Search

The patient's perspective of how their health affects their function is health-related quality of life (HRQOL). HRQOL is poorer in patients with systemic lupus erythematosus (SLE). Few HRQOL studies in SLE patients have focused on African Americans despite an increased disease burden compared with Caucasians. The African American Gullah population of South Carolina has a homogeneous genetic and environmental background and a high prevalence of multi-patient families with SLE. Demographics, medical history, and Short-Form 36 (SF-36) were measured within a cohort of Gullah SLE cases and related controls. Compared with related controls (n = 37), cases (n = 89) had a lower Physical Component Summary (PCS, 41.8 vs. 52.3, p < 0.01), but not Mental Component Summary (MCS, 55.0 vs. 56.0, p = 0.70). The difference in PCS was no longer significant upon adjustment for working status, disability, and medical conditions. None of the 11 SLE American College of Rheumatology criteria, disease duration, or Systemic Lupus International Collaborating Clinics Damage Index were associated with either PCS or MCS. Cases and controls had similar MCS scores. We hypothesize that this lack of effect of SLE on MCS may be due to disease-coping mechanisms interplaying with cultural factors unique to the Gullah.

Several studies have demonstrated the effectiveness of arginine analog nitric oxide synthase (NOS) inhibitor therapy in preventing and treating murine lupus nephritis. However, MRL/MpJ-FAS (MRL/lpr) mice lacking a functional NOS2 (inducible NOS [iNOS]) gene (NOS2) develop proliferative glomerulonephritis in a fashion similar to their wild-type (wt) littermates. This finding suggests that the effect of arginine analog NOS inhibitors is through a non-iNOS-mediated mechanism. This study was designed to address this hypothesis.NOS2 mice were given either vehicle or a NOS inhibitor (SD-3651) to determine if pharmacological NOS inhibition prevented glomerulonephritis, using wt mice as positive controls. Urine was collected fortnightly to measure albumin. At the time of full disease expression in wt mice, all mice were killed, and renal tissue was examined for light, immunofluorescence, and electron microscopic evidence of disease. Serum was analyzed for anti-double-stranded DNA antibody production.NOS2 mice had higher serum anti-double-stranded DNA antibody antibody levels than those of wt mice. SD-3651 therapy reduced proteinuria, glomerular immunoglobulin G deposition, and electron microscopic evidence of podocytopathy and endothelial cell swelling without affecting proliferative lesions by light microscopy.These studies confirm that genetic iNOS deficiency alone is insufficient to prevent proliferative glomerulonephritis and suggest that iNOS activity may inhibit autoantibody production. These results also suggest that SD-3651 therapy acts via a non-iNOS-mediated mechanism to prevent endothelial cell and podocyte pathology. Studies that elucidate this mechanism could provide a useful drug target for the treatment of nephritis.

Cytotoxic lymphocyte antigen-4 (CTLA-4) plays an important role in regulating T cell activation, and may help to limit T cell response under conditions of inflammation. Genetic variability in CTLA-4 has been implicated in the development of several autoimmune diseases. Some studies have described associations between CTLA-4 polymorphisms and systemic lupus erythematosus (SLE), but findings have been inconsistent. We examined polymorphisms in the CTLA-4 gene promoter region (-1722T/C, -1661 A/G, -318C/T) and exon I (+49G/A) with respect to SLE in a population-based case-control study in the southeastern US. Genotypes from 230 recently diagnosed cases and 276 controls were examined separately for African-Americans and whites. We observed no overall associations between SLE and the four CTLA-4 polymorphisms examined. Subgroup analyses revealed effect modification by age for the presence of the -1661G allele, yielding a significant positive association with SLE in younger (<35 years) African-Americans (OR = 3.3). CTLA-4 genotypes also interacted with HLA-DR2 and GM allotype to contribute to risk of SLE. These findings suggest allelic variation in this region of CTLA4 is not a major independent risk factor for SLE, but may contribute to risk of disease in younger African-Americans or in the presence of certain immunogenetic markers.

