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• W2051267756 abstract "Local B-cell infiltrates play a role in tissue fibrosis, neolymphangiogenesis, and renal allograft survival. We sought to characterize the B-cell infiltrates, factors involved in B-cell recruitment, and lymphangiogenesis in renal interstitial injury (ie, acute and chronic interstitial nephritis and chronic IgA nephropathy). CD20-positive B cells formed a prominent part of the interstitial infiltrating cells. Together with CD3-positive T cells, the CD20-positive B cells formed larger nodular structures. CD10-positive pre-B cells were rare, and the majority were mature CD27-positive B cells. Proliferating B cells were detected within nodular infiltrates. The level of mRNA expression of the chemokine CXCL13 was increased and correlated with CD20 mRNA in the tubulointerstitial space. CXCL13 protein was predominantly found at sites of nodular infiltrates, in association with CXCR5-positive B cells. Furthermore, sites of chronic interstitial inflammation were associated with a high number of lymphatic vessels. B-cell infiltrates form a prominent part of the interstitial infiltrates both in primary interstitial lesions and in IgA nephropathy. CXCR5-positive B cells might be recruited via the chemokine CXCL13 and seem to contribute to the formation of intrarenal lymphoid follicle-like structures. These might represent an intrarenal immune system. Local B-cell infiltrates play a role in tissue fibrosis, neolymphangiogenesis, and renal allograft survival. We sought to characterize the B-cell infiltrates, factors involved in B-cell recruitment, and lymphangiogenesis in renal interstitial injury (ie, acute and chronic interstitial nephritis and chronic IgA nephropathy). CD20-positive B cells formed a prominent part of the interstitial infiltrating cells. Together with CD3-positive T cells, the CD20-positive B cells formed larger nodular structures. CD10-positive pre-B cells were rare, and the majority were mature CD27-positive B cells. Proliferating B cells were detected within nodular infiltrates. The level of mRNA expression of the chemokine CXCL13 was increased and correlated with CD20 mRNA in the tubulointerstitial space. CXCL13 protein was predominantly found at sites of nodular infiltrates, in association with CXCR5-positive B cells. Furthermore, sites of chronic interstitial inflammation were associated with a high number of lymphatic vessels. B-cell infiltrates form a prominent part of the interstitial infiltrates both in primary interstitial lesions and in IgA nephropathy. CXCR5-positive B cells might be recruited via the chemokine CXCL13 and seem to contribute to the formation of intrarenal lymphoid follicle-like structures. These might represent an intrarenal immune system. During chronic kidney diseases an inflammatory process occurs within the tubulointerstitium, which finally results in fibrosis.1Strutz F Neilson EG New insights into mechanisms of fibrosis in immune renal injury.Springer Semin Immunopathol. 2003; 24: 459-476Crossref PubMed Scopus (98) Google Scholar The severity of interstitial leukocyte accumulation, monocytes/macrophages, and T lymphocytes, is associated with renal function at the time of biopsy.2Müller GA Markovic-Lipkovski J Frank J Rodemann HP The role of interstitial cells in the progression of renal diseases.J Am Soc Nephrol. 1992; 2: S198-S205PubMed Google Scholar, 3Alexopoulos E Seron D Hartley RB Cameron JS Lupus nephritis: correlation of interstitial cells with glomerular function.Kidney Int. 1990; 37: 100-109Crossref PubMed Scopus (194) Google Scholar, 4Segerer S Mack M Regele H Kerjaschki D Schlondorff D Expression of the C-C chemokine receptor 5 in human kidney diseases.Kidney Int. 1999; 56: 52-64Crossref PubMed Scopus (152) Google Scholar, 5Segerer S Banas B Wornle M Schmid H Cohen CD Kretzler M Mack M Kiss E Nelson PJ Schlondorff D Grone HJ CXCR3 is involved in tubulointerstitial injury in human glomerulonephritis.Am J Pathol. 