Tito Cavallo

Immune Complex Disease Complicating Diabetic Glomerulosclerosis

We report immunopathologic findings observed in renal biopsies of 18 patients with diabetic glomerulosclerosis and associated glomerulonephritis. 10 patients had nodular and 8 patients diffuse diabetic glomerulosclerosis. Focal proliferative glomerulonephritis (4 patients), membranous glomerulonephritis (3 patients), postinfectious glomerulonephritis, Henoch-Schönlein nephritis, IgA nephropathy of Berger (1 patient each), and mesangiopathic glomerulonephritis (8 patients) were the superimposed conditions. In patients with diabetic renal disease, a rapid loss of renal function or an atypical urinalysis could be the expression of a superimposed immune complex disease. Because of functional and biochemical alterations, the glomeruli of diabetic patients may be more susceptible to immune-mediated injury.

Complex aphthosis: A forme fruste of Behçet's syndrome?

The evaluation of the rare patient who presents with oral and genital aphthae or almost constant, multiple (greater than 3) oral aphthae, but no systemic signs or symptoms (i.e., complex aphthosis), is difficult because no laboratory test is available to exclude Behçets syndrome. Six patients with complex aphthosis were evaluated. In addition, patients with simple aphthosis, those with seronegative arthritis, and normal controls were assessed for circulating immune complexes (CIC) by in vitro and in vivo assays and for neutrophil migration by subagarose methods, since these tests have given significant results in patients with Behçets syndrome. Patient 1, with complex aphthosis, had Raji cell evidence for CIC (51.2 mg aggregated human gamma globulin Eq/ml), C1q, and C3 in dermal blood vessels 4 hours post intradermal histamine injection and had a Sweets syndrome-like vasculitis 24 hours post histamine injection. In addition, her serum enhanced the migration of patient neutrophils (3.6 +/- 0.6 to 4.6 +/- 0.5; N = 6, p less than or equal to 0.01). All other test and control patients had negative or normal CIC and neutrophil migration determinations. Sixteen-month clinical follow-up has confirmed that Patient 1, but not Patients 2 to 6, has developed overt manifestations of Behçets syndrome.

Immune deposits and mesangial hypercellularity in minimal change nephrotic syndrome: Clinical relevance

Occasional patients with nephrotic syndrome and minimal histologic change demonstrate glomerular deposition of small amounts of immunoglobulin and complement. Some consider this a disease distinct from MCNS. To investigate the clinical importance of immune deposits and mesangial hypercellularity in the initial biopsy, the clinical records, follow-up data, and renal biopsies of 68 patients (ages 6 months to 16 years) with MCNS by light microscopy were reviewed. Among 68 patients followed a mean of 6.2 years, eight of 25 patients with immune deposits on initial renal biopsy were steroid nonresponsive. Only one of 43 patients without immune deposits was steroid nonresponsive (P = 0.00005). Of 44 patients with normal mesangial cellularity, 31 experienced fewer than three relapses a year, whereas of 15 patients with mesangial hypercellularity, only six experienced fewer than three relapses a year (P = 0.035). The data suggest that immune deposits and increased mesangial cellularity in children with NS and minimal light microscopic change may predict the clinical course.

Primary idiopathic cutaneous pustular vasculitis

Pustular cutaneous vasculitis results from a heterogeneous group of disorders characterized by pustules on purpuric bases. Although the cause of this group of conditions is diverse, the histopathologic picture of the lesions is the same, showing a Sweets-like or leukocytoclastic vasculitis. These distinctive lesions may occur in patients with Behçets syndrome, bowel-associated dermatosis-arthritis syndrome, or chronic gonococcemia. We describe, for the first time, a patient with primary idiopathic cutaneous pustular vasculitis. This patient had evidence of both circulating immune complexes and serum enhancement of neutrophil migration. Extensive evaluation failed to reveal any underlying systemic disease. A classification of the pustular vasculitides is proposed.

Autoimmunity, Polyclonal B-Cell Activation and Infection:

It is widely believed that autoimmunity is an integral part of the immune system, and that genetic, immunologic, hormonal, environmental and other factors contribute to the pathogenesis of autoimmune disease. Thus, autoimmune disease may represent an abnormal expression of immune functions instead of loss of tolerance to self, and it can be organ specific or systemic in its manifestations. We review the various factors that contribute to the development of autoimmune disease; we also review the mechanisms of polyclonal B-cell activation, with emphasis on the role of infectious agents. We consider systemic lupus erythematosus in humans and in experimental animals as prototypic autoimmune disease, and we summarize data to indicate that polyclonal B-cell activation is central to the pathogenesis of systemic autoimmune disease. The effect of polyclonal B-cell activation, brought about by injections of a B-cell activator - lipopolysaccharide from Gram-negative bacteria—is sufficient to cause autoimmune disease in an immunologically normal host. In fact, autoimmune disease can be arrested if excessive polyclonal B-cell activation is suppressed; alternatively, autoimmune disease can be exacerbated if polyclonal B-cell activation is enhanced. We explore the mechanism of tissue injury when autoimmune disease is induced or exacerbated, and we consider the pathogenic roles of autoantibodies, immune complexes, complement, the blood cell carrier system, and the mononuclear phagocyte system. Although polyclonal B-cell activation may be the mechanism whereby various factors can cause or exacerbate systemic autoimmune disease, polyclonal B-cell activation may cause autoimmune disease on its own.

