Defects in the Leukocyte Adhesion Cascade

Leukocyte trafficking from bloodstream to tissue is important for the continuous surveillance for foreign antigens as well as for rapid leukocyte accumulation at sites of inflammatory response or tissue injury. Leukocyte interaction with vascular endothelial cells is a pivotal event in the inflammatory response and is mediated by several families of adhesion molecules. The crucial role of the β₂-integrin subfamily in leukocyte emigration was established after leukocyte adhesion deficiency (LAD) I was discovered. Patients with this disorder suffer from life-threatening bacterial infections, and in its severe form, death usually occurs in early childhood unless bone marrow transplantation is performed. The LAD II disorder clarifies the role of the selectin receptors and their fucosylated ligands. Clinically, patients with LAD II suffer not only from a less severe form of infectious episodes resembling the moderate phenotype of LAD I but also from severe psychomotor and growth retardation. LAD III emphasizes the importance of the integrin-activation phase in the adhesion cascade. All hematopoietic integrin activation processes are defective, which lead to severe infection as observed in LAD I and to marked increase tendency for bleeding problems (defective activation of β₁, β₂, and β₃ integrins). The various genetic defects leading to all adhesion molecules syndrome will be discussed.     

A Novel Mutation in Leukocyte Adhesion Deficiency Type II/CDGIIc

Leukocyte adhesion deficiencies (LAD) are autosomal recessive immunodeficiency syndromes characterized by severe and recurrent bacterial infections, impaired wound healing and leukocytosis. Block in different steps in the leukocyte adhesion cascade causes different types of leukocyte adhesion deficiencies, LAD type I, II and III. In LAD type II, the rolling phase of the leukocyte adhesion cascade is affected due to mutations in the specific fucose transporter GFTP (GDP fucose transporter), causing defect in the biosynthesis of selectin ligands on leukocytes. Thus this syndrome is also called congenital disorder of glycosylation IIc (CGDIIc). LAD II/CGDIIc is very rare and has been diagnosed in nine children to date. Fever, leukocytosis, typical dysmorphic features, growth, psychomotor retardation and the Bombay blood group, are characteristic findings in patients. Here, we describe two Turkish siblings with a novel mutation in GFTP. They both have the characteristic features of the syndrome. The older sibling died of severe bacterial pneumonia at the age of 3 years. The younger sibling, diagnosed at the age of 3 months, responded to high dose oral fucose supplementation. Secundum atrial septal defect which was not described in previously reported patients, but present in both of our patients, may primarily related to the defect in fucosylation.     

肺炎患儿白细胞变形能力和粘附功能的变化及临床意义

肺炎患儿白细胞变形能力和粘附功能的变化及临床意义林荣军１刘成玉２潘玉娟３徐丽园研究表明，白细胞与急性肺组织损伤有密切关系［１］，白细胞在肺内聚集是产生急性肺损伤的重要环节，而细胞粘附分子（ｃＡｍｓ）介导的各种白细胞的粘附，特别是中性粒细胞粘附和跨膜转...     

Mechanics of Leukocyte Deformation and Adhesion to Endothelium in Shear Flow

The mechanics of leukocyte [white blood cell (WBC)] deformation and adhesion to endothelial cells (EC) in shear flow has been investigated. Experimental data on transient WBC–EC adhesion were obtained from in vivo measurements. Microscopic images of WBC–EC contact during incipient WBC rolling revealed that for a given wall shear stress, the contact area increases with time as new bonds are formed at the leading edge, and then decreases with time as the trailing edge of the WBC membrane peels away from the EC. A two-dimensional model (2D) was developed consisting of an elastic ring adhered to a surface under fluid stresses. This ring represents an actin-rich WBC cortical layer and contains an incompressible fluid as the cell interior. All molecular bonds are modeled as elastic springs distributed in the WBC–EC contact region. Variations of the proportionality between wall shear stress ( _w ) in the vicinity of the WBC and the resulting drag force (F _s ), i.e., F_s/_w, reveal its decrease with WBC deformation and increasing vessel channel height (2D). The computations also find that the peeling zone between adherent WBC and EC may account for less than 5% of the total contact interface. Computational studies describe the WBC–EC adhesion and the extent of WBC deformation during the adhesive process. © 1999 Biomedical Engineering Society. PAC99: 8717-d, 8719Tt, 8717Aa     

Leukocyte Adhesion Deficiency Type II: Long-Term Follow-Up and Review of the Literature

Introduction  

Leukocyte adhesion deficiency (LAD) is a group of rare inherited disorders characterized by immune deficiency and peripheral neutrophilia. There are only seven reported cases of LAD type II worldwide, and no long-term follow-up data.     

