Mood Disorder in Systemic Lupus Erythematosus Induced by Antiribosomal P Protein Antibodies Associated with Decreased Serum and Brain Tryptophan.

Antiribosomal P protein (anti-P) autoantibodies commonly develop in patients with systemic lupus erythematosus. We have previously established hybridoma clones producing anti-P mAbs. In this study, we explored the pathogenesis of behavioral disorders induced by anti-P Abs using these mAbs. New Zealand Black × New Zealand White F1, New Zealand White, C57BL/6, and BALB/c mice were treated with 1 mg of anti-P Abs once every 2 wk. The behavioral disorder was evaluated by the tail suspension test, forced swim test, and open field test. Following administration of anti-P Abs, New Zealand Black × New Zealand White F1 and C57BL/6 mice developed depressive behavior and showed increased anxiety with elevated serum TNF-α and IL-6 levels. Anti-P Abs were not deposited in the affected brain tissue; instead, this mood disorder was associated with lower serum and brain tryptophan concentrations. Tryptophan supplementation recovered serum tryptophan levels and prevented the behavioral disorder. TNF-α and IL-6 were essential for the decreased serum tryptophan and disease development, which were ameliorated by treatment with anti-TNF-α neutralizing Abs or dexamethasone. Peritoneal macrophages from C57BL/6 mice produced TNF-α, IL-6, and IDO-1 via interaction with anti-P Abs through activating FcγRs, which were required for disease development. IVIg, which has an immunosuppressive effect partly through the regulation of FcγR expression, also prevented the decrease in serum tryptophan and disease development. Furthermore, serum tryptophan concentrations were decreased in the sera of systemic lupus erythematosus patients with anti-P Abs, and lower tryptophan levels correlated with disease activity. Our study revealed some of the molecular mechanisms of mood disorder induced by anti-P Abs.

Association of coexisting anti-ribosomal P and anti-dsDNA antibodies with histology and renal prognosis in lupus nephritis patients.

OBJECTIVES: Anti-ribosomal P protein autoantibodies (anti-P) specifically develop in patients with systemic lupus erythematosus. Associations of anti-P with lupus nephritis (LN) histological subclass and renal outcome remain inconclusive. We sought to determine the association of anti-P and anti-double-stranded DNA antibody (anti-dsDNA) with renal histology and prognosis in LN patients. METHODS: Thirty-four patients with LN, having undergone kidney biopsy, were included. The 2018 revised ISN/RPS classification system was used for pathophysiological evaluation. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 for > 3 months. RESULTS: Six patients (17.6%) were positive for anti-P and 26 (76.5%) for anti-dsDNA. Among the six patients with anti-P, one did not have anti-dsDNA, but did have anti-Sm antibody, and showed a histological subtype of class V. This patient maintained good renal function for over 14 years. The remaining five patients, who had both anti-P and anti-dsDNA, exhibited proliferative nephritis and were associated with prolonged hypocomplementemia, and the incidence of CKD did not differ from patients without anti-P. CONCLUSION: Although this study included a small number of patients, the results indicated that histology class and renal prognosis associated with anti-P depend on the coexistence of anti-dsDNA. Further studies with a large number of patients are required to confirm this conclusion.

