David Koffler

Avidity of anti-DNA antibodies in serum and IgG glomerular eluates from patients with systemic lupus erythematosus. Association of high avidity antinative DNA antibody with glomerulonephritis.

Significant differences in both specificity and avidity of anti-DNA antibodies were observed in the sera of groups of patients with active systemic lupus erythematosus glomerulonephritis, active systemic lupus erythematosus without nephritis, and in IgG eluates obtained by DNAase digestion of isolated glomeruli from glomerulonephritic kidneys. With methylated albumin-kieselguhr fractionated 3H-HeLa DNA as a source of native or single-strand DNA antigen in a modified Farr assay, an increased level of antibody to native DNA was associated with active systemic lupus erythematosus, particularly active nephritis. The avidity of antinative DNA estimated from plots of the reciprocals of bound and free antigen according to the Sips distribution formula was significanly lower in active glomerulonephritis sera than in sera from patients with active systemic lupus erythematosus without nephritis. However, antinative DNA of uniformly high avidity was found in the glomerular eluates. Avidity of single-strand DNA antibodies did not differ in the various patient groups. The data stronly supprot a major role for high avidity antinative-DNA in DNA/antiDNA immune complex-induced glomerular injury in systemic lupus erythematosus.

The Occurrence of Single-Stranded DNA in the Serum of Patients with Systemic Lupus Erythematosus and Other Diseases

Single-stranded DNA (SDNA) occurs in high incidence and in greatest concentration in the sera of patients with systemic lupus erythematosus (SLE), where levels as high as 250 mug/ml were observed. SDNA appears to be an imunogen for anti-SDNA antibodies and forms complexes in vivo of both anti-SDNA-SDNA and anti-NDNA-SDNA types, which apparently play a role in the pathogenesis of the glomerulonephritis found in patients with SLE, SDNA is also found in high incidence but at lower levels in the sera of patients with rheumatoid arthritis. Lesser amounts of SDNA are found in several other diseases in which a low incidence of anti-SDNA antibodies is observed.

Intrathecal IgG synthesis and blood-brain barrier impairment in patients with systemic lupus erythematosus and central nervous system dysfunction

Paired serum and cerebrospinal fluid specimens from 19 patients with SLE and central nervous system dysfunction were studied with respect to cerebrospinal fluid IgG index (a measure of intrathecal IgG synthesis), isoelectric focusing using immunoperoxidase staining techniques to detect oligoclonal IgG, and determination of the cerebrospinal fluid/serum albumin quotient (Q albumin) as a measure of blood-brain barrier integrity. Twenty-five patients without neurologic disease and 70 patients with a variety of non-SLE neurologic disorders were also studied for comparison. Of most interest was the observation that 42 percent of the patients with SLE had cerebrospinal fluid oligoclonal IgG, usually in association with elevation of the cerebrospinal fluid IgG index. In addition, two of the cerebrospinal fluid specimens that exhibited oligoclonal IgG also had increased titers of alpha-interferon. Q albumin was normal (under 9.0) in 12 of 13 patients with SLE, who had seizure, psychosis, or cranial neuropathy as principal central nervous system manifestations (mean +/- SD = 5.3 +/- 2.4), but was significantly elevated (mean +/- SD = 27.4 +/- 18.8, p less than 0.001) in five of six patients with diffuse, major central nervous system injury, for example, encephalopathy with coma, transverse myelopathy, paraparesis. Blood-brain barrier impairment was not correlated either with presence of circulating immune complexes or with other clinical or serologic evidence for extra-central nervous system disease activity. Taken together, the data suggest that, within the limitations of the techniques used, impairment of the blood-brain barrier in SLE may be secondary to the central nervous system lesion, rather than a result of systemic immune complex injury. In addition, substantial evidence is provided for an ongoing humoral immune response within the central nervous system in this disorder, which, in certain patients, may be associated with the production of intrathecal alpha-interferon.

Cutaneous Localization of the Membrane Attack Complex in Discoid and Systemic Lupus Erythematosus

Biopsy specimens of skin lesions from three patients with discoid lupus erythematosus and six patients with systemic lupus erythematosus contained the membrane attack complex, which comprises C5b through C9, as well as immune complexes at the dermal-epidermal junction. The basilar epithelium in these areas was vacuolated and edematous, and the dermis contained an inflammatory infiltrate. In contrast, 19 of 29 specimens of normal-appearing skin from patients with discoid or systemic lupus erythematosus showed only immune complexes at the dermal-epidermal junction, without the membrane attack complex. The other 10 specimens, all from patients without cutaneous involvement, showed neither immune complexes nor membrane attack complexes. These data suggest that immune complexes within skin lesions selectively generate the assembly of the membrane attack complex, which mediates membrane injury. A synergistic interaction of immune complexes and cofactors may be required to activate complement in areas of skin that are predisposed to tissue injury.

