Lymphocytotoxic antibodies in family members of patients with systemic lupus erythematosus.

57% of sera from 124 relatives of 28 patients with systemic lupus erythematosus (SLE) were found to have antibody directed against lymphocytes. The incidence in 60 members of 16 control families was 3%. Both consanguineous and nonconsanguineous relatives had the antibody in their sera. 68% of close household contacts of the SLE patients showed lymphocytotoxic antibody whereas only 23% of consanguineous relatives who had no household contact with the probands had this antibody. These data suggest that environmental factors may be important in the pathogenesis of SLE.

Anti-nucleic acid antibodies in systemic lupus erythematosus patients and their families. Incidence and correlation with lymphocytotoxic antibodies.

Anti-RNA antibodies were found in 82% of 28 systemic lupus erythematosus (SLE) probands and in 16% of 124 of their family members. The incidence in 76 control family members was only 5%. In the SLE family members, the antibodies were found exclusively in 21% of the 94 close household contacts of the probands. The incidence of anti-native DNA (nDNA) antibodies was 68% for the SLE probands. The incidence of anti-nDNA antibodies in close household contacts of the probands was 6%, which was not significantly different from the 1% incidence found in control families. Lymphocytotoxic antibodies occurred in 57% of the SLE family members as a whole and in 68% of the close household contacts. In the SLE probands, lymphocytotoxic antibodies correlated with anti-single-stranded RNA (poly A) and anti-nDNA but not with anti-double-stranded RNA (poly A-poly U). On the other hand, lymphocytotoxic antibodies in the household contacts correlated with anti-double-stranded RNA (poly A-poly U) but not with anti-poly A or anti-nDNA. The anti-RNA antibodies were present in consanguineous household contacts but not in nonconsanguineous household contacts. These findings strengthen the hypothesis that both an environmental agent, possibly a virus, as well as the genetic response are important in the pathogenesis of SLE. Family members may therefore be a logical population in whom to search for specific antibodies to a viral agent.

Presence of complement-fixing anti-endothelial cell antibodies in systemic lupus erythematosus.

Vasculitis in systemic lupus erythematosus (SLE) is associated with the deposition of IgG and complement in blood vessel walls. However, it is not known whether immune injury to endothelial cells is a part of this process. Therefore, we used a solid phase radioimmunoassay to study the ability of IgG from normal human sera and sera from patients with SLE to bind to endothelial cells. In this assay, cultured human umbilical venous endothelial cells were sequentially incubated with normal or SLE sera, goat anti-human IgG, and 125I-labeled staphylococcal protein A (*SPA). After exposure to normal sera, 2.5 +/- 0.5% (mean +/- SD) of the added *SPA bound to the cells, whereas after exposure to SLE sera 13.8 +/- 7.6% of the added *SPA bound to these cells. This difference in binding was highly significant (P less than 0.001). Binding was partially reduced when SLE sera were preincubated with B-lymphocytes or monocytes, but not after exposure to erythrocytes, platelets, or T lymphocytes. Incubation of endothelial cells with the 7S fraction of SLE sera or with the F(ab')2 fragment of SLE-IgG resulted in the deposition of greater than 80% as much IgG as was deposited on endothelial cells by whole serum. However, since higher molecular weight fractions (greater than 7S) of SLE sera were also active, we tested the capacity of endothelial cells to bind IgG complexes. Endothelial cells bound heat-aggregated IgG (HA-IgG) in a saturable manner at one log concentration below the binding of normal monomeric IgG. Binding of HA-IgG to endothelial cells was markedly enhanced by preincubation with a serum source of complement. Both HA-IgG and SLE-IgG also bound to freshly obtained endothelial cells in suspension, as detected by automated fluorescence flow cytometry. Binding of SLE-IgG and HA-IgG to endothelium initiated complement activation, deposition of the third component of complement, and disruption of the monolayer. In addition, SLE-IgG and HA-IgG caused endothelial cells to secrete prostacyclin and caused the adherence of platelets, confirmed by scanning electron microscopy. These studies demonstrate that IgG anti-endothelial antibodies are present in the sera of patients with active SLE. These sera may also contain IgG complexes that are capable of binding to endothelial cells. The association of IgG and complement with endothelial cells may initiate vascular injury in SLE and other human disorders.

Immunologic function in humans before and after hyperthermia and chemotherapy for disseminated malignancy.

