IgG and IgA classes of anti-neutrophil cytoplasmic autoantibodies in a 13-year-old girl with recurrent Henoch-Schonlein purpura

We describe a 13-year-old girl with recurrent Henoch-Schonlein purpura whose symptoms were precipitated by upper respiratory tract infections. Her serum was positive for both IgG and IgA classes of anti-neutrophil cytoplasmic autoantibodies by immunofluorescence. The titers of both autoantibodies correlated with disease activity. The immunopathology underlying these findings is discussed.     

白细胞介素1受体拮抗剂等位基因与紫癜性肾炎和IgA肾病的相关联系

目的 为了进一步阐明紫癜性肾炎(HSPN)及IgA肾病(IgAN)二者在发病机理上可能存在的联系。方法 用PCR方法对43例HSPN,97例IgAN患者和98名正常人IL-l受体拮抗剂(IL-lra)基因数目可变的串联重复(VNTR)多态性进行了分析。结果 HSPN患者白细胞介素l受体拮抗剂等位基因(IL IRN 2)的携带率明显高于正常人(P<0.02)和IgAN患者(P<0.05)。在IgAN患者中表现为反复发作性肉眼血尿者其IL IRN 2等位基因的携带率明显高于其它临床类型IgAN患者(P<0.o1),而与HSPN无显著性差异(P>0.05)。结论 HSPN患者IL-lra基因特定的遗传背景在其发病机理中可能起一定作用。IgAN患者中表现为反复发作性肉眼血尿者较其它临床类型IgAN患者与HSPN有更多的相似之处,而ILlRN 2等位基因高携带率可能是二者发病机理的共同点之一。     

Mutant mice provide new insight into the role of (mis-)glycation in IgA nephropathy and other glomerular diseases.

In the 24 October 2006 issue of PNAS, Alexander and colleagues[1] describe the results of a systematic search for thrombocytopenicmice generated by large-scale mutagenesis. Amongst 3523 mice,one pedigree indeed exhibited 50% reduction in platelet counts.Apart from thrombocytopenia, the only other notable featureof these mice was prominent renal disease (albuminuria/proteinuria,glomerulosclerosis and tubulointerstitial inflammatory infiltration)leading to uraemia and death at around 200 days after birth.This renal disease was not immune mediated, since it persistedin mutant mice crossed to     

Antineutrophil cytoplasmic autoantibodies in patients with systemic lupus erythematosus recognize a novel 69 kDa target antigen of neutrophil granules

OBJECTIVE: Antineutrophil cytoplasmic autoantibodies (ANCA) were found in patients with systemic lupus erythematosus (SLE). Cathepsin G and lactoferrin were the major target antigens. However, some ANCA-positive sera did not recognize either of them. The present study was to investigate the unknown target antigens of ANCA in patients with SLE and their clinical significance. METHODS: Sera were collected from 72 patients with SLE. ANCA were detected in both indirect immunofluorescence and antigen-specific enzyme-linked immunosorbent assay (ELISA). Mixed neutrophil granules were separated from normal human peripheral neutrophils; soluble acid extracts in non-reducing conditions were used as antigens in western blot analysis to detect ANCA. RESULTS: SLE sera could blot a few bands. Interestingly, 14/72 (19.4%) sera recognized a novel 69 kDa protein band and 10/72 (13.9%) sera recognized the 55 kDa protein band, which might be bactericidal/permeability-increasing protein (BPI). The 69 kDa target antigen was different from the known target ANCA antigens such as cathepsin G and lactoferrin. Further study revealed that the percentages of patients with photosensitivity and oral ulcer in the anti-69 kDa autoantibodies-positive group were significantly higher than those in the anti-69 kDa autoantibodies-negative group (57.1%vs 10.3%, P < 0.005 and 50.0%vs 12.1%, P < 0.05, respectively). CONCLUSIONS: A 69 kDa protein in human neutrophil granules was identified as a novel target antigen of ANCA in patients with SLE. The anti-69 kDa autoantibodies might be associated with photosensitivity and oral ulcer in patients with SLE.     

