Interleukin-13 in autoimmune rheumatic diseases: relationship with the autoantibody profile

OBJECTIVE: Several cytokines play a role in the production of autoantibodies such as RF and ANA by B-lymphocytes; the role of IL-13 in this process has not been previously studied. We investigated the relationship between the serum concentration of this cytokine and circulating autoantibodies. METHODS: IL-13 serum levels, as well as RF and ANA, were evaluated in 282 patients with autoimmune rheumatic diseases including RA (n=84), SLE (n= 114), SS (n=52) and Scl (n=32). RESULTS: Serum levels of IL-13 (pg/ml) were significantly higher in patients with RA (p < 0.00003), SLE (p < 0.03), SS (p < 0.0007), or Scl (p < 0.025) compared to controls. IL-13 serum levels correlated with those of RF in RA (p < 0.00001), SLE (p < 0.003) and Scl (p < 0.03). IL-13 levels were higher in RA (p<0.0003), SLE (p<0.005) and Scl (p<0.05) patients with RF than in patients without RF. SS patients with antiSSA/Ro antibodies had significantly higher IL-13 levels than SS patients without this autoantibody (p < 0.04). No statistically significant correlation was found between IL-13 levels and any other antinuclear autoantibody, total immunoglobulin levels or the main clinicalfeatures of each disease. CONCLUSION: The evidence of higher IL-13 levels in our RA, SLE, SS and Scl patients confirms that this cytokine is involved in the pathogenesis of autoimmune rheumatic diseases. The relationship of this cytokine with RF in RA, SLE and Scl, as well as with antiSSA/ Ro antibody in SS, strengthens the hypothesis that it plays a role in autoantibody production. However, the different autoantibody synthesis by B-cells recognises different pathways depending on the underlying autoimmune disease.     

Predictive and prognostic value of antinuclear antibodies and rheumatoid factor in primary Sjogren’s syndrome

Aims: To assess the predictive and prognostic value of antinuclear antibodies (ANA) and rheumatoid factor (RF) in primary Sjögren’s syndrome (pSS). Methods: This retrospective study includes 201 patients that fulfilled the 1993 European preliminary classification criteria for pSS. The patients were further categorized by the 2002 revised criteria, with or without the inclusion of ANA and RF as classification criteria, and were further subgrouped by the presence of ANA, RF, anti‐SS‐A, and anti‐SS‐B, and different ANA titers. The clinical manifestations, serological markers, and results of lip biopsies among these subgroups were compared. Results: Our results showed pSS patients who are seropositive for one of the following markers: ANA, RF, anti‐SS‐A, or anti‐SS‐B are younger, predominantly female, and had more serological abnormalities than those with seronegativity of ANA, RF, anti‐SS‐A, or anti‐SS‐B. Higher ANA titers (≥ 1 : 640) correlated with higher frequency of serum anti‐SS‐A+ and anti‐SS‐B+, and elevations of serum immunoglobulin G and A in all three different classification criteria groups. The clinical manifestations and laboratory results in the 2002 revised criteria groups with or without the inclusion of ANA and RF as classification criteria items were highly concordant. Conclusion: Regardless of the classification criteria for pSS, patients who are seropositive for one of the ANA, RF, anti‐SS‐A and anti‐SS‐B biomarkers are more likely to have autoimmune‐related Sjögren’s syndrome. ANA and RF have shown to possess the predictive and prognostic values for those who do not fulfill the higher stringent 2002 revised criteria but are indicated for immunomodulatory therapy. Thus we suggest that ANA and RF should be reconsidered as items of classification criteria for pSS.     

Placental abnormalities in systemic lupus erythematosus: in situ deposition of antinuclear antibodies

We studied 5 placentae from patients with systemic lupus erythematosus (SLE) for the presence of immunopathologic changes. We found antinuclear antibodies (ANA) deposited along the villi, trophoblast and amnion producing a lupus band-like pattern. The ANA were IgG class and had C3 fixing activity. Of the T cell subsets found in the placenta, OKT8 was the predominant type in patients with SLE and controls. All the patients were ANA positive, and 1 was also positive for anti-Ro(SSA). One newborn, positive for ANA and anti-Ro(SSA), developed neonatal lupus, 1 infant with a cardiac septal defect was ANA negative, and the other infants were normal. Our study demonstrates that in pregnant women with SLE, ANA deposition occurs in the placenta in situ.     