2004; 164: 635-649Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Because B cells are considered to be important mostly in lymph nodes, spleen, and in humoral immune responses, little attention has been paid to their potential role as intrarenal infiltrating cells.Several new aspects of B-cell function have surfaced. These include the release of proinflammatory cytokines and chemokines, antigen presentation, T-cell activation, a role in tissue fibrosis, neolymphangiogenesis (ie, de novo formation of lymphatic vessels), and ectopic lymphogenesis; ie, formation of tertiary lymphatic organs in inflamed tissues.6Angeli V Ginhoux F Llodra J Quemeneur L Frenette PS Skobe M Jessberger R Merad M Randolph GJ B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization.Immunity. 2006; 24: 203-215Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar, 7Martin F Chan AC B cell immunobiology in disease: evolving concepts from the clinic.Annu Rev Immunol. 2006; 24: 467-496Crossref PubMed Scopus (287) Google Scholar, 8Edwards JC Cambridge G B-cell targeting in rheumatoid arthritis and other autoimmune diseases.Nat Rev Immunol. 2006; 6: 394-403Crossref PubMed Scopus (406) Google Scholar Furthermore, therapeutic studies targeting B cells via anti-CD20 antibodies have renewed interest in B-cell biology during chronic diseases.At sites of chronic inflammation, ectopic formation of lymphoid follicle-like aggregates containing B cells has been described, eg, in autoimmune diseases such as thyroiditis and rheumatoid arthritis, as well as during renal allograft rejection.7Martin F Chan AC B cell immunobiology in disease: evolving concepts from the clinic.Annu Rev Immunol. 2006; 24: 467-496Crossref PubMed Scopus (287) Google Scholar, 9Kerjaschki D Regele HM Moosberger I Nagy-Bojarski K Watschinger B Soleiman A Birner P Krieger S Hovorka A Silberhumer G Laakkonen P Petrova T Langer B Raab I Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates.J Am Soc Nephrol. 2004; 15: 603-612Crossref PubMed Scopus (405) Google Scholar, 10Aloisi F Pujol-Borrell R Lymphoid neogenesis in chronic inflammatory diseases.Nat Rev Immunol. 2006; 6: 205-217Crossref PubMed Scopus (723) Google Scholar A contribution of B cells to the formation of lymphoid-like structures has been proposed.6Angeli V Ginhoux F Llodra J Quemeneur L Frenette PS Skobe M Jessberger R Merad M Randolph GJ B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization.Immunity. 2006; 24: 203-215Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar, 11Takemura S Klimiuk PA Braun A Goronzy JJ Weyand CM T cell activation in rheumatoid synovium is B cell dependent.J Immunol. 2001; 167: 4710-4718PubMed Google Scholar The accumulation of B cells could be mediated by chemokines.12Segerer S Nelson PJ Chemokines in renal diseases.Sci World J. 2005; 5: 835-844Crossref Scopus (26) Google Scholar, 13Segerer S Nelson PJ Schlondorff D Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies.J Am Soc Nephrol. 2000; 11: 152-176PubMed Google Scholar CXCR5 is a chemokine receptor expressed by B cells, which binds the chemokine CXCL13.14Murphy PM Baggiolini M Charo IF Hebert CA Horuk R Matsushima K Miller LH Oppenheim JJ Power CA International Union of Pharmacology. XXII. Nomenclature for chemokine receptors.Pharmacol Rev. 2000; 52: 145-176PubMed Google Scholar CXCR5 and the corresponding ligand CXCL13 play a role in B-cell migration to secondary lymphoid organs, and in lymphoid organogenesis.15Förster R Mattis AE Kremmer E Wolf E Brem G Lipp M A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen.Cell. 1996; 87: 1037-1047Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar, 16Müller G Lipp M Concerted action of the chemokine and lymphotoxin system in secondary lymphoid-organ development.Curr Opin Immunol. 2003; 15: 217-224Crossref PubMed Scopus (51) Google Scholar Furthermore, high expression of CXCL13 has been demonstrated in synovial tissue with large B-cell aggregates, suggesting a potential role of CXCL13 for B-cell accumulation.17Shi K Hayashida K Kaneko M Hashimoto J Tomita T Lipsky PE Yoshikawa H Ochi T Lymphoid chemokine B cell-attracting chemokine-1 (CXCL13) is expressed in germinal center of ectopic lymphoid follicles within the synovium of chronic arthritis patients.J Immunol. 