Serendipitous evidence of T lymphocyte activation in close female relatives of patients with systemic lupus erythematosus.

A well-recognized characteristic of the autoimmune disease, systemic lupus erythematosus (SLE), is the high level of activated T cells present in the blood. Because of the increased size and granularity of activated T cells, in flow cytometry one might expect to find increased numbers of cells falling outside a standard light-scatter lymphocyte gate, and indeed we now report that the percentage of T lymphocytes in the gate (% TiG) was below the normal range in 23 of 58 (40%) female patients because of increased scatter values. However, the surprising additional observation was made that 18 of 30 (60%) female first-degree relatives of the patients also fell below the normal % TiG range, suggesting the presence of T cell activation in these relatives. This view is strengthened by the strong inverse correlation between plasma total immunoglobulin G(IgG), which was raised in some relatives, and % TiG, as T cell activation is a requirement for IgG production. Conversely, there was no correlation with IgM, which has no comparable link with T cell activation. While a definitive interpretation must await the demonstration of activation antigen expression in relatives, these findings suggest the existence of a T cell activation trait, not harmful in itself, which, however, contributes to the development of disease in patients with SLE.

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.

Counter-proliferative effects of nucleosomal antigens in cultures from lupus patients.

Blood mononuclear cells from 20 lupus patients were cultured in the presence of nucleosomal antigens to determine whether they induce lymphocyte proliferation. The predominant effect seen, however, was one of inhibition of the background proliferation. Such inhibition was rare with cells from female or male controls. Nucleohistone (NH), crude histone and enriched preparations of histones H2A/H4, H2B and H3 showed this effect in approximately one-third of patients, but H1 and single-stranded (ss) DNA had no such activity. Double-stranded (ds) DNA may show this inhibitory action, but further tests are required. ssDNA was the only antigen that showed evidence (two patients) of disease-related stimulation of proliferation. Histones and NH induced proliferation in many subjects but the strongest responders were controls. Patients responded poorly to tuberculin PPD but gave an exceptionally strong proliferative response to pokeweed mitogen. It is suggested that the inhibition of background proliferation in patients is a consequence of the interaction of nucleosomal antigens with sensitised T cells. If T cell sensitisation to histones is an important factor in the development of lupus, the disease may be preventable in those at risk by inducing tolerance to the appropriate peptides.

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.

High-resolution diffusion imaging using a radial turbo-spin-echo sequence: implementation, eddy current compensation, and self-navigation.

This work describes a segmented radial turbo-spin-echo technique (DW-rTSE) for high-resolution multislice diffusion-weighted imaging and quantitative ADC mapping. Diffusion-weighted images with an in-plane resolution of 700 microm and almost free of bulk motion can be obtained in vivo without cardiac gating. However, eddy currents and pulsatile brain motion cause severe artifacts when strong diffusion weighting is applied. This work explains in detail the artifacts in projection reconstruction (PR) imaging arising from eddy currents and describes an effective eddy current compensation based on the adjustment of gradient timing. Application of the diffusion gradients in all three orthogonal directions is possible without degradation of the images due to eddy current artifacts, allowing studies of the diffusional anisotropy. Finally, a self-navigation approach is proposed to reduce residual nonrigid body motion artifacts. Five healthy volunteers were examined to show the feasibility of this method.

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.

B lymphocyte hyperactivity in families of patients with systemic lupus erythematosus.

Blood cells spontaneously secreting IgG and IgM and the level of plasma immunoglobulins and antibodies to dsDNA, ssDNA and influenza virus haemagglutinin have been determined in families of patients with SLE, in 'normal' families and groups of 'normal' individuals. IgM values were consistently higher in females than in males. About one in three of healthy blood relatives gave values in excess of the sex-matched control range in one or more of these test, particularly notable being raised values of IgG anti-dsDNA and total IgG shown by female relatives. High-scoring relatives were more likely to be offspring or parents than siblings of patients, suggesting, together with evidence from a spouse group, the involvement of environmental as well as genetic factors in these families. Correlation analysis between the various assays in the different groups showed a clear distinction between the female control group, where there were no associations, and the female relative group where there were strong associations, including a significant correlation between IgM and IgG antibodies to dsDNA. The male groups produced a more variable picture but the patients gave a remarkably consistent pattern of moderate positive associations. Pokeweed mitogen induced a higher level of IgG production in blood cells of relatives than in controls. These findings are suggestive of a breakdown in relatives of normal antibody regulation. Investigation of immunological abnormalities in family members provides a powerful tool for the analysis of a complex 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.