Aberrant mucosal immunoreaction to tonsillar microbiota in immunoglobulin A nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by mesangial polymeric IgA1 deposition. IgAN is believed to develop owing to aberrant mucosal immunoreaction against commensals in the tonsils. However, the exact interrelation between pathogenic IgA and mucosal microbiota in IgAN patients is unclear. METHODS: Biopsy-proven IgAN or recurrent tonsillitis (RT) patients who had undergone tonsillectomy were enrolled. We used 16S ribosomal RNA gene amplicon sequencing with a flow cytometry-based bacterial cell sorting technique) and immunoglobulin repertoire sequencing of the IgA heavy chain to characterize IgA-coated bacteria of the tonsillar microbiota (IgA-SEQ) and their corresponding IgA repertoire. Furthermore, we fractionated patient serum using gel-filtration chromatography and performed flow cytometry-based analysis of IgA binding to bacteria cultured from incised tonsils. RESULTS: Tonsillar proliferation-inducing ligand and B-cell activating factor levels were significantly higher in IgAN than in RT patients. IgA-SEQ for tonsillar microbiota revealed the preferential binding ability of IgA to Bacteroidetes in IgAN tonsils compared with those from RT patients. Expression of immunoglobulin heavy (IGH) constant alpha 1 with IGH variable 3-30 was significantly higher in IgAN than that in RT, and positively correlated with the IgA-coated enrichment score of Bacteroidetes. Serum polymeric IgA, comprising high levels of GdIgA1, exhibited considerable binding to Bacteroidetes strains cultured from the tonsils of IgAN patients. CONCLUSIONS: These findings provide evidence that aberrant mucosal immune responses to tonsillar anaerobic microbiota, primarily consisting of members of the phylum Bacteroidetes, are involved in IgAN pathophysiology.

Inorganic polyphosphate potentiates lipopolysaccharide-induced macrophage inflammatory response.

Inorganic polyphosphate (polyP) is a linear polymer of orthophosphate units that are linked by phosphoanhydride bonds and is involved in various pathophysiological processes. However, the role of polyP in immune cell dysfunction is not well-understood. In this study, using several biochemical and cell biology approaches, including cytokine assays, immunofluorescence microscopy, receptor-binding assays with quartz crystal microbalance, and dynamic light scanning, we investigated the effect of polyP on in vitro lipopolysaccharide (LPS)-induced macrophage inflammatory response. PolyP up-regulated LPS-induced production of the inflammatory cytokines, such as tumor necrosis factor α, interleukin-1ß, and interleukin-6, in macrophages, and the effect was polyP dose- and chain length-dependent. However, orthophosphate did not exhibit this effect. PolyP enhanced the LPS-induced intracellular macrophage inflammatory signals. Affinity analysis revealed that polyP interacts with LPS, inducing formation of small micelles, and the polyP-LPS complex enhanced the binding affinity of LPS to Toll-like receptor 4 (TLR4) on macrophages. These results suggest that inorganic polyP plays a critical role in promoting inflammatory response by enhancing the interaction between LPS and TLR4 in macrophages.

Indoxyl Sulfate Promotes Macrophage IL-1ß Production by Activating Aryl Hydrocarbon Receptor/NF-κ/MAPK Cascades, but the NLRP3 inflammasome Was Not Activated.

In chronic kidney disease (CKD) patients, accumulation of uremic toxins is associated with cardiovascular risk and mortality. One of the hallmarks of kidney disease-related cardiovascular disease is intravascular macrophage inflammation, but the mechanism of the reaction with these toxins is not completely understood. Macrophages differentiated from THP-1 cells were exposed to indoxyl sulfate (IS), a representative uremic toxin, and changes in inflammatory cytokine production and intracellular signaling molecules including interleukin (IL)-1, aryl hydrocarbon receptor (AhR), nuclear factor (NF)-κ, and mitogen-activated protein kinase (MAPK) cascades as well as the NLRP3 inflammasome were quantified by real-time PCR, Western blot analysis, and enzyme-linked immunosorbent assay. IS induced macrophage pro-IL-1ß mRNA expression, although mature IL-1 was only slightly increased. IS increased AhR and the AhR-related mRNA expression; this change was suppressed by administration of proteasome inhibitor. IS promoted phosphorylation of NF-κB p65 and MAPK enzymes; the reaction and IL-1 expression were inhibited by BAY11-7082, an inhibitor of NF-κB. In contrast, IS decreased NLRP3 and did not change ASC, pro-caspase 1, or caspase-1 activation. IS-inducing inflammation in macrophages results from accelerating AhR-NF-κB/MAPK cascades, but the NLRP3 inflammasome was not activated. These reactions may restrict mature IL-1ß production, which may explain sustained chronic inflammation in CKD patients.