2001; 166: 650-655PubMed Google Scholar, 18Takemura S Braun A Crowson C Kurtin PJ Cofield RH O'Fallon WM Goronzy JJ Weyand CM Lymphoid neogenesis in rheumatoid synovitis.J Immunol. 2001; 167: 1072-1080PubMed Google ScholarPreviously, the relative percentage of B cells in the renal interstitium of chronic kidney diseases was considered to be low.19Hooke DH Gee DC Atkins RC Leukocyte analysis using monoclonal antibodies in human glomerulonephritis.Kidney Int. 1987; 31: 964-972Crossref PubMed Scopus (291) Google Scholar, 20D'Agati VD Appel GB Estes D Knowles II, DM Pirani CL Monoclonal antibody identification of infiltrating mononuclear leukocytes in lupus nephritis.Kidney Int. 1986; 30: 573-581Crossref PubMed Scopus (78) Google Scholar, 21Husby G Tung KS Williams Jr, RC Characterization of renal tissue lymphocytes in patients with interstitial nephritis.Am J Med. 1981; 70: 31-38Abstract Full Text PDF PubMed Scopus (62) Google Scholar, 22Boucher A Droz D Adafer E Laure-Helene N Characterization of mononuclear cell subsets in renal cellular interstitial infiltrates.Kidney Int. 1986; 29: 1043-1049Crossref PubMed Scopus (129) Google Scholar In contrast, a prominent accumulation of CD20-positive B cells has recently been described in membranous nephropathy.23Cohen CD Calvaresi N Armelloni S Schmid H Henger A Ott U Rastaldi MP Kretzler M CD20-positive infiltrates in human membranous glomerulonephritis.J Nephrol. 2005; 18: 328-333PubMed Google Scholar Furthermore, in renal allografts a detrimental role for CD20-positive B cells has been postulated because they were associated with increased graft loss.24Sarwal M Chua MS Kambham N Hsieh SC Satterwhite T Masek M Salvatierra Jr, O Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling.N Engl J Med. 2003; 349: 125-138Crossref PubMed Scopus (625) Google ScholarHere, we describe that CD20-positive B cells form a prominent part of interstitial infiltrates in both primary interstitial disease as well as in secondary involvement during primary IgA nephropathy. The B-cell infiltrate is associated with increased local expression of the chemokine CXCL13 and the corresponding receptor CXCR5 on B cells. Furthermore, T- and B-cell infiltrates form lymphoid-like nodular structures, which are surrounded by newly formed lymphatic vessels in these chronic diseases. These data invite speculations about a role of these intrarenal B-cell-rich lymphoid follicle-like structures in a local immune response in chronic renal diseases.Materials and MethodsStudy PopulationThis study used archival renal biopsies from patients with primary acute interstitial nephritis (n = 10), chronic interstitial nephritis (n = 29), and IgA nephropathy (n = 18) (Table 1). The diagnosis was based on light microscopy, immunohistochemistry, and electron microscopy. Criteria for the diagnosis of chronic interstitial nephritis were the presence of an interstitial infiltrate, in combination with interstitial fibrosis, without significant glomerular lesions (by light and electron microscopy), and the absence of significant glomerular immune deposits. The diagnosis of acute interstitial nephritis was based on the presence of an interstitial infiltrate (commonly with tubulitis) and interstitial edema in the absence of significant glomerular lesions on light and electron microscopy, associated with rapid decline of renal function. IgA nephropathy was diagnosed when widening and/or hypercellularity of the mesangium in combination with IgA immune deposits in the mesangium were present. Excluded from the series were patients with lupus erythematodes, vasculitis, infectious interstitial nephritis (eg, leptospirosis, Hantaan nephritis), nephrotoxic renal failure, and other forms of glomerulonephritis. Five donor allograft biopsies taken before implantation served as normal controls. The results of the morphological evaluation are illustrated in Table 2. Biopsies were randomly chosen according to the availability of biopsy material remaining after diagnostic evaluation.Table 1Clinical Features of