Antibodies to Polynucleotides: Distribution in Human Serums

Hemagglutination procedures were used to determine the distribution of antibodies to native DNA, single-stranded DNA, and double-stranded RNA. Antibodies to all three polynucleotides were found in a high percentage of the serums of patients with systemic lupus erythematosus. Antibodies to native DNA occurred almost exclusively in serums of patients in the active stages of systemic lupus erythematosus, whereas antibodies to single-stranded DNA were observed in the serums of patients with several diseases and of some normal individuals.

Specific concentration of polynucleotide immune complexes in the cryoprecipitates of patients with systemic lupus erythematosus.

Although the association of cryoglobulinemia with hypocomplementemia and tissue injury in systemic lupus erythematosus is well recognized, composition of cryoprecipitates in terms of circulating antigens and antibodies in this disease is less clear. To clarify this question, cryoprecipitates from patients with SLE were examined with sensitive assay techniques for certain antipolynucleotide antibodies and DNA antigen. DNA antibodies were highly enriched relative to serum levels in the majority of cryoprecipitates. DNA antigen was also demonstrable. Antibody to ribonucleoprotein, although less frequently present, was similarly enriched in certain cryoprecipitates. In contrast, anti-double strand RNA, which was commonly detectable in relatively high titer in serum, was only minimally concentrated in a minority of cryoprecipitates. Absorption experiments using red blood cells heavily coated with polynucleotide antigen indicated that a major proportion of the IgG in certain cryoprecipitates was specific antibody. The data strongly suggest that the cryoprecipitates in systemic lupus erythematosus represent circulating immune complexes that are soluble at 37 degrees C and come out of solution in the cold. The marked concentration of immune complexes in the cryoglobulin offers a simple and direct method for determination of the nature of the complexes. The accumulated evidence obtained in the present study indicates that these complexes closely reflect, in their composition, the circulating immune complexes which are most significant pathogenetically in renal tissue injury.

Hemolytic uremic syndrome as a cause of postpartum renal failure

Abstract Four women are presented who, after uneventful pregnancy and delivery, developed hypertension and renal failure accompanied by hemolytic anemia and thrombocytopenia. In 2 of the patients the disease appeared within days after delivery and in the remaining 2 after an interval of several months. All patients died in uremia and at autopsy showed fibrinoid necrosis and thrombosis of renal arterioles and thrombosis and thickening of glomerular capillaries. In 2 of the patients scattered arteriolar lesions were also found in other organs. It is believed that the disease was caused by deposition of fibrin or of fibrinogen derivatives in the walls and the lumina of the affected vessels (thrombotic microangiopathy). The similarity between the hemolytic-uremic syndrome and the present cases is pointed out and their relation to the generalized Shwartzman phenomenon is discussed briefly.

Histologic screening for endometrial cancer

Abstract The techniques available for histologic sampling of endometrial tissue are reviewed and their relative accuracy is discussed. A newer modification of the suction curettage is described, and experience in screening 120 patients is presented. In 98 patients the correlation between the histology obtained by suction curettage and subsequent formal sharp curettage under anesthesia is compared. An absolute correlation of over 95% is demonstrated and the discrepancies are explained. No cancers or cancer precursors were missed. The technique is considered useful and accurate for screening patients at risk for endometrial cancer.

Immunology of myasthenia gravis

Anti-acetylcholine-receptor antibody is demonstrable in more than 90 per cent of patients with myasthenia gravis. Serum antibody titers do not show a direct correlation with disease severity, although in certain patients antibody levels increase in association with disease activity. Impairment of neuromuscular transmission results from the loss of junctional receptors, either as a result of receptor internalization or destruction of junctional folds containing the acetylcholine receptor. Myasthenia gravis manifests immunologic, genetic, and clinical similarities to rheumatic syndromes, suggesting a generic immune dysfunction common to these disorders.

Antipolynucleotide antibodies: The rheumatic connection

The diagnostic and pathogenetic significance of anti-polynucleotide-protein antibodies is discussed, with special attention to the clinical definition and evaluation of anti-DNA, antinucleoprotein, antiribosomal, and anti-RNA antibodies and to their diverse immunochemical specificities.