G protein-coupled receptor X2 (MRGPRX2). Ryanodine receptor (RYR) regulates intracellular calcium liberation. Calcium mobilization is critical in the regulation of MC functional programs. However, the role of RYR in MRGPRX2-mediated pseudo-allergic skin reaction has not been fully addressed. To study the role of RYR in vivo, we established a murine skin pseudo-allergic reaction model. RYR inhibitor attenuated MRGPRX2 ligand substance P (SP)-induced vascular permeability and neutrophil recruitment. Then, we confirmed the role of RYR in an MC line (LAD2 cells) and primary human skin-derived MCs. In LAD2 cells, RYR inhibitor pretreatment dampened MC degranulation (detected by β-hexosaminidase retlease), calcium mobilization, IL-13, TNF-α, CCL-1, CCL-2 mRNA, and protein expression activated by MRGPRX2 ligands, namely, compound 48/80 (c48/80) and SP. Moreover, the inhibition effect of c48/80 by RYR inhibitor was verified in skin MCs. After the confirmation of RYR2 and RYR3 expression, the isoforms were silenced by siRNA-mediated knockdown. MRGPRX2-induced LAD2 cell exocytosis and cytokine generation were substantially inhibited by RYR3 knockdown, while RYR2 had less contribution. Collectively, our finding suggests that RYR activation contributes to MRGPRX2-triggered pseudo-allergic dermatitis, and provides a potential approach for MRGPRX2-mediated disorders.
2023-05-29 | Substance P analogs devoid of key residues fail to activate human mast cells via MRGPRX2.
Mast cells play an important role in disease pathogenesis by secreting immunomodulatory molecules. Mast cells are primarily activated by the crosslinking of their high affinity IgE receptors (FcεRI) by antigen bound immunoglobulin (Ig)E antibody complexes. However, mast cells can also be activated by the mas related G protein-coupled receptor X2 (MRGPRX2), in response to a range of cationic secretagogues, such as substance P (SP), which is associated with pseudo-allergic reactions. We have previously reported that the in vitro activation of mouse mast cells by basic secretagogues is mediated by the mouse orthologue of the human MRGPRX2, MRGPRB2. To further elucidate the mechanism of MRGPRX2 activation, we studied the time-dependent internalization of MRGPRX2 by human mast cells (LAD2) upon stimulation with the neuropeptide SP. In addition, we performed computational studies to identify the intermolecular forces that facilitate ligand-MRGPRX2 interaction using SP. The computational predictions were tested experimentally by activating LAD2 with SP analogs, which were missing key amino acid residues. Our data suggest that mast cell activation by SP causes internalization of MRGPRX2 within 1 min of stimulation. Hydrogen bonds (h-bonds) and salt bridges govern the biding of SP to MRGPRX2. Arg1 and Lys3 in SP are key residues that are involved in both h-bonding and salt bridge formations with Glu164 and Asp184 of MRGPRX2, respectively. In accordance, SP analogs devoid of key residues (SP1 and SP2) failed to activate MRGPRX2 degranulation. However, both SP1 and SP2 caused a comparable release of chemokine CCL2. Further, SP analogs SP1, SP2 and SP4 did not activate tumor necrosis factor (TNF) production. We further show that SP1 and SP2 limit the activity of SP on mast cells. The results provide important mechanistic insight into the events that result in mast cell activation through MRGPRX2 and highlight the important physiochemical characteristics of a peptide ligand that facilitates ligand-MRGPRX2 interactions. The results are important in understanding activation through MRGPRX2, and the intermolecular forces that govern ligand-MRGPRX2 interaction. The elucidation of important physiochemical properties within a ligand that are needed for receptor interaction will aid in designing novel therapeutics and antagonists for MRGPRX2.
2023-04-27 | Myricetin served as antagonist for negatively regulate MRGPRX2 mediated pseudo-allergic reactions through CD300f/SHP1/SHP2 phosphorylation.
