Study on anti-IgA antibody in patients with IgA nephropathy.

Serum IgG antibodies to polyclonal IgA, IgA1 and IgA2 were evaluated by enzyme-linked immunosorbent assay in 50 patients with IgA nephropathy and 30 healthy controls to elucidate the relationship between IgA and IgG in IgA nephropathy. Anti-IgA antibody was considered positive if the titer exceeded the mean value in normal controls by greater than 2 SD. In patients with IgA nephropathy, 18 cases (36%) demonstrated anti-IgA antibody, 19 cases (38%) anti-IgA1 antibody and 7 cases (14%) anti-IgA2 antibody. Western blots confirmed the existence of anti-IgA antibody in these patients. There were no significant differences in serum IgA concentration, serum creatinine concentration, degree of hematuria, amount of urinary protein, and rate of glomerular IgG deposition between the "positive" group and "negative" group. Although the mechanism of production and the role of this antibody remain unknown, it may represent one of the diverse immune abnormalities of IgA nephropathy and may be involved in the pathogenesis of IgA nephropathy.     

Th2 predominance at the single-cell level in patients with IgA nephropathy.

BACKGROUND: Abnormalities of lymphocyte function have been reported to be involved in the pathogenesis of IgA nephropathy (IgA-N). The aim of this study was to investigate helper T (Th) predominance at the single-cell level, one of the abnormalities of lymphocyte function in IgA-N. METHODS: Using flowcytometry, we assessed the levels of circulating Th cells in IgA-N patients (n=30), and in normal individuals (n=30) based on the expression of intracellular Th1 cytokines for interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), and of intracellular Th2 cytokines for IL-4, IL-10, and IL-13. Because the production of each cytokine had a specific time course, we examined cytokine synthesis at 3, 6, 9, and 12 h after stimulation. RESULTS: The percentages of IL-2-positive Th cells from IgA-N patients were significantly lower than in normal individuals at 6, 9, and 12 h, with the difference becoming greater with time. The number of IFN-gamma-positive Th cells in IgA-N patients was significantly lower than in normal individuals at 9 h, and the number of IFN-gamma-positive Th cells increased more at 12 h than at 3 h in both groups. IL-4 and IL-13 expression was increased in patients with IgA-N at 6 h compared with normal individuals. In IgA-N patients, the percentage of IL-10-positive Th cells was significantly higher than that in normal individuals at each time-point. CONCLUSION: A polarization toward Th2 response at the stimulated lymphocyte level may lead to immune abnormalities in IgA-N.     

Humoral immunity against the proline-rich peptide epitope of the IgA1 hinge region in IgA nephropathy.

BACKGROUND: The human IgA1 hinge region is a unique mucin-like O-linked proline-rich glycopeptide, and its core peptide was found to be exposed aberrantly by the underglycosylation in IgA nephropathy (IgAN). We describe here the presence of humoral immunity against the IgA1 hinge peptide epitope in IgAN and evaluate the relationship between the underglycosylation of the IgA1 hinge region and humoral immunity. METHOD: The serum anti-IgA1 hinge peptide antibody (anti-alpha1HP ab) titre was measured and compared between the IgAN (n=37) and control groups (n=34) by enzyme-linked immunosorbent assay (ELISA) using a synthetic peptide corresponding to the human IgA1 hinge region, PVPSTPPTPSPSTPPTPSPS, as an antigen. Next, to evaluate the relationship between the underglycosylation of the IgA1 hinge region and the humoral immunity, the reactivity of the serum IgG from the patients with IgAN against monoclonal IgA1 which had been digested enzymatically to remove the carbohydrates from the IgA1 hinge region was measured by ELISA. RESULTS: The anti-alpha1HP ab titre was significantly higher in the IgAN group than in the control group (OD value: IgG class, 0.564+/-0.344 vs 0. 331+/-0.154, P=0.0014; IgM class, 0.272+/-0.148 vs 0.141+/-0.072, P<0.0001) and it was positive in approximately 40% of the patients with IgAN. In addition, the reactivity of the serum IgG from the IgAN patients against the monoclonal IgA1 was found to be increased as the carbohydrates were enzymatically removed from the IgA1 hinge region (when native=100; asialo, 122+/-9.5; agalacto, 167+/-11.5; naked, 188+/-3.9). CONCLUSION: These results suggested that the peptide epitope of the IgA1 hinge region which was aberrantly exposed by underglycosylation could induce the humoral immune response in IgAN.     

