John S. Davis

Rheumatoid Vasculitis: Effect of Cyclophosphamide on the Clinical Course and Levels of Circulating Immune Complexes

A study of five patients with severe rheumatoid vasculitis treated with cyclophosphamide was undertaken to determine whether immune complexes were present in serum and if their levels correlated with disease activity and response to treatment. Circulating immune complexes were measured by various techniques including the Clq binding and Raji cell radioimmunoassays and determination of the presence of cryoglobulins. Elevated levels of circulating immune complexes, hypocomplementemia, and high titer rheumatoid factor were present during active vasculitis. Clinical and serologic remissions were induced in all patients on cyclophosphamide. In two patients in remission, a rise in rheumatoid factor titer and immune complex levels was associated with an exacerbation of vasculitis and resolved on increased cyclophosphamide dosage. The Clq binding assay and rheumatoid factor titer correlated best with clinical activity. Thus, circulating immune complexes appear to be involved in the immunopathogenesis of rheumatoid vasculitis, which can be successfully treated with cyclophosphamide.

Homozygous C3 deficiency: Detection of C3 by radioimmunoassay

Abstract A 5 10 12 - year-old girl with recurrent infections was found to have homozygous C3 deficiency. Family studies demonstrated that the pattern of inheritance was consistent with that of an autosomal codominant trait. C3 levels have ranged from 5 mg/100 ml (electroimmunoassay) to 1.7 μg/100 ml (radioimmunoassay) 2 years later. C3 was also detected in two previous homozygous-deficient patients by radioimmunoassay. These findings suggest that an intact structural gene for C3 is present in these patients. In samples of the patients serum with a C3 level less than 3 mg/100 ml, properdin factor B conversion did not occur upon incubation with zymosan. Immune adherence was normal. The vasopermeability response following intradermal injection of C 1s was normal. The patients serum incubated with zymosan did not produce a chemotactic response of normal leukocytes. Phagocytosis of endotoxin-paraffin oil-oil red O particles by normal leukocytes was not enhanced following incubation with the patients serum. Humoral antibody response and lymphocyte number and function were normal.

Soluble Immune Complexes in Human Disease

The great variety in biochemical properties of immune complexes occurring in human and animal disease states has made the detection of such complexes a difficult task. Variability in immune complex size, specificity, and interaction with humoral or cellular receptor systems, such as complement and phagocytes, suggests different pathogenic properties. The introduction of radioimmunoassays and the recently improved knowledge of the immune complex-receptor interactions have lead to the description of a large number of detection procedures, which in turn has widened the catalogue of diseases associated with immune complexes. This widespread occurrence of soluble immune complexes has lead many investigators to think that such complexes may occur either as a transient physiological phenomenon, important for fast clearance of the antigen, or as primary pathogenic factors triggering inflammatory reactions. Among the 50 procedures for immune complex detection known today, the article will select some pertinent tests, which will be discussed with respect to their specificity, sensitivity, and reproducibility. Furthermore, it is well known that when applied to the study of a patient group with one particular immune complex disease, various tests will result in different percentages of patients having complexes. This observation is due to differences in the underlying principle on which the various tests are based. Thus immune complexes must be further characterized with respect to their size, to the antibody class or specificity involved and, most difficult, to the antigenic specificity which participates in the complex. Recent advances in such experimental characterization of immune complexes in vitro and in the clinical evaluation of patients with complement activation associated to the presence of immune complexes will be discussed.

Serum antibodies to DNA by counterimmunoelectrophoresis (CIE)

Abstract Counterimmunoelectrophoresis (CIE) is rapid, convenient, and a relatively sensitive method for detection of anti-DNA antibodies. Specificity of anti-DNA antibodies for SLE as measured by CIE is only fair with unfractionated DNA as antigen. The relative lack of specificity is related to contaminating denatured DNA in our preparation. Specificity regarding detection of anti-DNA is good, although there was a disturbingly high incidence of sera positive by CIE and negative by Farr assay (11% of sera tested). Again, these false positives occurred when commerical unfractionated DNA was used, and this problem was largely overcome by use of fractionated or purified DNA. Data obtained using methylated albumin-kieselguhr native DNA fractions suggest that anti-nDNA is quite specific for SLE. There remain, however, occasional patients who give positive reactions with native DNA by CIE, but who apparently have illnesses other than SLE.