Attenuated Macrophage Infiltration in Glomeruli of Aged Mice Resulting in Ameliorated Kidney Injury in Nephrotoxic Serum Nephritis.

Senescent cells have deleterious effects on the tissue microenvironment through proinflammatory senescence-associated secretory phenotypes; meanwhile, the onset of glomerulonephritis is predominant in younger adults. To clarify the influence of aging on the onset and development of glomerulonephritis, we used a murine model of antibody-mediated nephritis. Sheep nephrotoxic serum was administered in C57BL/6J mice at 12 weeks (adult) or 18 months old (aged) after pre-immunization with sheep IgG. Depositions of sheep IgG and autologous mouse IgG along the glomerular basement membrane and the serum titer of anti-sheep IgG-specific mouse IgG were similar between adult and aged mice. However, kidney injury was depressed in aged mice, accompanied by reduced macrophage infiltration in the glomeruli. The mRNA expression of most chemokines involved in monocyte/macrophage chemotaxis was not different between adult and aged mice, but the cell surface expression of C-C chemokine receptor (CCR) 1 and CCR2 was down-regulated in the monocyte/macrophage lineage cells infiltrating the kidneys of aged nephritic mice. Furthermore, expression of all four isotypes of the Fcγ receptor (FcγR) was reduced in these cells. Both CCR and FcγR expression were down-regulated in monocyte/macrophage lineage cells, resulting in attenuated glomerular infiltration of these cells and impaired glomerular injury in aged mice.

Kidney morphological parameters measured using noncontrast-enhanced steady-state free precession MRI with spatially selective inversion recovery pulse correlate with eGFR in patients with advanced CKD.

BACKGROUND: It is well known that atrophic renal changes are associated with chronic kidney disease (CKD) progression, but conventional diagnostic imaging methods such as noncontrast-enhanced computed tomography and magnetic resonance imaging (MRI) have been insufficient for precisely assessing kidney function because they cannot clearly distinguish between the medulla and cortex. Hence, here we used noncontrast-enhanced steady-state free precession (SSFP) MRI with a spatially selective inversion recovery (IR) pulse to improve visibility for renal corticomedullary differentiation and evaluated the association between morphological parameters and kidney function in patients with CKD. METHODS: Kidney corticomedullary contrast ratio, cortical and medullary areas, and minimal cortical thickness of 107 patients with CKD G1-G5 were measured using SSFP MRI with a spatially selective IR pulse and the association between these morphological parameters and kidney function were evaluated. RESULTS: Corticomedullary contrast ratio was significantly improved on SSFP MRI compared with conventional in-phase T1-weighted gradient-echo MRI and positively correlated with estimated glomerular filtration ratio (eGFR), raw eGFR, and 24-h creatinine clearance. The medullary and cortical areas and minimal cortical thickness also positively correlated with those of kidney functional markers and the age. In patients with CKD and diabetes mellitus (DM), the correlation coefficients between raw eGFR and morphological parameters were higher than those in patients without DM, while minimal cortical thickness was larger in CKD patients with DM with a raw eGFR ≥ 45 mL/min. CONCLUSION: Kidney morphological parameters measured with SSFP MRI were clearly correlated with kidney function in patients with CKD, including those with advanced kidney dysfunction.

Prolactin Upregulates Female-Predominant P450 Gene Expressions and Downregulates Male-Predominant Gene Expressions in Mouse Liver.

