The relationship between defects in lymphocyte production of transforming growth factor-beta1 in systemic lupus erythematosus and disease activity or severity.

Transforming growth factor beta (TGF-beta) comprises of a family of proteins with pleiotropic signaling properties and potent immunoregulatory effects. In SLE we recently reported that lymphocyte production of the total and active forms of TGF-beta1 was decreased. Here we asked whether these defects correlate with disease activity and/or severity. TGF-beta1 production by blood lymphocytes from 17 prospectively studied SLE patients was compared with 10 rheumatoid arthritis (RA) patients and 23 matched healthy controls. The RA levels of active TGF-beta1 were lower than controls, but were not deceased to the extent found in SLE. Levels of constitutive and anti-CD2 stimulated active TGF-beta1 detected in picomolar amounts were markedly reduced in six untreated patients hospitalized with recent onset, very active and severe SLE and similarly reduced in 11 patients with treated, less active disease. By contrast, decreased production of total TGF-beta1 inversely correlated with disease activity. These studies suggest, therefore, that although impaired lymphocyte secretion of the latent precursor of TGF-beta1 may result as a consequence of disease activity, a decreased capacity to convert the precursor molecule to its active form may pre-date disease onset. Insufficient exposure of T cells to picomolar concentrations of TGF-beta1 at the time they are activated can result in impaired down-regulation of Ig synthesis. Therefore, decreased lymphocyte production of active TGF-beta1 in SLE could be an immunologic defect which contributes to the B cell hyperactivity characteristic of this disease.

Synergistic effect between IL-10 and bcl-2 genotypes in determining susceptibility to systemic lupus erythematosus.

OBJECTIVE: To determine whether genes participating in programmed cell death, including bcl-2, IL-10, Fas-L, and CTLA-4, may contribute to the genetic predisposition to systemic lupus erythematosus (SLE). METHODS: First, intragenic markers for the bcl-2, IL-10, Fas-L, and CTLA-4 genes were characterized and their extent of polymorphism in normal populations was determined. The allelic distribution of these gene markers in a large Mexican American SLE cohort of 158 patients and 223 ethnically matched controls was determined using fluorescent-labeled primers and semiautomated genotyping. RESULTS: The bcl-2, Fas-L, and IL-10 loci showed significantly different allelic distribution in SLE patients compared with controls, indicating an association between these genes and SLE. No association was found between SLE and the CTLA-4 gene. Further analysis revealed a synergistic effect between susceptibility alleles of the bcl-2 and IL-10 genes in determining disease susceptibility. Alone, the presence of each of these alleles was associated with a moderate increase in SLE risk, while the occurrence of these alleles together increased the odds of developing SLE by more than 40-fold. CONCLUSION: The results suggest that individuals carrying specific genotypes of both bcl-2 and IL-10 are at significant risk of developing SLE.

Decreased production of TGF-beta by lymphocytes from patients with systemic lupus erythematosus.

TGF-beta has marked inhibitory effects on the immune system but also serves as a costimulatory factor in the development of T cells with down-regulatory activities. This cytokine is secreted as a latent complex and converted extracellularly to its active form. We have recently learned that anti-CD2 is a potent inducer of lymphocyte-derived TGF-beta and that NK cells are the predominant source. The objective of this study was to compare levels of constitutive, anti-CD2-induced and cytokine-regulated TGF-beta produced by blood lymphocytes from patients with systemic lupus erythematosus (SLE) in comparison with healthy controls. Using a highly sensitive and specific bioassay to assess TGF-beta, we report that unstimulated PBL from SLE patients, especially the NK cell subset, produced decreased levels of active TGF-beta. In response to anti-CD2, concentrations of active and total TGF-beta were also decreased in SLE. After learning that IL-2 and TNF-alpha enhance lymphocyte production of active TGF-beta, we found that the addition of these cytokines was unable to increase active TGF-beta to normal concentrations. Although we observed that IL-10 inhibited the production of active TGF-beta, antagonism of this cytokine was unable to completely correct the defect. In two SLE patients with B cell hyperactivity, spontaneous IgG production was almost abolished by the combination of TGF-beta and IL-2. Therefore, decreased production of each of these cytokines in SLE could be important in the perpetuation of B cell hyperactivity.