The role of IgA and IgG immune complexes in IgA nephropathy

The presence of circulating immune complexes in 54 patients with IgA nephropathy has been studied by two different techniques. 64% of the patients had IgG immune complexes and 37% had IgA immune complexes, both determined with the Raji cell assay, and 48% of patients had IgA immune complexes with the anti-IgA inhibition binding assay (anti-IgA Inh BA). In sequential sera from individual patients, immune complexes remained persistently positive or negative in more than 50% of the cases being intermittently in the rest. The immune complexes detected by the Raji cell assay were mostly of 7-13S in size, while those detected by anti-IgA Inh BA were bigger. There was a good correlation between the serum levels of polymeric IgA and the presence of IgA complexes (Raji cell assay). A certain correlation (p less than 0.05) was found between these IgA immune complexes and the clinical activity assessed by the hematuria. A similar correlation (p less than 0.05) was found with specific polymeric IgA immune complexes studied by a method recently described. No relationship was observed between the presence of any HLA antigens and the existence of circulating immune complexes. These results support the contention that IgA immune complexes, especially those composed of polymeric IgA, may have a role in the pathogenesis of IgA nephropathy. Moreover, the high serum levels of polymeric IgA observed in these patients could contribute to the slow clearance and long persistence in the circulation of IgA immune complexes with their subsequent deposition at the glomerular mesangium.     

Steroid therapy in IgA nephropathy in Japan

Summary: We performed prednisone (PSL) therapy which was done in the manner of a prospective multicentre paired controlled trial. We collected 196 patients with biopsy-proven IgA nephropathy (IgA-N). the patients were divided into prednisone group receiving prednisone (PSL group, n = 111) and antiplatelet group receiving anti-platelet drugs only (AP group, n = 85). the mean follow-up duration was 4.7 ± 2.5 years. We observed that PSL showed beneficial effects in maintaining renal function and decreasing proteinuria for the first 3 years. In stratified subgroups with proteinuria (UP>2 g/day) and with UP>2 g/day and creatinine clearance (Ccr)< = 70 mL/min, the renal death rate at the end of follow-up in patients of PSL group showed a tendency to be less than that of AP group ( P = 0.067, P =0.095, respectively) although the renal survival rate between both groups were not significantly different. We speculated that steroid therapy might be effective in IgA-N patients with UP>2 g/day and Ccr< = 70 mL/min. Further trials should be carried out in a properly controlled, randomized, stratified manner with long-term follow up.     

Enhanced expression of the CD71 mesangial IgA1 receptor in Berger disease and Henoch-Schönlein nephritis: association between CD71 expression and IgA deposits

ABSTRACT. IgA nephropathy (IgA-N) that comprises Berger disease and Henoch-Sch?nlein Purpura (HSP) nephritis is defined by mesangial IgA deposits. Recently, this group has characterized a new receptor for IgA, the transferrin receptor (CD71), expressed on mesangial cells. To assess whether CD71 was involved in the pathogenesis of IgA-N, its expression was analyzed together with IgA deposits on 16 kidney biopsies from 16 patients with Berger disease (n = 4) or HSP (n = 12). These biopsies were compared with 17 kidney biopsies of a group of 15 patients (control group) with other glomerulonephritis, including systemic lupus erythematosus, poststreptococcal acute glomerulonephritis, membranoproliferative glomerulonephritis, steroid-sensitive minimal change nephrotic syndrome, steroid-resistant idiopathic nephrotic syndrome with focal and segmental glomerulosclerosis, and persistent and isolated proteinuria with minimal change on kidney biopsy. In this control group, IgA deposits could be observed in eight kidney biopsies of seven patients. These biopsies were also compared with normal kidney specimens (normal group). In normal kidney, it was found that CD71 was linearly expressed on tubular epithelium but was either not expressed or very dimly in glomeruli. In contrast, CD71 was strongly expressed in 105 of the 107 glomeruli of the kidney biopsies from the IgA-N group. For the control group, it was found that expression of CD71 in glomeruli was correlated to the presence of IgA deposits. Indeed, among the 87 glomeruli of nine kidney biopsies (eight patients) without IgA fixation, 78 exhibited no CD71 expression and nine exhibited a very dim one. On the other hand, all 49 glomeruli of the eight kidney biopsies (seven patients) in which IgA deposits were detected exhibited CD71 expression (P < 10(-4)). Performance of dual-labeling studies with confocal microscopy on kidney biopsies of IgA-N patients demonstrated that most of the IgA deposits co-localized with CD71. It was also demonstrated that the intensity of the expression of CD71 was not linked to the intensity of clinical or biologic findings but to the intensity of cellular proliferation in both IgA-N and control groups. These results show that mesangial CD71 expression is not specific to IgA-N. However, the association between IgA deposits and CD71 expression and their co-localization in the mesangium provide strong evidence that CD71 is a major IgA receptor on mesangial cells.     