Pathogenesis of Sj?gren's syndrome.

Sj?gren's syndrome is a systemic autoimmune disease characterized by lymphocytic infiltrations of lacrimal and salivary glands. SS patients produce a variety of autoantibodies, including RF and ANA. Genetic factors, including HLA-DR3, predispose to primary SS. In contrast to normal SGs, the SS SG epithelial cells express high levels of HLA-DR antigens. This class II gene expression on the target organ may represent the structural basis for HLA-associated disease susceptibility. The glands are infiltrated with CD4+ T cells that can produce cytokines, including IL-2 and interferon-gamma. B cells within the SG produce autoantibodies, including RF. These SG B cells frequently use the VKIIIb subgroup of kappa light chain, a feature that SS patients share with Waldenstrom's macroglobulinemia patients. B cells undergo small clonal expansions that can be detected on Southern blot as immunoglobulin gene rearrangements, and SS patients have a markedly increased risk of developing non-Hodgkin's B-cell lymphoma involving the SGs and cervical lymph nodes. Due to accessibility of the SG for biopsy and the characteristic patterns of autoantibody production, SS provides an opportunity to study the target organ for autoimmune destruction and the transition from autoimmunity to lymphoma.     

Elevated IL-16 levels in patients with systemic lupus erythematosus are associated with disease severity but not with genetic susceptibility to lupus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by several immunological abnormalities. The pathogenic importance of T cells in this disease is well established. Interleukin-16 (IL-16) is a cytokine which is mainly produced by CD8+ T cells and induces chemotaxis of CD4+ T cells and monocytes. IL-16 levels have been shown to be elevated in SLE patients in a cross-sectional study, but the mechanism is unknown. To explore whether the increased IL-16 levels are associated with genetic background or the disease itself, we investigated the IL-16 level in healthy first-degree family members of SLE patients and SLE patients who were followed over time with regard to disease activity. We observed high IL-16 levels in SLE patients with severe disease compared to SLE patients with non-severe disease and healthy controls. Furthermore, IL-16 levels in first-degree relatives were not different from those in healthy controls. These results suggest that high IL-16 levels are associated with severity of SLE, but not with genetic susceptibility to SLE. Finally, we followed the disease activity of SLE patients over time, which showed significant correlation between the SLE disease activity index and IL-16, ESR and the complement components C3, C4 and CH50. In conclusion, these results implicate an association of IL-16 with SLE.     

Anti-tubulin-α-1C autoantibody in systemic lupus erythematosus: a novel indicator of disease activity and vasculitis manifestations

A variety of autoantibodies has been involved in the pathogenesis of systemic lupus erythematosus (SLE), some of which are well known and applied as disease biomarkers. This study aimed to determine the prevalence of a novel autoantibody, anti-tubulin-α-1C, in patients with SLE and investigate its clinical significance. Anti-tubulin-α-1C autoantibody levels were determined by enzyme-linked immunosorbent assay (ELISA) in 128 SLE patients, 38 primary Sjögren’s syndrome (pSS) patients, and 106 healthy controls (HCs).White blood cell (WBC) count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), IgM, IgG, C3, C4, RF, ANA, dsDNA, Sm, AnuA, aCL, anti-SSA, and anti-SSB were measured by standard laboratory techniques. SLE Disease Activity Index (SLEDAI) was evaluated accordingly. Anti-tubulin-α-1C antibody levels were significantly increased in SLE patients. Elevated anti-tubulin-α-1C were correlated with higher levels of SLEDAI, increased titers of anti-Sm antibody, and decreased titers of anti-dsDNA antibody and significantly associated with cutaneous and mucosal vasculitis and milder renal involvement. Anti-tubulin-α-1C may become a novel biomarker indicative of active vasculitis in SLE and could be applied in future clinical practice.     

