Jak3 expression in glomerular epithelia of IgA nephropathy (IgA-N) patients

Jak3 is a member of the Janus kinase family which plays an important role in cytokine signal transduction. Jak3 associates the γ_c chain of receptors for IL-2, IL-4, IL-7, IL-9 and IL-15, and is essential for the signal transduction of these cytokines. We have isolated Jak3 kinase from renal mesangial cells and demonstrated the constitutive expression of Jak3 in glomeruli in vivo. To investigate the physiological and pathological role of Jak3 in glomeruli, we prepared anti-Jak3 antibody and analysed the localization of Jak3 in glomeruli of renal biopsy samples from various nephritis patients and normal subjects. Among 61 nephritis patients and four normal subjects investigated in the present study, Jak3 was selectively localized to glomerular epithelia of IgA-N patients (14/34 cases) and focal glomerulosclerosis patients (1/5 cases), but not detected in minimal changes (n = 6), membranous glomerulonephropathy (n = 7), crescentic glomerulonephritis (n = 4), lupus nephritis patients (n = 5), and normal subjects (n = 4). The intense immunoreactivity for Jak3 is significantly associated with the decrease in creatinine clearance (81.5 ± 10.4 ml/min versus 104.3 ± 29.6 ml/min; P < 0.05, Student’s t-test) and the increase in level of serum creatinine (1.13 ± 0.33 mg/dl versus 0.75 ± 0.23 mg/dl; P < 0.01, Student’s t-test) in IgA-N patients. Furthermore, γ_c chain was concomitantly expressed with Jak3 in glomerular epithelia in vivo and in vitro, suggesting that signal transduction via γ_c-Jak3 cascade may be involved in the pathogenesis of glomerular injury of IgA-N. Taken together with the recent findings that IL-4-secreting T lymphocytes in affected glomeruli injure glomerular epithelium, the responsiveness of glomerular epithelium for IL-4 may be pathologically enhanced in IgA-N.     

Glomerular expression of alpha-smooth muscle actin reflects disease activity of IgA nephropathy

To elucidate the relationship between histological disease states and clinicopathological features in immunoglobulin A nephropathy (IgAN), 90 needle-biopsy specimens diagnosed as IgAN were analyzed. The specimens were divided into four groups according to histological grade and stage index. Immunohistochemical features of alpha-smooth muscle actin (alpha-SMA), macrophages positive for myeloid/histiocyte antigen (MAC387), and expression of type I, III and IV collagens were all examined. Glomerular expression scores of alpha-SMA and the degree of intraglomerular macrophage infiltration were highest in the active and non-sclerotic groups. Type I and IV collagens were significantly more abundant in the sclerotic groups than in the active groups. Type III collagen was strongly expressed in both the active and sclerotic groups. Double immunolabeling of alpha-SMA and intercellular adhesion molecule (ICAM)-1 revealed that ICAM-1 was expressed around the alpha-SMA-positive mesangial area. In multivariate analysis, the glomerular expression score of alpha-SMA was mostly correlated with histological grading in the 10 clinicopathological parameters. Type IV collagen score was mostly correlated with histological staging. These results suggest that glomerular alpha-SMA expression reflects the histological activity of IgAN. Immunohistological staining of alpha-SMA is valuable to estimate the degree of disease activity in IgAN.     

Renal Manifestations in 2007 Korean Patients with Beh?et's Disease

Purpose

Behçet''s disease (BD) theoretically affects all sizes and types of blood vessels and results in multi-organ involvement. However, renal BD has not been fully characterized, though the kidneys are histologically rich in blood vessels.

Materials and Methods

A total of 2007 patients who fulfilled the diagnostic criteria for BD were enrolled in this study. We reviewed the medical records and test results of the BD patients and used univariate and multivariate logistic regression analyses to determine the clinical significance of renal involvement in BD.

