Davin Jc

Increased Intestinal Permeability to (51 Cr) EDTA Is Correlated with IgA Immune Complex-Plasma Levels in Children with IgA-Associated Nephropathies

ABSTRACT. Intestinal permeability was investigated in 10 normal young adults, in 11 control children and in 9 children presenting with either Berger disease (4 cases) or Henoch‐Schönlein nephritis (5 cases), making use of (51 Cr) EDTA as a probe molecule. All subjects exhibited a normal creatinine clearance at the time of testing. After oral administration of (51 Cr) EDTA, 24‐hour urine radioactivity was measured and results were expressed in percentage of the oral dose administered. Means and SD were 2.35%±0.77, 2.51%±0.70, and 5.10%±2.35 for normal adults, control children and patients with IgA‐associated nephropathies, respectively. The differences of permeability between controls and patients were statistically significant (p < 0.01). In addition, a significant, direct, linear correlation has been established between the percentage of (51 Cr) EDTA excreted in 24‐hour urine and IgA immune complex‐plasma levels. Our results therefore support the hypothesis that increased gut permeability could play a role in the pathogenesis of IgA‐associated nephropathies.

Possible pathogenic role of IgE in Henoch-Schönlein purpura

The incidences of clinical and biological markers of atopy were investigated in 16 children with IgA nephropathy (IgAN) (group A) and in 22 with Henoch-Schönlein purpura nephritis (HSPN) (group B). The incidence of increased plasma IgE levels according to age-matched normal values was significantly higher in group B (17/22, 77%) than in group A (7/16, 44%) (P<0.05). Although not significant, the incidences of positive RAST tests and of a history of typical atopic symptoms were also higher in group B [10/22 (45%) and 11/22 (50%), respectively] than in group A [4/16 (25%) and 5/16 (31%), respectively]. Moreover, IgE deposits were demonstrated by a peroxidase/anti-peroxidase method on cutaneous Langerhans and mast cells in 4 of 6 patients with HSPN. Thus immunoallergy might account, in some cases, for the cutaneous, intestinal and pulmonary signs observed in HSPN, but not in IgAN. We postulate stimulation of IgE-sensitized mast cells by specific antigens in the presence of IgA circulating immune complexes (CIC), release of vasoactive substances, increased capillary permeability and perivascular deposition of IgA CIC.

Evidence that the interaction between circulating IgA and fibronectin is a normal process enhanced in primary IgA nephropathy

A solid-phase ELISA was set up to measure the direct binding capacity (BC) of different, commercially available, purified human IgA preparations to plates coated with human fibronectin (FN). It was found that secretory, polymeric, and, to a much lesser extent, monomeric IgA exhibited elevated FN-BC as compared to their BC to plates coated with bovine serum albumin. This binding was specific since not observed with human IgG or IgM antibodies. In addition, we noted that this interaction was dose dependent, Ca2+ dependent, saturable, and not covalent, was inhibited by soluble FN, but not by a prior incubation of FN-coated plates with anti-human fibronectin antibodies, and appeared to involve on the dimeric FN other structures than its heparin-binding, collagen-binding, or C1q-binding domains. Similar experiments conducted with normal plasma indicated that plasma IgA, but not plasma IgG or IgM, was also capable of significant binding to FN-coated plates. In contrast, serum IgA did not significantly bind to those plates under otherwise identical experimental conditions. Thus, the coagulation process induces a strong decrease in the FN-BC of circulating IgA, which implies the necessity of using plasma rather than serum to study such interactions. The apparent molecular weight of plasma IgA interacting with FN-coated plates ranged between 450 and 900 kd, and its major binding characteristics were quite similar to those observed with purified polymeric IgA. The FN-BC of plasma IgA was then measured by the same ELISA in 30 patients with primary IgA nephropathy (IgAN) and in 23 healthy controls. The mean FN-BC of plasma IgA was significantly higher in patients than in normal controls. This enhancement was due mainly to the augmentation in the concentration of circulating “macromolecular” IgA and was significantly correlated with the plasma levels of IgA-FN complexes. However, the pathogenetic role of these findings was probably not determinant since similar observations were made in alcoholic liver cirrhosis without urinary abnormalities and since the FN-BC of plasma IgA or the plasma levels of IgA-FN complexes were not correlated with the various biological parameters of evolutivity of primary IgAN. In conclusion, these studies suggest that the ability of polymeric IgA to directly bind to FN is involved in the formation of circulating IgA-FN complexes and that this normal binding process, although enhanced in IgAN, is probably not responsible for kidney injury, at least in the patients studied.

Acute experimental glomerulonephritis induced by the glomerular deposition of circulating polymeric IGA-concanavalin A complexes

