Chaim M. Brickman

Immunoregulatory disorders associated with hereditary angioedema: I. Clinical manifestations of autoimmune disease

Occasional reports have appeared linking hereditary angioedema (HAE) with autoimmune diseases. We have systematically evaluated 157 patients for manifestations of autoimmunity. Nineteen of these patients (12%) had clinical immunoregulatory diseases including glomerulonephritis (five patients), Sjögrens syndrome (three), inflammatory bowel disease (three), thyroiditis (two), systemic lupus erythematosus (one), drug-induced lupus (one), rheumatoid arthritis (one), juvenile rheumatoid arthritis with IgA deficiency (one), incipient pernicious anemia (one), and sicca syndrome (one). All eight patients with HAE who developed an autoimmune disease with a known human histocompatibility antigen association developed a disease associated with their histocompatibility antigen haplotype (p = 0.014). Although only four patients developed Sjögrens syndrome or sicca syndrome, an additional nine manifested part of the sicca complex. We also found patients with HAE with features suggestive of an immune-based abnormality. These features included idiopathic pancreatitis (three patients), Raynauds disease (two), partial lipodystrophy (one), chronic chorioretinitis (one), and alopecia universalis (one).

Abnormal clearance of immune complexes from the circulation of patients with primary sclerosing cholangitis.

The ability of fixed macrophages of the reticuloendothelial system to clear circulating immune complexes was studied in 6 patients with primary sclerosing cholangitis, 5 patients with various other forms of chronic liver disease, and 12 normal control subjects. Autologous red cells were radiolabeled with 51Cr and sensitized with anti-Rh(D) immunoglobulin G in vitro. After intravenous infusion of the labeled antibody-coated red cells, the radioactivity content of timed blood specimens was measured. The time required by the reticuloendothelial system to clear one-half the labeled cells from the circulation (t1/2) was then determined. The t1/2 clearance times were significantly prolonged in all 6 patients with primary sclerosing cholangitis, whereas the clearance times in 4 of the 5 liver disease control patients were either normal or shortened. Serum immunoglobulin G and immunoglobulin M immune complex levels did not correlate with t1/2 clearance times. These results suggest that in primary sclerosing cholangitis there is a defect in the ability of fixed macrophages of the reticuloendothelial system to mediate clearance of circulating particles that have been opsonized with immunoglobulin G. This finding further supports recent data that incriminates the immune system in the pathogenesis of primary sclerosing cholangitis.

Immunoregulatory disorders associated with hereditary angioedema: II. Serologic and cellular abnormalities

Hereditary angioedema is defined biochemically by a deficiency in the functional activity of the inhibitor of Cl, Cl esterase inhibitor (Cl INH). Deficiency of this regulator of the early classic pathway of complement results in chronic activation of this cascade with a resultant deficiency of C4 and C2. Ninety-seven patients with either complicated (associated with autoimmune disorders) or uncomplicated hereditary angioedema were evaluated for laboratory evidence of immunoregulatory defects. Specific cellular and humoral abnormalities were found and included increased mean total lymphocyte counts, increased mean Leu 4+ (total) and Leu 3+ (helper) T cells, an increased mean Leu 3/Leu 2 (helper/suppressor T cell) ratio, polyclonal B cell activation, and evidence of circulating immune complexes. C4 functional titers were negatively correlated with percent Leu 3+ cells and absolute Leu 3+ cell numbers. We failed to detect any evidence of immune deficiency in this population, and yet a statistically significant number of patients demonstrated elevated levels of antibodies to Epstein-Barr virus antigens when patients were compared to a control group. Thus, early classic complement pathway activation and/or partial complement component deficiency may effect T cell subpopulations and B cell activation. However, additional predisposing factors (e.g., genetic or viral) appear necessary for the development of a particular autoimmune disease in hypocomplementemic patients.

Management of the airway in patients with angioedema.

