HTLV-I associated Sjogren's syndrome is aetiologically distinct from anti-centromere antibodies positive Sjogren's syndrome.
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OBJECTIVE: To investigate whether Sjogren's syndrome (SS) with anti-HTLV-I antibodies is aetiopathologically distinguishable from SS without these antibodies, the study compared prevalence of autoantibodies in serum samples of SS patients with or without anti-HTLV-I antibodies. METHODS: The test group included 135 patients with primary SS and 97 patients with secondary SS. Serum samples of the patients were examined for the presence of anti-nuclear antibodies (ANA), anti-SS-A/Ro antibodies, anti-SS-B/La antibodies, anti-centromere antibodies (ACA), and anti-HTLV-I antibodies. RESULTS: Anti-HTLV-I antibodies were detected in 25.0% of primary SS patients and in 29.2% of secondary SS patients. There were no significant differences in the mean age, sex, values of asparate aminotransferase, alanine aminotransferase, alkaline phosphatase, serum complements and IgG between HTLV-I seropositive and seronegative SS patients. The rheumatoid factor, ANA, anti-SS-A/Ro, and anti-SS-B/La antibodies in serum samples of SS patients were detected in 60.0%, 84.0%, 51.9%, and 12.0%, respectively. There was no significant difference in the prevalence of these antibodies between HTLV-I seropositive and seronegative SS patients. Using the indirect immunofluorescence test, 14.2% showed a discrete speckled staining pattern. All serum samples contained significant amounts of ACA determined by enzyme linked immunosorbent assay. These antibodies were detected in only 4% of HTLV-I seropositive SS patients but were present in 19.9% of HTLV-I seronegative SS patients. Furthermore, the prevalences of anti-SS-A/Ro and anti-SS-B/La antibodies in serum samples of ACA positive patients were significantly lower than those in ACA negative SS patients. CONCLUSION: These results suggest that SS patients with anti-SS-A/Ro or anti-SS-B/La antibodies, or both, might be aetiopathologically distinct from SS patients with ACA. HTLV-I might be involved in the pathogenesis of SS in a subset of patients with anti-SS-A/Ro or anti-SS-B/La antibodies, or both, but not SS patients with ACA. (+info)
Distinct immunoglobulin class and immunoglobulin G subclass patterns against ganglioside GQ1b in Miller Fisher syndrome following different types of infection.
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We studied serum antibodies against gangliosides GQ1b and GM1 in 13 patients with Miller Fisher syndrome (MFS) and in 18 patients with Guillain-Barre syndrome (GBS) with cranial nerve involvement. Anti-GQ1b titers were elevated in all patients with MFS cases (immunoglobulin G [IgG] > IgA, IgM), and in 8 of the 18 with GBS. Lower frequencies of increased anti-GM1 titers were observed in MFS patients (3 of 13), as well as in GBS patients (5 of 18). During the course of MFS, anti-GQ1b titers of all Ig classes decreased within 3 weeks after onset. By contrast, anti-GM1 titers (mainly IgM) transiently increased during the course of MFS in five of six patients, suggesting a nonspecific secondary immune response. In patients with MFS following respiratory infections, IgG was the major anti-GQ1b Ig class (six of six patients) and IgG3 was the major subclass (five of six). In contrast, four of five patients with MFS following gastrointestinal infections showed predominance of anti-GQ1b IgA or IgM over IgG and predominance of the IgG2 subclass; anti-GQ1b IgG (IgG3) prevailed in one patient only. These distinct Ig patterns strongly suggest that different infections may trigger different mechanisms of anti-GQ1b production, such as via T-cell-dependent as opposed to T-cell-independent pathways. Thus, the origin of antibodies against GQ1b in MFS may be determined by the type of infectious agent that precipitates the disease. (+info)
Immunization with a peptide of Sm B/B' results in limited epitope spreading but not autoimmune disease.
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An experimental model of systemic lupus erythematosus has recently been described in normal animals. We sought to confirm and extend this model, which involved immunization of normal rabbits and mice with a peptide of Sm B/B', PPPGMRPP. This peptide is an early target of the immune response in anti-Sm-positive patients with lupus. The peptide was used in a multiple Ag peptide format, with multiple copies of PPPGMRPP bound to an inert lysine backbone. New Zealand White rabbits and A/J and C57BL/10ScSn mouse strains were immunized with PPPGMRPP-MAP. Pepscan assays were used to determine the epitope spreading of the anti-PPPGMRPP-MAP response to other octamers of SmB/B' following immunization. We obtained high titer anti-PPPGMRPP-MAP IgG responses in the New Zealand White rabbits and A/J mice. The rabbits immunized with PPPGMRPP-MAP showed varying degrees of epitope spreading, while the A/J mice showed no spreading. We observed no autoantibodies to dsDNA or other anti-nuclear autoantibodies in our animals by ELISA or immunofluorescence, although anti-nuclear autoantibodies were found by Western blotting in some of the rabbits. No evidence of clinical disease was seen in our normal animals. These data underline the difficulties often associated with the reproduction of animal models in different laboratories. (+info)
A major linkage region on distal chromosome 4 confers susceptibility to mouse autoimmune gastritis.
