Diabetic nephropathy (DN) is currently the most common complication of diabetes. It is considered to be one of the leading causes of end-stage renal disease (ESRD) and affects many diabetic patients. The pathogenesis of DN is extremely complex and has not yet been clarified; however, in recent years, increasing evidence has shown the important role of innate immunity in DN pathogenesis. Pattern recognition receptors (PRRs) are important components of the innate immune system and have a significant impact on the occurrence and development of DN. In this review, we classify PRRs into secretory, endocytic, and signal transduction PRRs according to the relationship between the PRRs and subcellular compartments. PRRs can recognize related pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), thus triggering a series of inflammatory responses, promoting renal fibrosis, and finally causing renal impairment. In this review, we describe the proposed role of each type of PRRs in the development and progression of DN.
Alarmins/physiology* ; C-Reactive Protein/physiology* ; Diabetic Nephropathies/etiology* ; Endocytosis ; Humans ; Immunity, Innate ; Mannose-Binding Lectin/physiology* ; Pathogen-Associated Molecular Pattern Molecules ; Receptors, Pattern Recognition/physiology* ; Serum Amyloid P-Component/physiology* ; Signal Transduction

BACKGROUND: Mannose-binding lectin (MBL) deficiency leads to increased susceptibility to infection. We investigated whether serial changes in MBL levels are associated with the prognosis of patients diagnosed with septic shock, and correlated with cytokine levels. METHODS: We enrolled 131 patients with septic shock in the study. We analyzed the serum samples for MBL and cytokine levels at baseline and 7 days later. Samples on day 7 were available in 73 patients. RESULTS: We divided the patients with septic shock into four groups according to serum MBL levels ( < 1.3 µg/mL or ≥1.3 µg/mL) on days 1 and 7. Patients with low MBL levels on day 1 and high MBL levels on day 7 showed a favorable prognosis for 28-day survival (odds ratio, 1.96, 95% confidence interval, 1.10–2.87; p=0.087). The high MBL group on day 7 showed a significant decrease in monocyte chemoattractant protein 1, interleukin (IL)-1β, IL-6, IL-8, interferon-γ, and granulocyte macrophage colony-stimulating factor levels compared with the low MBL group on day 7. CONCLUSION: The increase in MBL levels of patients with septic shock may suggest a favorable prognosis and attenuate pro-inflammatory and anti-inflammatory responses.
Chemokine CCL2 ; Cytokines ; Granulocytes ; Humans ; Interleukin-6 ; Interleukin-8 ; Interleukins ; Macrophage Colony-Stimulating Factor ; Mannose-Binding Lectin* ; Prognosis ; Sepsis* ; Shock, Septic

Baker's asthma is the most prevalent occupational asthma, and IgE-mediated response is known as a major pathogenesis. However, recent studies have suggested the involvement of innate immune response because wheat flour contains bacterial endotoxins or lipopolysaccharides. To further understand a role of innate immune response in the development of work-related respiratory symptoms (WRS) in bakery workers, we investigated mannose-binding lectin (MBL), one of the initiating components of the complement cascade in a single cohort of bakery workers. A total of 373 bakery workers completed a questionnaire regarding WRS. The bakery workers were divided into 2 groups according to previous history of allergic rhinitis (AR)/bronchial asthma (BA): those with history of AR/BA (group I) and those without (group II). We measured serum MBL levels by using enzyme-linked immunosorbant assay and genotyped 4 single nucleotide polymorphisms of the MBL2 gene (226G>A in exon 1, -554G>C, -431A>C, and -225G>C in the promoter) by using TaqMan assays. Fifty-nine subjects (15.5%) were previously diagnosed with AR/BA, and 64 subjects (16.8%) complained of WRS. No significant differences were found in serum MBL levels between groups I and II. However, in group II subjects, but not in group I subjects, the serum MBL levels were significantly higher in bakery workers with WRS than in those without. In addition, the serum MBL levels were significantly different according to genetic polymorphisms of the MBL2 gene and its haplotypes. In conclusion, serum MBL, affected by genetic polymorphisms, may be associated with WRS in bakery workers with no previous history of AR/BA.
Asthma ; Asthma, Occupational ; Cohort Studies ; Complement System Proteins ; Endotoxins ; Exons ; Flour ; Haplotypes ; Immunity, Innate ; Lipopolysaccharides ; Mannose-Binding Lectin ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Rhinitis, Allergic ; Triticum