Alpha-fodrin autoantibodies are reliable diagnostic markers for juvenile and adult Sjogren's syndrome

Sjogren's syndrome (SS) is like other systemic autoimmune diseases, characterized by a large number of autoantigens and autoantibodies and infiltration of glandular tissue by predominantly CD4 T lymphocytes. The presence of certain autoantibodies is required for the diagnosis to be made, especially Anti-Ro/SSA and anti-La/SSB. The aim of this study is to investigate the prevalence of anti-alpha fodrin and its association with anti-Ro and anti-La in juvenile and adult SS. Thirteen cases with juvenile SS and 11 old SS patients were examined. Selection and classification of the patients was based on the revised European Community Criteria. The Juvenile SS group included 10 girls and 3 boys, their age ranged from 7 to 14 years. Adult SS group included 2 males and 9 female, their age ranged from 21 to 54 years. Blood samples were subjected to Erythrocyte sedimentation rate (ESR) mm/1 degree h, Complete blood count (CBC), Latex agglutination test for estimating rheumatoid factor (RF) and antinuclear antibodies (ANA), and assessment of Anti-alpha Fodrin IgG/IgA, anti-Ro and anti-La using ELISA. The two groups were matched for sex ratio. There was a significant difference of age (10.1 +/- 2.4 vs 35.1 +/- 9.3 yr) between both groups (P < 0.05). There was no statistically significant difference of levels of ESR, ANA and anti-Ro, anti-La and anti-alpha fodrin IgG/IgA autoantibodies concentration in the sera of SS patients in both groups (P > 0.05) although their levels were elevated. The percentage of detection of anti-Ro, anti- La and anti-alpha fodrin IgG and IgA antibodies in the sera of Juvenile SS was 61.5%, 53.8%, 53.8% and 61.5% respectively, while in adult SS was 63.6%, 45.5%, 45.5% and 81.8%, respectively. Anti alpha fodrin IgA and IgG were positively detected in SS patients who had negative anti-Ro and/or anti-La. The anti-alpha fodrin IgG and IgA antibodies did not significantly correlated with antibodies against Ro and La, ESR and ANA (r < 0.25, P > 0.05). The detection of anti-alpha fodrin antibodies may prove to be a useful sensitive marker for SS. Routine screening of alpha fodrin antibodies is a valuable tool for the diagnosis of SS.     

Spontaneous and anti-Fas antibody-mediated apoptosis of the peripheral blood lymphocytes in Sjögren’s syndrome, rheumatoid arthritis and systemic lupus erythematosus

The objective of this study was to clarify possible roles of lymphocyte apoptosis in autoimmune rheumatic diseases. Spontaneous and anti-Fas antibody-mediated apoptosis of peripheral blood (PB) lymphocytes were measured by a flow cytometric method using propidium iodide in primary Sjögren’s syndrome (SS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Spontaneous apoptosis levels were significantly higher in 26 SLE patients than in 19 healthy controls. The apoptosis levels were not significantly different between 19 primary SS patients or 28 RA patients and the controls, but high apoptosis levels were observed in some of the patients. The apoptosis of PB lymphocytes was also enhanced in seven SS patients with RA and 16 SS patients with SLE. Anti-Fas antibody could induce apoptosis of PB lymphocytes from both healthy controls and patients’ groups. The antibody-mediated apoptosis levels were higher in RA, SLE and secondary SS patients with RA or SLE, but not in primary SS patients. Each patients’ group was further divided into two groups according to their mean apoptosis levels: patients with high and those with low spontaneous or antibody-mediated apoptosis levels. Clinical variables reflecting disease activity for each disease were then compared between the two groups. Serum rheumatoid factor (RF) and anti-SS-A/Ro antibody titers were higher in the RA or primary SS patients with high spontaneous apoptosis levels than those with low apoptosis levels, respectively. When all the patients’ groups were evaluated together, the spontaneous apoptosis levels negatively correlated with PB lymphocyte counts. In addition, the spontaneous apoptosis levels were decreased by the co-culture of PB lymphocytes with interleukin-2 (IL-2: 100 U/ml) in most individuals including patients and healthy controls. We conclude that spontaneous apoptosis of PB lymphocytes was enhanced in SLE and secondary SS patients. Production of RF or anti-SS-A/Ro antibodies was associated with enhanced apoptosis of PB lymphocytes in RA or primary SS patients. The apoptosis levels were related with lymphocytopenia observed in the patients examined, although various factors including IL-2 seemed to be protective against the apoptosis of circulating lymphocytes. Furthermore, anti-Fas antibody induced apoptosis of PB lymphocytes from the healthy controls and patients, and the antibody-mediated apoptosis levels were high in RA, SLE and secondary SS patients.     