Decreased T cell response to anti-CD2 in systemic lupus erythematosus and reversal by anti-CD28: evidence for impaired T cell-accessory cell interaction.

OBJECTIVE: To assess the ability of T cells from patients with systemic lupus erythematosus (SLE) to respond to a mitogenic combination of anti-CD2 monoclonal antibodies (MAb), and to learn the molecular basis of the documented defect. METHODS: Peripheral blood mononuclear cell (PBMC) populations from individuals with SLE and paired controls were stimulated in vitro with anti-CD2, and the proliferative response was compared with that evoked by stimulation with phytohemagglutinin (PHA) and anti-CD3. Surface markers on lymphocyte populations were assessed by flow cytometry after staining with specific MAb. RESULTS: The proliferative response to anti-CD2 was decreased to a greater extent than was the response to anti-CD3 or PHA in SLE patients. This defect was found in approximately one-half of the patients examined, was not associated with disease activity, and was maintained upon repeated testing. Since either monocytes or resting B cells can serve as accessory cells for T cells following activation by anti-CD2, we examined the T cell response after depletion of adherent cells. In approximately two-thirds of the individuals with a decreased response, depletion of monocytes or substitution of monocytes with allogeneic, resting B cells from normal donors corrected the defect. The addition to PBMC of anti-CD28, but not of a neutralizing antibody to interleukin-10, largely reversed the anti-CD2 proliferative defect. Significantly fewer CD8+ T cells expressed CD28 in SLE, and this defect was also documented, to a lesser extent, in CD4+ cells. CONCLUSION: This study provides evidence that some functional T cell defects in SLE may be due, at least in part, to decreased CD28-mediated costimulatory activity following the interaction of T cells with conventional accessory cells.

Infectious arthritis: tailoring initial treatment to clinical findings.

Infectious arthritis causes substantial morbidity and mortality. In patients with monoarticular involvement, careful history taking and attention to the clinical presentation aid in timely diagnosis. Certain factors (eg, patient age, structural changes in the joint, presence of chronic disease) provide clues to the likely infectious agent. Antibiotic treatment should be instituted immediately after culture specimens are obtained, and the choice of agent can be modified when antibiotic sensitivities are known. Surgical intervention may be necessary if medical therapy fails. An aggressive approach to evaluation and treatment is warranted when polyarticular infection is suspected.

Polyarteritis nodosa-like vasculitis in human immunodeficiency virus infection.

Human immunodeficiency virus (HIV) infection can present with musculoskeletal syndromes including systemic vasculitis. We describe vasculitis resembling polyarteritis nodosa (PAN) in 2 HIV-infected individuals and review reported cases to emphasize clinical features. Our patients presented with digital gangrene and had vasculitis confirmed by angiography. In reports in the literature, patients have presented with digital ischemia and gangrene, peripheral neuropathy and constitutional symptoms. The diagnosis has been confirmed by angiography and by nerve and muscle biopsy. Treatment with systemic corticosteroids has afforded short term benefits to patients; however the effectiveness of alternative therapy and longterm prognosis remain unclear.

Magnetic resonance imaging of the brain in neuropsychiatric systemic lupus erythematosus.