Immune Complexes Alter Cerebral Microvessel Permeability: Roles of Complement and Leukocyte Adhesion

Inflammation Research -     

怡开对白细胞粘附和血液流变性影响的研究

目的 :深入探讨怡开改善微循环及血液流变学的作用机理。方法 :利用活体肠系膜微循环观察、血液粘度和红细胞变形性测定方法。结果 :对照组用内毒素后明显引起静脉内白细胞粘附、游出和血小板聚集 ,血流减慢 ,内皮水肿、内皮细胞间间隙增大、血管内皮损伤、出血等对血管内皮有明显的损伤作用。用PK预防的大鼠明显减轻内毒素引起的白细胞粘附、游出和血小板聚集 ,未见血管内皮水肿和血栓形成 ,出血比对照组轻。结论 :用PK预防的大鼠能明显减轻白细胞粘附、游出和血小板聚集等 ,减轻血管内皮水肿和血栓形成 ,对血管内皮的损伤有一定预防作用     

Evidence for a Leukocyte Adhesion Factor Produced by the Early Embryo

PROBLEM : To determine if the embryo may induce adhesive molecules needed for implantation. METHOD : Determination of whether platelet rosetting around lymphocytes might occur when exposed to sera from pregnant, but not nonpregnant patients and from culture fluid from embryos but not oocytes. RESULTS : 90.2% of women with positive sera beta human chorionic gonadotropin (P-hCG) levels taken at least 12 days postovulation demonstrated platelet rosette factor (PRF) vs only 18.7% when β-hCG was negative. Using mid-luteal phase sera in women receiving hCG injection 1 wk before, 64.7% had positive PRF when serial β-hCG levels were positive as did 100% of samples taken from in vitro fertilization (IVF) patients; however, only 15.3% were positive with negative serial hCG levels. Culture media from fertilized oocytes and embryos tested positive for PRF, but follicular fluid and media from unfertilized oocytes were negative. CONCLUSION : The early embryo secretes a factor(s) that gains access to maternal serum and promotes increased lymphocyte/platelet adhesiveness.     

Function of Junctional Adhesion Molecules (JAMs) in Leukocyte Migration and Homeostasis

Homeostasis is a word widely used in the scientific community to refer to the property of a system to maintain its uniformity and functionality. In living organisms, the word refers to the concept enunciated 150 years ago by C. Bernard by which external variations must be compensated for in order to maintain internal conditions compatible with life. This is especially true in the case of highly dynamic system such as the hematopoietic system that requires the coordinated control of cell proliferation and death within specialized microenvironments that are anatomically distinct. As a consequence, hematopoietic cell adhesion and migration must be tightly controlled in order for hematopoietic cells to reach and to be maintained in appropriate microenvironments. The junctional adhesion molecules (JAMs) are adhesion molecules that belong to the immunoglobulin superfamily (IgSf) and that have been initially identified as important players controlling vascular permeability and leukocyte transendothelial migration. This involves the regulated localization of the JAMs at lateral endothelial cell/cell borders and their interaction with leukocyte integrins. More recently, some of the JAM family members have also been found to be expressed by stromal cells and to regulate chemokine secretion within lymphoid organs, acting not only on leukocyte transendothelial migration, but also on hematopoietic cell retention within specialized microenvironments. This review summarizes recent progress in understanding the role of the JAMs in leukocyte adhesion and migration to tentatively draw an integrated view of the homeostatic function of the JAMs within the hematopoietic system.     