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Although much is known about the pathology of human chronic atrophic (type A, autoimmune) gastritis, its cause is poorly understood. Mouse experimental autoimmune gastritis (EAG) is a CD4+ T cell-mediated organ-specific autoimmune disease of the stomach that is induced by neonatal thymectomy of BALB/c mice. It has many features similar to human autoimmune gastritis. To obtain a greater understanding of the genetic components predisposing to autoimmune gastritis, a linkage analysis study was performed on (BALB/cCrSlc x C57BL/6)F2 intercross mice using 126 microsatellite markers covering 95% of the autosomal genome. Two regions with linkage to EAG were identified on distal chromosome 4 and were designated Gasa1 and Gasa2. The Gasa1 gene maps within the same chromosomal segment as the type 1 diabetes and systemic lupus erythematosus susceptibility genes Idd11 and Nba1, respectively. Gasa2 is the more telomeric of the two genes and was mapped within the same chromosomal segment as the type 1 diabetes susceptibility gene Idd9. In addition, there was evidence of quantitative trait locus controlling autoantibody titer within the telomeric segment of chromosome 4. The clustering of genes conferring susceptibility to EAG with those conferring susceptibility to type 1 diabetes is consistent with the coinheritance of gastritis and diabetes within human families. This is the first linkage analysis study of autoimmune gastritis in any organism and as such makes an important and novel contribution to our understanding of the etiology of this disease. (+info)
Defective self-reactive antibody repertoire of serum IgM in patients with hyper-IgM syndrome.
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We have analyzed the self-reactive repertoires of IgM and IgG Abs in the serum of 19 patients with hyper-IgM syndrome (HIM) by means of a quantitative immunoblotting technique that allows for a quantitative comparison of Ab repertoires in health and disease by multiparametric statistical analysis. Normal tissue extracts of liver, lung, stomach, and kidney were used as sources of self Ags. Extracts of Pseudomonas aeruginosa and Staphylococcus epidermidis were used as sources of nonself Ags. We demonstrate a significant bias in repertoires of reactivities of IgM of patients with HIM with self Ags. Ab repertoires of IgM toward nonself Ags did not differ, however, between patients and controls. No difference was found between IgM repertoires of untreated patients and those of patients receiving substitutive treatment with i.v. IgG. IgG in the serum of HIM patients lacked reactivity with self Ags, although it exhibited a pattern of reactivity with nonself Ags that was similar to that of IgG of healthy controls. The data demonstrate that functional CD40-CD40 ligand interactions are essential for the selection of natural self-reactive B cell repertoires. (+info)
Antigen-specific therapy of murine lupus nephritis using nucleosomal peptides: tolerance spreading impairs pathogenic function of autoimmune T and B cells.
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In the (SWR x NZB)F1 mouse model of lupus, we previously localized the critical autoepitopes for nephritogenic autoantibody-inducing Th cells in the core histones of nucleosomes at aa positions 10-33 of H2B and 16-39 and 71-94 of H4. A brief therapy with the peptides administered i.v. to 3-mo-old prenephritic (SWR x NZB)F1 mice that were already producing pathogenic autoantibodies markedly delayed the onset of severe lupus nephritis. Strikingly, chronic therapy with the peptides injected into 18-mo-old (SWR x NZB)F1 mice with established glomerulonephritis prolonged survival and even halted the progression of renal disease. Remarkably, tolerization with any one of the nucleosomal peptides impaired autoimmune T cell help, inhibiting the production of multiple pathogenic autoantibodies. However, cytokine production or proliferative responses to the peptides were not grossly changed by the therapy. Moreover, suppressor T cells were not detected in the treated mice. Most interestingly, the best therapeutic effect was obtained with nucleosomal peptide H416-39, which had a tolerogenic effect not only on autoimmune Th cells, but autoimmune B cells as well, because this peptide contained both T and B cell autoepitopes. These studies show that the pathogenic T and B cells of lupus, despite intrinsic defects in activation thresholds, are still susceptible to autoantigen-specific tolerogens. (+info)
Binding of human neutrophils to cell-surface anchored Tamm-Horsfall glycoprotein in tubulointerstitial nephritis.
