Circulating and mesangial IgA in idiopathic IgA mesangial nephropathy.
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Biomedical subjects
Publications and source records attributed to A Fornasieri.
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A specific and sensitive enzyme-linked immunosorbent assay (ELISA) was used to detect IgA rheumatoid factor (RF) in sera from 88 patients with IgA nephropathy (IgA GN), a disease characterized by abnormalities of IgA production. Significantly higher levels of IgA antiglobulins were demonstrated in IgA GN patients than in normal healthy controls and patients with other forms of chronic primary glomerulonephritis (mean +/- SEM 28.4 +/- 6.6 vs 6.0 +/- 0.4 and 8.3 +/- 1.2 micrograms/ml respectively; p less than 0.002). Interestingly, in contrast to rheumatoid arthritis, IgA RF activity was not associated with IgM antiglobulins. Analysis of sera fractionated by gel chromatography at acid pH revealed that anti-IgG activity resided predominantly in the polymeric fractions of IgA as confirmed by the ability to bind "free" secretory component. Several findings in patients with IgA GN suggest that the IgA deposited in the glomeruli is polymeric, and levels of circulating macromolecular IgA are increased. Our findings confirm a general perturbation of IgA metabolism in this disease. Although the polymeric nature of the IgA RF is suggestive of a mucosal origin, additional evidence is needed to confirm this hypothesis.
In order to evaluate functional lymphocyte defects in type II essential mixed cryoglobulinaemia (EMC) in vitro production of immunoglobulins (Ig) and rheumatoid factor (RF) has been studied in basal conditions and under pokeweed mitogen (PWM) stimulation in 15 patients and in 17 control subjects. The major finding was a significantly high basal and inducible production of RF by EMC lymphocytes as compared with the RF production in controls, while synthesis of polyclonal Ig was unaffected. A good correlation existed between in vitro production and serum levels of RF. Peripheral blood SmIg+ and Ia+ cells were also significantly increased. The possibility that EMC shares some pathogenetic mechanism with rheumatoid arthritis on the one hand and with lymphoproliferative diseases on the other is considered.
Peripheral blood mononuclear cells (PBMC) from patients with Essential Mixed Cryoglobulinemia (EMC) were studied for their ability to synthesize polyclonal IgM and rheumatoid factor (RF) IgM in vitro. Our results indicate: that EMC-PBMC produce smaller amounts of polyclonal IgM but higher quantities of IgM-RF than normal PBMC after pokeweed mitogen (PWM) or Staphylococcus aureus activation, so that the IgM-RF to total IgM ratio is significantly greater in EMC than in normal cultures; that enriched EMC-B lymphocytes display a significantly higher spontaneous synthesis of IgM-RF than normal B lymphocytes and that the IgM-RF B cell clones are receptive to T cell regulation. Taken together these findings suggest an expansion of B cell clones committed to IgM RF production and the presence in peripheral blood of differentiated B lymphocytes capable of secreting IgM-RF in EMC.
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Plasma exchange is increasingly used for management of Essential Mixed Cryoglobulinemia. However little is known about the long term effects of this treatment. Therefore we have reviewed the clinical and laboratory data of 20 patients with type II EMC who were followed for a mean of 24 months. 16 patients had renal involvement, which was characterized histologically in all of them: 9 had diffuse proliferative GN plus endoluminal "thrombi" in 6 and vasculitis in 5, 4 had lobular membranoproliferative GN and 3 had focal proliferative GN. 14 patients had renal failure and 13 had proteinuria greater than or equal to 2 g/24 hr. PE (combined with immunosuppressive drugs in 18) was performed for a mean of 18 procedures. The combined treatment induced prompt remission of extrarenal and renal involvement. Serum creatinine and proteinuria decreased significantly in all but 2 patients during the treatment (s. creatinine from 2.9 to 1.6 mg/dl; proteinuria from 3.5 to 1.6 g/24 hr). Analysis of long term follow up revealed that these effects were long lasting in all the cases. We conclude that PE should be used for EMC nephropathy whenever prompt remission is not obtained by conventional therapy especially in consideration of its long term beneficial effects.