Results

Among the 2007 BD patients, we noted hematuria in 412 (20.5%) and proteinuria in 29 (1.4%). Univariate analysis showed that the BD patients with hematuria were predominantly female and older, had higher erythrocyte sedimentation rates (ESRs), and more frequently presented with genital ulcerations. BD patients with proteinuria had higher ESR levels compared to BD patients without proteinuria. In the multivariate analysis, age, sex, and ESR were found to be significantly associated with hematuria in BD patients, whereas only ESR was associated with proteinuria in BD patients. We also found that IgA nephropathy was the most common pathologic diagnosis in 12 renal BD patients who underwent renal biopsies.

Conclusion

We suggest that routine urinalysis and serum renal function tests be performed for the early detection of renal BD, especially in older female BD patients with recurrent hematuria, high ESR levels, and frequent genital ulcers, as well as in BD patients with proteinuria and high ESR levels.     

Distribution of four polymorphisms in the tumour necrosis factor (TNF) genes in patients with inflammatory bowel disease (IBD)

In 153 patients with IBD, 64 with Crohn's disease (CD), and 89 with ulcerative colitis (UC), as well as in 54 healthy controls (HC), the frequencies of four known di-allelic polymorphisms in the genes for TNF-α and lymphotoxin alpha (LTα) were investigated. In the Dutch population, the alleles of these four polymorphisms are present in only five combinations, called TNF haplotypes: TNF-C, -E, -H, -I, -P. Furthermore, the relation with the presence of perinuclear anti-neutrophil cytoplasmic autoantibodies (P-ANCA) was studied. A small, but statistically significant, association between the polymorphism at position -308 in the promoter region of the TNF-α gene and UC was found. The frequency of the uncommon TNF-α -308 allele 2 was found to be decreased in patients with UC compared with HC (allele frequency of allele 2 in UC patients 0·15 versus 0·25 in HC, P = 0·044). No significant differences in distribution of the TNF haplotypes were found between IBD patients and HC, although there was a tendency towards a higher frequency of the TNF-C haplotype in UC patients compared with controls (haplotype frequency 22% versus 13%; P = 0·19). No statistically significant differences in distribution of the TNF haplotypes were observed between P-ANCA-positive and P-ANCA-negative UC patients. The strength of the associations indicates that TNF genes are not markers for the predisposition to suffer from IBD. They may, however, be markers of subsets of patients with UC and CD.     

Genetic neuropathology of Parkinson's disease

Parkinson's disease (PD) has long been considered to be a sporadic entity, perhaps with an environmental etiology. However, recent genetic discoveries have challenged this view, as there are many families with diseases of Mendelian inheritance that clinically resemble PD. Here, we will review in detail the neuropathological data relating to familial cases of PD. We will discuss the complicated relationships between the genetically defined cases and the two key pathological events seen in PD, namely loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of protein inclusions, Lewy bodies, in the neurons that survive to the end stage of the disease course. These observations will be synthesized into an overall scheme that emphasizes the two key aspects of the neuropathology as distinct events and suggest that each gene tells us something a little different about the neuropathology of PD.     

Role of γδ T lymphocytes in the development of Behçet's disease

Phenotypic and functional properties of γδ T cells, which play an important role in mucocutaneous immunity, were examined to elucidate whether immunological abnormality in Behc¸et's disease may be related to a specific T cell population. We found that CD45RA⁺Vγ9⁺Vδ2⁺γδ T cells, which constitute a minor population of γδ T cells in healthy individuals, were increased in number in Behc¸et's disease irrespective of disease activity. This CD45RA⁺ subset of γδ T cells in the active, but not inactive, phase of this disease expressed IL-2Rβ and HLA-DR, suggesting that they are activated in vivo in active Behc¸et's disease. In addition, the CD45RA⁺γδ T cells produced extreme amounts of tumour necrosis factor and contained perforin granules. These data indicate that a phenotypically distinct subset of γδ T cells, CD45RA⁺CD45RO⁻Vγ9⁺Vδ2⁺, may contribute to immunological abnormalities which may lead to complexity of pathophysiology in Behc¸et's disease.     

