In systemic lupus erythematosus (SLE), autoantibody production can lead to kidney damage and failure, known as lupus nephritis. Basophils amplify the synthesis of autoantibodies by accumulating in secondary lymphoid organs. Here, we show a role for prostaglandin D 2 (PGD 2 ) in the pathophysiology of SLE. Patients with SLE have increased expression of PGD 2 receptors (PTGDR) on blood basophils and increased concentration of PGD 2 metabolites in plasma. Through an autocrine mechanism dependent on both PTGDRs, PGD 2 induces the externalization of CXCR4 on basophils, both in humans and mice, driving accumulation in secondary lymphoid organs. Although PGD 2 can accelerate basophil-dependent disease, antagonizing PTGDRs in mice reduces lupus-like disease in spontaneous and induced mouse models. Our study identifies the PGD 2 /PTGDR axis as a ready-to-use therapeutic modality in SLE.

The association between membranous nephropathy (MN) and immunological disorder-related liver disease has not been extensively investigated, and the specific features of this uncommon association, if any, remain to be determined.We retrospectively identified 10 patients with this association. We aimed to describe the clinical, biological, and pathological characteristics of these patients and their therapeutic management. The possible involvement of the phospholipase A2 receptor (PLA2R) in these apparent secondary forms of MN was assessed by immunohistochemistry with renal and liver biopsy specimens.The mean delay between MN and liver disease diagnoses was 3.9 years and the interval between the diagnosis of the glomerular and liver diseases was <1.5 years in 5 patients. MN was associated with a broad spectrum of liver diseases including primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC). AIH whether isolated (n=3) or associated with PBC (n=2) or PSC (n=2) was the most frequent autoimmune liver disease. Circulating PLA2R antibodies were detected in 4 out of 9 patients but the test was performed under specific immunosuppressive treatment in 3 out of 9 patients. Seven of the 9 patients with available renal tissue specimens displayed enhanced expression of PLA2R in glomeruli whereas PLA2R was not expressed in liver parenchyma from these patients or in normal liver tissue. The study of immunoglobulin (Ig) subclasses of deposits in glomeruli revealed that the most frequent pattern was the coexistence of IgG1 and IgG4 immune deposits with IgG4 predominating.Detection of PLA2R antibodies in glomeruli but not in liver parenchyma is a common finding in patients with MN associated with autoimmune liver disease, suggesting that these autoantibodies are not exclusively detected in idiopathic MN.

IgA1 complexes containing deglycosylated IgA1, IgG autoantibodies, and a soluble form of the IgA receptor (sCD89), are hallmarks of IgA nephropathy (IgAN). Food antigens, notably gluten, are associated with increased mucosal response and IgAN onset, but their implication in the pathology remains unknown. Here, an IgAN mouse model expressing human IgA1 and CD89 was used to examine the role of gluten in IgAN. Mice were given a gluten-free diet for three generations to produce gluten sensitivity, and then challenged for 30 days with a gluten diet. A gluten-free diet resulted in a decrease of mesangial IgA1 deposits, transferrin 1 receptor, and transglutaminase 2 expression, as well as hematuria. Mice on a gluten-free diet lacked IgA1-sCD89 complexes in serum and kidney eluates. Disease severity depended on gluten and CD89, as shown by reappearance of IgAN features in mice on a gluten diet and by direct binding of the gluten-subcomponent gliadin to sCD89. A gluten diet exacerbated intestinal IgA1 secretion, inflammation, and villous atrophy, and increased serum IgA1 anti-gliadin antibodies, which correlated with proteinuria in mice and patients. Moreover, early treatment of humanized mice with a gluten-free diet prevented mesangial IgA1 deposits and hematuria. Thus, gliadin-CD89 interaction may aggravate IgAN development through induction of IgA1-sCD89 complex formation and a mucosal immune response. Hence, early-stage treatment with a gluten-free diet could be beneficial to prevent disease.

