Peter F. Kohler

DNA:Anti-DNA Complexes: Their Detection in Systemic Lupus Erythematosus Sera

Antibody to DNA was measured before and after treatment of systemic lupus erythematosus (SLE) sera with bovine pancreatic deoxyribonuclease (DNase I). In 11 of 15 cases of SLE with active renal disease there was a significant increase in DNA-binding after DNase digestion, while no such increase was noted in inactive SLE, normal controls or in patients with nonlupus renal disease. The significant rise in DNA-binding after digestion indicated that DNA had bound in vivo to the anti-DNA in these sera. A striking correlation between the occurrence of these complexes and disease activity was shown. In eight cases of SLE nephritis where serial blood samples were obtained, the greatest increase in DNA-binding after DNase digestion occurred at the time of the severest renal disease. In addition, serum from a case of SLE with acute cerebritis but without evidence of renal disease also had a significant rise in binding during the acute phase. This assay provides proof of the existence of circulating DNA:anti-DNA complexes in some cases of SLE and can also be used to measure an apparently critical parameter of disease activity.

Prevalence of Congenital or Acquired Complement Deficiency in Patients with Sporadic Meningococcal Disease

We evaluated the complement system in 20 patients presenting with a first episode of meningococcal meningitis, meningococcemia, or meningococcal pericarditis. Assays of total serum complement activity were performed prospectively in 12 patients and retrospectively in 8. Six of the twenty patients had a complement deficiency (CH50 greater than 2 S.D. below the normal mean). Three of these six had a deficiency of a terminal-pathway protein (C6 in two and C8 in one), and the other three had deficiencies of multiple complement proteins associated with underlying systemic lupus erythematosus or multiple myeloma. Patients with decreased amounts of complement were similar to normal patients in terms of sex, age, type of infection, and meningococcal serogroup, but 3 of the 6 patients with a complement deficiency were black, as compared with none of the 14 patients with normal function (P = 0.018). Complement deficiency is common in patients with a first episode of meningococcal disease and may be due to either a deficiency in a single terminal protein or a complement-depleting underlying illness.

Onset of polyarteritis nodosa during allergic hyposensitization treatment

In six of 20 consecutive patients with polyarteritis nodosa, the onset of vasculitic symptoms coincided with hyposensitization therapy for presumptive atopic (immunoglobulin E-mediated) respiratory disease. Atopic symptoms had been present for less than three months in half of the patients and over 10 years in the remainder. Active vasculitis persisted in all patients despite immediate cessation of the hyposensitization treatment. Three patients died within eight months. When compared with the 14 other patients with polyarteritis nodosa, those undergoing hyposensitization had significantly greater skin involvement and peripheral blood eosinophilia (p = less than 0.05). Evidence for circulating immune complexes with decreased hemolytic complement, increased cryoglobulins or increased Clq binding was present in both groups. No single allergen was used in all patients, no antiallergen precipitating antibodies were detected and less than 16 mg of allerginic protein had been injected in five of the patients.

Prevention of chronic neonatal hepatitis B virus infection with antibody to the hepatitis B surface antigen.

Abstract The efficacy of specific-antibody treatment in preventing hepatitis B virus infection in infants born to mothers positive for the hepatitis B surface antigen was evaluated. Four babies wer...

Treatment of chronic idiopathic urticaria with combined HI and H2 blockers

Combined H1 (cyproheptadine) and H2 antihistamines (cimetidine) were tried in eight patients with chronic urticaria who were previously unresponsive to conventional anti‐urticarial regimens, including type I antihistamines, hydroxyzine, ephedrine and corticosteroids. 50 % of the patients responded with 90 % or greater improvement within 10 days. The remaining 50% showed no benefit. Side effects of the medications were minimal. These results indicate that a 10 day trial of both H1 and H2 antihistamines may be useful in patients with chronic urticaria resistant to all other standard treatment modalities.

Skin histamine in chronic urticaria

Abstract To further study the role of histamine in the pathogenesis of chronic urticaria, the concentration of histamine in tissue extracts from skin biopsy samples and in plasma from patients with chronic urticaria was measured by a sensitive radioenzymatic assay. Tissue histamine levels from urticarial lesions and uninvolved skin were compared with extracts of biopsy samples taken from normal controls. The average tissue histamine content in 15 biopsy samples from the chronic urticaria patients was significantly higher than in those of 15 normal controls. Forty percent of the patients had levels 2 SD greater than the mean of the control group. Elevated histamine levels were also found in biopsy samples of uninvolved skin from some urticaria patients. Circulating histamine levels from chronic urticaria patients were rarely elevated and did not correlate with skin concentration. No correlation was noted between tissue histamine concentration and estimated mast cell concentration on Giemsa-stained sections of five biopsy samples. These results indicate that tissue histamine levels are increased in some patients with chronic urticaria. This suggests that local histamine elevations may be important in the pathogenesis of many patients with this disease. In addition, increased tissue histamine in these patients is not reflected by elevated circulating levels.