Prolactin is a polypeptide hormone with over 300 separate biologic activities. Its serum level is increased during pregnancy and lactation, and it has been reported that pregnancy and lactation affect drug and steroid metabolism in mice and humans. Several studies reported that pregnancy or lactation influences liver cytochrome P450 (P450) expression and its activity, affecting the biosynthesis of steroids and xenobiotics through growth hormone or sex hormones; however, the role of prolactin as the regulator of liver P450 expression has not been elucidated so far. In the present study, we focused on prolactin as the regulator of expression of liver sex-predominant genes, including P450s. To investigate the role of prolactin in the hepatic gene expressions, pCAGGS expression vector containing mouse prolactin cDNA was transfected by hydrodynamic injection into both male and female mice. Hyperprolactinemia phosphorylated signal transducer and activator of transcription 5 in the liver and augmented female mouse liver mRNA expression of Cyp3a16, Cyp3a41, Cyp3a44, Cyp2b9, and prolactin receptor genes, whose expressions were female-predominant in hepatocytes. Moreover, liver expression of male-predominant genes such as Cyp2d9, Cyp7b1, Mup1, and Alas2 were reduced in male mice with hyperprolactinemia. The serum levels of conventional regulators of hepatic gene expressions, growth hormone, and testosterone were not affected by hyperprolactinemia. We demonstrated that prolactin upregulated female-predominant genes in female mice and downregulated male-predominant genes in male mice. We conjecture that higher concentration of prolactin would alter steroid and xenobiotic metabolisms by modulating hepatic P450 gene expressions during pregnancy and lactation.

Extracapillary proliferation and arteriolar hyalinosis are associated with long-term kidney survival in IgA nephropathy.

BACKGROUND: The Oxford classification of IgA nephropathy consists of four markers as prognosticators. We retrospectively examined the relevance of extracapillary proliferation involving cellular and fibrocellular crescents (Ex) and arteriolar hyalinosis (A) on the long-term outcome of renal function. METHODS: A total of 314 Japanese patients who were diagnosed with IgA nephropathy, with 12 months or more of follow-up period were included in this study. A total of 186 patients were with UP ≥ 0.5 g/day. Patients with diabetes mellitus or severe kidney injury (eGFR < 30 ml/min/1.73 m(2)) were excluded. The presence of Ex and A were scored 0 in the absence, and 1 in the presence, of each lesion. The end point was determined as a 50 % reduction in initial eGFR or end-stage renal disease defined as eGFR < 15 ml/min/1.73 m(2). RESULTS: In univariate analyses, the kidney survival rate was significantly lower in patients with Ex1 and A1 if UP ≥ 0.5 g/day. In the patients with UP < 0.5/day, none of the clinical and pathological parameters was determined as a risk factor. In the multivariate model including pathological parameters, Ex1 and A1 were independent risk factors for renal outcome if UP ≥ 0.5 g/day. In those patients treated with RAS-blocker or treated before introduction of methylprednisolone pulse therapy, Ex was the only independent risk factor. In multivariate analysis including clinical parameters, eGFR alone was a risk factor, due to strong correlation with other parameters. CONCLUSION: Ex and A would be associated with the renal outcome of the patients with UP ≥ 0.5 g/day.

Leptin deficiency down-regulates IL-23 production in glomerular podocytes resulting in an attenuated immune response in nephrotoxic serum nephritis.