IgA nephropathy with myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO ANCA): a discrepancy between the histological activity and MPO ANCA

Anti-neutrophil cytoplasmic antibodies (ANCA) of the immunoglobulin (Ig)G type are associated with rapidly progressive glomerulonephritis. Such antibodies have been detected only rarely in patients with Henoch-Schönlein purpura (HSP) or IgA nephropathy (IgAN). We report a patient with biopsy-proven IgAN with fibrous crescents in whom high titers of IgG ANCA occurred and were confirmed to be anti-myeloperoxidase antibodies (MPO ANCA) by solid-phase enzyme-linked immunosorbent assay (ELISA) and inhibition studies. During a 1-year follow-up period, high titers of MPO ANCA persisted but creatinine clearance remained over 50 ml/min per 1.48 m.² This case suggests the lack of a reliable association between fulminant outcome of IgAN with crescents and high titers of IgG MPO ANCA, and indicates the involvement of subsets of IgG MPO ANCA which recognize important or unimportant epitopes of MPO in the pathogenesis.     

IgA nephritis in a child with human immunodeficiency virus: a unique form of human immunodeficiency virus-associated nephropathy?

A 9-year-old boy is presented who was antibody positive for human immunodeficiency virus (HIV) and who had recurrent episodes of gross hematuria. Renal biopsy revealed findings typical of IgA nephropathy but also showed electron-microscopic abnormalities seen with HIV-associated nephropathy. In addition, IgA antibodies to multiple HIV proteins were detected in serum by Western blot analysis, and circulating immune complexes of the IgA class were present. Although HIV-associated nephropathy and IgA nephropathy are thought to be distinct conditions, five adults with a similar combination of findings have been reported, and our patient adds to the evidence for a link between these two entities in some patients. We propose that the histological parallels between the conditions may merely represent the limited renal responses available to multiple types of injuries, and we support the attempts underway to probe renal tissue for the HIV genome.     

Immunologic evidence for the in situ deposition of a cytoplasmic streptococcal antigen (endostreptosin) on the glomerular basement membrane in rats

Endostreptosin (ESS) is an antigen derived from the cytoplasm and the plasma membrane of nephritogenic group A and to a lesser extent group C and G streptococci. It is immunologically not related to streptococcal exoenzymes or the streptococcal cell wall and can be detected on the endothelial side of the glomerular basement membrane of kidney biopsies of patients with acute poststreptococcal glomerulonephritis (ASGN) during the early phase of the disease. Highest and most persistent antibody titers to this antigen are found in patients with ASGN. Immunoaffinity isolated ESS was injected i.v. into the tail vein of Wistar Furth (W/FU) rats for up to five successive days. The animals were sacrificed on days 1, 2, 3, 4, 5, 8, 9, 10, 11 and 12. Frozen sections of the rat kidneys were tested by immunofluorescence against rabbit anti-ESS-antibody and against sera from patients who had recently recovered from ASGN as well as against anti-rat-IgG and C3. The basement membranes of rat kidneys were positive for ESS deposition starting from day one on, but were negative for anti-rat IgG and C3 during the first four days. Rats sacrificed on days 8-12 showed increasing deposition of IgG and C3 with decreased staining for ESS. The sera of rats sacrificed on days 1-3 had no detectable anti-ESS antibodies; whereas animals from day 4 on had low levels of anti-ESS antibodies as determined by microcomplement fixation. Control animals showed no staining for ESS, IgG, C3 as well as no detectable anti-ESS antibodies.     

Treatment of IgA nephropathy with eicosapentanoic acid (EPA): a two-year prospective trial

Thirty-seven patients with biopsy proven mesangial IgA nephropathy were prospectively allocated to either two years of treatment with eicosapentanoic acid (EPA) 10 g per day or no treatment. At entry treated and untreated patients with renal dysfunction (Group A) or patients with normal serum creatinine less than 0.12 mmol/l (Group B) did not differ in serum creatinine, creatinine clearance, urinary protein excretion, or quantitative urinary red cell counts. Compliance with EPA therapy was excellent as assessed by plasma fatty acid profiles. At the end of the trial creatinine clearance in treated patients had gone from 80 +/- 16 to 57 +/- 17 ml/min (p less than 0.05) and in untreated patients from 76 +/- 18 to 55 +/- 14 (p less than 0.05). There were no beneficial effects in either Group A or Group B patients. The only two patients who had improvement in renal function were in the EPA treatment group. Although no side effects of treatment were noted, EPA does not alter the course of established mesangial IgA nephropathy.     

