Natural killer cell activity in families of patients with systemic lupus erythematosus: demonstration of a killing defect in patients.

Natural killer (NK) cell cytotoxic activity and cell frequency, expressed as a percentage of total lymphocytes, have been determined in peripheral blood mononuclear cells from first-degree relatives of patients with systemic lupus erythematosus (SLE), the patients themselves, a group of rheumatoid arthritis (RA) patients and controls. Low levels of killing activity relative to controls were found in some members of all groups with the extent of depression falling into two ranges. Moderate reductions were seen in female (3/31, 10%) and male (4/14, 29%) relatives of SLE patients, female (12/60, 20%) and male (3/4, 75%) SLE patients and female RA patients (6/17, 35%). A more profound depression of killing activity was confined to other female SLE patients (15/60, 25%). There were strong correlations in all groups between killing activity and percentage of NK cells, but analysis of the ratio of these parameters and studies with purified preparations of NK cells suggest that the reduced activity in SLE frequently involves a defect in the killing capacity of the individual cells in addition to the reduced levels of NK cells. Azathioprine (AZA), which was used in treatment of 12 SLE patients, was invariably associated with low values of killing activity. It appears to substantially reduce the percentage of NK and B cells in an action unconnected with the NK cell abnormalities associated with SLE. The finding of low killing activity in relatives and a correlation between their activity and that of their patients support the view that NK cell deficiency is a genetic determinant of SLE. NK cells in SLE may produce insufficient levels of cytokines required for the regulation of IgG production.

Reiter's syndrome following intravesical BCG immunotherapy.

A 71 year old woman developed conjunctivitis, asymmetrical oligoarthritis, and cystitis (Reiter's syndrome) secondary to intravesical BCG treatment for transitional cell carcinoma of the bladder. She received oral prednisolone, izoniazid, and pyridoxine and made a full recovery. Increasing use of BCG as immunotherapy will lead to an increase in the incidence of BCG associated reactive arthritis. Prompt recognition and early diagnosis will facilitate treatment and recovery.

Spontaneous immunoglobulin-producing capacity of cultures from lupus patients and normal donors following depletion of cells expressing CD19 or CD38.

Cells spontaneously secreting IgG or IgM (ISC) are present at a high level in the blood of patients with systemic lupus erythematosus (SLE). By use of magnetic-bead techniques, mononuclear cells from such patients and healthy donors were fractionated according to expression of CD19 or CD38 and the cell fractions were then cultured in the absence of added mitogen/antigen for 5/6 days. Supernatant IgG and IgM were determined and, in addition, in the CD38 experiments ISC were enumerated both before and after culture. Much of the immunoglobulin-producing capacity of unfractionated cells (UFC) from both donor groups was recovered in the CD19- fraction, and no immunoglobulin was produced by CD19+ cells suggesting, unexpectedly, that ISC were not expressing CD19. By contrast, CD38 fractionation resulted in nearly all ISC passing to the CD38+ fraction which produced levels of immunoglobulin approaching 50% that of UFC. On culture of CD38- cells there was a build up in the number of IgG and IgM ISC, this being particularly striking in the controls with numbers well in excess of those in UFC. Not all these new ISC became CD38+, but the maturation process was more efficient in the SLE patients. The possibility is discussed that the spontaneous response in the CD38- populations is due to removal of CD38+ natural killer (NK) cells. Removal of ISC that are present preculture is a helpful initial step in studying ISC generation in the disease.

Does mitogen-induced antibody production by normal blood cells mimic spontaneous production in lupus?

Blood cells from patients with systemic lupus erythematosus (SLE) showed a raised level of spontaneous IgG production that included antibodies to DNA and to common environmental antigens (influenza virus haemagglutinin, adenovirus hexon and mannan from Candida albicans). In contrast, no IgG antibody was produced against an antigen not normally encountered in the UK (egg antigen from Schistosoma mansoni) or a self-antigen not generally associated with SLE (thyroglobulin). IgM production was raised to a lesser extent and only antibodies to DNA were detected. When normal cells were stimulated with pokeweed mitogen or S. aureus organisms, the specificity pattern of IgG production was similar to that described above for SLE with the major exception of the absence of IgG anti-DNA. IgM antibodies to DNA and all the other antigens were detected, but the specificity of the IgM ELISA assays for the protein antigens needs further clarification. The activity of IgM anti-DNA relative to total IgM was far greater in the SLE system. These results provide further evidence that a response to self-antigen is required for production of pathogenic IgG autoantibodies in SLE.

Spontaneous antibody-secreting cells against DNA and common environmental antigens in systemic lupus erythematosus.