Spontaneous and anti-Fas antibody-mediated apoptosis of the peripheral blood lymphocytes in Sjögren’s syndrome,rheumatoid arthritis and systemic lupus erythematosus

Abstract

The objective of this study was to clarify possible roles of lymphocyte apoptosis in autoimmune rheumatic diseases. Spontaneous and anti-Fas antibody-mediated apoptosis of peripheral blood (PB) lymphocytes were measured by a flow cytometric method using propidium iodide in primary Sjögren’s syndrome (SS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Spontaneous apoptosis levels were significantly higher in 26 SLE patients than in 19 healthy controls. The apoptosis levels were not significantly different between 19 primary SS patients or 28 RA patients and the controls, but high apoptosis levels were observed in some of the patients. The apoptosis of PB lymphocytes was also enhanced in seven SS patients with RA and 16 SS patients with SLE. Anti-Fas antibody could induce apoptosis of PB lymphocytes from both healthy controls and patients’ groups. The antibody-mediated apoptosis levels were higher in RA, SLE and secondary SS patients with RA or SLE, but not in primary SS patients. Each patients’ group was further divided into two groups according to their mean apoptosis levels: patients with high and those with low spontaneous or antibody-mediated apoptosis levels. Clinical variables reflecting disease activity for each disease were then compared between the two groups. Serum rheumatoid factor (RF) and anti-SS-A/Ro antibody titers were higher in the RA or primary SS patients with high spontaneous apoptosis levels than those with low apoptosis levels, respectively. When all the patients’ groups were evaluated together, the spontaneous apoptosis levels negatively correlated with PB lymphocyte counts. In addition, the spontaneous apoptosis levels were decreased by the co-culture of PB lymphocytes with interleukin-2 (IL-2: 100 U/ml) in most individuals including patients and healthy controls. We conclude that spontaneous apoptosis of PB lymphocytes was enhanced in SLE and secondary SS patients. Production of RF or anti-SS-A/Ro antibodies was associated with enhanced apoptosis of PB lymphocytes in RA or primary SS patients. The apoptosis levels were related with lymphocytopenia observed in the patients examined, although various factors including IL-2 seemed to be protective against the apoptosis of circulating lymphocytes. Furthermore, anti-Fas antibody induced apoptosis of PB lymphocytes from the healthy controls and patients, and the antibody-mediated apoptosis levels were high in RA, SLE and secondary SS patients.     

The diagnostic associations of patients with antinuclear antibodies referred to a community rheumatologist

The referral of patients with positive antinuclear antibodies (ANA) to a rheumatologist for evaluation occurs commonly in clinical practice. We report our experience in a large community setting. Two hundred seventy-six patients (8.8% of total referrals) had ANA titers greater than or equal to 1:40 without a diagnosis. A specific diagnosis was made in 239 patients (86.6%) and no diagnosis in 37 (13.4%). Of those diagnosed, 142 (51.4%) had connective tissue diseases, 44 (15.9%) had organ-specific autoimmune diseases, 23 (8.3%) had infectious diseases, 8 (2.9%) had neoplasia and 30 (10.9%) had miscellaneous other diseases. The commonest were systemic lupus erythematosus (SLE) in 52 (18.8%) and autoimmune thyroid disease in 29 (10.5%). Undiagnosed autoimmune thyroid disease and SLE are common diagnostic associations of positive ANA in patients referred to a community rheumatologist and positive ANA are frequently associated with clinical disease.     

Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome

OBJECTIVE: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that predominantly affects women. Despite isolated reports of patients with coexisting Klinefelter's syndrome (47,XXY) and SLE, no association of Klinefelter's syndrome with SLE or any other autoimmune disease has been established. The present study was undertaken to investigate the prevalence of Klinefelter's syndrome in a large population of patients with SLE. METHODS: Sex chromosome genotyping was performed in 981 SLE patients, of whom 213 were men. A first group of 844 SLE patients from 378 multiplex families and a second group of 137 men with nonfamilial SLE were evaluated. In selected cases, chromosomes were enumerated by fluorescence in situ hybridization (FISH) and karyotyping in transformed B cell lines. RESULTS: Of 213 men with SLE, 5 had Klinefelter's syndrome (1 in 43). Four of them were heterozygous at X markers, and Klinefelter's syndrome was confirmed by FISH and karyotyping in the fifth. An overall rate of 47,XXY of 235 per 10,000 male SLE patients was found (95% confidence interval 77-539), a dramatic increase over the known prevalence of Klinefelter's syndrome in an unselected population (17 per 10,000 live male births). Asking men with SLE about fertility was highly sensitive (100%) for Klinefelter's syndrome. All 768 women with SLE were heterozygous at X. CONCLUSION: The frequency of Klinefelter's syndrome (47,XXY), often subclinical, is increased in men with SLE by approximately 14-fold compared with its prevalence in men without SLE. Diagnostic vigilance for 47,XXY in male patients with SLE is warranted. These data are the first to show an association of Klinefelter's syndrome with an autoimmune disease found predominantly in women. The risk of SLE in men with Klinefelter's syndrome is predicted to be similar to the risk in normal women with 46,XX and approximately 14-fold higher than in men with 46,XY, consistent with the notion that SLE susceptibility is partly explained by an X chromosome gene-dose effect.     

Lymphocyte subpopulations in bronchoalveolar lavage in Sj?gren's syndrome. Evidence for an expansion of cytotoxic/suppressor subset in patients with alveolar neutrophilia

We initiated this study to determine the cellular composition and T-lymphocyte subpopulations of fluid from bronchoalveolar lavage from 15 patients with primary Sj?gren's syndrome (1SS), six patients with secondary Sj?gren's syndrome associated with primary biliary cirrhosis (2SS-PBC), eight patients with secondary Sj?gren's syndrome associated with collagen-vascular diseases (2SS-CVD), and 12 normal subjects. All were nonsmokers who were free of clinical pulmonary symptoms and had normal findings on chest roentgenograms. Lymphocyte subsets were identified by mouse monoclonal antibodies that were specific for T-cells, helper/inducer, and suppressor/cytotoxic (namely, OKT3, OKT4, and OKT8). Patients with 1SS, patients with 2SS-PBC, and patients with 2SS-CVD had a significantly increased percentage of lymphocytes in fluid from bronchoalveolar lavage (respectively, 21.6 +/- 3.7 percent, 24.3 +/- 6.1 percent, and 25.6 +/- 3.9 percent) compared with the normal value of control subjects (9.9 +/- 1.5 percent). In addition, two of the 15 patients with 1SS and five of the eight patients with 2SS-CVD demonstrated an increased percentage of alveolar neutrophils. The predominant T-cell subset in patients with 1SS was T4+, and the mean T4:T8 ratio was normal. The percentage of T4+ cells was increased in patients with 2 SS-PBC, resulting in an increased T4:T8 ratio. In contrast, patients with 2 SS-CVD demonstrated a markedly increased percentage of T8+ cells, reflected by a shift in the T4:T8 ratio which was inverted. Patients with Sj?gren's syndrome and with neutrophilia on bronchoalveolar lavage had a marked expansion of the T8+ lymphocyte subpopulation, where as patients with Sj?gren's syndrome and with pure lymphocytosis on bronchoalveolar lavage showed predominantly T4+ cells. In addition, we found a strong positive correlation between the number of neutrophils and the number of T8+ cells in bronchoalveolar lavage from patients with Sj?gren's syndrome (r = 0.74; p less than 0.05). Until the functional activities of OKT4+ and OKT8+ cells are better defined, the role that these cells play in the pathogenesis of pulmonary disease in Sj?gren's syndrome remains unclear.     