The presence of autoantibodies in systemic lupus erythematosus, particularly those of the IgG subclass, have long been associated with disease onset and activity. Here we explored the prevalence of autoreactive IgE in SLE and its relevance to disease in French (n = 79) and United States (US) (n = 117) cohorts with a mean age of 41.5 ± 12.7 and 43.6 ± 15.3 years and disease duration of 13.5 ± 8.5 and 16.6 ± 11.9 years, respectively. Our findings show that approximately 65% of all SLE subjects studied produced IgE antibodies to the seven autoantigens tested. This positivity was increased to almost 83% when only those subjects with active disease were considered. SLE subjects who were positive for anti-dsDNA, -Sm, and -SSB/La -specific IgE showed a highly significant association in the levels of these antibodies with disease activity similar to that of the corresponding IgG's. A strong association of IgE autoantibodies with active nephritis was also found in the combined cohort analysis. A test of the predictive value of autoreactive IgE's and IgGs for disease activity (SLE Disease Activity Index (SLEDAI) ≥ 4) revealed that the best predictors were dsDNA-specific IgE and IgG, and that the age of an SLE subject influenced this predictive model. The finding argue that the overall levels of IgE autoantibodies, independently or in combination with IgG autoantibodies, may serve as indicators of active disease.

Atypical hemolytic uremic syndrome (aHUS) is a genetic ultrarare renal disease associated with overactivation of the alternative pathway of complement. Four gain-of-function mutations that form a hyperactive or deregulated C3 convertase have been identified in Factor B (FB) ligand binding sites. Here, we studied the functional consequences of 10 FB genetic changes recently identified from different aHUS cohorts. Using several tests for alternative C3 and C5 convertase formation and regulation, we identified two gain-of-function and potentially disease-relevant mutations that formed either an overactive convertase (M433I) or a convertase resistant to decay by FH (K298Q). One mutation (R178Q) produced a partially cleaved protein with no ligand binding or functional activity. Seven genetic changes led to near-normal or only slightly reduced ligand binding and functional activity compared with the most common polymorphism at position 7, R7. Notably, none of the algorithms used to predict the disease relevance of FB mutations agreed completely with the experimental data, suggesting that in silico approaches should be undertaken with caution. These data, combined with previously published results, suggest that 9 of 15 FB genetic changes identified in patients with aHUS are unrelated to disease pathogenesis. This study highlights that functional assessment of identified nucleotide changes in FB is mandatory to confirm disease association.

The (patho)physiological role of IgE in nonallergic inflammatory diseases is not well understood. Here, we explored the effect of IgE deficiency on the inflammatory response in FcγRIIB-deficient mice as well as in mice carrying both a deletion of FcγRIIB and the chromosomal translocation of Y-linked autoimmune acceleration (Yaa) that hastens and results in a more aggressive lupuslike disease in these mice. The findings show that deficiency of IgE delays disease development and severity as demonstrated by reduced autoantibody production and amelioration of organ pathologies. This was associated with decreased numbers of plasma cells and reduced levels of IgG2b and IgG3. Unexpectedly, the loss of IgE also caused a striking decrease of immune cell infiltration in secondary lymphoid organs with a marked effect on the presence of dendritic cells, monocytes, neutrophils, and eosinophils in these organs and decreased activation of basophils. The presence of autoreactive IgE in human systemic lupus erythematosus subjects was also associated with increased basophil activation and enhanced disease activity. These findings argue that IgE facilitates the amplification of autoimmune inflammation.

Genetic studies have shown that mutations of complement inhibitors such as membrane cofactor protein, Factors H, I, or B and C3 predispose patients to atypical hemolytic uremic syndrome (aHUS). Factor I is a circulating serine protease that inhibits complement by degrading C3b and up to now only a few mutations in the CFI gene have been characterized. In a large cohort of 202 patients with aHUS, we identified 23 patients carrying exonic mutations in CFI. Their overall clinical outcome was unfavorable, as half died or developed end-stage renal disease after their first syndrome episode. Eight patients with CFI mutations carried at least one additional known genetic risk factor for aHUS, such as a mutation in MCP, CFH, C3 or CFB; a compound heterozygous second mutation in CFI; or mutations in both the MCP and CFH genes. Five patients exhibited homozygous deletion of the Factor H-related protein 1 (CFHR-1) gene. Ten patients with aHUS had one mutation in their CFI gene (Factor I-aHUS), resulting in a quantitative or functional Factor I deficiency. Patients with a complete deletion of the CFHR-1 gene had a significantly higher risk of a bad prognosis compared with those with one Factor I mutation as their unique vulnerability feature. Our results emphasize the necessity of genetic screening for all susceptibility factors in patients with aHUS.