Cells spontaneously secreting IgG or IgM antibodies to DNA or to common environmental antigens--influenza virus haemagglutinin, adenovirus hexon and mannan from Candida albicans--have been enumerated by ELISA spot in blood from patients with systemic lupus erythematosus (SLE) and normal donors. Mean values were raised for all antigens in the disease, with those for DNA being no greater than for the other antigens. In normal donors, levels of IgM-secreting cells were similar for DNA and the environmental antigens whereas virtually no IgG anti-DNA secreting cells were found. When results were expressed relative to total numbers of IgG or IgM-secreting cells, the differences between the groups disappeared or were greatly reduced in all systems except IgG anti-DNA. These findings are consistent with a requirement for both polyclonal activation and a self-antigen response in the production of IgG autoantibodies in SLE.

Rheumatological lesions in individuals with human immunodeficiency virus infection.

One hundred and twenty-three patients with human immunodeficiency virus infection have been referred to rheumatologists at our hospitals between October 1985 and April 1989 because of musculoskeletal symptoms. Thirty-four homosexual men presented with acute, peripheral, non-erosive arthritis (mean number of four joints affected) with the knees being involved in 23. Other features developing concurrently with arthritis included psoriasis, keratoderma blenorrhagica, plantar fasciitis, urethritis, conjunctivitis and anterior uveitis. Four of five patients investigated were HLA-B27-positive; none of 15 patients tested had raised titres of rheumatoid or antinuclear factors. Various infections were associated with the onset of arthritis and two patients with a recent history of diarrhoea had serological evidence of yersinia infection. No micro-organisms were identified within the joint except for HIV itself. At the time of onset of arthritis four of these individuals had the acquired immunodeficiency syndrome (AIDS); 11 were not known to be HIV-positive before testing which was performed following referral for arthritis. Six patients have since developed AIDS and four have died. In 15 individuals, including those who progressed to AIDS, joint symptoms have been severe, persistent and poorly responsive to non-steroidal anti-inflammatory drugs. In only five patients has the arthritis been known to resolve. Synovitis has also been seen in two women: in one of these HIV infection was thought to have been acquired through intravenous drug abuse. Other rheumatic lesions included myalgia/myositis, non-inflammatory peripheral arthritis, spinal pain, soft tissue lesions, arthralgia or myalgia of unknown cause and infective lesions including septic arthritis and bony infection due to histoplasmosis and atypical mycobacterial infection. It appears likely that HIV infection is a risk factor for the development of seronegative arthritis and other rheumatic lesions.

B lymphocyte activation in systemic lupus erythematosus: spontaneous production of IgG antibodies to DNA and environmental antigens in cultures of blood mononuclear cells.

IgG antibodies to DNA, influenza virus haemagglutinin (HA), adenovirus hexon (HX) and mannan from Candida albicans (MN) have been determined in supernatants from 2-day unstimulated cultures of peripheral blood mononuclear cells from SLE patients and controls. Mean values were much higher in the SLE group, with from 20% (MN) to 85% (DNA) of patients giving values above the normal range. Although a significant correlation was observed between anti-DNA and anti-HA production, anti-HX and anti-MN showed no such correlations. The specificity of the ELISA assays was demonstrated by inhibition tests. It is concluded that a selective form of polyclonal activation in SLE results in the production of antibodies to foreign as well as to self antigens.

Evaluation of an ELISA system for determination of class-specific antibodies to native and denatured DNA in man.

Enzyme-linked immunosorbent assays (ELISA) have been set up for determination of plasma IgG and IgM antibodies to native (n) and denatured (d) DNA. Normal male and female donors generally gave low values in the assays for IgG; IgM control values were higher, particularly in females. Mean values for patients with systemic lupus erythematosus (SLE) were greatly raised in all four categories of assay in relation to the control (female) group. Levels of IgG anti-nDNA in SLE correlated well with a standard diagnostic test (Farr), and this ELISA assay was more successful than Farr in discriminating between patients and normal females. No such correlation with Farr was found for IgM anti-nDNA. Correlations were found in SLE between levels of antibodies to nDNA and dDNA. Inhibition tests--including those with a plasmid DNA preparation containing no single-stranded regions--showed that most of the IgG antibodies determined in the 'native' assay were able to bind to nDNA and dDNA with comparable avidity, whereas most of those reacting in the 'denatured' assay could only bind dDNA. The former antibodies were probably directed against shared determinants on the deoxyribose-phosphate backbone and the latter against base-dependent structures not exposed in nDNA. Inhibition results for IgM assays were similar, though the predominance of antibodies specific for dDNA appeared less marked. ELISA assays could well prove more useful than established methods in diagnosis and monitoring of SLE and other diseases.

Comparison between local injections of silicone oil and hydrocortisone acetate in chronic arthritis.

One of three preparations-silicone oil, hydrocortisone acetate, and hydrocortisone acetate plus saline-was injected into 22 osteoarthritic and 49 rheumatoid knees. Silicone injected into stiff, dry, grating knees which were the site of chronic arthritis did not promote better movement than did hydrocortisone alone. Hydrocortisone plus saline, however, appeared to be more effective than silicone or hydrocortisone alone in increasing movement in rheumatoid knees. The maximum increase in movement was found to occur three weeks after each of the three different injection preparations.