Evaluating the diagnostic and prognostic value of lone anti-Sm for autoimmune diseases using Euroimmun line immunoassays

To investigate the value of lone anti-Smith antibody (anti-Sm) using Euroimmun line immunoassay (LIA) in a Chinese population. One thousand two hundred eight of 39,766 patients who were analyzed for anti-Sm had positive anti-Sm, and were divided into true group (having both positive Sm and nRNP/Sm bands) and lone group (only having Sm band without nRNP/Sm band). The proportions of clinical diagnosis of autoimmune diseases (AIDs), non-autoimmune diseases (NAIDs), concentration of C3, C4, and rheumatoid factor (RF), positive rate of autoantibodies of antinuclear antibody (ANA) profile, and titer of anti-Sm and ANA in systemic lupus erythematosus (SLE) patients were analyzed. Lone anti-Sm was evident in 271/1208 (22.42%) of all positive cases. One hundred seventy-five of them had definitive diagnoses with AIDs being the most prominent (69.71%, 122/175). Compared to the true group, SLE patients in the lone group showed significantly lower ANA and anti-Sm titers (both P?<?0.001). There was no difference in frequency of other autoantibodies or C3, C4, and RF levels of SLE patients between the two groups. In NAIDs patients, lone anti-Sm indicates less incidence of kidney injury than true anti-Sm (P?=?0.05). Lone anti-Sm has great diagnostic value in AIDs, especially SLE. Lone anti-Sm has relationship with mild kidney impairment. Positive anti-Sm patients with no clinical findings or SLE diagnosis should be submitted to new testing to identify changes in anti-Sm, because turning of lone anti-Sm to true anti-Sm indicates evolving kidney injury.     

系统性红斑狼疮患者Bcl-2蛋白的表达及其临床意义

目的 探讨Ｂｃｌ－２蛋白在秕生红斑狼疮（ＳＬＥ）发病机制的作用及其临床意义。方法 以流式细胞仪双标记法和免疫组化方法分别检测３１列ＳＬＥ病人外周血Ｔ、Ｂ细胞和肾组织Ｂｃｌ－２ｘ蛋白表达。结果 活动期ＳＬＥ病人ＣＤ３＾＋、ＣＤ４＾＋和ＣＤ８＾＋Ｔ细胞Ｂｃｌ－２蛋白表达明显高于非活动期ＳＬＥ病人和正常对照组。ＣＤ１９＾＋Ｂ细胞Ｂｃｌ－２蛋白表达在各组之间并无统计学差异。ＣＤ３＾＋Ｔ细胞Ｂｃｌ－２蛋白表     

Dysfunction of T cell receptor AV24AJ18+, BV11+ double-negative regulatory natural killer T cells in autoimmune diseases

OBJECTIVE: We examined the reduction of T cell receptor (TCR) AV24+,BV11+ CD4-,CD8- (double-negative [DN]) natural killer T (NKT) cells in peripheral blood lymphocytes (PBLs) from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and Sjogren's syndrome (SS) to analyze why NKT cells are selectively reduced in autoimmune diseases, and to examine whether nonresponse to alpha-galactosylceramide (alpha-GalCer) is due to an abnormality in the antigen-presenting cells (APCs) or NKT cells. METHODS: Peripheral blood from patients with RA (n = 20), SLE (n = 18), SSc (n = 13), and SS (n = 17), as well as from healthy donors (n = 13) and patients with Beh?et's disease (BD; n = 20), was examined by flow cytometry to determine the number of TCR AV24+,BV11+ DN T cells. PBLs from 10 RA, 10 SLE, 8 SSc, and 9 SS patients, as well as from 7 healthy subjects, were cultured in vitro with alpha-GalCer, and the number of TCR AV24+,BV11+ DN NKT cells was estimated. APCs from responder and nonresponder patients were cocultured with NKT cells from responder and nonresponder patients. RESULTS: The mean +/- SEM number of TCR AV24+,BV11+ DN NKT cells per ml of whole blood was found to be 48.8+/-10.0 in RA patients, 50.6+/-12.9 in SLE patients, 80.8+/-30.6 in SSc patients, and 40.0+/-11.7 in SS patients, while 290.0+/-69.6 and 321.2+/-103.4 NKT cells were present in healthy subjects and BD patients, respectively (P < 0.01). Three of 10 RA patients, 5 of 10 SLE patients, 4 of 8 SSc patients, and 6 of 9 SS patients (a total of 18 of 37 patients, or 48.6%) responded to alpha-GalCer, indicating that patients could be divided into two groups: alpha-GalCer responders and nonresponders. In contrast, NKT cells from all healthy subjects proliferated against alpha-GalCer. APCs from all nonresponder patients were found to function as alpha-GalCer-presenting cells, while NKT cells from nonresponders did not expand even in the presence of APCs from normal responders. CONCLUSION: These findings strongly suggest that patients with autoimmune diseases can be divided into two groups (alpha-GalCer responders and nonresponders). They also suggest that the reduced numbers of NKT cells in patients with autoimmune diseases may be due to an inadequate amount of alpha-GalCer-like natural ligands (i.e., adequate in only 48.6% of patients) for the induction of NKT cells in vivo, or to a dysfunction in the NKT cells themselves (in 51.4% of patients).     