Leptin, one of the typical adipokines, is reported to promote Th17 cell responses and to enhance production of proinflammatory cytokines. To clarify the role of leptin in the regulation of the IL-23/IL-17 axis and the development of kidney disease, we used a murine model of nephrotoxic serum (NTS) nephritis (NTN). Sheep NTS was administered in wild-type C57BL/6J mice and food-restricted, leptin-deficient C57BL/6J-ob/ob(FR-ob/ob) mice after preimmunization with sheep IgG. The profile of mRNA expression relevant to T helper lymphocytes in the kidneys was analyzed by quantitative real-time PCR (qRT-PCR). Cultured murine glomerular podocytes and peritoneal exudate macrophages (PEMs) were used to investigate the direct effect of leptin on IL-23 or MCP-1 production by qRT-PCR. Kidney injury and macrophage infiltration were significantly attenuated in FR-ob/obmice 7 days after NTS injection. The Th17-dependent secondary immune response against deposited NTS in the glomeruli was totally impaired in FR-ob/obmice because of deteriorated IL-17 and proinflammatory cytokine production including IL-23 and MCP-1 in the kidney. IL-23 was produced in glomerular podocytes in NTN mice and cultured murine glomerular podocytes produced IL-23 under leptin stimulation. MCP-1 production in PEMs was also promoted by leptin. Induction of MCP-1 expression was observed in PEMs regardless of Ob-Rb, and the leptin signal was transduced without STAT3 phosphorylation in PEMs. Leptin deficiency impairs the secondary immune response against NTS and down-regulates IL-23 production and Th17 responses in the NTN kidney, which is accompanied by decreased MCP-1 production and macrophage infiltration in the NTN kidney.

Increased Proinflammatory Cytokine Production and Decreased Cholesterol Efflux Due to Downregulation of ABCG1 in Macrophages Exposed to Indoxyl Sulfate.

One of the possible causes of enhanced atherosclerosis in patients with chronic kidney disease (CKD) is the accumulation of uremic toxins. Since macrophage foam cell formation is a hallmark of atherosclerosis, we examined the direct effect of indoxyl sulfate (IS), a representative uremic toxin, on macrophage function. Macrophages differentiated from THP-1 cells were exposed to IS in vitro. IS decreased the cell viability of THP-1 derived macrophages but promoted the production of inflammatory cytokines (IL-1ß, IS 1.0 mM: 101.8 ± 21.8 pg/mL vs. 0 mM: 7.0 ± 0.3 pg/mL, TNF-α, IS 1.0 mM: 96.6 ± 11.0 pg/mL vs. 0 mM: 15.1 ± 3.1 pg/mL) and reactive oxygen species. IS reduced macrophage cholesterol efflux (IS 0.5 mM: 30.3% ± 7.3% vs. 0 mM: 43.5% ± 1.6%) and decreased ATP-binding cassette transporter G1 expression. However, lipid uptake into cells was not enhanced. A liver X receptor (LXR) agonist, T0901317, improved IS-induced production of inflammatory cytokines as well as reduced cholesterol efflux. In conclusion, IS induced inflammatory reactions and reduced cholesterol efflux in macrophages. Both effects of IS were improved with activation of LXR. Direct interactions of uremic toxins with macrophages may be a major cause of atherosclerosis acceleration in patients with CKD.

A case of membranoproliferative glomerulonephritis developed over twenty years with three different findings of renal pathology.

A 31-year-old woman with proteinuria, hypocomplementemia, rheumatoid factor, and high serum polyclonal IgM concentration was admitted to our hospital for renal biopsy. She had a past history of two renal biopsies. When she was 12 years old, she developed proteinuria, microscopic hematuria, and hypocomplementemia. She was diagnosed as having 'IgM nephropathy' based on minor glomerular abnormalities as determined by light microscopy and IgM and C3 deposition in the mesangial region by immunofluorescence microscopy at the first biopsy. Despite corticosteroid treatment, her proteinuria did not improve and she discontinued regular outpatient checkups. When she was 29 years old and pregnant, she developed preeclampsia and, after delivery, a second renal biopsy was implemented. She was diagnosed as having progressed 'IgM nephropathy' with endotheliosis induced by preeclampsia. She was treated with angiotensin II receptor blocker and her proteinuria diminished; however, 1 year after the delivery, she developed proteinuria again, along with microscopic hematuria and hypocomplementemia. A third renal biopsy was conducted at 31 years of age and she was diagnosed as having membranoproliferative glomerulonephritis (MPGN) type I on the basis of diffuse mesangial proliferation, endocapillary hypercellularity with double contour of the capillary wall, and lobular formation in glomeruli, as determined by light microscopy. Immunofluorescence staining demonstrated deposits of C3, C4, C1q, and IgM in the mesangial region and capillary wall. She underwent corticosteroid therapy followed by normalization of urinalysis and serum complement level. Although she had initially been diagnosed with 'IgM nephropathy', she was finally diagnosed with secondary MPGN and was successfully treated by corticosteroid therapy.