Mas-related G protein-coupled receptor X2 (MRGPRX2) plays a vital role in mast cells (MCs) degranulation and pseudo-allergic reactions. Leukocyte mono-immunoglobulin-like receptor 3 (CD300f) can negatively regulate MCs degranulation. Identification of drug candidates which target CD300f represents a promising prospect in drug development. Myricetin is widely distributed in plants and has been reported to inhibit allergic reactions in OVA-induced murine models. This study aims to determine whether myricetin can activate CD300f to arrest MCs degranulation mediated by MRGPRX2. Myricetin inhibited the allergic mediator and cytokine release triggered by MRGPRX2 in vivo and in vitro. Under C48/80 stimulation, the release of β-hexosaminidase, TNF-α, IL-8 and MCP-1 in CD300f knockdown in LAD2 cells was significantly increased compared with NC-LAD2 cells. Myricetin displayed good structural affinity (KD = 7.21 × 10-5) with CD300f by SPR. Molecular docking results showed that hydrogen bonds were formed between myricetin and CD300f, indicating high binding ability (5.6653). Myricetin can upregulate the phosphorylation of SHP-1 and SHP-2 and dephosphorylation in the MRGPRX2 signaling pathway, involving PLCγ1, AKT, P38, and ERK1/2. In the present study, myricetin is identified as an exogenous ligand for CD300f, which negatively regulates MRGPRX2-mediated MCs activation via CD300f to inhibit MCs degranulation and pseudo-allergic reactions.
2021-12-22 | PeracetylN-cyclobutanoyl-D-mannosamine enhances expression of sialyl-Lewis X (sLeX / CD15s) and adhesion of leukocytes
Abstract Sialyl-Lewis-X (sLeX/CD15s) epitopes regulate cell adhesion via interactions with selectins. High levels of sLeX are associated with chronic inflammation. Intense efforts have been devoted for the development of sLeX mimetics for the prevention of atherosclerosis. By contrast, low levels of sLeX are associated with leukocyte adhesion deficiency (LAD) disorders. In this context, we employed metabolic glycan engineering to alter the fine structures of sialoglycans. Treatment of HL-60 (human acute myeloid leukemia) cells with peracetyl N -cyclobutanoyl-D-mannosamine (Ac 4 ManNCb) resulted in a four-fold increase in both sLeX levels and adhesion to E-selectin-Fc chimera. Enhanced sLeX levels on CD162/PSGL-1, CD43, and CD44 were observed through immunoprecipitation. Molecular dynamics (MD) simulations on interactions with E-selectin revealed dramatic differentials in the conformational dynamics of sLeX-Cb compared to sLeX, highlighting the significance of remote N -acyl side chains of sialic acids in facilitating bio-active conformations. These results provide opportunities for pharmacological interventions in both LAD and chronic inflammation. Table of Contents Remote substituents on the tetrasaccharide sialyl-Lewis X (sLeX / CD15s) influence ensembles of bio-active conformations and alter biological outcomes. Treatment with peracetyl N -cyclobutanoyl-D-mannosamine (Ac 4 ManNCb) results in four-fold enhancement in the expression of sialyl-Lewis-X (sLeX / CD15s) and adhesion to E-selectin (CD62E). Molecular dynamics simulations show that the sLeX-Cb prefers a flatter bio-active conformation (gray) compared to wild-type sLeX (cyan). Institute and/or researcher Twitter usernames: @NImmunology @Gops_GlycoIndia
proteins
2022-06-14 | Defining the mild variant of leukocyte adhesion deficiency type II (SLC35C1-congenital disorder of glycosylation) and response to l-fucose therapy: Insights from two new families and review of the literature.
Leukocyte adhesion deficiency type II (LAD II, also known as SLC35C1-congenital disorder of glycosylation) is an autosomal recessive disorder characterized by growth and cognitive impairment, peripheral neutrophilia, recurrent infections, and the Bombay blood phenotype. A subset of patients with a milder presentation has been described with short stature and developmental delay but minimal immune and hematologic features. Some patients with LAD II benefit from oral fucose therapy, though this has not been previously studied in patients with milder disease. In this study, we describe two new patients from separate families with the milder variant of LAD II and review the published literature on this rare disorder. We demonstrate improvement in speech and cognition, CD15 expression, and core fucosylation of serum glycoproteins after 27 months of oral fucose supplementation in one patient. These patients further support the stratification of this disorder into distinct subtypes, a classical severe and an attenuated variant, and provide preliminary evidence of benefit of fucose therapy in the latter group.
2005-04-11 | CD44 is a physiological E-selectin ligand on neutrophils
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.