Abnormal adenosine-induced immunosuppression and cAMP metabolism in T lymphocytes of patients with systemic lupus erythematosus

Normal human T lymphocytes incubated with adenosine (10 muM) for 30 min at 37 degrees C show an increase in the percentage of cells expressing receptors for the Fc portion of IgG (RFc(gamma)) and the OKT8 antigen, while the proportion of OKT4(+) cells decreases. These effects occur exclusively in a subset of T cells with theophylline-resistant sheep erythrocyte receptors (T(R) cells) that is enriched for OKT4(+) cells. Untreated normal T(R) cells express helper/inducer cell activity for T-cell-dependent B-cell differentiation, while adenosine-treated T(R) cells suppress B-cell differentiation. In contrast, in T(R) cells isolated from patients with systemic lupus erythematosus (SLE), adenosine fails to induce immunosuppressor activity or to increase the percentage of OKT8(+) and RFc(gamma) (+) cells. In addition, although incubation of normal T(R) cells with adenosine causes a transient increase in cAMP levels (up to 160% of control within 5 min), in SLE T(R) cells, cAMP levels fall by 50% within 10 min. The photoaffinity label 8-azidoadenosine cyclic [(32)P]monophosphate has been used to show that human T lymphocytes have a single cAMP receptor site that appears to be the regulatory subunit of type I protein kinase. In normal T(R) cells, this receptor becomes occupied in response to adenosine. In contrast, in SLE T(R) cells, no change in cAMP receptor occupancy is detected. Although adenosine has a differential effect on normal and SLE T(R) cells, cAMP derivatives that can traverse the cell membrane (8-bromo- and 8-azidoadenosine cyclic monophosphates) induce an increase in the RFc(gamma) (+) cell subset in both normal and SLE T(R) cells. These results suggest that cAMP mediates the effects of adenosine on cell surface markers of T lymphocytes. The lack of an adenosine receptor-coupled adenylate cyclase activity in SLE T(R) cells may account, in part, for their lack of immunosuppressive activity.     

Mitral valve prolapse in autoimmune thyroid disease: an index of systemic autoimmunity?

A coexistence of mitral valve prolapse (MVP) with autoimmune thyroid disease (AITD) has been described, but there are not sufficient data to explain this association. The aim of the present study was to investigate the prevalence of MVP in patients with AITD and to evaluate whether any correlation between MVP and certain immunological parameters exists. M-mode, two-dimensional Doppler echocardiography was performed in 29 patients with Graves' disease (GD), 35 with Hashimoto's thyroiditis (HT), 20 with nonautoimmune goiter, and 30 normal controls. Serum samples were examined for antinuclear antibodies (ANA), antibodies against extractable nuclear antigen (ENA), antiphospholipid antibodies (aCL), rheumatoid factor (RF), thyroid autoantibodies (TAAb), immunoglobulins and C3, C4. Eight of 29 GD patients and 8 of 35 HT patients had MVP, while none of the control group and 2 of 20 of the simple goiter group had MVP (p < 0.05). ANA were detected at low titers in 5 of 8 in MVP(+) GD versus 3 of 21 in MVP(-) GD (p < 0.05). In the HT group the MVP(+) patients had a significantly higher incidence of ANA and ENA, 5 of 8 and 2 of 8 versus 5 of 27 and 0 of 27 of MVP(-) patients, respectively, p < 0.05. A statistically significant higher incidence of aCL was found in HT MVP(+) patients. (3/8) versus HT MVP(-) 1/27, p < 0.05. RF levels (immunoglobulin A [IgA]) were significantly higher in MVP(+) patients. The association of MVP with nonorgan-specific autoantibodies indicates that MVP may also be an autoimmune disease. It is possible that patients with AITD who also have MVP may be at an increased risk to develop systemic autoimmunity.     