Protective role of anti-synthetic hinge peptide antibody for glomerular deposition of hypoglycosylated IgA1

Background The KM mouse lacks endogenous genes for immunoglobulins and carries the entire human IgH locus and the IgLk transgene. Therefore, human IgA1 does not provoke a hetero-immune response. We had observed mesangial IgA deposits in KM mice given desialo-degalacto (DeS/DeGal) IgA1. Methods In this study, the mice were immunized with synthetic IgA1 hinge (glyco-)peptide before administration of DeS/DeGal IgA1, and the effects of the pre-immunization were evaluated. Mice were divided into sHP, 5GalNAc-sHP and non-immunization groups. In two pre-immunization groups, KLH-conjugated sHP or KLH-5GalNAc-sHP, which has five GalNAc residues, was subcutaneously given three times every 2 weeks. Two weeks after the final pre-immunization, DeS/DeGal IgA1 was administered daily for 5 weeks. Serial serum levels of anti-sHP and anti-IgA1 antibodies were evaluated by ELISA. On the day of the last administration of IgA1, renal biopsy was performed. Results Mesangial IgA deposits were observed in all non-immunized mice. In pre-immunized mice, IgA deposition was not detected in 6 of 13 sHP mice and 1 of 4 5GalNAc-sHP mice. The intensities of IgA deposits were significantly different between sHP groups and non-immunized (P = 0.003) groups. There was a significant inverse correlation between the intensities of IgA deposits and the anti-sHP antibody titers (P = 0.016). Conclusions These results suggest that the anti-IgA1 hinge peptide antibody plays a role in the inhibition of glomerular IgA deposition.     

Improved renal survival in Japanese children with IgA nephropathy

Since the beginning of the 1990s, Japanese medical practitioners have extensively prescribed angiotensin-converting enzyme (ACE) inhibitors for children with mild IgA nephropathy (IgA-N) and steriods for those with severe IgA-N. We have performed a retrospective cohort study to clarify whether the long-term outcome has improved in Japanese children with IgA-N. Renal survival was defined as the time from onset to end-stage renal disease (ESRD). We divided the study period into two time periods based on the occurrence of the initial renal biopsy:1976–1989 and 1990–2004. Actuarial survivals were calculated by Kaplan–Meier method, and comparisons were made with the logrank test. The Cox proportional hazard model was used for multivariate analysis. Between 1976 and 2004, 500 children were diagnosed as having IgA-N in our hospitals. The actuarial renal survival from the time of apparent disease onset was 96.4% at 10 years, 84.5% at 15 years and 73.9% at 20 years. Renal survival in the 1990–2004 period was significantly better than that in 1976–1989 (p = 0.008), and a marked improvement in renal survival in patients with severe IgA-N was also observed (p = 0.0003). Multivariate analysis indicated that diagnosis year was a significant factor for ESRD-free survival independently of baseline characteristics. The results of this study show that there has been an improvement in terms of renal survival in Japanese children with IgA-N.     

IgG, IgA and IgM rheumatoid factors in patients with glomerulonephritis

Rheumatoid factors (RF), autoantibodies to IgG, have been postulated to have some pathogenetic role in the development of some types of glomerulonephritis. A simple and sensitive solid-phase fluorescence immunoassay was employed to determine whether IgG, IgA and IgM RF were detectable in sera from patients with various types of glomerulonephritis, rheumatoid arthritis (RA) and those with various streptococcal infections. IgG, IgA and IgM RF were significantly increased in the majority of patients with RA, lupus nephritis (SLE), acute poststreptococcal glomerulonephritis (APSGN) and various streptococcal infections. The titers of IgG and IgA RF were significantly higher in patients with APSGN than in those with simple pharyngitis. IgM RF was increated in patients with IgA nephropathy (IgA-N) and in those with membranoproliferative glomerulonephritis type I (MPGN). No significantly high RF was observed in membranous nephropathy (MN) or chronic mesangial proliferative glomerulonephritis without IgA deposition (PGN). It is suggested that some autologous immune mechanisms may be involved in the pathogenesis of some types of glomerulonephritis.     