Lymphocytotoxic antibodies in multiple sclerosis

Abstract The presence of cold-reactive lymphocytotoxic antibodies has been demonstrated in patients with viral infections and various “autoimmune” diseases thought to be related to viral infection. In the present study we have examined the incidence and possible significance of these antibodies in patients with multiple sclerosis, another disease probably associated with a viral agent. The incidence of lymphocytotoxic antibodies was significantly increased in patients with multiple sclerosis as compared to their siblings, patients with other neurological disease, and normal controls. The level of these antibodies correlated significantly with serum measles antibody titers in the affected patients. No correlation was found between lymphocytotoxic antibody levels and parameters or clinical disease or other viral antibody titers in the serum and cerebrospinal fluid. It was concluded that lymphocytotoxic antibodies in patients with multiple sclerosis probably serve as markers of viral infection.

Metabolism of Human C1q STUDIES IN HYPOGAMMAGLOBULINEMIA, MYELOMA, AND SYSTEMIC LUPUS ERYTHEMATOSUS

The in vivo metabolism of radioiodinelabeled C1q was determined in patients with hypogammaglobulinemia, multiple myeloma, systemic lupus erythematosus (SLE), and in healthy controls. Marked differences in metabolic behavior were observed with a much more rapid disappearance of plasma radioactivity in patients as compared with controls. Estimated plasma volumes at 10 min after injection (time 0) were normal in controls and the SLE patient, mean 40 ml/kg, whereas they were grossly elevated, 57-82 ml/kg, in the hypogammaglobulinemic and myeloma patients, indicating significant loss of C1q-(125)I during the initial mixing period. Absence of a distinct initial equilibration phase of radioactivity loss from the plasma suggested significant reversible interaction of the labeled C1q with plasma proteins and density gradient studies provided evidence for in vivo uptake into the circulating trimolecular first component complex (C1q, r, s). In controls and the SLE patient 0.51-0.75 of the C1q was retained in the plasma space while only 0.28 or less was in the others. The daily plasma pool fractional C1q catabolism was 0.65-0.67 in controls compared with 0.95-4.80 in the patients. C1q synthetic rates in controls were 4.64 and 4.34 mg/kg per day while higher rates, 4.94-37.40 occurred in the patients. These experiments clearly indicate that the metabolism of C1q is markedly influenced by serum IgG concentrations, probably related to the reversible interactions of C1q with IgG, and also affected by interactions with C1r and C1s. The decreased serum C1q often present in hypogammaglobulinemia and myeloma relates to an increased catabolism and higher extravascular distribution rather than impaired C1q synthesis. In contrast, a second distinctly different basis for decreased C1q occurs in SLE; increased utilization by an ongoing immunopathogenic process.

Maturation of the Human Complement System. I. ONSET TIME AND SITES OF FETAL C1q, C4, C3, AND C5 SYNTHESIS

The onset times and sites of human C1q, C4, C3, and C5 synthesis were determined by culturing tissues from 23 fetuses, 8-25 wk old, in the presence of [(14)C]lysine and isoleucine. In parallel, IgG and IgM production was followed. Liver, spleen, placenta, peritoneal and bone marrow cells, thymus, and colon were cultured for 48 h and the concentrated media studied by immunoelectrophoresis and subsequent autoradiography using adult human serum as carrier and specific antisera. The quantitative synthesis was approximated by scoring the intensity of the labeled precipitin lines using uniform conditions. C5 production was detected earliest at 8 wk gestation and by 11 wk and thereafter, C3, C4, and C5 synthesis was uniformly present in multiple tissues. C1q synthesis, however, was limited almost exclusively to the spleen, began at 14 wk, and was not uniformly present. In contrast IgG and IgM production did not occur in three fetuses synthesizing complement and while detected as early as 11 wk. was inconstant, occurred predominantly in the spleen, and was quantitatively much less compared to C3, C4, and C5. These findings suggest that developmentally the complement system is a more primative biological defense mechanism than antibody.

Vasculitis in chronic urticaria

Abstract We have explored the problem of the histologic basis of chronic urticaria and its relation to vasculitis and immune complex disease. In a prospective study, 42 consecutive patients with chronic urticaria (from twice weekly to daily episodes lasting more than 6 wk) had skin biopsies and were studied for immunologic variables. Twenty-two patients (52%) had vasculitis on biopsy as defined by the presence of cellular infiltrates within the vessel wall. The other 20 patients (48%) had either edema only or perivascular infiltrates with mononuclear cells (perivasculitis). The group with vasculitis could be subdivided into seven patients with neutrophilic venulitis including three with fibrinoid change, seven with mixed-cellular vasculitis, four with lymphol monocytic vasculitis, and four with eosinophilic vasculitis. Vascular deposits of immunoreactants were found in only four (18%) of the vasculitis patients, compared with 65% of concurrently studied patients who had cutaneous venulitis manifested as palpable purpura, i.e., Henoch-Schonlein syndrome. Urticarial patients with vasculitis were more often male and had a longer mean duration of hives compared with the nonvasculitis group. We saw no differences between the vasculitis and nonvasculitis cases of urticaria with regard to the incidence of arthralgia, elevated erythrocyte sedimentation rate (ESR), or hypocomplementemia. The group with vasculitis did not have more generalized disease nor were the hives more resistant to therapy. We have discussed the definition and histologic criteria for the diagnosis of vasculitis when it occurs in very small blood vessels.