Integrin α1/ß1 and α2/ß1 as a receptor for IgA1 in human glomerular mesangial cells in IgA nephropathy.

IgA nephropathy (IgAN) is characterized by mesangial deposition of IgA1 and galactose-deficient IgA1 is expected to play a pathogenic role. However, the identity of the receptor for IgA1 is still controversial. Hence, the aim of this study was to explore the receptor for galactose-deficient IgA1. Human monoclonal IgA1 was treated with exoglycosidase and FITC-conjugated control, asialo- and agalactosyl-IgA1 was used as a probe to detect the receptor in cultured human mesangial cells. Tumor necrosis factor-α or transforming growth factor-ß1 treatment accelerated IgA1-binding on mesangial cells, and these effects were diminished by the addition of dexamethasone, whereas these changes were not dependent on galactose-deficiency of IgA1. According to comprehensive gene expression analysis, we focused on integrin ß1. Pre-treatment by Mn(2+), which activates integrin by changing its structure, enhanced the binding of IgA1 in cultured mesangial cells. Furthermore, pre-incubation with collagens specifically enhanced binding of IgA1 in the cultured human mesangial cells without activation by Mn(2+). Collagen type IV distributed in the mesangial region of the glomeruli as well as Bowman's capsule and tubular basal membrane in IgAN patients, and the IgA1 with collagen type IV induced proliferative signals on mesangial cells by phosphorylating extracellular signal-regulated kinase more effectively than the IgA1 alone. Immunoprecipitation assay revealed the binding of IgA1 and integrin α1/ß1 and α2/ß1 heterodimer and down-regulation of integrin α1, α2 and ß1 expression in human mesangial cells induced by each specific small interfering RNA diminished the ability to bind IgA1 probe. Integrin α1/ß1 and α2/ß1 would be a candidate receptor for IgA1.

Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors.

Introduction of heterologous anti-glomerular basement membrane antiserum (nephrotoxic serum, NTS) into presensitized mice triggers the production of IgG anti-NTS antibodies that are predominantly IgG2b and the glomerular deposition of pathogenic immune complexes, leading to accelerated renal disease. The pathology observed in this model is determined by the effector cell activation threshold that is established by the coexpression on infiltrating macrophages of the IgG2a/2b restricted activation receptor FcgammaRIV and its inhibitory receptor counterpart, FcgammaRIIB. Blocking FcgammaRIV with a specific monoclonal antibody thereby preventing IgG2b engagement or treatment with high dose intravenous gamma-globulin (IVIG) to down-regulate FcgammaRIV while up-regulating FcgammaRIIB, protects mice from fatal disease. In the absence of FcgammaRIIB, IVIG is not protective; this indicates that reduced FcgammaRIV expression alone is insufficient to protect animals from pathogenic IgG2b immune complexes. These results establish the significance of specific IgG subclasses and their cognate FcgammaRs in renal disease.

Monocyte chemoattractant protein-1 A-2518G gene polymorphism and renal survival of Japanese patients with immunoglobulin A nephropathy.