Efficacy and safety of lisinopril for mild childhood IgA nephropathy: a pilot study

Even in children with mild immunoglobulin (Ig)A nephropathy (IgA-N) showing minimal/focal mesangial proliferation, persistent proteinuria seems to be a risk factor for progression of the disease, indicating the need for an effective and safe treatment even in such cases. Studies carried out to date have indicated that angiotensin-converting enzyme inhibitors (ACEIs) reduce urinary protein excretion and preserve renal function in adult IgA-N. However, no prospective study of ACEI only for childhood IgA-N has yet been carried out. In this prospective single-arm pilot trial, we administered lisinopril (0.4 mg/kg per day) as therapeutic treatment to 40 children with mild IgA-N with proteinuria [morning urinary protein/creatinine ratio (uP/Cr) ≥ 0.2 g/g]. Thirty-three patients reached the primary endpoint (uP/Cr < 0.2) during the 2-year treatment period. The cumulative disappearance rate of proteinuria determined by the Kaplan–Meier method was 80.9%. Mean uP excretion was reduced from 0.40 to 0.18 g/m²/day (p < 0.0001). Of the 40 patients treated, five (12.5%) showed dizziness, and four of these five needed the lisinopril dose reduced. However, lisinopril therapy was continued in all patients during the 2-year treatment period. No other side effect, such as cough, was observed. We conclude that the efficacy and safety of lisinopril is seemingly acceptable for the treatment of children with mild IgA-N. The participants in the Japanese Pediatric IgA Nephropathy Treatment Study Group are listed in the Appendix.     

Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy

Background. IgA nephropathy (IgA-N) is considered the most common glomerular disease in the world and leads to renal failure in a substantial number of patients. Although many studies have looked at the pathogenesis of the disease, many points need to be clarified, including the mechanism of complement activation. Recent studies have shown that mannose-binding lectin (MBL or mannose binding protein, MBP) initiates activation of the complement cascade (lectin pathway) utilizing two types of MBP-associated serine protease, namely MASP-1 and MASP-2. The present study was undertaken to elucidate whether the lectin pathway was involved in the pathogenic mechanism of IgA-N. Methods. Forty-five renal biopsy cases with IgA-N, 35 cases with other forms of glomerulonephritis (GN), and normal kidney tissues were collected and an immunohistochemical study was performed using monoclonal antibodies against MBL and MASP-1. Furthermore, clinicopathological and serological features were also analysed in the patients with IgA-N. Results. Glomerular deposition of MBL, which was accompanied by MASP-1, was detected in 11 of 45 (24.4%) cases with IgA-N, while it was detected in only one case with other forms of GN. The deposited MBL/MASP-1 was observed to associate with C3b/C3c and C5b-9 but not with IgG, IgM, Clq, C4c, or properdin. Compared with MBL/MASP-1 negative cases with IgA-N, the positive cases with IgA-N were young and the renal biopsies had been performed at an early stage of the disease. No significant correlation was found between glomerular deposition of MBL/MASP-1 and proteinuria, haematuria, creatinine clearance, and serum levels of IgA, C3, or C4 at the time of renal biopsy. There were also no significant differences between MBL/MASP-1 positive cases and negative cases in the plasma levels of circulating immune complexes or soluble C5b-9. Conclusion. The lectin pathway of complement activation, which is initiated by the MBL/MASPs complex, evidently contributes to the development of glomerular injury in a significant number of cases with IgA-N. In addition, these findings will add insight to the pathogenesis of IgA-N, including its relation to infection, since MBL plays a crucial role in the host defence against various pathogens.     