Study PatientsGender m/fMean age and range in yearsMean serum-creatinine and range in mg/dlMean proteinuria (g/24 hours)Acute interstitial nephritis5/564 (12 to 76)4.9 (1.1 to 21.5)0.5 (0.3 to 11.5)Chronic interstitial nephritis14/1542 (9 to 84)4.2 (2 to 11.8)1.0 (0.1 to 15.5)IgA nephropathy11/737 (18 to 74)3.6 (1.1 to 10)2.5 (0.2 to 5.5)m, male; f, female. Open table in a new tab Table 2Pathological Features of the Study Population (Mean, SEM)% GlomerulosclerosisInterstitial sclerosis scoreTubulitis scoreTubular atrophy scoreAcute interstitial nephritis94 4 (±0.7)2.1 (±0.23)0.9 (±0.2)Chronic interstitial nephritis327.5 (±0.4)‡P < 0.001 versus acute interstitial nephritis.1.2 (±0.12)†P < 0.01,2.2 (±0.13)†P < 0.01,IgA nephropathy536.6 (±0.6)*P < 0.05,1.2 (±0.16)†P < 0.01,1.8 (±0.2)* P < 0.05,† P < 0.01,‡ P < 0.001 versus acute interstitial nephritis. Open table in a new tab Tubulitis was quantified in analogy to the Banff classification as 0 to 3 (with 1: one to four infiltrating leukocytes; 2: 5 to 10 infiltrating leukocytes; 3: >10 infiltrating leukocytes per tubular cross-section). Interstitial fibrosis was quantified as the area involved in interstitial fibrosis (grade 1: <1/3 of the biopsy; grade 2: > 1/3 but <2/3; grade 3: >2/3). The severity of interstitial fibrosis was graded from 0 to 3 (semiquantitatively mild to severe). Severity and involved area were multiplied and illustrated as a score (Table 2). Immunohistochemistry was routinely performed for IgG, IgA, IgM, C3, and C1q in all biopsies. The glomerular immune deposits were scored semiquantitatively and described in the text.For mRNA quantification, parts of human renal biopsies, performed for diagnostic purposes, were obtained according to the local ethical committees’ directives and samples processed according to the protocol of the European Renal cDNA Bank/Kroener-Fresenius Biopsy Bank (ERCB/KFB).25Cohen CD Frach K Schlondorff D Kretzler M Quantitative gene expression analysis in renal biopsies: a novel protocol for a high-throughput multicenter application.Kidney Int. 2002; 61: 133-140Crossref PubMed Scopus (220) Google Scholar Glomerular and tubulointerstitial samples were manually microdissected and RNA-isolated. Histology reports and clinical data were stored anonymously. Included were RNAs extracted from 51 biopsies: acute interstitial nephritis (n = 22), chronic interstitial nephritis (n = 4), IgA nephropathy (n = 15), and pretransplant controls (n = 10). The biopsies used for mRNA evaluation were from a different patient cohort than those used for the histomorphology because insufficient material remained after the histological studies.ImmunohistochemistryImmunohistochemistry was performed on formalin-fixed, paraffin-embedded renal biopsies similar to that as described previously.5Segerer S Banas B Wornle M Schmid H Cohen CD Kretzler M Mack M Kiss E Nelson PJ Schlondorff D Grone HJ CXCR3 is involved in tubulointerstitial injury in human glomerulonephritis.Am J Pathol. 2004; 164: 635-649Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 26Segerer S Bohmig GA Exner M Kerjaschki D Regele H Schlondorff D Role of CXCR3 in cellular but not humoral renal allograft rejection.Transpl Int. 2005; 18: 676-680Crossref PubMed Scopus (22) Google Scholar In brief, tissue sections were dewaxed and rehydrated. Incubation in 3% hydrogen peroxide was used to block endogenous peroxidases. An autoclave oven was used for antigen retrieval. An avidin/biotin blocking kit (Vector, Burlingame, CA) was used to block endogenous biotin. Incubation with the primary antibody for 1 hour was followed by incubation with biotinylated secondary reagents (Vector) and the ABC reagent (Vector). 3′,3′-Diaminobenzidine (Sigma, Taufkirchen, Germany) metal enhancement (resulting in a black color product) was used as a detection system.The anti-human CD20 antibody (clone L26; DakoCytomation, Dako Deutschland, Hamburg, Germany), the anti-CD3 antibody (clone CD3-12, rat anti-human; Serotec, Oxford, UK), and the anti-podoplanin antibody (D2-40; Signet Laboratories, Dedham, MA) were used on consecutive sections.5Segerer S Banas B Wornle M Schmid H Cohen CD Kretzler M Mack M Kiss E Nelson PJ Schlondorff D Grone HJ CXCR3 is involved in tubulointerstitial injury in human glomerulonephritis.Am J Pathol. 