Amyloid generation and dysfunctional immunoproteasome activation with disease progression in animal model of familial Alzheimer's disease

Double-transgenic amyloid precursor protein/presenilin 1 (APP/PS1) mice express a chimeric mouse/human APP bearing the Swedish mutation (Mo/HuAPP695swe) and a mutant human PS1-dE9 both causative of familial Alzheimer's disease (FAD). Transgenic mice show impaired memory and learning performance from the age of 6 months onwards. Double-transgenic APP/PS1 mice express altered APP and PS1 mRNAs and proteins, reduced β-secretase 1 (BACE1) mRNA and normal BACE1 protein, all of which suggest a particular mechanism of amyloidogenesis when compared with sporadic AD. The first β-amyloid plaques in APP/PS1 mice appear at 3 months, and they increase in number and distribution with disease progression in parallel with increased levels of brain soluble β-amyloid 1-42 and 1-40, but also with reduced 1-42/1-40 ratio with age. Amyloid deposition in plaques is accompanied by altered mitochondria and increased oxidative damage, post-translational modifications and accumulation of altered proteins at the dystrophic neurites surrounding plaques. Degradation pathways are also modified with disease progression including activation of the immunoproteasome together with variable alterations of the different protease activities of the ubiquitin-proteasome system. Present observations show modifications in the production of β-amyloid and activation and malfunction of the subcellular degradation pathways that have general implications in the pathogenesis of AD and more particularly in specificities of FAD amyloidogenesis.     

The increased but non-predominant expression of Th17- and Th1-specific cytokines in Hashimoto's thyroiditis but not in Graves' disease

Hashimoto''s thyroiditis (HT) is considered to be mediated mainly by Th1 cells, but it is not known whether Graves'' disease (GD) is associated with Th1 or Th2 predominance. Th17 cells, a novel subset of Th cells, play a crucial role in the pathogenesis of various autoimmune disorders. In the present study, the expression of IL-17A and IFN-γ was investigated in patients with HT or GD. mRNA expression of IL-17A and IFN-γ in peripheral blood mononuclear cells (PBMC) from 43 patients with autoimmune thyroid disease (AITD) and in thyroid tissues from 40 AITD patients were measured by real-time quantitative PCR. The protein expression of IL-17A and IL-23p19 was examined by immunohistochemistry in thyroid tissues from 28 AITD patients. The mRNA levels of IL-17A and IFN-γ were higher in both PBMC and thyroid tissues of HT patients than in controls (mRNA levels are reported as the cytokine/β-actin ratio: IL-17 = 13.58- and 2.88-fold change and IFN-γ = 16.54- and 2.74-fold change, respectively, P < 0.05). Also, the mRNA levels of IL-17A and IFN-γ did not differ significantly in GD patients (P > 0.05). The high protein expression of IL-17A (IOD = 15.17 ± 4.8) and IL-23p19 (IOD = 16.84 ± 7.87) in HT was confirmed by immunohistochemistry (P < 0.05). The similar high levels of IL-17A and IFN-γ suggest a mixed response of Th17 and Th1 in HT, where both cells may play important roles in the destruction procedure by cell-mediated cytotoxicity.     

Buerger's disease as an indicator of socioeconomic development in different societies,a cross-sectional descriptive study in the North-East of Iran

Introduction

Nowadays, Buerger''s disease (BD) is more common in the developing countries of Asia. Although its prevalence is going to decrease in the developed countries, its decline rate is not in parallel with that for smoking in these countries. Since the number of BD patients reported to MVasRc is increasing annually and its pathogenesis is unknown, the aim of the study was to investigate the smoking habits and socioeconomic status of the patients corresponding with Shionoya''s criteria.

Material and methods

Poverty line was the key factor of economic condition. Hygiene, education, professional occupation, long-term unemployment and healthy work were considered as social indices. Patients under the poverty line in addition to weakness in more than two social indices were included in low socioeconomic classification.