Parenteral nutrition inhibits tumor necrosis factor-alpha-mediated IgA response to injury

BACKGROUND: Parenteral nutrition (PN) increases the incidence of pneumonia in severely injured patients compared with enteral feeding (ENT). Injury induces an innate airway IgA response in severely injured patients; similar responses occur in mice. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) stimulate the production of polymeric immunoglobulin receptor (pIgR), the protein required to transport immunoglobulin A (IgA) to mucosal surfaces. We have shown that PN alters levels of lung and nasal passage IgA and several IgA-stimulating cytokines. We hypothesized that TNF-alpha and IL-1beta blockade, as well as PN, would blunt the airway IgA response to injury. METHODS: Male Institute of Cancer Research (ICR) mice were randomized to uninjured controls (n = 10) or to intra-peritoneal phosphate-buffered saline (PBS) (n = 9), antagonistic TNF-alpha antibody (100 mcg, n = 7), or antagonistic IL-1beta antibody (50 mcg, n = 8) 30 min prior to surgical stress with laparotomy and neck incisions. Mice were sacrificed at 8 h for nasal and bronchoalveolar lavage (NAL, BAL) to measure IgA by enzyme-linked immunosorbent assay. In a separate experiment, 12 mice underwent intravenous cannulation followed by chow (n = 5) or PN (n = 7) feeding for 5 days prior to the same stress and IgA measurement. RESULTS: Injury significantly increased NAL and BAL IgA (225 +/- 104 ng) compared with baseline (145 +/- 38 ng; p = 0.01). Blockade of TNF-alpha eliminated the innate airway IgA response to injury (130 +/- 47 ng; p = 0.01), whereas IL-1beta blockade blunted and PN eliminated it completely. CONCLUSIONS: Tumor necrosis factor-alpha is involved in the respiratory IgA immune response to injury. Both TNF-alpha blockade and PN impair this innate response, and blockade of IL-1beta impairs it to a degree. We hypothesize that these cytokines blunt this response via their known effects on the polymeric immunoglobulin receptor (pIgR), whereas the PN-induced deficit likely is multifactorial.     

Intraglomerular monocytes in human glomerulonephritis.

A total of 246 cases of 166 primary glomerulonephritis (GN) and 80 secondary GN were examined for the presence of intraglomerular monocytes using nonspecific esterase reaction of alpha-naphthyl butyrate methods. The high score of monocyte index (MI) as the numbers of monocytes per glomerulus was found in crescentic GN (n = 5, MI = 3.72 +/- 1.98), endocapillary proliferative GN (n = 8, MI = 2.17 +/- 2.13), lupus nephritis (n = 43, MI = 2.21 +/- 3.35), and cryoglobulinemia-related GN (n = 1, MI = 11.5). The intermediate score of MI was observed in IgA nephropathy (IgA-N, n = 64, MI = 0.63 +/- 0.42) and Henoch-Sch?nlein purpura nephritis (HSP-N, n = 11, MI = 1.09 +/- 0.87). Out of IgA-N and HSP-N, the scores of MI in patients with more severe proliferation and/or with segmental lesions were higher than those without this histological finding. However, there was not a significant correlation between the glomerular monocytic infiltration and clinical findings in each group. In primary GN including minor glomerular abnormalities, focal glomerular sclerosis and membranous GN, and in secondary renal diseases except for SLE, HSP, and cryoglobulinemia, the score of intraglomerular monocytic infiltration was of little value. The participation of monocytes was predominant in extra- and intracapillary GN, lupus nephritis, and cryoglobulinemia-related GN, as previously reported. Moreover, in some types of proliferative GN, especially IgA-N and HSP-N, some parts of glomerular hypercellularity result from the participation of monocyte-macrophage series, although the main parts of cell proliferation are intrinsic mesangial cells.     