Angiodema can be frequently encountered in clinical practice, and usually represents transient areas of tissue edema and erythema. In general, lesions involve the deep dermis as well as subcutaneous or submucosal sites and can affect multiple organ systems, including the respiratory and gastrointestinal tracts. Although the underlying cause for the angioedema is frequently not known, it can result from atopy, specific antigen sensitivities, physical stimuli, as well as disorders that affect the complement cascade. These latter entities may be congenital or acquired. Pathogenesis for angioedema is generally thought to be activation of mast cells or basophils, with subsequent release of histamine and other mediator products which can induce inflammatory changes.

Characterization of plasma lipids and lipoproteins in patients with β2-glycoprotein I (Apolipoprotein H) deficiency

The fasting plasma lipids, lipoproteins, and apolipoproteins were evaluated in 5 subjects with undetectable levels of the plasma protein beta 2-glycoprotein I (apolipoprotein H). Family studies confirmed an autosomal co-dominant inheritance pattern for the concentrations of apo H. The total lack of this protein is rare and less than 0.3% of clinic patients demonstrated levels undetectable by radial immunodiffusion. Plasma lipoprotein evaluation in these subjects with beta 2-glycoprotein I absence by analytical ultracentrifugation and compositional analysis demonstrated low concentrations of HDL2b and HDL3. More striking, however, was the lack of a consistent marked effect on the plasma lipoproteins as is found in other apolipoprotein deficiency states. We conclude that the lack of apolipoprotein H does not result in a significant perturbation of normal lipoprotein metabolism as reflected by analysis of fasting plasma lipoproteins. Further study is required to evaluate the role of this glycoprotein in the metabolism of triglyceride-rich lipoproteins.

Danazol-Induced Cystitis: An Undescribed Source of Hematuria in Patients with Hereditary Angioneurotic Edema

From 1975 through 1983, 69 patients with hereditary angioneurotic edema were treated with danazol, a semisynthetic anabolic steroid. Hematuria developed in 13 of these patients (19 per cent). Careful evaluation of the genitourinary tract showed the presence of a distinct form of hemorrhagic cystitis in 10 patients. Clinically, 9 patients presented with microscopic and 1 with intermittent gross hematuria. Irritative bladder symptoms were reported by 2 patients. Neither the dose nor duration of danazol therapy correlated with the severity of the cystoscopic or pathological findings. Cystoscopically, a rather nonspecific pattern of erythema, submucosal telangiectasia and neovascularity was observed. Histopathologically, bladder biopsy typically showed numerous dilated submucosal vessels with hemorrhage, mucosal ulceration and occasional inflammatory cells. These changes regressed in all but 1 patient when danazol therapy was discontinued. Further studies are needed to elucidate the role of danazol itself or of the danazol-hereditary angioneurotic edema interaction in the pathogenesis of these abnormalities.

Urine-histamine levels in patients with hereditary angioedema (HAE)

Hereditary angioedema (HAE) is defined clinically by recurrent, self-limited episodes of angioedema. The disease is defined biochemically by a deficiency in the functional activity of C1 esterase inhibitor. To date, the actual serum or tissue mediator(s) responsible for the angioedematous lesion remains controversial. Although antihistaminics have been clearly demonstrated to have no efficacy in the long-term treatment of this disorder, instances of elevated urine-histamine levels in patients with HAE raises the possibility of a role for histamine in the pathophysiology of this disease. Urine samples were collected from 28 asymptomatic and from 11 symptomatic patients with HAE. The urine-histamine levels were compared with levels of 41 normal control subjects. With the exception of one asymptomatic patient with HAE whose diagnoses also included rheumatoid arthritis and secondary Sjögrens syndrome, the urine-histamine levels from asymptomatic patients with HAE were similar to values obtained from normal control subjects. Except for data from two patients with HAE, urine-histamine levels from symptomatic patients with HAE were also indistinguishable from levels of normal volunteers. These data suggest that the vast majority of patients with HAE have normal urine-histamine levels both during and between attacks. Consequently, histamine is unlikely to play a pathophysiologic role in HAE.