1995-09-01 | A central role for microvillous receptor presentation in leukocyte adhesion under flow
Leukocyte adhesion to endothelium requires specialized mechanisms for contact initiation under flow. L-selectin (CD62L), an efficient initiator of adhesion, is clustered on the tips of leukocyte microvilli. To test whether microvillous presentation is critical for contact formation ("tethering"), we transfected lymphoid cells with chimeras of L-selectin and CD44, an adhesion molecule that is excluded from microvilli. CD44 transmembrane and intracellular (TM-IC) domains targeted the L-selectin ectodomain to the planar body, whereas L-selectin TM-IC segments conferred CD44 ectodomain clustering on microvilli. Wild-type and chimeric transfectants bound similarly to anti-ectodomain MAbs in static assays, but MAb binding under flow was much more efficient in the context of microvillous presentation. Similarly, wild-type and chimeric L-selectin possessed equivalent lectin activity, but microvillous presentation dramatically enhanced contact initiation on a native ligand. These findings demonstrate a critical role for receptor topography in leukocyte adhesion and suggest a novel regulatory mechanism of leukocyte trafficking.
small molecules
2023-07-07 | Activation of ryanodine-sensitive calcium store drives pseudo-allergic dermatitis via Mas-related G protein-coupled receptor X2 in mast cells.
Mast cell (MC) activation is implicated in the pathogenesis of multiple immunodysregulatory skin disorders. Activation of an IgE-independent pseudo-allergic route has been recently found to be mainly mediated via Mas-Related G protein-coupled receptor X2 (MRGPRX2). Ryanodine receptor (RYR) regulates intracellular calcium liberation. Calcium mobilization is critical in the regulation of MC functional programs. However, the role of RYR in MRGPRX2-mediated pseudo-allergic skin reaction has not been fully addressed. To study the role of RYR in vivo, we established a murine skin pseudo-allergic reaction model. RYR inhibitor attenuated MRGPRX2 ligand substance P (SP)-induced vascular permeability and neutrophil recruitment. Then, we confirmed the role of RYR in an MC line (LAD2 cells) and primary human skin-derived MCs. In LAD2 cells, RYR inhibitor pretreatment dampened MC degranulation (detected by β-hexosaminidase retlease), calcium mobilization, IL-13, TNF-α, CCL-1, CCL-2 mRNA, and protein expression activated by MRGPRX2 ligands, namely, compound 48/80 (c48/80) and SP. Moreover, the inhibition effect of c48/80 by RYR inhibitor was verified in skin MCs. After the confirmation of RYR2 and RYR3 expression, the isoforms were silenced by siRNA-mediated knockdown. MRGPRX2-induced LAD2 cell exocytosis and cytokine generation were substantially inhibited by RYR3 knockdown, while RYR2 had less contribution. Collectively, our finding suggests that RYR activation contributes to MRGPRX2-triggered pseudo-allergic dermatitis, and provides a potential approach for MRGPRX2-mediated disorders.
2023-05-29 | Substance P analogs devoid of key residues fail to activate human mast cells via MRGPRX2.
Mast cells play an important role in disease pathogenesis by secreting immunomodulatory molecules. Mast cells are primarily activated by the crosslinking of their high affinity IgE receptors (FcεRI) by antigen bound immunoglobulin (Ig)E antibody complexes. However, mast cells can also be activated by the mas related G protein-coupled receptor X2 (MRGPRX2), in response to a range of cationic secretagogues, such as substance P (SP), which is associated with pseudo-allergic reactions. We have previously reported that the in vitro activation of mouse mast cells by basic secretagogues is mediated by the mouse orthologue of the human MRGPRX2, MRGPRB2. To further elucidate the mechanism of MRGPRX2 activation, we studied the time-dependent internalization of MRGPRX2 by human mast cells (LAD2) upon stimulation with the neuropeptide SP. In addition, we performed computational studies to identify the intermolecular forces that facilitate ligand-MRGPRX2 interaction using SP. The computational predictions were tested experimentally by activating LAD2 with SP analogs, which were missing key amino acid residues. Our data suggest that mast cell activation by SP causes internalization of MRGPRX2 within 1 min of stimulation. Hydrogen bonds (h-bonds) and salt bridges govern the biding of SP to MRGPRX2. Arg1 and Lys3 in SP are key residues that are involved in both h-bonding and salt bridge formations with Glu164 and Asp184 of MRGPRX2, respectively. In accordance, SP analogs devoid of key residues (SP1 and SP2) failed to activate MRGPRX2 degranulation. However, both SP1 and SP2 caused a comparable release of chemokine CCL2. Further, SP analogs SP1, SP2 and SP4 did not activate tumor necrosis factor (TNF) production. We further show that SP1 and SP2 limit the activity of SP on mast cells. The results provide important mechanistic insight into the events that result in mast cell activation through MRGPRX2 and highlight the important physiochemical characteristics of a peptide ligand that facilitates ligand-MRGPRX2 interactions. The results are important in understanding activation through MRGPRX2, and the intermolecular forces that govern ligand-MRGPRX2 interaction. The elucidation of important physiochemical properties within a ligand that are needed for receptor interaction will aid in designing novel therapeutics and antagonists for MRGPRX2.