Complement is a major innate immune defense against pathogens, tightly regulated to prevent host tissue damage. Atypical hemolytic uremic syndrome (aHUS) is characterized by endothelial damage leading to renal failure and is highly associated with abnormal alternative pathway regulation. We characterized the functional consequences of 2 aHUS-associated mutations (D(254)G and K(325)N) in factor B, a key participant in the alternative C3 convertase. Mutant proteins formed high-affinity C3-binding site, leading to a hyperfunctional C3 convertase, resistant to decay by factor H. This led to enhanced complement deposition on the surface of alternative pathway activator cells. In contrast to native factor B, the 2 mutants bound to inactivated C3 and induced formation of functional C3-convertase on iC3b-coated surface. We demonstrated for the first time that factor B mutations lead to enhanced C3-fragment deposition on quiescent and adherent human glomerular cells (GEnCs) and human umbilical vein endothelial cells (HUVECs), together with the formation of sC5b-9 complexes. These results could explain the occurrence of the disease, since excessive complement deposition on endothelial cells is a central event in the pathogenesis of aHUS. Therefore, risk factors for aHUS are not only mutations leading to loss of regulation, but also mutations, resulting in hyperactive C3 convertase.

BACKGROUND AND OBJECTIVES:Clinically relevant kidney involvement is uncommonly described in adult patients with cystic fibrosis (CF). We sought to report on a series of patients with CF and kidney biopsy-documented renal involvement. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:A retrospective study was undertaken in two referral centers for adult patients with CF in Paris, France. Patients who had undergone a biopsy of native kidneys between 1992 and 2008 were identified, and their medical records were reviewed. RESULTS:We identified 13 adult patients with CF and renal disease. Proteinuria was present in all but two cases and was associated with progressive renal impairment in four patients (median serum creatinine 85 micromol/L; range 53 to 144 micromol/L). Renal biopsy disclosed a heterogeneous spectrum of nephropathies including AA amyloidosis (n = 3), diabetic glomerulopathy (n = 3), FSGS (n = 2), minimal-change disease (n = 1), postinfectious glomerulonephritis (n = 1), IgA nephropathy related to Henoch-Schönlein purpura (n = 1), membranous nephropathy (n = 1), and chronic interstitial nephropathy (n = 1). Chronic renal failure occurred in five patients, and one patient reached ESRD. CONCLUSIONS:Although rare, clinically significant renal disease may arise in young adult patients with CF. Given the wide spectrum of diseases that may be encountered, definite diagnosis by kidney biopsy is mandatory to optimize clinical treatment of these complex patients, particularly in the perspective of organ transplantation.

Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation, characterized by hemolytic anemia, thrombocytopenia and acute renal failure. Mutations in complement inhibitors are major risk factors for development of aHUS. The three aHUS patients reported in this study had several previously identified alterations in complement inhibitors; e.g. risk haplotypes in CD46 and factor H but we also identified two novel heterozygous non-synonymous CD46 alterations (p.E142Q and p.G259V). Presence of G259V caused decreased expression of the recombinant mutant CD46 compared to wild type (WT). Western blot analysis showed that the majority of the expressed G259V protein was in the precursor form, suggesting that it is processed less efficiently than WT. Low CD46 expression on the surface of the patient's neutrophils confirmed the in vitro results. Further, G259V had a substantially impaired ability to act as a cofactor to factor I, in the degradation of both C3b and C4b. The E142Q mutant showed neither decreased expression nor impaired function. Two of the patients also had a heterozygous non-synonymous alteration in factor H (p.Q950H), reported previously in aHUS but not functionally tested. This variant showed moderately impaired function in hemolytic assays, both using patient sera and recombinant proteins. The recombinant Q950H also showed a somewhat decreased expression compared to WT but the complement inhibitory function in fluid phase was normal. Taken together, we report a novel CD46 alteration showing both a decreased protein expression and substantially impaired cofactor function (G259V) and another without an effect on expression or cofactor function (E142Q). Moreover, mild consequences of a previously reported aHUS associated rare variant in factor H (Q950H) was also revealed, underlining the clear need for functional characterization of each new aHUS associated mutation.