BACKGROUND: Human mannose-binding lectin (MBL) is a serum lectin taking part in the innate immunity by opsonizing various microorganisms for phagocytosis. The MBL serum concentration is affected by several single-nucleotide polymorphisms (SNPs) in the promoter region of the MBL2 gene. OBJECTIVE: The purpose of this study was to examine the relationship between MBL2 polymorphisms and atopic dermatitis (AD) susceptibility. METHODS: To examine whether the MBL2 SNPs are related to AD susceptibility, we examined 237 patients with AD and 94 controls by polymerase chain reaction (PCR)-restriction fragment length polymorphism and PCR-sequence specific primer analyses of four polymorphic loci: two (H/L and X/Y) within the promoter region and the other two (P/Q and A/B) within exon 1. MBL concentrations in the blood were estimated by ELISA. RESULTS: The prevalence of haplotype HYPB, leading to MBL deficiency, was significantly decreased in the AD patients compared to the controls (p=0.002), while the prevalence of haplotype HYPA was increased with a clear trend toward significance (p=0.056). The frequency of MBL2 LYPB/LXPA (odds ratio, 0.08; 95% confidence interval, 0.009~0.655; p=0.021) were significantly decreased in the AD patients. The blood log [total immunoglobulin E, IgE] levels of MBL2 HYPA/HYPA, HYPA/LYPA, HYPA/LYPB, HYPA/LYQA, and LYQA/LXPA haplotype pairs were significantly increased in the AD patients. CONCLUSION: The frequency of MBL2 HYPB haplotype was significantly decreased in the AD patients compared to the controls. The frequency of LYPB/LXPA had a possibly protective effect on AD. Moreover, the MBL2 HYPA haplotype pairs, which were related to higher blood total IgE levels, were possibly associated with extrinsic AD.
Dermatitis, Atopic* ; Enzyme-Linked Immunosorbent Assay ; Exons ; Haplotypes ; Humans ; Immunity, Innate ; Immunoglobulin E ; Immunoglobulins ; Mannose-Binding Lectin ; Phagocytosis ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Prevalence ; Promoter Regions, Genetic

OBJECTIVETo investigate the effect of low-selenium diet on the liver and kidneys of rats and explore the role of macrophage polarization into M1 and M2 phenotypes in liver and kidney injuries.

METHODSTwenty-four rats (12 female and 12 male) were randomly divided into control group and low-selenium group and fed with normal chow (dietary selenium of 0.18 mg/kg) and low-selenium diet (dietary selenium of 0.02 mg/kg) for 109 days. After the feeding, the rats were sacrificed for HE staining to observe liver and kidney pathologies, and immunohistochemistry was performed for analyzing CCR7, CD206, CD163-positive cell numbers in the liver and kidneys.

RESULTSThe rats in low-selenium group showed severer fibrosis in the liver and kidney than the control group. In either male or female rats in low-selenium group, CCR7 and CD206 expressions in the liver were comparable with those in control group, but CD163 expression was lower than that in the control group (P<0.05 for both female and male rats). In the kidney, the proximal tubule showed a slightly higher while the distal tubule showed a slightly lower CCR7 expression in low selenium group than in the control group (P>0.05). In low-selenium group, a significantly lower CD163 expression in the distal tubule and a significantly higher CD206 expression in the proximal tubule were noted as compared with the control group (P<0.05 in both female and male rats). Compared with the control rats, the male rats in low-selenium group, but not the female rats, showed a significantly lower CD163 expression in the proximal tubule of the kidney (P<0.05); the female but not the male rats in low-selenium group show a higher CD206 expression in the distal tubule (P<0.05).

CONCLUSIONLow-selenium diet can cause liver and kidney fibrosis in rats and may inhibit macrophage activation into the M2 phenotype.

