1 Department of Nephrology, Dunedin School of Medicine, University of Otago, Dunedin and 2 Department of Immunology and Nephrology, Waikato Hospital, Hamilton, New Zealand
Correspondence and offprint requests to: Assoc. Prof. Robert Walker, Department of Medicine, Dunedin School of Medicine, University of Otago, PO Box 913, Dunedin, New Zealand.
Keywords: anti-GBM antibodies; Goodpasture's disease; insulin-dependent diabetes mellitus; simultaneous presentation
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Introduction |
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Case |
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On the second admission, the patient's blood pressure was 160/80 mmHg, creatinine was 980 µmol/l, and urea was 32 mmol/l. His ESR was 156 and CRP 377. Urinalysis showed microscopic haematuria and proteinuria. Anti GBM antibodies (in house assay, Immunology Department) were strongly positive to a titre of 252 IU. Antineutrophil cytoplasmic antibodies (ANCA) (in house assay), rheumatoid factor, and cryoglobulins were negative. A renal biopsy demonstrated a florid crescentic glomerulonephritis with all glomeruli involved. Immunofluorescence showed strongly positive IgG and C3 linear staining and weakly positive linear IgA staining consistent with anti-GBM antibody disease. His renal function failed to improve and he remained dialysis dependent.
He was managed with intravenous methylprednisolone (1 g) daily for 3 days followed by oral prednisolone 40 mg daily, together with plasma exchange and azathioprine 200 mg daily, predominantly to control his respiratory manifestations. Over the next 8 months, his anti-GBM antibodies returned to baseline and he had no further relapses. He has subsequently undergone successful renal transplantation.
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Discussion |
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A number of autoantibodies may be associated with IDDM, including antialbumin, ssDNA, dsRNA, tubulin and thyroglobulin, and soluble immune complexes [4]. Up to 36% of diabetics have circulating antibodies that bind at diverse epitopes to the GBM [5] including reticulin FxIa, and the sulphatide antigen, GD has rarely complicated IDDM, possibly through increased subepithelial expression of collagen IV [1]. In this milieu, the production of pathogenic anti-GBM antibodies is conceivable. However, the simultaneous occurrence of GD with IDDM has never previously been described.
Recent reports suggest that genetic susceptibility to GD is strongly associated with the HLA DRB1 genes and more specifically the DRB1*1501/1502 locus [6]. Our patient was homozygous for the DRB1*1501 allele present in over 90% of patients with GD compared to 20% of the general population. It is thought that the same DRB1*15 alleles are usually protective against the development of IDDM [4]. The HLA-DR region is characteristically very tightly linked making cross-over unlikely for this disease association.
There are also recent reports that suggest a possible role for viral agents in the pathogenesis of GD, with virus-like structures seen in electron microscopy and with a distinctive seasonal clustering in some cases [7]. It has long been felt that IDDM may have a viral aetiology (especially Coxsackie virus B4), and similar seasonal clustering is seen in IDDM [8]. Autoreactivity may be an indirect consequence of viral infection with resultant local infection, inflammation, and tissue damage leading to the release of sequestered antigen and the re-stimulation of resting autoreactive T cells (bystander T-cell activation). It is thought that IDDM could be induced in this manner [8]. Lung injury by anti-GBM antibodies is perceive to be dependent on local inflammation with the expression of adhesion molecules and cytokines, including TNF and IL-1. An infecting virus may also initiate an immune response against self proteins by immunogenic similarities to foreign epitopes (molecular mimicry). Another possibility is the expression of a super-antigen in response to an infecting agent, with stimulation of large number of T-cells, irrespective of their antigen specificity, leading to a proliferation of autoreactive T-cells. Our patient described a `flu-like' illness and diarrhoea preceding the onset of IDDM and again prior to his admission with GD. It is therefore possible that, in our case, an infectious agent led to a breakdown of immune tolerance in a genetically susceptible individual and that this resulted in the simultaneous production of both IDDM and GD.
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References |
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