Multiple immunologic parameters were studied in three patients prior to and after hyperthermia treatment for disseminated malignancy. Two patients had malignant melanoma and received chemotherapy during the hyperthermia treatment. One had adenocarcinoma of the stomach and received no concomitant chemotherapy. Rapid rosettes as a measure of thymus-derived lymphocytes (T-lymphocytes) were found to increase significantly after therapy (P less than 0.05) both in percentage and absolute numbers. There was no change in the numbers or percentages of other markers for T-lymphocytes or bone marrow-derived B-lymphocytes. Complement profiles revealed a significant decrease in C3 (P less than 0.005) after hyperthermia but no change in levels of other components of the alternate pathway. Antibody-dependent lymphocyte-mediated cytotoxicity and polymorphonuclear cell-mediated antibody-dependent cytotoxicity were also depressed after hyperthermia. No change was observed in immunoglobulin levels with hyperthermia therapy. Results indicated that hyperthermia may favorably alter the immune balance between tumor and host in selected instances.

Serratia marcescens - caused arthritis with negative and positive birefrengent crystals.

We encountered an unusual case of arthritis caused by Serratia marcescens, with both positive and negative birefringent crystals in the same inflammatory synovial fluid. This combination of events is most likely to occur in men over 40 years old who have a predisposing illness or are receiving immunosuppressive drugs. This case shows the need to consider multiple pathological processes occurring in the same joint.

Cellular immune function in rheumatic disease.

Investigation of the cellular immune function in patients with rheumatic diseases is important in elucidating the pathogenesis of the disease processes and in determining the associated abnormalities of recognition and regulation exerted by the immune system. However, because of the lack of specificity and the variations noted from laboratory to laboratory, tests of cellular immune function are, at present, of little value in the laboratory diagnosis of these diseases. The abnormalities found in the rheumatic diseases occur with many autoimmune diseases and other inflammatory states. The common pathway of immune abnormalities appears to be influenced by several factors. They include several genetic loci, possible environmental factors, and immunologic mechanisms, which appear to interact in an intimate way to induce various autoimmune diseases.

Arthritis problem indicator: preliminary report on a new tool for use in the primary care setting.

Improving the quality of life for people with rheumatic disease involves timely identification of problem areas and application of appropriate interventions. In response to a 1987 Commonwealth of Pennsylvania study, which reported a wide variety of unmet needs in arthritis patients and their families, the Arthritis Problem Indicator (API) was developed. It is a single-page, self-report, low-cost tool. A mixed rheumatology population (n = 50) and their primary care physicians participated in a pilot study. The study revealed that the seven most common areas of patient concern were pain, weight control, sleep, mobility/walking, activities of daily living, community access, and depression/anxiety. The physicians reported that the patient's answers on the API led them to initiate new treatment or referral for 32% of the patients. The physicians also stated that for 80% of the patients, the API was helpful in providing information about the patient. The API is easily interpreted by health professionals and designed to be an indicator of problem areas frequently associated with arthritis.

Renal vascular lesions in systemic lupus erythematosus.

In the past, necrotizing vasculitis has been considered to be one of the dominant intrarenal vascular abnormalities in systemic lupus erythematosus (SLE). To test the validity of this statement, 70 consecutive renal biopsies from patients with SLE were reviewed. Light microscopy (LM) and immunofluorescence (IF) studies documented abnormalities, including thrombosis and nephrosclerosis, in 30 patients (43 percent), but no cellular infiltration of the vessel walls or other evidence of acute necrotizing vasculitis was seen. It is concluded that while intrarenal vasculopathy with thrombosis and nephrosclerosis is a common finding in SLE, our data and recently published studies suggest that acute necrotizing vasculitis occurs rarely, if at all, in SLE nephritis.

Lymphocytotoxic antibodies.

LCTA are a heterogenous group of antibodies found in many disease states. The recurring observation is that they are able to modulate immune function in vitro. The exact mechanism of this modulation is unknown, however, alteration of cell surface antigens appears to be important. Recent advances in molecular biological techniques have made the surface antigen, against which LCTA is directed, more accessible. Once the surface antigen is identified, the exact role of LCTA may then be elucidated. Endothelial cell damage is a recurring pathologic finding in many of the diseases discussed. Again, identification of the antigen and its similarity to antigens on various cell types may help explain the immunopathogenesis of the different disease processes.

Acute visual loss in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) often presents as a multisystem disease that can be difficult to diagnose. Although ocular symptoms are infrequent, actual acute visual loss has been reported. A review of four cases of acute visual loss from a lupus clinic revealed that two patients had visual loss as a presenting sign of SLE. One had bilateral occipital lobe infarctions, the other multiple cotton wool spots and an attenuated retinal vascular system. Of the two patients with documented SLE prior to the onset of visual problems, one presented with a coincidental retinal tear and the other with retinal phlebitis.

Lymphocyte subsets in patients with systemic lupus erythematosus.