Results

From the total of 86 patients who reported to MVasRc during the 22-month study period, 71.6% and > 95% were new cases of BD and in low socioeconomic status respectively. Smoking ranged from 2 to 80 cigarettes/day. The duration of smoking before the onset of BD varied from 2 months to 35 years.

Conclusions

There is a lack of correspondence between BD and decline in the prevalence of smoking in developed countries. Also, duration and smoking habit varied in the studied patients. On the other hand, the strong dependence of BD on low socioeconomic conditions, as revealed in this research, implies that socioeconomic status may be a risk factor for initiation of BD. Moreover, the prevalence of BD might be an indicator of socioeconomic development in different societies.     

Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) gene interactions with the apolipoprotein E epsilon4 allele as risk factors in Alzheimer's disease and in Parkinson's disease with coexisting Alzheimer pathology

Alzheimer's disease (AD) and Parkinson's disease (PD) are genetically heterogeneous. Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) genes may modify the risk of these disorders. We investigated whether common polymorphisms present in these genes operate as risk factors for AD and PD in Finnish subjects, independently or in concert with the apolipoprotein E ε4 allele (APOE ε4). Eighty late onset sporadic AD patients, 53 PD patients (34 of whom had concomitant AD pathology), and 67 control subjects were genotyped for the insertion (I)/deletion (D) polymorphism of DCP1 and the K variant of BCHE. In logistic regression analysis, the DCP1 *I allele in combination with APOE ε4 significantly increased the risk of AD (OR 30.0, 95% CI 7.3-123.7), compared to subjects carrying neither of the alleles. Similar analysis showed that the risk of AD was significantly increased in subjects carrying both the BCHE wild type (*WT/*WT) genotype and ε4 (OR 9.9, 95% CI 2.9-33.8), compared to those without this BCHE genotype and ε4. Further, the risk of PD with AD pathology was significantly increased for carriers of DCP1 *I and ε4 (OR 8.0, 95% CI 2.1-31.1). We thus conclude that, in Finns, interaction between DCP1 *I and ε4 increases the risk of AD as well as of PD with coexisting Alzheimer pathology, which underlines the importance of the DCP1 I/D polymorphism in the development of Alzheimer neuropathology, whereas the wild type BCHE genotype in combination with ε4 had a combined effect with regard to the risk of AD.


Keywords: Alzheimer's disease; Parkinson's disease; dipeptidyl carboxypeptidase 1; butyrylcholinesterase     

Tissue transglutaminase, protein cross-linking and Alzheimer's disease: review and views

Extensive protein cross-linking and aggregation are some of the most common molecular events in the pathogenesis of Alzheimer's disease (AD). Both beta-amyloid (Abeta) plaques and neurofibrillary tangles, which are extracellular and intracellular proteinaceous aggregates, respectively, contribute to neuronal death and progressive cognitive decline. Although protein cross-linking has been recognized and extensively studied for many years, the underlying mechanisms are largely unknown. Recent data indicates that tissue transglutaminase (tTG), which catalyzes the cross-linking of a wide spectrum of proteins including Abeta, tau, alpha-synuclein and neurofilament proteins, may be involved in protein aggregation in AD. Many AD risk factors, such as trauma, inflammation, ischemia and stress, up-regulate tTG protein and activity levels. In this review, we summarize the evidence that tTG plays a role in AD, especially in cross-linking of Abeta, tau, alpha-synuclein and neurofilament proteins. An experimentally testable hypothesis is that tTG may play a central role in AD pathogenesis and that it provides a conceptual link between sporadic and familial AD through a shared pathogenic pathway.     

Capsaicin induces high expression of BAFF and aberrantly glycosylated IgA1 of tonsillar mononuclear cells in IgA nephropathy patients

Background

IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis in the world. Hot pepper is the most favorite vegetable for Chinese in Hunan and Sichuan provinces. It can be assumed that capsaicin, the active ingredient of hot pepper, is a possible risk factor in diet in the pathogenesis of IgAN.