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BACKGROUND: Human Tamm-Horsfall glycoprotein (T-H) is a glycosylphosphatidylinositol-anchored protein exposed at the surface of distal nephron cells, and urinary T-H is the released soluble counterpart. The latter has been implicated in tubulointerstitial nephritis, and the proinflammatory potential has been related to its ability to bind in vitro human neutrophils (PMNs). We have examined the conditions required for the binding of neutrophils to cell-surface anchored T-H and the consequent effects. METHODS: A HeLa cell-line derivative permanently transformed with human T-H cDNA and expressing T-H at the cell surface was used throughout the study. The adhesion of PMNs to cells expressing T-H was analyzed by immunofluorescence microscopy before and after the opsonization of cells with anti-T-H antibodies. The oxidative burst induced by adhesion of PMNs to the cells was determined by the activation of myeloperoxidase. Quantitative and qualitative changes in the release of T-H under the adhesion of activated PMNs were determined by dot-blot and Western blot analysis. RESULTS: No binding of neutrophils to cell-surface-anchored T-H was observed. On the contrary, the opsonization of cells with anti-T-H antibodies resulted in a dramatic adhesion of neutrophils. Such an adhesion induced the oxidative burst of PMNs and a large increment in the release of T-H, as well as the release of the slightly faster migrating T-H form, which is normally retained intracellularly. CONCLUSIONS: These results support the notion that, after the autoimmune response, the adhesion of neutrophils to cell-surface T-H contributes to the pathogenesis of tubulointerstitial nephritis, favoring a further accumulation of T-H in the interstitium and inducing the loss of cell integrity via reactive oxygen metabolites generated by activated neutrophils. (+info)
Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure.
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BACKGROUND: Atherosclerotic cardiovascular disease and malnutrition are widely recognized as leading causes of the increased morbidity and mortality observed in uremic patients. C-reactive protein (CRP), an acute-phase protein, is a predictor of cardiovascular mortality in nonrenal patient populations. In chronic renal failure (CRF), the prevalence of an acute-phase response has been associated with an increased mortality. METHODS: One hundred and nine predialysis patients (age 52 +/- 1 years) with terminal CRF (glomerular filtration rate 7 +/- 1 ml/min) were studied. By using noninvasive B-mode ultrasonography, the cross-sectional carotid intima-media area was calculated, and the presence or absence of carotid plaques was determined. Nutritional status was assessed by subjective global assessment (SGA), dual-energy x-ray absorptiometry (DXA), serum albumin, serum creatinine, serum urea, and 24-hour urine urea excretion. The presence of an inflammatory reaction was assessed by CRP, fibrinogen (N = 46), and tumor necrosis factor-alpha (TNF-alpha; N = 87). Lipid parameters, including Lp(a) and apo(a)-isoforms, as well as markers of oxidative stress (autoantibodies against oxidized low-density lipoprotein and vitamin E), were also determined. RESULTS: Compared with healthy controls, CRF patients had an increased mean carotid intima-media area (18.3 +/- 0.6 vs. 13.2 +/- 0.7 mm2, P < 0.0001) and a higher prevalence of carotid plaques (72 vs. 32%, P = 0.001). The prevalence of malnutrition (SGA 2 to 4) was 44%, and 32% of all patients had an acute-phase response (CRP > or = 10 mg/liter). Malnourished patients had higher CRP levels (23 +/- 3 vs. 13 +/- 2 mg/liter, P < 0.01), elevated calculated intima-media area (20.2 +/- 0.8 vs. 16.9 +/- 0.7 mm2, P < 0.01) and a higher prevalence of carotid plaques (90 vs. 60%, P < 0.0001) compared with well-nourished patients. During stepwise multivariate analysis adjusting for age and gender, vitamin E (P < 0.05) and CRP (P < 0.05) remained associated with an increased intima-media area. The presence of carotid plaques was significantly associated with age (P < 0.001), log oxidized low-density lipoprotein (oxLDL; P < 0.01), and small apo(a) isoform size (P < 0.05) in a multivariate logistic regression model. CONCLUSION: These results indicate that the rapidly developing atherosclerosis in advanced CRF appears to be caused by a synergism of different mechanisms, such as malnutrition, inflammation, oxidative stress, and genetic components. Apart from classic risk factors, low vitamin E levels and elevated CRP levels are associated with an increased intima-media area, whereas small molecular weight apo(a) isoforms and increased levels of oxLDL are associated with the presence of carotid plaques. (+info)