Expression of connective tissue growth factor mRNA in human IgA nephropathy

Background. Connective tissue growth factor (CTGF) is a cysteine-rich member of a new family of growth regulators. Its upregulation is an important factor in the pathogenesis of mesangial matrix accumulation and progressive glomerulosclerosis. Methods. We evaluated the expression and localization of CTGF mRNA in renal tissues of 20 patients with IgA nephropathy (IgA-N) and 5 normal human kidneys (NHK), using high-resolution in situ hybridization with digoxigenin-labeled oligonucleotide. The expression level of CTGF mRNA was quantitated by counting all nuclei, as well as nuclei surrounded by CTGF mRNA-positive cytoplasm in at least ten randomly selected cross-sections of nonsclerotic glomeruli, and expressing the results as percentage of positive cells. Results. In both IgA-N and NHK, CTGF mRNA was mainly expressed in glomerular intrinsic cells, including mainly glomerular mesangial and epithelial cells, and some endothelial cells and cells of Bowman's capsule. CTGF mRNA-positive cells were abundant in tubulointerstitial fibrotic areas, especially in IgA-N with severe tissue damage. CTGF mRNA expression was also increased in vascular cells in IgA-N. The percentage of cells positive for CTGF mRNA was significantly higher in IgA-N than in NHK. Furthermore, the percentage of cells positive for CTGF mRNA was significantly greater in IgA-N with moderate mesangial proliferative lesions than in IgA-N with mild mesangial proliferative lesions and/or sclerotic lesions. Conclusions. Our study indicates that CTGF may play an important role in the development and progression of glomerulosclerosis and tubulointerstitial fibrosis in IgA-N. Received: July 17, 2000 / Accepted: October 21, 2000     

Decreased B cells and IgA-secreting B cells partially explain the high prevalence of IgA deficiency in dialysis patients

AIMS: We previously reported 2 hemodialysis (HD) patients with recurrent infections and selective immunoglobulin A deficiency (IgAD). We further demonstrated that serum IgA levels were lower and the prevalence of IgAD was higher in uremic patients. The exact mechanisms of IgAD in uremic patients largely remained unclear. In some patients, it was caused by anti-IgA antibody neutralization and subsequent destruction. We performed the present study to survey if there is any defect in IgA production. MATERIALS AND METHODS: 288 patients were initially included for examination of serum immunoglobulins. 16 normal persons, 16 dialysis patients without IgAD, and 12 dialysis patients with IgAD were enrolled after the initial examination. Blood was drawn into heparinized tubes. WBC counts and lymphocyte percentage were examined by a CBC counter. Lymphocytes were separated by the Ficoll-Paque method. Flow cytometry was utilized to isolate the B cell and IgA-secreting B cell after staining with CD 19 phycoerythrin and FITC-conjugated rabbit anti-human IgA antibody. RESULTS: There is no significant difference between WBC counts or total lymphocyte counts of these 3 groups. However, we found a lower percentage of total lymphocyte counts in dialysis patients, either with or without IgAD. The total B cell numbers were lower in dialysis patients with IgAD. In addition, there were fewer IgA-secreting B cells in dialysis patients with IgAD. CONCLUSION: Decreased B cell and IgA-secreting B cell counts are seen in uremic patients with IgAD. This, in turn, indicates that there might be a defect of IgA production in some patients, rather than IgA destruction by anti-IgA antibodies as seen in some other patients. Further study is needed to investigate the mechanisms of decreased B cells and IgA-secreting B cells.     

Correlation between the severity of clinicopathological parameters and whole blood interferon-alpha production capacity in active phase IgA nephropathy patients.

BACKGROUND/AIMS: Patients with IgA nephropathy (IgA-N) are thought to have immune system disorders that frequently result in high serum IgA levels and a relatively high susceptibility to upper respiratory infections. AIMS: To clarify the influence of the specific immune response of IgA-N patients on the clinicopathological features of the disease, we measured the whole-blood-producing capacity of interferon-alpha (IFNalpha-PC). We then compared these findings with clinical and histopathological parameters, including tissue macrophage infiltration, during both histologically active and latent phases. PATIENTS AND METHODS: Fifty-one inpatients with IgA-N and 70 healthy controls were examined. According to the histological findings, 32 patients had disease in the active phase (AP), and 19 were in the latent phase (LP). RESULTS: In AP patients, IFNalpha-PC showed positive correlations to serum creatinine, blood urea nitrogen, serum beta2-microglobulin (s-beta2MG), urinary total protein (U-TP), and urinary beta2MG, in addition to the number of infiltrated macrophages per area of interstitium. In LP patients, negative correlations were shown between IFNalpha-PC and s-beta2MG, U-TP, and U-N-acetyl-beta-D-glucosaminidase. CONCLUSION: A significant positive relationship exists between IFNalpha-PC and the clinicopathological parameters of deteriorated renal lesions in the AP but not in the LP. Thus, the immune status influencing the functional damage may differ between these two phase.     