High incidence of herpes zoster in patients with systemic lupus erythematosus: an immunological analysis.

The incidence of herpes zoster was determined in patients with systemic lupus erythematosus (SLE) and the cellular and humoral immunity to varicella zoster virus (VZV) investigated in 45 of these 92 patients. The incidence of herpes zoster was high, occurring in 40 patients (43%), though it was benign in all. Patients with SLE who had had zoster showed significantly higher antibody titres than normal subjects. On the other hand, only 13 of 43 (30%) patients with SLE showed positive delayed hypersensitivity skin reactions to VZV antigen, despite a history of infections with VZV, whereas all 15 normal subjects had positive reactions. Skin reactions to VZV correlated directly with the ratio of OKT4+ to OKT8+ T cells and inversely with the dose of corticosteroids. These results suggest that the high incidence of herpes zoster in patients with SLE is probably due to defects in cellular immunity and that normal or higher titres of antibodies to VZV will not act as a preventive against zoster. In addition, reactivation of VZV, whether symptomatic or not, seemed often to occur in patients with SLE.     

系统性红斑狼疮患者干扰素诱导基因的表达及其与疾病活动性的相关性研究

目的 探讨系统性红斑狼疮(SLE)患者外周血单个核细胞(PBMCs)中5个干扰素(IFN)诱导基因(IFIT1、IFIT4、OAS1、OASL、ISG15)的表达及其与SLE疾病活动度的相关性.方法 运用SYBRgreen dye I实时定量聚合酶链反应(RT-PCR)方法检测76例SLE患者与54名健康对照人的IFIT1、IFIT4、OASL、OASL及ISG15 mRNA表达水平(以-AACt值表示),并且与红细胞沉降率(ESR)、C反应蛋白(CRP)、补体C3、C4、抗核抗体(ANA)及抗dsDNA抗体等指标比较,分析IFIT1、IFIT4、OAS1、OASL、ISG15 mRNA表达水平以及上述常规检测指标与SLE疾病活动指数(SLEDAI)积分之间的相关性.结果 ①SLE组与正常对照组相比,IFIT1、IFIT4、OAS1、OASL及ISG15 mRNA表达显著增高(P＜0.01);SLE活动组与SLE缓解组比较,IFIT1、IFIT4、OAS1、OASL及ISG15 mRNA表达增高(P＜0.05);SLE组IFIT1、IFIT4、OAS1、OASL及ISG15 mRNA表达水平之间呈正相关(r＞0.5,P＜0.05).②SLE组IFIT1、IFIT4、OAS1、OASL及ISG15 mRNA表达水平均与SLEDAI积分呈显著正相关(r＞0.5,P＜0.05).③ESR、CRP、补体C3、C4、ANA与IFIT1、IFIT4、OAS1、OASL、ISG15 mRNA表达水平及SLEDAI积分均无相关性,抗dsDNA抗体与IFIT1、IFIT4、OAS1、OASL、ISG15 mRNA表达水平及SLEDAI积分呈正相关(r＞0.5,P＜0.05).结论 SLE患者IFIT1、IFIT4、OAS1、OASL及ISG15的表达水平在SLE患者中显著增高,并且与SLEDAI积分呈显著正相关,对SLE患者病情活动度和病情严重度的判断均有较大价值,抑制这5个基因的表达可能为SLE的治疗提供新的靶点.