Clinical and immunologic studies in identical twins discordant for systemic lupus erythematosus

Abstract Middle-aged female identical twins, one of whom had systemic lupus erythematosus (SLE), were evaluated for immunologic reactivity to previous antigenic challenges, including primary immunization with a foreign antigen, keyhole limpet hemocyanin (KLH). These two women had lived together for all of their 58 years and neither was receiving anti-inflammatory or immunosuppressive drugs at the time of these studies. Both twins demonstrated comparable 7S and 198 humoral antibody response to KLH, as well as similar viral antibody titers. However, the twin with SLE was anergic to common antigens, streptokinase-streptodornase, Trichophyton and Candida; furthermore delayed hypersensitivity to KLH did not develop after immunization. This observed discrepancy between humoral and cellular immunity in genetically similar subjects may be significant in the pathogenesis of SLE.

Arthropathy in hemochromatosis.

Arthritis may be the presenting manifestation of iron overload. The metacarpophalangeal joints are often involved, producing a condition that resembles osteoarthritis but at a site typically affected by rheumatoid arthritis. Treatment of the arthritis is often disappointing, but identification of the underlying disease permits institution of life-saving phlebotomy therapy.

Current Management of Rheumatoid Arthritis: Commentary

Armed with new regimens for established drugs and new agents that block the inflammatory cascade, rheumatologists are taking a more aggressive approach to rheumatoid arthritis. Early diagnosis and prompt institution of disease-modifying drugs may minimize the progression of joint damage.

Meeting the Frustrations of Chronic Fatigue Syndrome: Case Commentary

Patients face long-term disability, a variable prognosis, and too often, skeptical or misinformed doctors. Physicians lack laboratory markers or definitive treatment. Nevertheless, the diagnosis can be made with confidence by applying established diagnostic criteria- and selected laboratory studies to exclude other disorders-while symptomatic medication can provide support until recovery begins.

Mitogen stimulation of human lymphocytes. II. Effect of exogenous DNA on lymphocyte function in systemic lupus erythematosus.

Abstract The responses of peripheral blood lymphocytes from normal donors and from systemic lupus erythematosus (SLE) patients to phytohemagglutinin (PHA), concanavalin A (Con A), and pokeweed mitogen (PWM) were determined for 6 days of culture. Lymphocytes from SLE patients showed impaired responses to Con A and PWM over the whole culture period, whereas the response to PHA was delayed by approximately 24 hr compared with lymphocytes from normals. Exogenous DNA inhibited the responses of lymphocytes from SLE patients to mitogens to a greater extent than in normals. This inhibition was greatest for PHA. In the absence of mitogen, DNA induced slight blastogenesis in lymphocytes from normals but decreased the blastogenesis in lymphocytes from SLE patients.

Mitogen stimulation of human lymphocytes. I. The effect of exogenous deoxyribonucleic acid.

Abstract Peripheral blood lymphocytes from normal donors were incubated with mitogens in the presence or absence of exogenous DNA. The addition of DNA inhibited the response of the cells to the mitogens by up to 40% but did not alter the time course of the response. Similar inhibition was seen with the synthetic deoxyribonucleotides poly(dAdT) and poly(dA). Addition of the DNA up to 24 hr after the addition of mitogen to the cells did not affect the extent of inhibition. The inhibition was apparently due to a decrease in the total number of cells responding to the mitogen rather than to a general decrease in response of each cell. Furthermore, no specific cytotoxic effect of the exogenous DNA could be detected, and the degree of inhibition was approximately constant for different mitogen concentrations. In contrast, DNA alone induced a low degree of stimulation in the cells.