The HELLP syndrome, defined by the existence of hemolysis, elevated liver enzymes, and low platelet count, is a serious complication of pregnancy-related hypertensive disorders and shares several clinical and biologic features with thrombotic microangiopathy (TMA). Several recent studies have clearly shown that an abnormal control of the complement alternative pathway is a major risk for the occurrence of a peculiar type of TMA involving mainly the kidney. The aim of this study was to screen for complement abnormalities in 11 patients with HELLP syndrome and renal involvement. We identified 4 patients with a mutation in one of the genes coding for proteins involved in the regulation of the alternative pathway of complement. Our results suggest that an abnormal control of the complement alternative pathway is a risk factor for the occurrence of HELLP syndrome.

A 56-year-old man with a history of kidney transplantation was admitted to our institution for an acute swelling of his right forearm. Clinical examination revealed an enormous aneurysm (3 3.5 inch) of the radiocephalic arteriovenous fistula as shown in the figure. Ultrasonography revealed a large circumferential thrombus. A surgical procedure was performed, allowing thrombectomy and the definitive closure of the fistula.

Aneurysms and pseudoaneurysms complicating aorta–coronary bypasses with the saphenous vein are a rare but possibly underestimated complication. Riahi and associates1Riahi M. Vasu C.M. Tomatis L.A. Schlosser R.J. Zimmerman G. Aneurysm of saphenous vein bypass graft to coronary artery.J Thorac Cardiovasc Surg. 1975; 70: 358-359PubMed Google Scholar reported the first case in 1975. We report the first case of a saphenous bypass pseudoaneurysm treated with a homemade endograft in the ascending aorta. A 78-year-old man was referred to our hospital with an enlarging left hilar mass found on a routine chest x-ray film. His medical history included chronic renal insufficiency with dialysis, chronic heart failure, aorta–bifemoral bypass, and double aorta–coronary bypass grafting 17 years ago. He had undergone a pedicled left internal thoracic artery graft to the left anterior descending artery and a reversed saphenous vein graft to the first obtuse marginal branch. Since that time, the patient had remained free of symptoms. On examination, the patient was afebrile with stable hemodynamics. He did not have any cardiac or pulmonary symptoms. A computed tomographic scan revealed a 75-mm proximal pseudoaneurysm resulting from a disruption of the aortic anastomosis (Figure 1, A). Cardiac catheterization showed a saccular dilatation of the saphenous vein graft. The bypass graft was occluded distal to the dilatation. The left internal thoracic artery graft was still patent (Figure 1, B). Surgery was elected, but we felt that the risk of conventional surgery was prohibitive (American Society of Anesthesiologists score 3). After pluridisciplinary discussion, we decided to exclude this pseudoaneurysm by an endovascular procedure. Nine days after admission, a covered endograft was positioned in the ascending aorta. Our endograft was a homemade device built according to the method that we described earlier.2Koskas F. Cluzel P. Benhamou A.C. Kieffer E. Endovascular treatment of aortoiliac aneurysms: made-to-measure stent-grafts increase feasibility.Ann Vasc Surg. 1999; 13: 239-246Abstract Full Text PDF PubMed Scopus (23) Google Scholar In brief, the Gianturco arterial Z stent is an auto-expandable stainless steel structure (316L) made of a circular wire plied in a zigzag pattern (W. Cook Europe, Bjaeverskov, Denmark). Two Gianturco arterial Z stents were assembled with polyester ligatures (Cardioflon; Laboratoires Péters, Bobigny, France) and placed in a tube of uncrimped woven polyester (Twillweave; Vascutek, Incchinnan, Scotland) with a diameter of 36 mm. The right common carotid artery was exposed through a transverse incision and punctured. Through the needle, a J-tipped 0.35-inch guide wire was pushed into the aorta under fluoroscopy. A 5F sheath was then pushed over the wire. An Amplatz Superstiff guide wire (Boston Scientific, Natick, Mass) was then pushed into the sheath. Heparin, 1 mg/kg, was given intravenously. Through a transverse arteriotomy centered by the