Effects of skeletal loading on bone mass and compensation mechanism in bone: a new insight into the "mechanostat" theory

 We have suggested that: (i) osteocalcin carboxylation is related to bone material properties (bone quality), and (ii) impairment of bone material properties could be compensated by bone mass increase. The aim of the present prospective study was to investigate whether the effects of skeletal loading on bone mass were associated with the compensation mechanism between bone mass and bone material properties. The subjects were 56 healthy female volunteers aged around 50 years. They were classified into pre- and postmenopausal groups, and each group was then subdivided into a no-exercise (control) and a vertical jumping exercise group. Bone mineral density (BMD) was measured at baseline and after the 6-month study period. Urinary γ-carboxyglutamate (Gla), a possible parameter of osteocalcin carboxylation, was also measured at baseline. Among the premenopausal women, hip BMD in the exercise group increased significantly in comparison to the control value. Among the postmenopausal women, however, there was no significant difference in the BMD change between the control and the exercise group. In addition, the baseline urinary Gla level showed an inverse correlation with the change in whole body BMD in the premenopausal exercise group. These results suggest that: (i) estrogen plays a certain role in the high-impact exercise-induced bone gain, and (ii) the effects of skeletal loading on bone mass are involved in the compensation mechanism, i.e., bone gain due to high-impact exercise becomes greater in accordance with the degree of deterioration in bone material properties. Our concept of the compensation mechanism could provide a new insight into the understanding of the skeleton's adaptability to load-bearing. Received: April 16, 2001 / Accepted: February 8, 2002     

Correlation of macrophage location and plaque stress distribution using USPIO-enhanced MRI in a patient with symptomatic severe carotid stenosis: a new insight into risk stratification

High resolution, USPIO-enhanced MR imaging can be used to identify inflamed atherosclerotic plaque. We report a case of a 79-year-old man with a symptomatic carotid stenosis of 82%. The plaque was retrieved for histology and finite element analysis (FEA) based on the preoperative MR imaging was used to predict maximal Von Mises stress on the plaque. Macrophage location correlated with maximal predicted stresses on the plaque. This supports the hypothesis that macrophages thin the fibrous cap at points of highest stress, leading to an increased risk of plaque rupture and subsequent stroke.     

Plasmapheresis in a patient with rapidly progressive idiopathic IgA nephropathy: removal of IgA-containing circulating immune complexes and clinical recovery

Primary IgA nephropathy is generally considered a benign disease, but progression to renal failure is not uncommon and a rapidly progressive course is observed in some cases, especially when extensive epithelial crescents are present. Circulating IgA-containing immune complexes (IgAIC) seem to play the most important pathogenetical role, hence the authors adopted plasmapheretic treatment in association with immunosuppressive drugs for 1 patient affected by primary IgA nephritis, with florid crescents and progressive renal failure. IgAIC decreased significantly after each plasma exchange and finally returned to normal values; over the same period urinary protein loss and heavy microscopic hematuria gradually disappeared and renal function was completely recovered.     

Studies on a pancreatic oncofetal antigen (POA) in patients with pancreatic cancer

An enzyme immunoassay for POA prepared by Gelder et al. was developed in our laboratory. Elevated serum POA levels were shown in 70.6% (36/51) of patients with pancreatic cancer. POA levels were related neither to the stage nor to the degree of differentiation of pancreatic cancer. Although POA levels were not elevated in patients with benign diseases of the pancreas, they were elevated in patients with cancer of the hepato-biliary tract. In pancreatic cancer patients with pre-operative high POA levels, serial POA determinations following tumor resection are considered to be useful for detecting recurrence of disease. Employing the unlabeled antibody peroxidase-antiperoxidase (PAP) method, POA was detected in the cytoplasm of cancer cells in 80.0% (28/35) of pancreatic cancer patients, but not in histologically normal pancreatic tissue. Well differentiated cancer cells showed higher POA stainability than less differentiated ones. POA was also detected in fetal pancreas tissues of 22 weeks gestation, but not in those of 12-16 weeks gestation. This result suggests that POA is an oncofetal antigen.     