T-lymphocyte subsets, using the monoclonal antibodies OKT3 (peripheral T-cells), OKT4 (helper/inducer T-cells) and OKT8 (suppressor/cytotoxic T-cells) were measured in peripheral blood from 110 patients with various forms of primary and secondary glomerulonephritis (GN) (Berger's disease, membranous GN, focal glomerulosclerosis, membranoproliferative GN, lupus nephritis and mixed essential cryoglobulinaemia with GN). We have found a significantly higher OKT4+/OKT8+ ratio in patients with Berger's disease and membranous GN and a rather low OKT4+/OKT8+ ratio in patients with lupus nephritis and mixed essential cryoglobulinaemia, due to a significant decrease in OKT4+ cells. Our results suggest an imbalance in immunoregulatory mechanisms in some forms of GN.
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Intensive plasma exchange and immunosuppression have been used in 13 patients affected by severe forms of glomerulonephritis (GN) associated with systemic lupus erythematosus (SLE) and essential mixed cryoglobulinaemia (EMC). The patients were divided into two groups.
Ten adult patients with RPCGN (crescents in greater than 70% of glomeruli), primary in 6 and associated with systemic diseases in 4, were treated with PE, associated with oral steroids (P) and cyclophosphamide (C) in all cases and with intravenous methylprednisolone pulses (MP) in 7 cases. Four out of ten patients were anuric and needed dialysis treatment at the start of treatment. Therapeutic benefit, i.e. reversal of the trend to further deterioration and substantial improvement of GFR, was achieved in 8 out of 10 patients (80%), including 2 of 4 anuric patients, and in 7 of those (8) who had still active cellular crescents (87.5%). Similar therapeutic benefit had been achieved only in 10% of a comparable population of 10 patients with RPCGN treated before 1980 with P and C, without PE or MP pulses. It is difficult to establish whether the better therapeutic results in the more recently treated group were due to PE or to MP pulses of to both the new approaches, even though the clinical improvement obtained in all the 3 patients treated with PE without concomitant MP suggest a specific beneficial role for PE. RPCGN is a catastrophic illness characterized by progressive deterioration of kidney function, resulting in oliguria and uremia, usually within weeks or months. The most consistent histopathologic finding is the presence of extensive glomerular crescents resulting from proliferation of the extracapillary epithelial cell lining of Bowman's capsule. It is apparent that RPCGN is not a homogeneous entity, clinically, histologically or immunohistologically, but rather a clinicopathologic syndrome, the features of which may be seen in a variety of systemic disorders, including SLE, polyarteritis nodosa, Wegener's granulomatosis, Henoch-Schönlein purpura, cryoglobulinemia, and subacute bacterial endocarditis.(ABSTRACT TRUNCATED AT 250 WORDS)
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Recently, the induction of SLE in naive mice employing monoclonal anti-DNA antibodies (anti-DNA Ab) carrying the pathogenic idiotype 16/6 (16/6 Id) has been reported. In the current study we report on the induction of experimental SLE by polyclonal IgG anti-DNA Ab derived from a patient with active SLE and carrying the 16/6 Id. Two different experiments were conducted in which BALB/c mice were immunized in the footpads with 1 microgram/ml or 5 micrograms/ml of anti-DNA Ab. The first experiment showed the appearance in the immunized mice of high titre anti-DNA Ab together with antinuclear antibodies, alopecia and proteinuria. In the second experiment we compared, as immunizing agents, 16/6 positive anti-DNA Ab and 16/6 negative anti-tetanus toxoid antibodies (anti-TT Ab) obtained from the serum of the same patients. Our results show that only mice immunized with 16/6 positive antibodies produced anti-DNA Ab, while mice immunized with anti-TT Ab did not show any DNA-binding activity but, surprisingly, developed high titre anti-cardiolipin antibodies.
Several studies have established a strong association between hepatitis C virus (HCV) infection and essential mixed cryoglobulinemia (EMC). However, the mechanisms by which HCV infection may result in cryoglobulinemia in some patients but not in others remain unknown. In this paper we shall summarize some of the work done in our laboratories on certain aspects of HCV in patients with EMC.