To determine the utility of magnetic resonance imaging (MRI) of the brain in diagnosing active neuropsychiatric disease in systemic lupus erythematosus (NP-SLE), a prospective study of 51 hospitalized systemic lupus erythematosus (SLE) patients during 64 separate episodes of suspected NP-SLE was initiated. In addition to standard hematology, chemistry, and serological tests, the workup included MRI in all patients. A computed tomographic scan of the brain was obtained in patients enrolled in the first year of the study. Of the 64 neuropsychiatric episodes, 42 were attributable to NP-SLE and 22 were attributed to causes other than SLE. Neuropsychiatric complaints unrelated to lupus included depression (n = 6), seizures (n = 5), headache (n = 3), altered mental status (n = 2), aseptic meningitis (n = 2), cardiovascular accident (n = 2), transient ischemic attack (n = 1), and vertigo (n = 1). The MRI was abnormal in 34 of 64 (53%) episodes. MRI abnormalities were more common in patients with focal neurological deficits (19/26) than in those without focal findings (15/38; P = .008) and in patients with nephritis (19/24) than in those without renal disease (15/40; P = .002). MRI abnormalities were as frequent in NP-SLE (25/42) as in cases with non-NP-SLE-related causes (9/22). Periventricular increased signal (PIS) was a frequent MRI finding (10/64). Enlargement of the prepontine cistern, an MRI finding not previously described in NP-SLE, was seen (14/64). Both findings were associated with the presence of hypertension and lupus nephritis. PIS similar to that seen in our patients has been described in otherwise healthy elderly individuals with risk factors for stroke, suggesting that vascular abnormalities may be important in the etiology of these lesions. In conclusion, abnormalities in brain MRI occur frequently in NP-SLE, especially in patients with focal neurological deficits. However, the presence of similar MRI abnormalities in SLE patients with neuropsychiatric symptoms and findings with non-SLE-related causes limits the specificity of the MRI for diagnosing NP-SLE.

Trimethoprim-sulfamethoxasole induced meningitis in systemic lupus erythematosus.

Most reports of drug induced meningitis in systemic lupus erythematosus (SLE) have implicated ibuprofen. We describe a 46-year-old woman with SLE who developed aseptic meningitis abruptly after ingesting trimethoprim-sulfamethoxasole (TMP-SMX). This patient had received TMP-SMX twice before; each was associated with increasingly severe reactions, whose relationship with the use of TMP-SMX became apparent only in retrospect. A history of medication use should be sought in all patients with meningitis who have an underlying autoimmune disorder.

Anticardiolipin antibodies in acquired immunodeficiency syndrome.

We undertook a prospective study of IgG and IgM anticardiolipin antibodies (ACAs) to determine their clinical significance in patients with acquired immunodeficiency syndrome (AIDS). IgG ACAs were found in 24 (92.3%) of 26 patients with AIDS who were hospitalized for pulmonary complaints (group 1) and in 13 (93%) of 14 patients with AIDS-related complex (group 2). In addition, 17 (94%) of 18 patients with AIDS (group 3) who had coagulation tests and were studied retrospectively had IgG ACAs. The prevalence of IgG ACAs in these three groups was significantly higher than in healthy controls, but was comparable to that in 31 consecutive patients with systemic lupus erythematosus (67.7%). The mean titer of IgG ACAs in group 1 was higher than in groups 2 and 3 but was not different from that in the patients with systemic lupus erythematosus. The frequency and titer of IgM ACAs in group 1 (7.6%) or group 2 (14.3%) were not significantly different from those in normal controls (4.7%). In contrast, half of the patients in group 3 had low-titer IgM ACAs. The serum titer of IgG ACAs in patients with AIDS with thrombocytopenia was significantly higher than it was in those with normal platelet counts. There was no association between ACAs and Pneumocystis carinii pneumonia or other infections, cancer, thrombosis, positive VDRL test, or presence of the lupus anticoagulant. The prevalence and titer of IgG or IgM ACAs were not associated with abnormal results of any coagulation test. Although we found IgG ACAs to be associated with thrombocytopenia in AIDS, their presence does not carry exactly the same clinical significance as it does in systemic lupus erythematosus. The high prevalence of ACAs in AIDS, in AIDS-related complex, and in otherwise healthy contacts with antibodies to human immunodeficiency virus suggests that their occurrence may be related to the underlying human immunodeficiency virus infection.