中性粒细胞与淋巴细胞比值与2型糖尿病肾病进展的相关性

目的探讨中性粒细胞与淋巴细胞比值与2型糖尿病肾病进展的相关性。方法2014年9月—2016年12月间采用回顾性队列研究纳入2型糖尿病患者492例,据24 h尿蛋白总量将492例2型糖尿病患者分为糖尿病无肾病组(DM组)424例,糖尿病肾病组(DN组)68例。收集其临床资料,追踪其3年后DN进展情况。将基线中性粒细胞与淋巴细胞比值(NLR)水平按四分位法分为四组,即最低四分位数组(I组)≤1.37、第二四分位数组(II组)1.38~1.83、第三四分位数组(III组)1.84~2.21、最高4分位数组(IV组)≥2.22。按DN是否进展,将研究对象分为进展组(A组)和未进展组(B组),比较两组基线资料,采用二元Logistic回归,评估糖尿病病程、SBP、HbA1c、BMI及基线NLR水平与DN进展之间的相关性。结果3年后,64例(13.00%)患者糖尿病肾病进展,其中新发糖尿病肾病42例(8.53%)。单因素分析中,A组与B组相比较,年龄、病程、BMI、收缩压、NLR、FPG、HbA1c、TC、TG差异有统计学意义(P<0.05)。结论NLR水平>1.83是T2DM患者DN进展的独立危险因素。     

Lipocalin allergens

Most animal-derived major allergens causing respiratory sensitization belong to the family of proteins called lipocalins. Their sequential identity varies but the three-dimensional structure is conserved. They are present in body fluids and secretions. Several lipocalins are able to bind and transport small hydrophobic ligands like retinol. The immunological characteristics of lipocalin allergens are poorly known. Cow dust-derived allergen, Bos d2, which is a potent inducer of IgE production, was observed to induce the weak proliferative responses of peripheral blood mononuclear cells of asthmatic patients upon stimulation in vitro . The responses were Th2-deviated and directed to a few epitopes in Bos d2. One of the epitopes, situated adjacent to a structurally conserved region of lipocalins, was recognized by the T cells of all patients. Computer predictions suggested that human endogenous lipocalins may contain epitopes in the corresponding region. We have proposed that the allergenicity of lipocalins may be associated with the adaptation of the immune system to the presence of endogenous lipocalins.     

The antimicrobial peptide LL‐37 modulates the inflammatory and host defense response of human neutrophils

The human cathelicidin antimicrobial peptide acts as an effector molecule of the innate immune system with direct antimicrobial and immunomodulatory effects. The aim of this study was to test whether the cathelicidin LL‐37 modulates the response of neutrophils to microbial stimulation. Human neutrophils were exposed to LPS, Staphylococcus aureus and Pseudomonas aeruginosa subsequent to incubation with LL‐37 and cytokine release was measured by ELISA. The incubation with LL‐37 significantly decreased the release of proinflammatory cytokines from stimulated human neutrophils. ROS production of neutrophils was determined by a luminometric and a flow cytometry method. The peptide induced the production of ROS and the engulfment of bacteria into neutrophils. Peritoneal mouse neutrophils isolated from CRAMP‐deficient and WT animals were treated with LPS and TNF‐α in the supernatant was measured by ELISA. Antimicrobial activity of neutrophils was detected by incubating neutrophils isolated from CRAMP‐knockout and WT mice with bacteria. Neutrophils from CRAMP‐deficient mice released significantly more TNF‐α after bacterial stimulation and showed decreased antimicrobial activity as compared to cells from WT animals. In conclusion, LL‐37 modulates the response of neutrophils to bacterial activation. Cathelicidin controls the release of inflammatory mediators while increasing antimicrobial activity of neutrophils.     

How squalene GLAdly helps generate antigen‐specific T cells via antigen‐carrying neutrophils and IL‐18

The mechanisms by which squalene, which in oil‐and‐water emulsions has been shown to be an excellent formulation for TLR agonists, enhances the magnitude and quality of adaptive immune responses are not thoroughly defined. In this issue of the European Journal of Immunology [Eur. J. Immunol. 2015. 45: 407–417], Desbien et al. show that a squalene/TLR4‐based adjuvant augments antigen‐specific Th1 responses in vaccinated mice through a caspase/IL‐18‐dependent mechanism. This commentary will discuss the authors’ findings in the context of elucidating the mechanism of action of squalene as an adjuvant, and the new questions that the work generates.     