Familial Adult Glomerulocystic Kidney Disease

During an evaluation for nephrotic syndrome, a 20-year-old woman was found by ultrasonographic examination to have large kidneys with multiple renal cysts suggestive of polycystic kidney disease. A subsequent renal biopsy revealed membranous glomerulopathy due to systemic lupus erythematosus, as well as the unexpected finding of glomerulocystic kidney disease (GCKD), an uncommon disorder previously reported to occur primarily in infants and children. No evidence of renal dysplasia was present and no cysts were found in any abdominal or pelvic organs. Other than one bifid renal pelvis, no significant congenital anomalies or structural chromosomal abnormalities were present. Ultrasonographic evaluation of the patients family revealed similar-appearing cortical cysts in several members, all of whom had no clinical evidence of renal dysfunction. The pattern of involvement was compatible with autosomal dominant inheritance. Follow-up ultrasonograms of the patient and affected family members 1 year after the initial study showed enlargement of the cysts with development of additional cysts in two individuals and no change in the other family members. Although renal failure was present and progressed in our patient, renal function remained normal in all affected family members 1 year after detection of the renal cysts. This patient and her family provide additional insight into the inheritance and natural history of GCKD and demonstrate that this condition should be considered in the evaluation of multicystic renal disease in adults. In contrast to several previously reported cases, it appears that GCKD may be associated with normal renal function for many years.

Rapidly progressive glomerulonephritis in children: a report of thirteen cases and a review of the literature.

Summary: The clinical course and outcome of rapidly progressive glomerulonephritis (RPGN) of variable etiology are not well defined in children. The present investigation reports on the clinical characteristics, the course and outcome, as well as the results of treatment of 13 children with apparent postinfectious RPGN. Three of 7 patients with documented streptococcal RPGN and 3 of 6 patients with RPGN of nonstreptococcal etiology progressed to chronic renal failure. In some patients, anticoagulant and anti-platelet therapy appear to have improved survival. The severity of crescent formation, not the presumable etiology, appears to be a reliable prognosticator.Speculation: A number of disease processes can result in renal damage of sufficient severity to cause crescent formation. The induction, resolution, or progression of crescents to sclerosis may be influenced by anticoagulant therapy.

Malignant atrophic papulosis: Absence of circulating immune complexes or vasculitis†

A 26-year-old woman presented with the classic manifestations of malignant atrophic papulosis, a rare disease of unknown cause. We report the results of our immunologic studies, which may help to explain why treatment with systemic immunosuppressant therapy has not been effective.

Histamine-triggered localized vasculitis in patients with seropositive rheumatoid arthritis

To gain some insight into the pathogenesis of vasculitis in rheumatoid arthritis, and to investigate its relation to circulating immunoreactants, we injected 50 microliters of histamine intradermally in four seropositive and four seronegative patients with rheumatoid arthritis. Skin biopsies obtained before histamine and at 4 hours after histamine were studied by immunofluorescence microscopy, and skin biopsies 24 hours after histamine were studied by light microscopy. At 4 hours after histamine, all seropositive patients demonstrated deposits of IgM and complement components in dermal vessels; by 24 hours, various degrees of leukocytoclastic vasculitis were noted. Circulating material reactive with Raji cells, C1q, or both, was present in 3/3 seropositive patients. In contrast, none of the seronegative patients exhibited vascular deposits of immunoreactants or vasculitis. The results indicate that patients with rheumatoid arthritis who are seropositive may have circulating complexes with appropriate characteristics to induce vasculitis and that vasoactive substances may be used to trigger their local deposition in vessels.

Cutaneous secondary syphilis: Preliminary immunohistopathologic support for a role for immune complexes in lesion pathogenesis

A circulating immune complex-mediated pathogenesis for lesions of secondary syphilis has been postulated. Textbook descriptions of a lymphoplasmacytic histopathologic picture have contradicted a role for circulating immune complexes in lesion pathogenesis. Four patients with early cutaneous lesions of secondary syphilis were studied. All four patients had serum Raji cell and/or Clq binding assay evidence for circulating immune complexes. Three patients showed a neutrophilic vascular reaction on histologic study of early lesions. The patients studied had immunofluorescence microscopic evidence of immunoreactant deposition in dermal blood vessels (4 hours) and/or a neutrophilic vascular reaction (24 hours) after intradermal histamine injection. Dieterle staining of lesional tissue from all patients showed the presence of treponemal organisms in dermal blood vessels. This new preliminary evidence adds some support to a circulating immune complex-mediated pathogenesis of cutaneous lesions in human secondary syphilis.