2004; 164: 635-649Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 26Segerer S Bohmig GA Exner M Kerjaschki D Regele H Schlondorff D Role of CXCR3 in cellular but not humoral renal allograft rejection.Transpl Int. 2005; 18: 676-680Crossref PubMed Scopus (22) Google Scholar D2-40 has been described as a reliable marker for lymphatic endothelium in paraffin-embedded tissue and binds to human podoplanin.27Schacht V Dadras SS Johnson LA Jackson DG Hong YK Detmar M Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors.Am J Pathol. 2005; 166: 913-921Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar, 28Ordóñez NG D2-40 and podoplanin are highly specific and sensitive immunohistochemical markers of epithelioid malignant mesothelioma.Hum Pathol. 2005; 36: 372-380Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar As negative controls the primary antibody was replaced by isotype-matched irrelevant immunoglobulins on tissue sections from human tonsils and renal allografts. Triple immunohistochemistry for podoplanin, MIB1, and either CD3 or CD20 was performed as previously described.9Kerjaschki D Regele HM Moosberger I Nagy-Bojarski K Watschinger B Soleiman A Birner P Krieger S Hovorka A Silberhumer G Laakkonen P Petrova T Langer B Raab I Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates.J Am Soc Nephrol. 2004; 15: 603-612Crossref PubMed Scopus (405) Google ScholarB-cell infiltrates were further characterized by staining for CD10 (clone 65C6; NeoMarkers, Fremont, CA), a marker preferentially expressed by immature B cells (pre-B cells). Double immunofluorescence for CD20/CD27 (clone 137B4; Dianova, Hamburg, Germany) was performed on selected biopsies because CD27 is mainly expressed by memory B cells. Immunohistochemistry of CXCL13 (anti-human CXCL13; R&D Systems, Wiesbaden, Germany) was performed as described.29Steinmetz OM Panzer U Kneissler U Harendza S Lipp M Helmchen U Stahl RA BCA-1/CXCL13 expression is associated with CXCR5-positive B-cell cluster formation in acute renal transplant rejection.Kidney Int. 2005; 67: 1616-1621Crossref PubMed Scopus (64) Google Scholar CXCR5 was localized using a monoclonal rat anti-CXCR5 antibody (a gift from Elisabeth Kremmer, GSF, Munich, Germany).30Breitfeld D Ohl L Kremmer E Ellwart J Sallusto F Lipp M Forster R Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production.J Exp Med. 2000; 192: 1545-1552Crossref PubMed Scopus (1084) Google ScholarEstablishment of the Staining ProceduresSections from human tonsils and allograft nephrectomies were used to establish the staining procedures (Figure 1). The anti-CD20 antibody produced a very reliable staining pattern of B-cell areas (Figure 1A). No positive color product was found in tissue sections exposed to isotype IgG controls (Figure 1, B and F). As expected the staining pattern was different for CD3-positive T cells (Figure 1C), and double immunofluorescence demonstrated separation of CD20-positive B cells and CD3-positive T cells (Figure 1, D and E). Podoplanin as a lymphatic endothelial marker was stained with the antibody D2-40, which produces a reliable staining pattern after heat-based antigen retrieval in archival tissue (Figure 1H). Larger lymphatic vessels were present in the allograft nephrectomy in association with arteries. Smaller lymphatic vessels were found in association with interstitial infiltrates (Figure 1H). Isotype controls were negative (Figure 1I). CXCL13 was expressed within follicles, and CXCR5-positive B cells were present in consecutive sections (Figure 1, J and K).Digital Image AnalysisMorphometric analysis was performed on 15 consecutive high-power fields (×400) by the use of Qwin software (Leica, Bensheim, Germany). The area of positive signal was measured for CD3- and CD20-positive cells by an observer blinded to the diagnosis and expressed as fraction of the area of the high-power field. Biopsies were only included when