Abnormal osteocalcin binding in rheumatoid arthritis.

Studies of osteocalcin in the serum and synovial fluid of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) showed the presence of significant amounts of osteocalcin in synovial fluid and that the values in RA synovial fluid were significantly lower than in OA synovial fluid. In addition, the osteocalcin in OA synovial fluid bound almost completely to hydroxyapatite, whereas a significant proportion of the osteocalcin in RA synovial fluid did not. These studies suggest that patients with severe RA produce low amounts of active osteocalcin and higher than expected amounts of inactive osteocalcin in the synovial fluid. They provide some evidence that osteoblast function may be abnormal in the osteoporosis of RA.

Men's expectations of physicians in sexual health concerns.

This study assessed 62 men for their expectations of primary care physicians in attending to sexual health concerns. The physician was the professional most preferred for consultation regarding sexual concerns, and men look for qualities of professionalism, empathy, trust, and comfort in their physician. While 97% of the men reported prior sexual concerns, only 19% had discussed these issues with their doctor. Most were hesitant, but wanted to deal with sex problems. They preferred that the physician initiate the discussion. These findings suggest an under-utilization of sexual health care by men and support the role of the primary care physician as an important sexual health provider.

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.

Inflammatory joint disease and human immunodeficiency virus infection.

Nine men positive for antibody to human immunodeficiency virus (HIV) who developed peripheral, non-erosive arthritis were followed up. The clinical features were compatible with reactive arthritis but were atypical in several respects: the joint symptoms were generally severe, persistent, and unresponsive to non-steroidal anti-inflammatory drugs. The onset of arthritis was associated with various infections, none of which are known to be associated with the development of reactive arthritis. HLA typing was performed for three patients, all of whom were positive for HLA-B27. HIV was isolated from the synovial fluid of one patient. No patient had AIDS before developing arthritis, but four progressed to having AIDS after a mean of 7.5 months, and two died. Arthritis resolved in only one patient. The possibility of HIV infection should be considered in all patients with conditions suggesting reactive arthritis. Synovitis in patients with severe immunodeficiency has important pathogenetic implications.

Women's expectations of physicians in sexual health concerns.

This study surveyed 56 women to assess their expectations for the primary care physician to inquire about sexual concerns and to diagnose and treat sexual problems. The study indicates that the physician is the professional most frequently consulted about sexual concerns and that patients expect even more leadership from the physician in raising the issue of sexual health. Women look for empathy, warmth, confidentiality, and professional competence in discussions with their doctor about sexual matters; and they are open to referrals for treatment of sexual problems and physician-sponsored sex education programs.

Sodium aurothiomalate toxicity and sulphoxidation capacity in rheumatoid arthritic patients.

The association between sulphoxidation capacity and sodium aurothiomalate toxicity was investigated in 65 patients undergoing treatment for rheumatoid arthritis. Of those showing side-effects, 30/37 (81%) were also poor sulphoxidizers compared with only 9/28 (32%) in the group not displaying adverse reactions. A patient with poor sulphoxidation had a nine-fold greater risk of developing toxicity. The prior measurement of sulphoxidation capacity may help to identify those patients most susceptible to the deleterious effects of this drug.

Vitamin D metabolites in synovial fluid.

This study has shown that it is possible to measure vitamin D metabolites and vitamin D binding protein (DBP) in synovial fluid as well as serum. Significant amounts of 25-OHD, 24,25-(OH)2D, and DBP are present in synovial fluid. The 25-OHD and DBP maintain a serum:synovial fluid ratio of approximately 2:1 irrespective of the type of joint disease, whereas no such relationship was detected for 24,25-(OH)2D. The possible reasons for these findings are diffusion of the metabolites into synovial fluid or local production from suitable precursors, or both.