Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications

Rose, Domenico Umberto De; Giliani, Silvia; Notarangelo, Lucia Dora; Lougaris, Vassilios; Lanfranchi, Arnalda; Moratto, Daniele; Martire, Baldassarre; Specchia, Fernando; Tommasini, Alberto; Plebani, Alessandro; Badolato, Raffaele

doi:10.1016/j.clim.2018.03.005

Cited by 31 publications

(27 citation statements)

References 23 publications

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“…This might be because of under-diagnosis of mild LAD1 phenotype. Late-onset autoimmune complications have been reported previously (38). However, it was not observed in our patients as most of them expired in infancy.…”

Section: Discussioncontrasting

confidence: 51%

Clinical and Genetic Spectrum of a Large Cohort of Patients With Leukocyte Adhesion Deficiency Type 1 and 3: A Multicentric Study From India

et al. 2020

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Leukocyte adhesion deficiency (LAD) syndrome is a group of inborn errors of immunity characterized by a defect in the cascade of the activation and adhesion leading to the failure of leukocyte to migrate to the site of tissue injury. Three different types of LAD have been described. The most common subtype is LAD type 1 (LAD1) caused due to defects in the ITGβ2 gene. LAD type 2 (LAD2) is caused by mutations in the SLC35C1 gene leading to a generalized loss of expression of fucosylated glycans on the cell surface and LAD type 3 (LAD3) is caused by mutations in the FERMT3 gene resulting in platelet function defects along with immunodeficiency. There is a paucity of data available from India on LAD syndromes. The present study is a retrospective analysis of patients with LAD collated from 28 different centers across India. For LAD1, the diagnosis was based on clinical features and flow cytometric expression of CD18 on peripheral blood leukocytes and molecular confirmation by Sanger sequencing. For patients with LAD3 diagnosis was largely based on clinical manifestations and identification of the pathogenic mutation in the FERMT3 gene by next-generation Sequencing. Of the total 132 cases diagnosed with LAD, 127 were LAD1 and 5 were LAD3. The majority of our patients (83%) had CD18 expression less than 2% on neutrophils (LAD1°) and presented within the first three months of life with omphalitis, skin and soft tissue infections, delayed umbilical cord detachment, otitis media, and sepsis. The patients with CD18 expression of more than 30% (LAD1+) presented later in life with skin ulcers being the commonest manifestation. Bleeding manifestations were common in patients with LAD3. Persistent neutrophilic leukocytosis was the characteristic finding in all patients. 35 novel mutations were detected in the ITGβ2 gene, and 4 novel mutations were detected in the FERMT3 gene. The study thus presents one of the largest cohorts of patients from India with LAD, focusing on clinical features, immunological characteristics, and molecular spectrum.

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Section: Discussioncontrasting

confidence: 51%

Clinical and Genetic Spectrum of a Large Cohort of Patients With Leukocyte Adhesion Deficiency Type 1 and 3: A Multicentric Study From India

et al. 2020

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“…A growing body of research suggests that β2 integrins play an important role in tolerance induction [247][248][249] and suppression of inflammation [83,250,251]. Already decades ago, it was noted that LAD-I patients suffer not only from bacterial infections but also from renal or intestinal autoimmune diseases [252,253], and some of them presented type 1 diabetes or autoimmune cytopenia after hematopoietic stem cell transplantation [254]. Likewise, CD18 −/− mice are characterized by chronic dermatitis and splenomegaly, which indicates a circulating inflammation [179].…”

Section: Functions Of β2 Integrins In Autoimmunitymentioning

confidence: 99%

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

Bednarczyk

Stege

Grabbe

et al. 2020

IJMS

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β2 integrins are heterodimeric surface receptors composed of a variable α (CD11a-CD11d) and a constant β (CD18) subunit and are specifically expressed by leukocytes. The α subunit defines the individual functional properties of the corresponding β2 integrin, but all β2 integrins show functional overlap. They mediate adhesion to other cells and to components of the extracellular matrix (ECM), orchestrate uptake of extracellular material like complement-opsonized pathogens, control cytoskeletal organization, and modulate cell signaling. This review aims to delineate the tremendous role of β2 integrins for immune functions as exemplified by the phenotype of LAD-I (leukocyte adhesion deficiency 1) patients that suffer from strong recurrent infections. These immune defects have been largely attributed to impaired migratory and phagocytic properties of polymorphonuclear granulocytes. The molecular base for this inherited disease is a functional impairment of β2 integrins due to mutations within the CD18 gene. LAD-I patients are also predisposed for autoimmune diseases. In agreement, polymorphisms within the CD11b gene have been associated with autoimmunity. Consequently, β2 integrins have received growing interest as targets in the treatment of autoimmune diseases. Moreover, β2 integrin activity on leukocytes has been implicated in tumor development.

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“…Third, we do not know how IgE levels were increased in the PB and BM fluid in β2 −/− mice. Even though, a recent study reported that patients with type I LAD have increased risk of autoimmune complications . And fourth, we do not know which partner of β2 participated in GMP proliferation in the study.…”

Section: Discussionmentioning

confidence: 81%

The Impact of Integrin β2 on Granulocyte/Macrophage Progenitor Proliferation

et al. 2019

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Previously, we reported that although the HSPC frequency in bone marrow cells (BMC) was comparable between β2−/− and β2+/+ mice, transplantation of β2−/− BMC into lethally irradiated CD45.1 recipient resulted in more myeloid cell production than β2+/+ BMC. The objective of this study is to address if integrin β2 deficiency skews granulocyte/macrophage progenitor (GMP) proliferation. FACS analysis demonstrated that GMP frequency and cell number were higher and megakaryocyte/erythrocyte progenitor frequency and cell number were lower in β2−/− mice than β2+/+ mice. However, the common myeloid progenitors (CMP) frequency and cell number were similar between the two groups. The increased GMP number was due to GMP proliferation as evidenced by the percentage of BrdU‐incorporating GMP. Whole genome transcriptome analysis identified increased FcεRIα expression in β2−/− CMP compared to β2+/+ CMP. FcεRIα expression on β2−/− GMP was detected increased in β2−/− mice by qRT‐PCR and FACS. Although transplantation of FcεRIαhi GMP or FcεRIαlo GMP into lethally irradiated CD45.1 recipient resulted in comparable myeloid cell production, transplantation of β2 deficient FcεRIαhi GMP generated more myeloid cells than β2+/+ FcεRIαhi GMP. GATA2 expression was increased in β2−/− GMP. Using a luciferase reporter assay, we demonstrated that mutation of the GATA2 binding site in the FcεRIα promoter region diminished FcεRIα transcription. In vitro, the addition of IgE, the ligand of FcεRIα, promoted GMP expansion, which was abrogated by inhibition of JNK phosphorylation. Integrin β2 deficiency promoted GMP proliferation and myeloid cell production, which was mediated via FcεRIα/IgE‐induced JNK phosphorylation in GMP. Stem Cells 2019;37:430–440

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Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications

Cited by 31 publications

References 23 publications

Clinical and Genetic Spectrum of a Large Cohort of Patients With Leukocyte Adhesion Deficiency Type 1 and 3: A Multicentric Study From India

Clinical and Genetic Spectrum of a Large Cohort of Patients With Leukocyte Adhesion Deficiency Type 1 and 3: A Multicentric Study From India

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

The Impact of Integrin β2 on Granulocyte/Macrophage Progenitor Proliferation

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