positive cells could be clearly identified. Figures represent means (bars indicate SEM). For the comparison of means the nonparametric Mann-Whitney U-test was used. P < 0.05 was considered to be statistically significant.Real-Time Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR)Real-time RT-PCR was performed on a TaqMan ABI 7700 sequence detection system (Applied Biosystems, Darmstadt, Germany) using heat-activated TaqDNA polymerase (Amplitaq Gold; Applied Biosystems, Darmstadt, Germany). Quantification of the given templates was performed according to the standard curve method. Serial dilutions of standard cDNA from a human nephrectomy were included in all PCR runs and served as standard curve. Commercially available predeveloped TaqMan reagents were used for the target genes (CD20, CXCL13, CXCR5, interleukin-6, transforming growth factor-β1) and three endogenous control genes (18S rRNA, cyclophilin, GAPDH; Applied Biosystems). The normalization to any of the three reference (housekeeping) genes gave comparable results. The data shown in the text and figures are normalized to 18S rRNA. All measurements were performed in duplicates. Controls consisting of bidistilled H2O were negative in all runs.ResultsInterstitial NephritisBiopsies from patients with acute, primary interstitial nephritis (n = 10, Figure 2) and from patients with chronic, primary interstitial nephritis (n = 29, Figure 3) were evaluated for CD20-positive B cells and CD3-positive T cells. The clinical information about the study population is summarized in Table 1 and the morphological evaluation in Table 2. Patients with acute interstitial nephritis demonstrated less glomerulosclerosis and less interstitial fibrosis as expected, but more tubulitis than patients with chronic interstitial nephritis (for details about the morphological evaluation, see Materials and Methods). Glomerular IgG or IgA deposits were not detectable; minor deposits of IgM in the mesangial area were present in 5 of 10 biopsies.Figure 2Immunohistochemistry performed on sections from biopsies with acute interstitial nephritis (A–G), or a pretransplant biopsy as control (H), with a monoclonal antibody against CD20 (A, C, E, G, H) and on consecutive section against CD3 (B, D, F). CD20-positive infiltrating B cells were found in diffuse infiltrates (A), in small cellular aggregates (C), and in larger nodular formations (E). CD3-positive T cells commonly infiltrated the tubular epithelium (arrows in F). A single CD20-positive B cell in a peritubular capillary is illustrated in the control (H, arrow). Original magnifications, ×200.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Immunohistochemistry performed on sections from biopsies with chronic interstitial nephritis with a monoclonal antibody against CD20 (A, C, E, G, H) and on consecutive section against CD3 (B, D, F). Original magnifications, ×200.View Large Image Figure ViewerDownload Hi-res image Download (PPT)In chronic interstitial nephritis the biopsies contained more fibrosis, less tubulitis, and more tubular atrophy than in acute interstitial nephritis. Glomerular IgG was not detectable, minor deposits of IgA in the mesangium were described in three biopsies (but attributable to the degree considered insignificant), and minor mesangial IgM deposits were common (14 of 29). Five donor allograft biopsies taken before implantation served as normal controls. Only a small number of CD20-positive cells, scattered through the tubulointerstitium, were detectable in histologically normal tissue from donor kidneys (Figure 2H).CD20-positive B cells formed a prominent part of the interstitial infiltrate in both acute and chronic interstitial nephritis (Figure 2, Figure 3). The CD20-positive B-cell infiltrates could be assigned to three general patterns of distribution, albeit with considerable overlap (Table 3). Six of 10 biopsies with acute interstitial nephritis and 14 of 29 biopsies with chronic interstitial nephritis demonstrated diffuse interstitial infiltrates of CD20-positive cells as single or double layers of cells between the tubuli (Figure 