Studies in patients with hyperparathyroidism using a new two-site immunochemiluminometric assay for circulating intact (1-84) parathyroid hormone

A recently developed chemiluminescent immunoassay for 1-84 intact parathyroid hormone (PTH) demonstrated increased specificity by virtue of two-site antibody binding and increased sensitivity by use of a chemiluminescent technique. Basal PTH levels were measured in three groups of subjects: (1) normal (n = 82), (2) hyperparathyroidism (n = 31), and (3) patients with hypercalcemia of malignancy (n = 16). There was good discrimination between normal (1.2 to 9.4 pmol/L) and hyperparathyroid subjects (9.2 to 53.4 pmol/L). In persons with hypercalcemia of malignancy all PTH levels were within the normal range (0.8 to 5.2 pmol/L) or suppressed. PTH release was stimulated by the intramuscular injection of 100 IU salmon calcitonin in 6 normal controls, 10 patients with primary hyperparathyroidism due to adenoma, and 5 with four-gland hyperplasia. There was no significant rise in PTH concentration and out of the normal range in the control subjects, but the adenoma patients demonstrated a mean rise of 24.4%, 26%, and 33%, and hyperplasia patients, a mean rise of 37%, 47%, and 37% over basal levels at 120, 180, and 240 minutes. The mean absolute rise in PTH concentration was 13.4 +/- 7.7 pmol/gm of parathyroid tissue in the adenomas and 27.2 +/- 9.5 pmol/gm of parathyroid tissue in the hyperplastic glands; this difference was significant (p less than 0.05). Serial blood samples from a central vein were taken at surgery for hyperparathyroidism, and the rate of decay of the intact hormone was studied in 9 patients after removal of the parathyroid tissue. This decay was rapid with a half-life of 300 seconds. We conclude that this new specific and sensitive intact PTH assay will provide a valuable means of investigating dynamic aspects of parathyroid physiology.     

Reduced level of sex-specific antigen (H-Y antigen) on lymphocytes in some patients with bilateral cryptorchidism

Sex-specific (Sxs) antigen on the surface of nucleated cells from normal human males seems to be essential for the formation of testes. The relative quantity of the antigen on lymphocytes was evaluated by absorption experiments in a complement-dependent cytotoxicity test or in an ELISA technique using antisera against Sxs antigen produced by immunization of female rats. Lymphocytes from 13 normal males were Sxs-antigen positive, and cells from 12 normal females were characterized as Sxs-antigen negative. However, in the testing of lymphocytes from nine boys with bilateral cryptorchidism, only six revealed a normal male absorption pattern, whereas the antigen level on cells from three boys, all of them with normal karyotype, was reduced compared with the normal male level. No correlation between Sxs-antigen level and testosterone response after treatment with hCG could be demonstrated.     

The effects of a neutrophil elastase inhibitor (ONO-5046.Na) and neutrophil depletion using a granulotrap (G-1) column on lung reperfusion injury in dogs.

BACKGROUND: Activated neutrophils are reported to be closely involved in ischemia-reperfusion injury after lung transplantation. We investigated the beneficial effects of a new recombinant specific neutrophil elastase inhibitor, ONO-5046.Na, and an extracorporeal-type granulotrap (G-1) column on ischemia-reperfusion lung injury, by using an in situ warm lung ischemia model in dogs. METHODS: Warm ischemia was induced for 3 hours by clamping the pulmonary arteries and veins. The left main bronchus was bisected and reanastomosed prior to reperfusion. The left lung was collapsed for 3 hours. A total of 27 adult mongrel dogs were divided into three groups: the control group (n = 9) treated with a saline vehicle; the ONO group (n = 9), in which ONO-5046.Na was continuously administrated from before induced ischemia and to ending 2 hours after reperfusion; and the G-1 group (n = 9), in which a G-1 column was applied for 90 minutes starting 30 minutes before reperfusion under passive bypass support. RESULTS: Circulating neutrophils in the G-1 group decreased significantly (p<.05) compared to preischemia, and significantly decreased compared with the other groups after reperfusion. Oxygenation was improved actually and pulmonary vascular resistance was kept lower level after the administration of ONO-5046.Na. The increase of lung weight was significantly ameliorated in both the G-1 and ONO groups. In the histopathological study, lungs from the control group demonstrated diffuse alveolar edema, neutrophil infiltration, massive alveolar exudate and hemorrhage, and thickening of the interstitium. Lungs from the G-1 group showed mild swelling of the alveolar wall and neutrophil infiltration. Lungs from the ONO group showed virtually no abnormalities. CONCLUSION: This study demonstrated that a neutrophil elastase inhibitor and neutrophil depletion prevented lung reperfusion injury. These treatments may prevent ischemia and reperfusion injury in lung transplantation.