Background: MRL/MpJ-Tnfrsf6lpr(MRL/lpr) mice, a murine model of systemic lupus erythematosus (SLE), have defective expression of Fas, substantially reducing signaling for apoptosis via this mechanism. However, it is known that MRL/lpr mice have increased spontaneous apoptosis of leukocytes. These conflicting observations have stimulated interest in apoptosis in this SLE model. MRL/lpr mice overproduce nitric oxide (NO) as autoimmune disease progresses. In vitro administration of NO may induce or decrease apoptosis depending on the cell type. Therefore, we hypothesized that NO induces MRL/lpr spleen lymphocyte apoptosis independent of Fas receptor engagement., Methods: Percentages of apoptotic spleen lymphocytes from MRL/lpr and BALB/cJ mice were determined ex vivo after in vivo treatment with NG-monomethyl-L-arginine (NMMA), a nitric oxide synthase (NOS) inhibitor. After culture in varying concentrations of a slow-acting NO donor, the following were determined in spleen lymphocytes: (1) levels of apoptosis, (2) the effect of phorbol myristate acid (PMA) on levels of NO-induced apoptosis, and (3) protein kinase C (PKC) activity., Results: Spleen lymphocytes from MRL/lpr mice with active disease had increased levels of ex vivo apoptosis when compared with BALB/cJ controls. This increase was reduced by pharmacologic inhibition of NOS in MRL/lpr but not in BALB/cJ mice. Exogenous administration of NO in vitro reduced PKC activity and induced apoptosis in MRL/lpr spleen lymphocytes, an effect that could be reduced via coadministration of PMA in vitro., Conclusion: These results suggest that NO plays a role in spleen lymphocyte apoptosis in MRL/lpr mice, possibly via inhibition of PKC, despite a Fas defect.

We examined the prevalence of clinical and immunologic features of systemic lupus erythematosus (SLE) by race, sex and age in a population-based study of 265 SLE patients. Patients fulfilled the American College of Rheumatology classification criteria. The median time between diagnosis and study enrollment was 13 months. The clinical and hematologic data were limited to occurrences up to 6 months after the diagnosis date, as documented in medical records. We used sera collected at study enrollment from 244 (92%) patients for serologic testing of autoantibodies. The associations between clinical and immunological features of SLE and age, sex and race were examined using logistic regression. The effect of each of these variables was examined adjusting for the other two demographic factors. Mean age at diagnosis was 6 years younger among African-Americans and other minorities compared with white patients (P < 0.01). Discoid lupus, proteinuria, anti-Sm and anti-RNP autoantibodies were more commonly seen in African-American patients, with odds ratios higher than 3.0. Photosensitivity and mucosal ulcers were noted less often in African-American patients. Proteinuria, leukopenia, lymphopenia and thrombocytopenia were approximately three times more common in men compared with women. The prevalence of oral or nasal ulcers and anti-DNA autoantibodies declined with age. The extent to which the differences we observed reflect genetic or environmental influences on the disease process should be investigated.

Immunization of normal mice with bacterial DNA elicits a significant IgG anti-DNA response and has been explored as a model of systemic lupus erythematosus. To determine whether this induced response is influenced by sex, we have measured anti-DNA levels in normal male and female BALB/c mice immunized with single stranded DNA from E. coli as complexes with methylated bovine serum albumin (mBSA) in adjuvant. By ELISA assays, anti-DNA levels of immunized females were approximately 16-fold higher than those of immunized males; levels of antibodies to the mBSA carrier were similar, however. The antibodies from females and males showed a similar degree of cross-reactivity when assayed using other natural and synthetic DNA antigens, including mammalian DNA. These findings suggest the potentiation of anti-DNA production in females by antigen-specific mechanisms and provide further evidence that immunization with bacterial DNA replicates features of autoantibody production in SLE.