puncture site, a 22F introducer (Keller-Timmermans; W. Cook Europe, Bjaeverskov, Denmark) was placed under fluoroscopic control over the guide into the ascending aorta. The endograft loaded into this introducer was then deployed by retraction of the sheath of this latter over its pusher. The postoperative course was simple. No electrocardiographic change was noticed. Postprocedure cardiac enzymes were negative. On the fourth postoperative day, computed tomography confirmed the total exclusion of the pseudoaneurysm and the good position of the endograft (Figure 2). The patient was discharged on the sixth postoperative day. The follow-up was uneventful (no cardiac symptoms, good recovery). Six months later, the patient remains free of symptoms. Computed tomography does not show any anomaly. This case demonstrates that selected cases of proximal aneurysm or pseudoaneurysm complicating coronary bypass with the saphenous vein are amenable to endovascular repair with endografts. Severe dilatations complicating aorta–coronary bypass with the saphenous vein must be treated because of their potential complications, such as rupture and distal embolization. These dilatations often occur in old and polypathologic patients. Moreover, when a surgical treatment is decided, redo surgery can be difficult and hazardous because of adhesions. Considering these problems, endovascular treatment was proposed in this indication. It was first described by Shapeero and associates3Shapeero L.G. Guthaner D.F. Swerdlow C.D. Wexler L. Rupture of a coronary bypass graft aneurysm: CT evaluation and coil occlusion therapy.Am J Roentgenol. 1983; 141: 1060-1062Crossref PubMed Scopus (41) Google Scholar in 1983. They treated a midgraft dilatation with occlusion therapy using coils. To our knowledge, 11 other cases of endovascular procedures have reported with good results. Several endovascular procedures have been used, such as coil occlusion therapy, covered stent in the saphenous vein graft,4Mahy I.R. Walton S. Successful treatment of false aneurysm of a saphenous vein bypass graft with fistula to the anterior chest wall using "covered" intracoronary stents.Heart. 1998; 80: 527-529PubMed Google Scholar and Amplatzer vascular plug.5Mylonas I. Sakata Y. Salinger M.H. Feldman T. Successful closure of a giant true saphenous vein graft aneurysm using the Amplatzer vascular plug.Catheter Cardiovasc Interv. 2006; 67: 611-616Crossref PubMed Scopus (32) Google Scholar In these cases, endovascular repair was performed only for body or distal saphenous vein graft dilatations. In our case, conventional repair was not performed because of the patient's health status. As has been suggested for abdominal and thoracic aortic aneurysm, endografts could decrease morbidity and mortality in high-risk surgical patients. An endovascular procedure using an ascending aortic endograft seemed to be a reasonable option to exclude the pseudoaneurysm. No suitable endograft was commercially available in our national market. The use of a commercially available endograft would have necessitated covering the supra-aortic trunks. We therefore preferred to use a specially tailored homemade endograft.2Koskas F. Cluzel P. Benhamou A.C. Kieffer E. Endovascular treatment of aortoiliac aneurysms: made-to-measure stent-grafts increase feasibility.Ann Vasc Surg. 1999; 13: 239-246Abstract Full Text PDF PubMed Scopus (23) Google Scholar To our knowledge, our case is the first of a saphenous vein graft dilatation treated with an ascending aortic endograft.

A 58-year-old patient with a history of end-stage renal disease due to multiple myeloma was admitted for tonicoclonic movements of the jaw that had started 3 d earlier. An episode of generalised seizure occurred during hospitalisation. The diagnosis of partial, secondarily generalised, seizure was made and the patient was started on valproate sodium. Laboratory tests showed no abnormalities that could account for seizures. X-rays of the skull (top left) and cerebral magnetic resonance imaging (right) showed a 5-cm-diameter plasmacytoma (* and arrow) of the left temporal bone that was absent on a radiograph performed at first evaluation 6 months earlier (bottom left). Temporal lobe compression due to plasmacytoma accounted for the occurrence of seizures.