The role of abnormal numbers and function of lymphocyte subsets in SLE remains, to date, unclear. Evidence exists for both functional T lymphocyte and B lymphocyte defects although the data for T lymphocyte defects appear more compelling. The role of autoantibodies on these cellular defects is also unclear. They may take on an important pathophysiologic role in depletion of certain lymphocyte subsets with subsequent alteration of function or they may, in fact, be interesting epiphenomena since an inverse relationship of depressed T lymphocyte numbers and function to increased levels of LCTA are frequent. Many other factors clearly influence lymphocyte function and disease expression including genetics and endocrine factors. As methodologies improve, a clearer understanding of the pathogenesis of SLE will emerge.

Acute rheumatic fever.

During the first half of this century rheumatic fever was a common disease with significant morbidity and mortality in the United States. In the 1980s, when many clinicians were hoping this disease was a disease of the past, anxieties were renewed when outbreaks were reported in several areas around the country. Although the etiology still eludes us, insight has been gained. Environmental and genetic factors are believed to play a role in the epidemiology of this disease. Additionally, the implicated organism, the group A streptococcus, has many strains, and differences in its many proteins may determine their potential for rheumatic fever. The mechanisms leading to disease are not clear, but the streptococcus has been implicated as a source of antigens with cross-reactivity with human tissues and has been shown to modify immune mechanisms. Clinical aspects are briefly reviewed and physicians are reminded to consider rheumatic fever as a diagnostic possibility in the appropriate settings.

Deficient autologous mixed lymphocyte reactions correlate with disease activity in systemic lupus erythematosus and rheumatoid arthritis.

We have examined autologous mixed lymphocyte culture (AMLC) reactions in patients with systemic lupus erythematosus (SLE), classical rheumatoid arthritis (RA), and in normal age and sex matched healthy control individuals. AMLC responses were found to be lower than the median of all controls and patients in 30 of 31 individuals with SLE and RA and in only 2 of 15 healthy controls. In both SLE and RA there was a statistically significant correlation of decreased AMLC reaction with disease activity. On an individual basis, there was no direct correlation between decreased AMLC reactivity, concomitant steroid therapy, or the occurrence of clinical or laboratory parameters of autoimmunity.

Methotrexate in the treatment of rheumatoid arthritis.

Methotrexate is an effective agent for the treatment of rheumatoid arthritis. It is now widely prescribed for patients who have not tolerated or responded to gold compounds or penicillamine. Minor adverse reactions are common, and fatal pulmonary toxicity or cirrhosis can occur. The drug does not produce disease remissions, but continued administration helps reduce pain, stiffness and swelling. Within the past year, the Food and Drug Administration has approved methotrexate for use in treating rheumatoid arthritis.

Study of circulating immune complex size in systemic lupus erythematosus.

The molecular size of circulating immune complexes in patients with systemic lupus erythematosus was determined by the C1q solid-phase assay after the sera were fractionated by sucrose-gradient ultracentrifugation. Circulating immune complexes in patients with membranous glomerulonephritis were uniformly large, sedimenting exclusively above 19S, whereas the immune complexes in patients with cerebritis were small, at or just above 7S. In lupus patients with diffuse proliferative glomerulonephritis and patients without renal involvement, immune complexes of both large and small sizes were found. Of patients without renal involvement, more circulating immune complexes were associated with active disease (n = 22, prevalence = 82%, mean level = 24 standard deviations) than with inactive disease (n = 17, prevalence = 41%, mean level = 41%, mean level = 6 . 5 standard deviations). In patients with clinical evidence for renal involvement, circulating immune complexes were detected in all of five patients with membranous glomerulonephritis, in 88% of 17 patients with diffuse proliferative glomerulonephritis and in one of four patients with mesangial nephritis. Thus, in addition to the finding of an overall positive correlation between disease activity and circulating immune complex levels, circulating immune complexes of certain general molecular size ranges appear to be associated with different clinical manifestations of systemic lupus erythematosus.

Systemic lupus erythematosus presenting with lingual infarction.

A 73-year-old woman developed a lingual infarction, Raynaud's phenomenon, cutaneous lesions, pancytopenia, and pleuritis. Serologic studies supported a diagnosis of systemic lupus erythematosus (SLE), and anticardiolipin antibodies were detected in significant titers. This is the first reported case of SLE presenting with an infarction of the tongue.

Lymphocytotoxins in acute and chronic hepatitis. Characterization and relationship to changes in circulating T lymphocytes.

Serum lymphocytotoxicity (LCT) was detected in 49% of fifty-one patients with acute viral hepatitis and 72% of twenty-nine patients with chronic hepatitis. LCT was not detected in ten chronic carriers of hepatitis B surface antigen. Characterization of LCT revealed it to be active at physiologic temperatures and to be reactive against both T and B lymphocytes. The occurrence of LCT was transient in acute hepatitis and intermittent in chronic hepatitis. There was a significant inverse relationship between the percentage change in LCT over time and peripheral blood T-cell proportions amongst the patients studied. These findings indicate the importance of liver damage in the appearance of LCT and suggest that LCT may contribute to depressed lymphocyte function in liver disease.