2A, Figure 3A). Larger nodular aggregates were present in 2 of 10 biopsies with acute interstitial nephritis and in 8 of 29 biopsies with chronic interstitial nephritis (Figure 2, E and F; and Figure 3, E–G). Two of 10 biopsies with acute and 7 of 29 with chronic interstitial nephritis contained aggregates of CD20-positive cells, smaller than the nodular structures, but larger than the diffuse infiltrates (Figure 2, C and D; and Figure 3, C and D). These patterns are not exclusive because biopsies with nodular aggregates also contain smaller CD20-positive B-cell aggregates and/or diffuse infiltrates. Whereas T cells commonly infiltrated the tubular epithelium in acute interstitial nephritis (Figure 2F, arrows), CD20-positive cells were only occasionally found within the tubular epithelium. Both cell types were rare in glomeruli and, if present, localized to glomerular capillaries. There was no correlation between these three patterns of cell infiltrations and the serum creatinine level at the time of biopsy.Table 3Distribution of the Patterns of the CD20-Positive Cell Infiltrates in the BiopsiesInterstitial CD20-positive infiltratesDiffuse infiltratesSmall aggregatesNodular infiltratesAcute interstitial nephritis6/102/102/10Chronic interstitial nephritis14/297/298/29IgA nephropathy7/187/184/18 Open table in a new tab The three groups defined by the main distribution pattern did not demonstrate differences in the area of CD3-positive T cells or area of CD20-positive B cells. The overall area of CD3-positive T cells and CD20-positive B cells were comparable (Figure 4A). In general, CD3-positive T-cell infiltrates occurred in parallel with CD20-positive B cells. Because B cells might be involved in neolymphangiogenesis, lymphatic vessels were stained by immunohistochemistry for D2-40, an antibody against podoplanin as a marker for lymphatic endothelium. As expected, larger lymphatic vessels were found in association with arteries (Figure 5A).9Kerjaschki D Regele HM Moosberger I Nagy-Bojarski K Watschinger B Soleiman A Birner P Krieger S Hovorka A Silberhumer G Laakkonen P Petrova T Langer B Raab I Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates.J Am Soc Nephrol. 2004; 15: 603-612Crossref PubMed Scopus (405) Google Scholar, 31Kerjaschki D Huttary N Raab I Regele H Bojarski-Nagy K Bartel G Krober SM Greinix H Rosenmaier A Karlhofer F Wick N Mazal PR Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants.Nat Med. 2006; 12: 230-234Crossref PubMed Scopus (297) Google Scholar There was a clear difference in the pattern of podoplanin-positive vessels in acute versus chronic interstitial nephritis (Figure 4, Figure 5). In acute interstitial nephritis, the number of lymphatic vessels was small, and predominantly found along larger arteries, as is the case in the normal kidney (Figure 5). Some lymphatic vessels were filled with inflammatory cells (Figure 5B). In contrast, in primary chronic interstitial nephritis, a high number of small lymphatic vessels was present throughout the cortex, and these were not associated with arteries. A morphological association was found between these small lymphatic vessels within the cortex and areas of inflammation because podoplanin-positive vessels were rarely found in areas of well-preserved renal tissue. The number of podoplanin-positive vessels was significantly higher in chronic, primary interstitial nephritis compared with acute interstitial nephritis (Figure 4B).Figure 4A: Quantification of the infiltrates by digital morphometry, determined as the percentage of area staining positive (bars show SEM). B: Quantification of podoplanin-positive lymphatic vessels per high-power field (bars show SEM). a.Int., acute interstitial nephritis; c.Int., chronic interstitial nephritis; IgA N., IgA nephropathy.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 5Immunohistochemistry was performed for CD20 (C," @default.
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• W2051267756 title "The Contribution of B Cells to Renal Interstitial Inflammation" @default.
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