Methods

22 subjects, including 11 IgAN patients and 11 non-IgAN patients were enrolled in this study. Tonsillar mononuclear cells were isolated and cultured for 3 days with or without capsaicin.

Results

In the absence and presence of capsaicin, the BAFF expression and IgA1 secretion were higher in IgAN patients than that in non-IgAN patients, meanwhile, the gene expression of C1GALT1 and Cosmc and IgA1 O-glycosylation level were significantly lower. In IgAN group, coincubated with capsaicin, IgA1 and BAFF secretion and BAFF expression by TMCs were significantly higher than that without capsaicin, furthermore, the level of mRNA encoding C1GALT1 and Cosmc and the level of IgA1 O-glycosylation were evidently lower.

Conclusion

Capsaicin may induce IgA1 secretion by activating BAFF expression, and bring to aberrantly IgA1 O-glycosylation by suppressing C1GALT1 and Cosmc expression. Therefore, to limit the consumption of hot pepper would be beneficial to patients with IgA nephropathy.     

Expression of functional Toll-like receptors by salivary gland epithelial cells: increased mRNA expression in cells derived from patients with primary Sjögren's syndrome

Alpha-fodrin, an intracellular organ-specific cytoskeleton protein, was identified recently as an autoantigen associated with Sicca- and Sjögren''s syndrome (SS). Identification of the antigenic determinants of α-fodrin is a prerequisite to developing highly sensitive and specific anti-α-fodrin antibodies, which provides potential means for the diagnosis of primary Sjögren''s syndrome (pSS) in patients. Based on the structure and predicted antigenic sites of α-fodrin protein with 560 amino acids (α-fodrin 560), we prepared a set of overlapping recombinant protein fragments covering antigenic epitopes and synthesized a set of peptides derived from the α-fodrin protein. These recombinant proteins and synthesized peptides were subjected to screening with pSS patients sera, respectively. The peptide with the strongest immunoreactivity was used as antigenic peptide to define further the role of anti-α-fodrin-peptide antibodies in the sera of 135 patients with pSS, 48 patients with systemic lupus erythematosus (SLE), 88 patients with rheumatoid arthritis (RA) and 83 normal controls. Our data showed that the N-terminal peptide of amino acids 46–59 (N46) of α-fodrin 560 was the epitope with strongest antigenicity. The prevalences of anti-N46 peptide antibodies (α-N46PA) in patients with pSS, SLE, RA and normal controls were 78.5%, 10.4%, 21.6% and 6.0%, respectively. The sensitivity and specificity of the autoantibodies in pSS were 78.5% and 86.8%, respectively. These results suggest the α-N46PA which shows highest sensitivity and specificity is of significance to develop an effective diagnostic approach for pSS.     

Increase in B-cell-activation factor (BAFF) and IFN-gamma productions by tonsillar mononuclear cells stimulated with deoxycytidyl-deoxyguanosine oligodeoxynucleotides (CpG-ODN) in patients with IgA nephropathy