Animals ; Antigens, CD ; metabolism ; Antigens, Differentiation, Myelomonocytic ; metabolism ; Diet ; Female ; Fibrosis ; Kidney ; metabolism ; pathology ; Lectins, C-Type ; metabolism ; Liver ; metabolism ; pathology ; Macrophage Activation ; Male ; Mannose-Binding Lectins ; metabolism ; Rats ; Receptors, CCR7 ; metabolism ; Receptors, Cell Surface ; metabolism ; Selenium ; administration & dosage

OBJECTIVETo investigate the correlation among serum levels of manning-binding lectin (MBL), MBL-associated serine proteases-2 (MASP-2), complement Cand high-sensitive C reactive protein (HsCRP) in patients with rheumatoid arthritis (RA).

METHODSFasting venous blood were collected from 50 RA patients (25 in active stage and 25 in remission) and 40 healthy subjects for detecting serum levels of MBL, MASP-2, complement Cand HsCRP using enzyme-linked immunosorbent assay (ELISA) and immune turbidity assay.

RESULTSThe serum levels of MBL and MASP-2 were significantly lower and HsCRP level was significantly higher in patients with RA (in both acute stage and remission) than in the healthy control group (P<0.05), but complement Clevel was similar between the RA patients and control group. Bivariate Pearson correlation analysis showed that in RA patients, MBL was positively correlated with MASP-2 level (r=0.550, P=0.001) and negatively with HsCRP (r=-0.323, P=0.022) but not correlated with C(r=-0.022, P=0.882); MASP-2 was negatively correlated with HsCRP (r=0.453, P=0.453) and was not correlated with C(r=0.049, P=0.738). ROC curve analysis revealed the largest area under curve (AUC) of HsCRP (0.844, P=0.001) and smaller AUCs of MBL (0.025, P=0.001) and MASP-2 (0.266, P=0.001). HsCRP had a much higher sensitivity (84%) than MBL (10%) and MASP-2 (40%) in the diagnosis of RA.

CONCLUSIONIn RA patients, MBL and MASP-2 are negatively correlated with HsCRP level. Serum MBL and MASP-2 levels decrease with the progression of joint injury in RA patients, suggesting their involvement in the pathological process of RA; but due to their low sensitivity, they are not appropriate indicators for evaluating the disease activity of RA.

Arthritis, Rheumatoid ; blood ; C-Reactive Protein ; analysis ; Case-Control Studies ; Complement C3 ; analysis ; Enzyme-Linked Immunosorbent Assay ; Humans ; Mannose-Binding Lectin ; blood ; Mannose-Binding Protein-Associated Serine Proteases ; analysis

Polymeric micelles have exhibited attractive properties as drug carriers, such as high stability in vivo and good biocompatibility, and been successfully used to dissolve various drugs of poor aqueous solubilities. In this study, we developed a new type of polymeric micelles with mannose-mediated targeting and pH-responsive drug release properties for anticancer drug delivery. The polymeric micelles were prepared from an amphiphilic polymer, poly (glycidyl methacrylate)-g-mannose (PGMA-Mannose). An anticancer drug, doxorubicin (DOX), was encapsulated into the micelles during the micellization, and could be released rapidly under acidic condition. The specificity of cellular uptake of the micelles by two different cell lines was studied using confocal laser scanning microscopy and the MTT assay. DOX-loaded micelles were efficiently trapped by mannose-receptor-overexpressing cancer cells MDA-MB-231, whereas mannose- receptor-poor cells HEK293 showed much lower endocytosis towards the micelles under the same conditions. Thus, DOX-loaded micelles displayed higher cytotoxicity to MDA-MB-231 cancer cells as compared with free DOX. The present study demonstrates that PGMA-Mannose micelles are a promising targeted drug delivery system for cancer therapy.
Cell Line, Tumor ; Doxorubicin ; pharmacology ; Drug Delivery Systems ; HEK293 Cells ; Humans ; Lectins, C-Type ; metabolism ; Mannose ; chemistry ; Mannose-Binding Lectins ; metabolism ; Micelles ; Receptors, Cell Surface ; metabolism