Differences in glomerular leukocyte infiltration between IgA nephropathy and membranoproliferative glomerulonephritis

Background: An important aspect in glomerular nephritic processes is the enhanced influx of leukocytes into the glomerulus. Methods: To investigate the mechanisms of intraglomerular leukocyte infiltration in IgA nephropathy (IgA-N) and membranoproliferative glomerulonephritis type I (MPGN-I), we immunohistochemically examined the intraglomerular expression of leukocyte function-associated antigen-1 (LFA-1, CD11a/CD18), macrophage-1 (Mac-1, CD11b/CD18) and intercellular adhesion molecule-1 (ICAM-1, CD54) together with glomerular deposition of C3c and fibrinogen. Results: In IgA-N (n=42), LFA-1⁺ cells were distributed mainly in glomeruli with intense expression of ICAM-1, and there was a positive correlation (P<0.001) between the number of LFA-1⁺ cells and the degree of ICAM-1 expression. Mac-1⁺ cells had no correlation with glomerular C3c deposition, but had a significant correlation with fibrinogen deposition (P<0.05). The number of LFA-1⁺ cells was significantly greater than of Mac-1⁺ cells (P<0.05). The number of LFA-1⁺ cells was strongly correlated with that of CD68⁺ cells (P<0.00001). In MPGN-I (n=43), on the contrary, Mac-1⁺ cells correlated only with C3c deposition (P<0.001), and they were observed mainly in peripheral loops of glomerular capillaries where C3c was deposited with a similar distribution. However, there was no relationship between LFA-1⁺ cells and ICAM-1 expression. The number of Mac-1⁺ cells was greater than that of LFA-1⁺ cells (P<0.0001), and most Mac-1⁺ cells were identical to CD15⁺ cells. Conclusion: These results indicate the possibility that different mechanisms may cause glomerular leukocyte infiltration in various forms of human glomerulonephritis. The LFA-1/ICCAM-1 pathway may play an important role in glomerular leukocyte infiltration in IgA-N, while the Mac-1/complement pathway may be important in MPGN-I. The former may promote mainly the infiltration of CD68⁺ cells, and the latter may promote that of CD15⁺ cells. In addition, Mac-1⁺ cells may act as fibrinogen and complement receptors in IgA-N and MPGN-I, respectively. Key words: adhesion molecules; complements; glomerular leukocytes infiltration; IgA nephropathy; membranoproliferative glomerulonephritis      

Immunoglobulin-antiimmunoglobulin interactions and immune complexes in IgA nephropathy

IgA nephropathy (IgAN) is characterized by mesangial co-deposition of IgA and C3. Elevated levels of circulating immune complexes containing these components in significant numbers of patients have been found in several studies; IgAN is therefore assumed by many investigators to be an immune complex-mediated disease. Our studies have shown that IgG is often co-complexed with IgA within circulating immune complexes, and we have begun to examine the potential mechanisms for these observations. In this regard, elevated levels of IgA rheumatoid factor and of IgG anti-IgA antibodies were found in some patients. Nevertheless, we were unable to correlate levels of circulating immune complexes with any clinical index of disease. Furthermore, many individuals with the acquired immune deficiency syndrome (AIDS) also have elevated levels of circulating immune complexes containing IgG and IgA, IgA rheumatoid factor, and IgG anti-IgA antibodies, although these patients apparently do not have mesangial IgA deposits. Therefore, the role of circulating IgA-containing immune complexes in the pathogenesis of IgAN requires further evaluation.     

Role of endothelial cells in IgA nephropathy

Summary: Various polyspecific autoantibodies have been described in the sera of patients with IgA nephropathy, including anti-IgG, anti-IgA, antigalactosyl, antifibronectin and antimesangial antibodies. We and other authors have demonstrated the presence of antivascular endothelial cell (VEC) antibodies, in up to 32% of patients with IgA nephropathy. These antibodies were directed against molecules on the endothelial cell surface. Some of these antibodies were directed against HLA class I antigens; the majority, however, were reactive against antigens present on unstimulated endothelial cells, as prior stimulation of the cells with interferon-γ or interleukin 1 did not result in an increase in anti-VEC activity of the sera. The clinical significance of these anti-VEC antibodies in IgA nephropathy is unknown. A significant correlation was demonstrated between these antibodies and the presence of heavy proteinuria. A significant association was also shown between the presence of these antibodies and the histopathologic markers of activity such as crescents and focal and segmental necrotizing lesions, as well as immunoglobulin and C3 deposition in the vessel walls.