IgA nephropathy (IgAN), the most common form of primary glomerulonephritis, is recognized as a tonsil-related diseases since it often gets worse after and/or during acute tonsillitis and the disease progression is often prevented by tonsillectomy. Although several reports showed an increase in IgA production of tonsillar mononuclear cells (TMCs), its mechanism has not yet been fully clarified. Recently, B-cell-activation factor (BAFF), which stimulates B-cell proliferation and immunoglobulin production, was identified. Unmethylated deoxycytidyl-deoxyguanosine oligodeoxynucleotide (CpG-ODN), which is able to mimic the immunostimulatory activity of microbial DNA, is known to be involved in the production of immunoglobulins and some cytokines. In this study, we focused on roles of BAFF and IFN-gamma in IgA production of TMCs stimulated with CpG-ODN in IgAN patients. Two-color flow cytometric analysis revealed that the intercellular expression of IFN-gamma on the T-cells freshly isolated from tonsils was significantly higher in IgAN patients than in non-IgAN patients (p=0.032). The spontaneous productions of IgA and IFN-gamma of TMCs were significantly higher in IgAN patients than in non-IgAN patients (p=0.023 and p=0.02). Under stimulation with CpG-ODN, the productions of IgA, BAFF and IFN-gamma of TMCs were significantly higher in IgAN patients than in non-IgAN patients (p=0.013, p=0.005 and p=0.039). The IgA production of TMCs stimulated by CpG-ODN was inhibited by the treatment with anti-BAFF antibody and/or anti-IFN-gamma antibody. Under stimulation with IFN-gamma, the BAFF expression on the CD1c cells and the BAFF production of TMCs were significantly higher in IgAN patients than in non-IgAN patients (p=0.004 and p=0.042). These data suggest that hyper-immune response to microbial DNA may be present in IgAN patients and may lead to hyperproduction of BAFF up-regulated by IFN-gamma, resulting in hyperproduction of IgA in IgAN patients.     

miR-375 enhances palmitate-induced lipoapoptosis in insulin-secreting NIT-1 cells by repressing myotrophin (V1) protein expression

Lipoapoptosis of pancreatic β cells caused by elevated circulating free fatty acids (FFAs) has now been recognized to be a pivotal factor contributing to β cellular dysfunction and β-mass lose in type 2 diabetes. Although recent studies suggested an important role for the ceramide pathway in the late destructive phase of lipid overload in the pancreatic β cells, the overall underlying mechanisms leading to lipoapoptosis, however, remained poorly understood. mir-375 was recently characterized to be a pancreatic islet-specific miRNA implicated in the regulation of insulin secretion and β-mass turnover. In the present study we further examined its effect on palmitate-induced lipoapoptosis in NIT-1 cells, a NOD-derived β-cell line. It was found that NIT-1 cells with ectopic mir-375 expression were much more susceptible to palmitate-induced lipoapoptosis. In contrast, knockdown of endogenous pri-mir-375 expression by a modified antisense oligo, 2''-O-me-375, almost completely protected NIT-1 cells from palmitate-induced lipoapoptosis. We further demonstrated that mir-375 could target V1 mRNA and repress its translation. Consistent with this assumption, NIT-1 cells transfected with 2''-O-me-375 showed significant higher levels of V1 protein after palmitate induction. Together, our data suggest that mir-375 could be a potential therapeutic target for prevention and intervention of β-cell dysfunction and β-mass lose in type 2 diabetes.     

Perivascular neuritic dystrophy associated with cerebral amyloid angiopathy in Alzheimer's disease

Cerebral amyloid angiopathy (CAA) affects both leptomeningeal and parenchymal blood vessels and is common in Alzheimer's disease (AD). In some vessels, CAA is accompanied by localized neuritic dystrophy around the affected blood vessel. The aim of this study was to assess the distribution and severity of perivascular neuritic dystrophy in primary visual and visual association cortices. The severity of perivascular neuritic dystrophy and Abeta deposition was scored in an association cortex (Brodmann area 18) and a primary cortex (Brodmann area 17) with double labeling immunohistochemistry for tau and Abeta in 31 cases of AD with severe CAA. The perivascular tau neuritic dystrophy score was significantly worse in visual association cortex than in primary visual cortex. On the other hand, there was no difference in the perivascular Abeta score between the two cortices. There were positive correlations between the severity of perivascular tau and perivascular Abeta scores for both primary and association cortices. The results suggest that the local neuronal environment determines the severity and nature of the perivascular neuritic pathology more than the severity of the intrinsic vascular disease and suggest a close association between perivascular amyloid deposits, so-called dyshoric angiopathy, and perivascular neuritic dystrophy.     