BACKGROUND: Monocyte chemoattractant protein (MCP)-1 is closely related to the pathogenesis of the progression of various chronic renal diseases, including IgA nephropathy (IgAN), through its chemoattractant effect on macrophages. However, the correlation of MCP-1 gene polymorphism with the long-term prognosis of Japanese patients with IgAN has not been clearly determined yet. METHODS: We investigated 277 Japanese patients diagnosed with IgAN based on renal biopsy to clarify the association between the progression of IgAN and MCP-1 gene polymorphism at position A-2518G, which regulates the transcription of the MCP-1 gene. RESULTS: The incidence of endstage renal disease was significantly higher in patients with the AA genotype (47.1%) compared to those with the AG (24.1%) or GG (27.4%) genotype (P = 0.024). Moreover, Kaplan-Meier analysis revealed that the AA genotype significantly facilitated the progression of renal disease (log rank; P = 0.0029), and Cox proportional hazards regression model analysis showed that the AA genotype represented a 2.058-fold risk for the progression of renal disease (P = 0.026) compared to the AG/GG genotype. However, when the patients were treated with angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker, or corticosteroid, homozygosity for the -2518A allele was not associated with a higher rate of incidence of endstage renal disease. Serum MCP-1 levels were higher although not significantly so, in the patients with IgAN possessing the AA genotype. CONCLUSIONS: The AA genotype at MCP-1 -2518 was an independent risk factor for the progression of renal disease in Japanese patients with IgAN, and was closely associated with renal survival.

Osteopontin expression in acute renal allograft rejection.

BACKGROUND: Osteopontin (OPN) is a potent chemoattractant for mononuclear cells that is up-regulated in various inflammatory states of the kidney. The role of OPN and its expression in human renal allograft rejection are unknown. METHODS: We examined by immunohistochemistry and in situ hybridization, renal biopsies from patients with acute rejection (N= 22), protocol biopsies without rejection (N= 9), and perioperative donor biopsies (N= 35) for intrarenal expression of OPN, and its correlation with clinical, laboratory, and histopathologic parameters. In the rejection biopsies, interstitial monocyte/macrophage infiltration, tubulointerstitial cell proliferation/regeneration and apoptosis were investigated. RESULTS: In the majority of rejection biopsies, OPN expression by proximal tubular epithelium was widespread, and tended to be enhanced in the tubules surrounded by numerous inflammatory cells. Conversely, in patients that did not experience episodes of rejection and in donor biopsies, OPN expression by proximal tubules was nil or weak. OPN mRNA was colocalized with its translated protein in the renal tubular epithelium. OPN expression positively correlated with the degree of interstitial inflammation (P < 0.05), CD68+ monocyte infiltration (P < 0.01), Ki-67+ regenerating tubular and interstitial cells (P < 0.05 and P < 0.005, respectively), but not with terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL)-positive apoptotic tubular cells. CONCLUSION: These data suggest that inducible expression of OPN in the tubular epithelium may have a pathogenic role in acute renal allograft rejection by mediating interstitial monocyte infiltration and possibly tubular regeneration.

Impaired IFN-gamma production of Valpha24 NKT cells in non-remitting sarcoidosis.

Sarcoidosis is a systemic disorder associated with granuloma characterized by an abnormal T(h)1-type cytokine production and accumulation of T(h)1 CD4 T cells in the granuloma lesions, suggesting an importance of T(h)1 responses in sarcoidosis. However, the pathogenesis of sarcoidosis remains to be solved. Here, we investigated the nature of V(alpha)24 NKT cells with immunoregulatory functions in sarcoidosis. Patients with non-remitting sarcoidosis displayed a decrease in the number of V(alpha)24 NKT cells in peripheral blood, but an accumulation of these cells in granulomatous lesions. When stimulated with the specific glycolipid ligand, alpha-galactosylceramide, peripheral blood V(alpha)24 NKT cells from patients with non-remitting disease produced significantly less IFN-gamma than those from healthy volunteers, but normal levels of IL-4. The reduced IFN-gamma production was observed only in V(alpha)24 NKT cells and not conventional CD4 T cells, but was normal in patients with remitting disease, suggesting that non-remitting sarcoidosis involves an insufficient IFN-gamma production of V(alpha)24 NKT cells which is well correlated with disease activity. Thus, these results suggest that V(alpha)24 NKT cells play a crucial role in the disease status of sarcoidosis.