2023-04-27 | Myricetin served as antagonist for negatively regulate MRGPRX2 mediated pseudo-allergic reactions through CD300f/SHP1/SHP2 phosphorylation.
Mas-related G protein-coupled receptor X2 (MRGPRX2) plays a vital role in mast cells (MCs) degranulation and pseudo-allergic reactions. Leukocyte mono-immunoglobulin-like receptor 3 (CD300f) can negatively regulate MCs degranulation. Identification of drug candidates which target CD300f represents a promising prospect in drug development. Myricetin is widely distributed in plants and has been reported to inhibit allergic reactions in OVA-induced murine models. This study aims to determine whether myricetin can activate CD300f to arrest MCs degranulation mediated by MRGPRX2. Myricetin inhibited the allergic mediator and cytokine release triggered by MRGPRX2 in vivo and in vitro. Under C48/80 stimulation, the release of β-hexosaminidase, TNF-α, IL-8 and MCP-1 in CD300f knockdown in LAD2 cells was significantly increased compared with NC-LAD2 cells. Myricetin displayed good structural affinity (KD = 7.21 × 10-5) with CD300f by SPR. Molecular docking results showed that hydrogen bonds were formed between myricetin and CD300f, indicating high binding ability (5.6653). Myricetin can upregulate the phosphorylation of SHP-1 and SHP-2 and dephosphorylation in the MRGPRX2 signaling pathway, involving PLCγ1, AKT, P38, and ERK1/2. In the present study, myricetin is identified as an exogenous ligand for CD300f, which negatively regulates MRGPRX2-mediated MCs activation via CD300f to inhibit MCs degranulation and pseudo-allergic reactions.
2021-12-22 | PeracetylN-cyclobutanoyl-D-mannosamine enhances expression of sialyl-Lewis X (sLeX / CD15s) and adhesion of leukocytes
Abstract Sialyl-Lewis-X (sLeX/CD15s) epitopes regulate cell adhesion via interactions with selectins. High levels of sLeX are associated with chronic inflammation. Intense efforts have been devoted for the development of sLeX mimetics for the prevention of atherosclerosis. By contrast, low levels of sLeX are associated with leukocyte adhesion deficiency (LAD) disorders. In this context, we employed metabolic glycan engineering to alter the fine structures of sialoglycans. Treatment of HL-60 (human acute myeloid leukemia) cells with peracetyl N -cyclobutanoyl-D-mannosamine (Ac 4 ManNCb) resulted in a four-fold increase in both sLeX levels and adhesion to E-selectin-Fc chimera. Enhanced sLeX levels on CD162/PSGL-1, CD43, and CD44 were observed through immunoprecipitation. Molecular dynamics (MD) simulations on interactions with E-selectin revealed dramatic differentials in the conformational dynamics of sLeX-Cb compared to sLeX, highlighting the significance of remote N -acyl side chains of sialic acids in facilitating bio-active conformations. These results provide opportunities for pharmacological interventions in both LAD and chronic inflammation. Table of Contents Remote substituents on the tetrasaccharide sialyl-Lewis X (sLeX / CD15s) influence ensembles of bio-active conformations and alter biological outcomes. Treatment with peracetyl N -cyclobutanoyl-D-mannosamine (Ac 4 ManNCb) results in four-fold enhancement in the expression of sialyl-Lewis-X (sLeX / CD15s) and adhesion to E-selectin (CD62E). Molecular dynamics simulations show that the sLeX-Cb prefers a flatter bio-active conformation (gray) compared to wild-type sLeX (cyan). Institute and/or researcher Twitter usernames: @NImmunology @Gops_GlycoIndia
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Drug Discovery Landscape
1 orphan drug designation for Leukocyte adhesion deficiency type II.
1 orphan drug designation for Leukocyte adhesion deficiency type II.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
L-fucose | small molecules | FDA | Orpha Labs, AG |
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