Leukocyte Rolling in Rat Mesentery Venules: Distribution of Adhesion Bonds and the Effects of Cytoactive Agents

A new method of analyzing in vivo measurements of leukocyte WBC rolling along venular endothelium (EC) has been developed to extract insightful information on the dynamics of WBC–EC bond formation and disruption. The rolling velocity of WBCs was obtained by intravital microscopy of rat mesenteric venules. For the spontaneous rolling observed following exteriorization of the mesentery, we estimated that the average distance between clusters of adhesion bonds which tether a rolling cell to the venular wall was about 2 m, and that the average lifetime of a bond cluster at the trailing edge of the rolling cell, from its exposure to the tensile force to its release, was on the order of 0.05 s. Both the inter-cluster distance and the lifetime were significantly reduced by treatments with the chemoattractant N-formyl-methionyl-leucyl-phenylalanine and the cytokine interleukin-1, while the average lifetime of the stretched bond clusters was not significantly changed by treatment with the cytoskeleton-modifying agents cytochalasin B and colchicine. Each of the four treatments significantly reduced the heterogeneity in the cell rolling velocity, presumably by the selective recruitment of WBC subsets from the circulating WBC population or by a reduction in the heterogeneity of endothelial adhesiveness. These results were analyzed in the context of in vitro data in the literature on molecular bonds of cell adhesion. The findings suggest that, in the case of spontaneous rolling, there are on average approximately 2–3 clusters of adhesion bonds between a rolling cell and the vessel wall, and approximately five bonds in each cluster. © 2001 Biomedical Engineering Society. PAC01: 8719Uv, 8717-d, 8714Ee, 8715By     

咖啡酸对高同型半胱氨酸引起的小鼠软脑膜细静脉内白细胞滚动和黏附的抑制作用

目的:研究咖啡酸(CA)对同型半胱氨酸(Hcy)引起的小鼠软脑膜细静脉内滚动和黏附白细胞的抑制作用。方法:取雄性C576J/BL小鼠(体重18~22g)分成3组,每组5只,Hcy组皮下注射Hcy(0.1mg/g体重)0.2ml,Hcy+CA组皮下注射Hcy(0.1mg/g体重)0.1ml后即刻肌肉注射CA(10mg/kg体重)0.1ml,Control组皮下注射生理盐水0.2ml,4h后采用研磨法建立脑非创伤性观察窗,用动态微循环观察系统观测各组小鼠软脑膜细静脉内滚动和黏附的白细胞数量。之后取脑组织,石蜡切片,用免疫组织化学方法观察脑皮层组织中微血管内皮细胞E-选择素(E-selectin)及细胞间黏附分子-1(ICAM-1)的表达。结果:与Control组相比,Hcy组小鼠软脑膜细静脉内滚动和黏附的白细胞数量显著增加(P<0.01),且脑皮层微血管内皮E-selectin及ICAM-1的阳性区域也增加。Hcy+CA组小鼠软脑膜细静脉内白细胞的滚动和黏附数量明显少于Hcy组(P<0.05),微血管内皮的E-selectin及ICAM-1表达也明显下调。结论:CA可以抑制Hcy引起的小鼠软脑膜细静脉内白细胞的滚动和黏附,该作用与其抑制脑微血管内皮E-selectin及ICAM-1的表达有关。     

Molecular Mechanism and Physiology of Apoptosis

Objective and design

High mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions. Rutin (RT), an active flavonoid compound, is well known to possess potent antiplatelet, antiviral and antihypertensive properties. In this study, we investigated the anti-inflammatory effects of RT against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) induced by HMGB1 and the associated signaling pathways.

Methods

The anti-inflammatory activities of RT were determined by measuring permeability, monocytes adhesion and migration, and activation of pro-inflammatory proteins in HMGB1-activated HUVECs and mice.

Results

We found that RT potently inhibited HMGB1 release, down-regulated HMGB1-dependent inflammatory responses in human endothelial cells, and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with RT resulted in reduced cecal ligation and puncture-induced release of HMGB1 and sepsis-related mortality. Further studies revealed that RT suppressed the production of tumor necrosis factor-α and interleukin 6 and the activation of nuclear factor-κB and extracellular regulated kinases 1/2 by HMGB1.

Conclusion

Collectively, these results indicate that RT could be a candidate therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.