The molecular basis of pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) comprises a heterogenous group of diseases characterized by abnormal surfactant accumulation resulting in respiratory insufficiency, and defects in alveolar macrophage- and neutrophil-mediated host defense. Basic, clinical and translational research over the past two decades have raised PAP from obscurity, identifying the molecular pathogenesis in over 90% of cases as a spectrum of diseases involving the disruption of GM-CSF signaling. Autoimmune PAP represents the vast majority of cases and is caused by neutralizing GM-CSF autoantibodies. Genetic mutations that disrupt GM-CSF receptor signaling comprise a rare form of hereditary PAP. In both autoimmune and hereditary PAP, loss of GM-CSF signaling blocks the terminal differentiation of alveolar macrophages in the lungs impairing the ability of alveolar macrophages to catabolize surfactant and to perform many host defense functions. Secondary PAP occurs in a variety of clinical diseases that presumedly cause the syndrome by reducing the numbers or functions of alveolar macrophages, thereby impairing alveolar macrophage-mediated pulmonary surfactant clearance. A similar phenotype occurs in mice deficient in the production of GM-CSF or GM-CSF receptors. PAP and related research has uncovered a critical and emerging role for GM-CSF in the regulation of pulmonary surfactant homeostasis, lung host defense, and systemic immunity.     

Administration of recombinant human granulocyte-colony stimulating factor to septic neonates induces neutrophilia and enhances the neutrophil respiratory burst and β2 integrin expression Results of a randomized controlled trial

The objective of this study was to investigate the effect of treatment with recombinant human granulocyte-colony stimulating factor (rhG-CSF) on the neutrophil count and function of preterm neonates with documented sepsis. For this purpose 62 preterm neonates with proven sepsis and 19 healthy preterm ones were studied. Of the 62 patients, 27 septic neonates had an absolute neutrophil count (ANC) >5000/mm³ (group A) and were scheduled not to receive rhG-CSF and 35/62 had an ANC <5000/mm³ (n= 35) and were randomly assigned either to receive rhG-CSF (group B) or not to receive it (group C). rhG-CSF (10 μg/kg) was administered for 3 consecutive days (0, 1, 2). The ANC, plasma levels of G-CSF (ELISA), neutrophil respiratory burst activity (NRBA) and neutrophil expression of CD11a, CD11b and CD11c (flow cytometry) were measured in all septic neonates on days 0 (onset of sepsis), 1, 3 and 5 and in the healthy neonates once within the first 2 days of life. We found that on day 0, G-CSF levels of all groups of septic neonates were significantly higher than those of the healthy ones. The highest levels were observed in group A. NRBA was diminished only in groups B and C and the expression of CD11a and CD11c was reduced in all groups of septic neonates. Administration of rhG-CSF resulted in a rapid and significant increase in ANC, NRBA and CD11a, CD11b and CD11c expression that persisted throughout the follow up. Conclusion The administration of granulocyte colony stimulating factor to septic neonates significantly increases the absolute granulocyte count and enhances the neutrophil respiratory burst and β₂ integrin expression. Received: 25 March 1997 and in revised form: 5 August 1997 / Accepted: 14 October 1997     

Intravascular clearance of disseminating Cryptococcus neoformans in the brain can be improved by enhancing neutrophil recruitment in mice

Extrapulmonary dissemination of Cryptococcus neoformans (C. neoformans) is one of the most critical steps in the development of meningoencephalitis. Here, we report that clearance of the disseminating C. neoformans occurs within the brain microvasculature. Interestingly, the efficiency of the intravascular clearance in the brain is reduced compared to that in the lung. Intravascular clearance is mainly mediated by neutrophils, and complement C5a receptor signaling is crucial for mediating neutrophil recruitment in the vasculature. C. neoformans stimulated actin polymerization of neutrophils is critically involved in their recruitment to the lung, which is associated with the unique vascular structure detected in the lung. The relatively lower efficiency of fungal clearance in the brain vasculature correlates with less efficient recruitment of neutrophils. Accordingly, intravascular clearance of C. neoformans in the brain could be remarkably improved by increasing the recruitment of neutrophils. We conclude that neutrophils have the ability to eliminate C. neoformans arrested in the vasculature. However, insufficient recruitment of neutrophils limited the optimal clearance of this microorganism in the brain. These results imply that a therapeutic strategy aimed at enhancing the accumulation of neutrophils could help prevent cryptococcal meningoencephalitis.