The perfusion of polymeric or secretory IgA-Concanavalin A complexes into the aorta of rats led to a mannose-dependent binding of both IgA and lectin to the glomerular capillary wall, as shown by double immunolocalization experiments, by quantitative analysis of the amount of radiolabelled complexes bound per g of kidney, and by blocking experiments with the corresponding carbohydrate. Rats injected with amounts of those complexes as low as 500 micrograms developed, one hour later, a focal and segmental proliferative glomerulonephritis characterized by the deposition of injected complexes and of rat C3 and rat fibrin/fibrinogen in most glomeruli; focal thrombosis and small areas of necrosis in 10 to 15% of glomeruli, confined to the periphery of a single lobule of the tuft and segmental infiltration of these glomeruli by polymorphonuclear leucocytes and platelets. At the same time, many mesangial cells exhibited a hyperactive appearance, and red blood cells were noted in tubular lumens. In contrast, rats similarly injected with either monomeric IgA-ConA complexes, multimeric or secretory IgA-peanut agglutinin complexes or polymeric or monomeric IgA aggregates of comparable apparent molecular weight did not develop obvious glomerular lesions within one hour. The data indicate that performed polymeric IgA-ConA complexes can specifically bind to glomerular structures in vivo and trigger acute glomerular lesions locally, analogous to those observed in some glomerular diseases associated with a cryoglobulinaemia.The perfusion of polymeric or secretory IgA-Concanavalin A complexes into the aorta of rats led to a mannose-dependent binding of both IgA and lectin to the glomerular capillary wall, as shown by double immunolocalization experiments, by quantitative analysis of the amount of radiolabelled complexes bound per g of kidney, and by blocking experiments with the corresponding carbohydrate. Rats injected with amounts of those complexes as low as 500 µg developed, one hour later, a focal and segmental proliferative glomerulonephritis characterized by the deposition of injected complexes and of rat C3 and rat fibrin/ fibrinogen in most glomeruli; focal thrombosis and small areas of necrosis in 10 to 15% of glomeruli, confined to the periphery of a single lobule of the tuft and segmental infiltration of these glomeruli by polymorphonuclear leucocytes and platelets. At the same time, many mesangial cells exhibited a hyperactive appearance, and red blood cells were noted in tubular lumens. In contrast, rats similarly injected with either monomeric IgA-ConA complexes, multimeric or secretory IgA-peanut agglutinin complexes or polymeric or monomeric IgA aggregates of comparable apparent molecular weight did not develop obvious glomerular lesions within one hour. The data indicate that preformed polymeric IgA-ConA complexes can specifically bind to glomerular structures in vivo and trigger acute glomerular lesions locally, analogous to those observed in some glomerular diseases associated with a cryoglobulinaemia.

Sequential Measurements of the Reticulo-Endothelial System Function in Henoch-Schönlein Disease of Childhood: Correlations with Various Immunological Parameters

ABSTRACT. Different immunological parameters were studied in 16 children suffering from Henoch‐Schönlein purpura. The following results were observed during the acute phases in some patients: (1) an increase in C3d plasma levels; (2) the presence of circulating immune complexes (CIC); (3) an increase in IgA plasma levels and (4) an impairment of the reticuloendothelial system (RES) function asssessed by an in vitro and an in vivo test. After the acute phase, all the altered parameters were almost normalized in recovering patients. On the contrary, all 5 patients with persistent urinary findings or relapsing purpura continued to present increased IgA plasma levels and/or CIC and/or impaired RES function. Our results therefore show that, in Henoch‐Schönlein disease of childhood, a correlation exists betwen persisting clinical signs and persisting high IgA plasma levels, CIC and RES function impairment

Elevated antigalactosyl antibody titers reflect renal injury after gold or D-penicillamine in rheumatoid arthritis

Titers of circulating antigalactosyl antibodies (a-Gal Ab) were assessed by passive hemagglutination using rabbit red blood cells in 40 normal subjects, in 14 patients with immunodeficient states, in 47 patients with active rheumatoid arthritis (RA), and in 15 patients with an Henoch-Schönlein disease (HS). Titers of controls ranged from 1:16 to 1:64. All immunodeficient patients exhibited very low titers (1:1). On the contrary, the existence of an enhanced humoral immune response status, as observed in RA, was not reflected by a parallel increase of a-Gal Ab titers. However, in this disease, a strong relationship existed between titers exceeding control values (greater than 1:64) and the prior occurrence of renal injury under gold or D-penicillamine therapy. Lastly, the discovery of elevated titers (greater than 1:64) in HS only when renal involvement occurred further suggests that such antibodies reflect a renal injury.

A Case of Congenital Nephrotic Syndrome

This case of congenital nephrotic syndrome is not easy to classify. Treatment with usually effective doses of cyclophosphamide and prednisolone was unsuccessful, whereas a treatment with gammaglobulin was concomitant with a decrease in the frequency of infections, improvement of the nephrotic syndrome, growth, psychomotor development and bone maturation. Electron microscopy shows basal membrane abnormalities not yet described.

Electron Microscopic Studies in a Long-Term Follow-Up of a Case of Congenital Nephrotic Syndrome

A boy presenting with a severe congenital nephrotic syndrome diagnosed by histological analysis at the age of 3 weeks was biopsied again 7 years later. The ultrastructural glomerular basement membrane abnormalities depicted in the first biopsy were no longer present in the second one. The number of completely hyalinized glomeruli was not significantly decreased. The GFR remained normal, but a moderate persistent, non-selective proteinuria (800 mg/24 h) was noted without oedema. The patient however developed a progressive perceptive deficit of hearing.

Relation between urinary proteinases and proteinuria in rats with a glomerular disease.

Electronegative charges of the glomerular filtration barrier play probably an important role in its impermeability to anionic proteins 1–9. Sialic acid 10 (present in laminin) and glycosaminoglycans 11 seem to be the major molecules responsible for this propriety. Neutral proteinases synthetized either by mesangial cells or by monocytes and neutrophils, infiltrating glomeruli in some pathologic states, are able to degrade GBM glycoproteins in vitro 12–14.