Fibrinogen-like protein 2 expression correlates with microthrombosis in rats with type 2 diabetic nephropathy

Fibrinogen-like protein 2 (fgl2),a novel prothrombinase,is involved in microthrombosis.We examined fgl2 expression in the glomerular and tubulointerstitial capillaries and its correlation with microthromsis in rats with streptozocin-induced type 2 diabetic nephropathy.Our RT-PCR and immunoblotting analysis showed that fgl2 mRNA and protein levels were increased in microvascular endothelial cells of the glomeruli and renal interstitia at week 19 and became significantly elevated with the development of diabetic nephropathy (P < 0.01).Fgl2 was not or only weakly expressed in the renal tissues of normal rats.Furthermore,a direct significant correlation (r=0.543,P < 0.01) was found between fgl2 expression and microthrombotic capillaries in the renal tissues.Enzyme linked immunosorbent assays (ELISA) additionally showed that circulating TNF-α levels in rats with type 2 diabetes were significantly elevated and closely correlated with fgl2 expression (r=0.871,P < 0.01).Our results suggest that fgl2 may activate renal microthrombosis,thus contributing to glomerular hypertension and renal ischemia.     

Plasma seprase and DPP4 levels as markers of disease and prognosis in cancer

Seprase (fibroblast activation protein α) has been examined as an invasion biomarker for various types of solid tumors. We studied whether plasma levels of seprase and homologous protease, DPP4 in cancer might serve as tumor biomarkers. We developed sensitive and specific Enzyme-Linked Immunosorbent Assays (ELISAs) to measure these proteases. In 747 plasma samples (from 139 healthy volunteers and 561 cancer patients), mean seprase and DPP4 levels were 0.51 ± 0.30 and 4.65 ± 6.37 μg/mL, respectively, and they were correlated with each other (R(2) = 0.382). Plasma DPP4 and seprase levels were significantly lower in cancer patients compared with healthy subjects (4.38 versus 5.65 μg/mL, p< 0.001 for DPP4; 0.46 versus 0.66 μg/mL, p< 0.001 for seprase). Higher DPP4 was associated with better survival in all cancers combined (n=346) as well as in head and neck malignancies (n=38). Higher seprase was associated with better survival in all non-metastatic cancers combined (n=151) as well as head and neck malignancies, but worse survival in colorectal cancers (n=47). This study demonstrates that in contrast to the high expression in solid tumors, plasma concentrations of seprase and DPP4 are reduced and correlate inversely with survival in most types of cancer, suggesting that these circulating proteases represent useful tumor markers.     

Differential distribution of B7.1 (CD80) and B7.2 (CD86) costimulatory molecules on mucosal macrophage subsets in human inflammatory bowel disease (IBD)

The molecules B7.1 and B7.2 deliver costimulatory signals of critical importance to naive T cells, and may thus be involved in abrogation of oral tolerance in IBD. Functional disparity apparently exists among antigen-presenting cells in vivo. We wanted to examine if differential B7 expression occurs on mucosal macrophage subsets. Cryosections of bowel specimens from patients with IBD and normal controls were subjected to immunofluorescence and immunoperoxidase staining. In normal mucosa, selective subepithelial accumulation of B7.2⁺ cells was found. In inflamed IBD mucosa, however, subsets appeared consisting of both B7.2^hi and B7.1^hi cells as well as CD14^hi macrophages. Notably, outside lymphoid aggregates the prominent fraction of recently recruited CD14^hi macrophages comprised most (≈ 80%) of the B7.1^hi cells, whereas most (≈ 70%) B7.2^hi cells were identified as resident mucosal macrophages (CD14^lo or CD14⁻). Differential expression of B7.1 and B7.2 on two functionally different subsets of intestinal macrophages implies separate immunoregulatory roles for the two molecules. This finding is in keeping with recent experimental data demonstrating that monocyte-derived cells are crucial for immune responses at mucosal surfaces. Preferential B7.1 up-regulation might be critical in breaking the immunological tolerance to luminal antigens in IBD, but it cannot be excluded that it is a secondary pathogenic event.