BACKGROUND/AIMS: This animal study aimed to define the underlying cellular mechanisms of intestinal barrier dysfunction. METHODS: Rats were fed 4% with dextran sodium sulfate (DSS) to induce experimental colitis. We analyzed the sugars in 24-hour urine output by high pressure liquid chromatography. The expression of claudins, mannan-binding lectin (MBL), and MBL-associated serine proteases 2 (MASP-2) were detected in the colonic mucosa by immunohistochemistry; and apoptotic cells in the colonic epithelium were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method assay. RESULTS: The lactulose and sucralose excretion levels in the urine of rats with DSS-induced colitis were significantly higher than those in the control rats. Mannitol excretion was lower and lactulose/mannitol ratios and sucralose/mannitol ratios were significantly increased compared with those in the control group (p<0.05). Compared with the controls, the expression of sealing claudins (claudin 3, claudin 5, and claudin 8) was significantly decreased, but that of claudin 1 was increased. The expression of pore-forming claudin 2 was upregulated and claudin 7 was downregulated in DSS-induced colitis. The epithelial apoptotic ratio was 2.8%+/-1.2% in controls and was significantly increased to 7.2%+/-1.2% in DSS-induced colitis. The expression of MBL and MASP-2 in the intestinal mucosa showed intense staining in controls, whereas there was weak staining in the rats with colitis. CONCLUSIONS: There was increased intestinal permeability in DSS-induced colitis. Changes in the expression and distribution of claudins, increased epithelial apoptosis, and the MASP-2-induced immune response impaired the intestinal epithelium and contributed to high intestinal permeability.
Animals ; Apoptosis/*physiology ; Claudins/*metabolism ; Colitis/chemically induced/immunology/*physiopathology ; Colon/immunology/physiopathology ; Dextran Sulfate ; Intestinal Mucosa/*physiopathology ; Lactulose/metabolism ; Mannitol/metabolism ; Mannose-Binding Lectin/*immunology ; Permeability ; Rats ; Rats, Sprague-Dawley ; Sucrose/analogs & derivatives/metabolism ; Up-Regulation

No abstract available.
Animals ; Apoptosis/*physiology ; Claudins/*metabolism ; Colitis/*physiopathology ; Intestinal Mucosa/*physiopathology ; Mannose-Binding Lectin/*immunology

Diisocyanate (DI) is the most common cause of occupational asthma (OA) in Korea. Mannose-binding lectin (MBL) initiates the lectin complement activation pathway following oxidative stress and plays an important role in the regulation of inflammatory processes. To determine whether there is a genetic association between MBL2 polymorphisms and DI-OA, 99 patients with DI-OA, 99 asymptomatic exposed controls (AECs) and 144 unexposed normal controls were enrolled in this study. Three polymorphisms (-554 G>C, - 431A>C and - 225 G>C) in the MBL2 promoter were genotyped, and serum MBL levels were determined by enzyme-linked immunosorbent assay. Functional variabilities in the promoter polymorphisms were analyzed by a luciferase reporter assay and electrophoretic mobility shift assay (EMSA). A significantly higher frequency of haplotype (ht) 2 [CAG] was noted in the DI-OA group compared with the AEC group (P=0.044). The patients with DI-OA carrying ht2 [CAG] had significantly lower PC20 methacholine levels (P<0.001) than the non-carriers. The serum MBL levels were significantly higher in the DI-exposed subjects (both the DI-OA patients and AECs) carrying ht1 [GAG] (P=0.028). Luciferase activity was significantly enhanced in ht1 [GAG] compared with ht2 [CAG] in human hepatocarcinoma cells (Hep3B) (P=0.002). The EMSA showed that a - 554G probe produced a specific shifted band compared with the - 554C probe. These findings suggest that decreased serum MBL levels due to polymorphisms of the MBL2 gene may increase susceptibility to the development of DI-OA in DI-exposed individuals.
Adult ; Alleles ; Asthma, Occupational/diagnosis/*etiology ; Cell Line ; Female ; Forced Expiratory Volume ; Gene Frequency ; Genotype ; Haplotypes ; Humans ; Immunoglobulin E/immunology ; Immunoglobulin G/immunology ; Isocyanates/*adverse effects/immunology ; Male ; Mannose-Binding Lectin/blood/*genetics ; Middle Aged ; *Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Protein Binding ; Transcriptional Activation ; Young Adult