Intracellular β<sub>2</sub> integrin (<scp>CD</scp>11/<scp>CD</scp>18) interacting partners in neutrophil trafficking

Thome, Sarah; Begandt, Daniela; Pick, Robert; Salvermoser, Melanie; Walzog, Barbara

doi:10.1111/eci.12966

Cited by 20 publications

(17 citation statements)

References 105 publications

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“…Anti‐TIF‐1γ + skeletal muscles showed compared to anti‐Mi‐2 + , only scarce inflammatory infiltrates (1), which goes in line with the downregulation of different genes involved in immune response, such as CD74 (HLA class II histocompatibility antigen gamma chain) (71), leucocyte differentiation antigen CD84 (72, 73) as well as Chemokine (C‐C motif) ligand 5 ( CCL5 ), which plays an active role recruiting leukocytes to inflammatory sites and which is also relevant to induce immune responses against tumors (74). Further downregulated genes were Integrin beta chain‐2 ( ITGB2 , CD18), which together with Integrin alpha L ( ITGAL , CD11A, lymphocyte function‐associated antigen 1) form the lymphocyte function‐associated antigen‐1 (LFA‐1) playing a major role in neutrophil and T‐cell trafficking, extravasation, and emigration (75, 76).…”

Section: Discussionmentioning

confidence: 99%

NanoString technology distinguishes anti‐TIF‐1γ⁺ from anti‐Mi‐2⁺ dermatomyositis patients

et al. 2021

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Dermatomyositis (DM) is a systemic idiopathic inflammatory disease affecting skeletal muscle and skin, clinically characterized by symmetrical proximal muscle weakness and typical skin lesions. Recently, myositis‐specific autoantibodies (MSA) became of utmost importance because they strongly correlate with distinct clinical manifestations and prognosis. Antibodies against transcription intermediary factor 1γ (TIF‐1γ) are frequently associated with increased risk of malignancy, a specific cutaneous phenotype and limited response to therapy in adult DM patients. Anti‐Mi‐2 autoantibodies, in contrast, are typically associated with classic DM rashes, prominent skeletal muscle weakness, better therapeutic response and prognosis, and less frequently with cancer. Nevertheless, the sensitivity of autoantibody testing is only moderate, and alternative reliable methods for DM patient stratification and prediction of cancer risk are needed. To further investigate these clinically distinct DM subgroups, we herein analyzed 30 DM patients (n = 15 Mi‐2+ and n = 15 TIF‐1 γ+) and n = 8 non‐disease controls (NDC). We demonstrate that the NanoString technology can be used as a very sensitive method to clearly differentiate these two clinically distinct DM subgroups. Using the nCounter PanCancer Immune Profiling Panel™, we identified a set of significantly dysregulated genes in anti‐TIF‐1γ+ patient muscle biopsies including VEGFA, DDX58, IFNB1, CCL5, IL12RB2, and CD84. Investigation of type I IFN‐regulated transcripts revealed a striking type I interferon signature in anti‐Mi‐2+ patient biopsies. Our results help to stratify both subgroups and predict, which DM patients require an intensified diagnostic procedure and might have a poorer outcome. Potentially, this could also have implications for the therapeutic approach.

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Section: Discussionmentioning

confidence: 99%

NanoString technology distinguishes anti‐TIF‐1γ⁺ from anti‐Mi‐2⁺ dermatomyositis patients

et al. 2021

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“…It is well known that integrins are normally expressed in a low affinity state on the cell surface with a bent closed headpiece ( Figure 3). Activation of high-affinity binding and of intracellular signal transduction can occur via extracellular ('outside-in signaling´) or via intracellular signals ('inside-out signaling´) [22]. The inactive state of β2 integrins enables circulation of leukocytes in non-inflamed vessels [23].…”

Section: Activation Of β2 Integrinsmentioning

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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“…Kindlin and talin connect the integrin to the actin cytoskeleton and stabilize the extended-open conformation of the integrin through actin cytoskeleton exerted tensile force (6, 13). In addition, many other proteins, such as 14-3-3 proteins, alpha-actinin, coronin 1A, cytohesin 1, filamin A, and Dok1 can interact directly with the integrin beta-chain and modulate integrin function (14–16). These interactions are often regulated by phosphorylation of the integrin beta-chain cytoplasmic domain (15–18).…”

Section: Integrins and Integrin Regulationmentioning

confidence: 99%

Beta2-Integrins and Interacting Proteins in Leukocyte Trafficking, Immune Suppression, and Immunodeficiency Disease

et al. 2019

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Beta2-integrins are complex leukocyte-specific adhesion molecules that are essential for leukocyte (e.g., neutrophil, lymphocyte) trafficking, as well as for other immunological processes such as neutrophil phagocytosis and ROS production, and T cell activation. Intriguingly, however, they have also been found to negatively regulate cytokine responses, maturation, and migratory responses in myeloid cells such as macrophages and dendritic cells, revealing new, and unexpected roles of these molecules in immunity. Because of their essential role in leukocyte function, a lack of expression or function of beta2-integrins causes rare immunodeficiency syndromes, Leukocyte adhesion deficiency type I, and type III (LAD-I and LAD-III). LAD-I is caused by reduced or lost expression of beta2-integrins, whilst in LAD-III, beta2-integrins are expressed but dysfunctional because a major integrin cytoplasmic regulator, kindlin-3, is mutated. Interestingly, some LAD-related phenotypes such as periodontitis have recently been shown to be due to an uncontrolled inflammatory response rather than to an uncontrolled infection, as was previously thought. This review will focus on the recent advances concerning the regulation and functions of beta2-integrins in leukocyte trafficking, immune suppression, and immune deficiency disease.

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Intracellular β₂ integrin (CD11/CD18) interacting partners in neutrophil trafficking

Abstract: The knowledge of proteins interacting with β integrins and their regulation during neutrophil trafficking does not only improve our basic understanding of innate immunity but may pave the way to novel therapeutic strategies in the treatment of inflammatory diseases.

Cited by 20 publications

References 105 publications

NanoString technology distinguishes anti‐TIF‐1γ⁺ from anti‐Mi‐2⁺ dermatomyositis patients

NanoString technology distinguishes anti‐TIF‐1γ⁺ from anti‐Mi‐2⁺ dermatomyositis patients

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

Beta2-Integrins and Interacting Proteins in Leukocyte Trafficking, Immune Suppression, and Immunodeficiency Disease

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Intracellular β2 integrin (CD11/CD18) interacting partners in neutrophil trafficking

Abstract: The knowledge of proteins interacting with β integrins and their regulation during neutrophil trafficking does not only improve our basic understanding of innate immunity but may pave the way to novel therapeutic strategies in the treatment of inflammatory diseases.

Cited by 20 publications

References 105 publications

NanoString technology distinguishes anti‐TIF‐1γ+ from anti‐Mi‐2+ dermatomyositis patients

NanoString technology distinguishes anti‐TIF‐1γ+ from anti‐Mi‐2+ dermatomyositis patients

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

Beta2-Integrins and Interacting Proteins in Leukocyte Trafficking, Immune Suppression, and Immunodeficiency Disease

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Intracellular β₂ integrin (CD11/CD18) interacting partners in neutrophil trafficking

NanoString technology distinguishes anti‐TIF‐1γ⁺ from anti‐Mi‐2⁺ dermatomyositis patients

NanoString technology distinguishes anti‐TIF‐1γ⁺ from anti‐Mi‐2⁺ dermatomyositis patients