Primary Sj Research Articles

Subacute aseptic meningitis as neurological manifestation of primary Sj ögren's syndrome

Sjögren's syndrome (SS) is an autoimmune disease characterized by inflammatory infiltration and secondary chronic dysfunction of exocrine glands. Systemic (extraglandular) manifestations of the disease occur in one-third of the patients, including a wide spectrum of peripheral and central neurological disorders. We report a case of subacute afebrile aseptic meningitis (AM) as neurological manifestation of primary SS. The neurological symptomatology presented gradual onset and progression, including diplopia, mild headache, pain and stiffness of the neck. The clinical examination pointed out xerostomia and xerophthalmia. Diagnosis of SS was confirmed by Schirmer's tear test and histopathology of the labial salivary glands. The neurological involvement was highlighted by gadolinium-enhanced magnetic resonance imaging of the brain which displayed an increased diffuse leptomeningeal enhancement. Cerebrospinal fluid (CSF) analysis showed moderate pleocytosis with prevalence of polymorphonuclear leukocytes and increased protein level but no evidence of Ig intrathecal synthesis. A cycle of intravenous steroid therapy led to a complete disappearance of the neurological symptomatology and to normalization of the CSF inflammatory pattern. Given the unusual presentation of this case of AM, which resembled the characteristics of a chronic meningitis rather than those of an acute form, in patients affected by SS we must stress the importance of cephalic symptoms such as headaches and cervical stiffness (even if mild and without fever) as possible signs of central neurological involvement of the disease.

Rituximab shows potential in patients with primary Sj??gren's syndrome,

Rituximab shows potential in patients with primary Sj??gren's syndrome,

Distribution of CXCR3- or CCR4-positive cells in interstitial pneumonia associated with primary Sjogren's syndrome.

Patients with primary Sjogren's syndrome (SS) occasionally develop interstitial pneumonia (SS-IP), the prognosis of which is less grave compared with that of idiopathic pulmonary fibrosis (IPF). We examined distribution of helper T-cell subsets in open lung biopsy specimens from seven patients with SS-IP and, for comparison, ten patients with IPF. The expression of CXCR3 and CCR4, chemokine receptors associated in vitro with Th1 and Th2 cells, respectively, was analyzed in the mononuclear infiltrate using immunohistochemistry. The expression of CD4, CD8, and CD20 in the infiltrate was similarly examined. The positive cells were semiquantified in fibrosing areas and lymphoid clusters of both SS-IP and IPF. In fibrosing areas, CXCR3-positive cells were dominant over CCR4-positive cells in all cases of SS-IP, whereas the two types of cells showed no such difference in cases of IPF. Each of the CXCR3/CD4 and CXCR3/CCR4 ratios was significantly higher in SS-IP than in IPF ( P<0.05 and P<0.05, respectively). The CCR4/CD4 ratio showed a significantly lower value in SS-IP than in IPF ( P<0.05). In lymphoid clusters, prominent in SS-IP and few and small in IPF, CXCR3-positive cells predominated over CCR4-positive cells in both lung lesions. There was no significant difference of CXCR3/CCR4 ratio in lymphoid clusters between SS-IP and IPF ( P=0.33). These findings in SS-IP are in accordance with those reported in previous studies of the salivary glands of SS patients, where most of the infiltrating lymphocytes expressed CXCR3, and the expression of interferon-gamma was upregulated. In contrast, the Th2 cell dominance was reported in IPF in the previous studies. The present findings suggest that the pathogenesis of interstitial pneumonia is different between SS-IP and IPF in regard to the roles of helper T-cell subsets.

2692 Cardiovascular autonomic dysfunction in primary Sj�grens syndrome

2692 Cardiovascular autonomic dysfunction in primary Sj�grens syndrome

Myositis in primary Sj�gren's syndrome: clinical and pathological report

To clarify the clinical features of myositis complicated with primary Sjögren's syndrome (SS), we studied 89 patients with Sjögren's syndrome (one male and 88 females; mean age 56.0 ± 15.31 years). Myositis was diagnosed from clinical findings, muscle enzymes, electromyographic findings, and muscle biopsy findings. Myositis was diagnosed in 5 of 89 SS patients (5.6%). One patient developed myositis 7 months after the onset of SS. The other four patients were diagnosed with myositis and SS simultaneously. Muscular weakness was mild and slowly progressive over 4–14 months (mean 8.4 months). All patients were able to walk without any assistance at the start of prednisolone therapy. Muscular enzymes were slightly elevated (from 1.5- to 12-fold). All patients tested negative for anti-Jo1 antibody and tested positive for antinuclear antibody. Anti-Ro(SSA) antibody was positive in 4/5 (90%); anti-La(SSB) was positive in 2/5 (40%). Although the clinical features of all patients met the criteria for polymyositis of Bohan, they responded well to small or moderate doses of prednisolone, which could be decreased without a recurrence of muscular weakness in all patients. Myositis with Sjögren's syndrome showed relatively moderate symptoms and responded well to prednisolone. A prospective follow-up of patients may provide further information.

Detecting abnormal regional cerebral blood flow in patients with primary Sjögren's syndrome by technetium-99m ethyl cysteinate dimer single photon emission computed tomography of the brain--a preliminary report.

Technetium-99m ethyl cysteinate dimer (Tc-99m ECD) brain single photon emission computed tomography (SPECT) was used to detect abnormal regional cerebral blood flow (rCBF) in 32 female patients with primary Sjögren's syndrome (PSS) showing definite neuropsychiatric symptoms/signs and normal brain magnetic resonance imaging (MRI) findings. It demonstrated hypoperfusion brain lesions in 18 (56.3%) of the patients, most frequently in the parietal lobes, and appears to be a sensitive tool for this clinical application.

シェーグレン症候群改訂診断基準 (1999年) による1次性, 2次性シェーグレン症候群症例における各種検査結果の比較検討

シェーグレン症候群改訂診断基準 (1999年) による1次性, 2次性シェーグレン症候群症例における各種検査結果の比較検討

Genetic association between interleukin-10 promoter region polymorphisms and primary Sjögren's syndrome.

To determine whether the haplotypes formed on the basis of single-base-exchange polymorphisms at positions -1082, -819, or -592 of the interleukin-10 (IL-10) gene predispose subjects to primary Sjögren's syndrome (SS). The frequency of IL-10 polymorphisms was analyzed in 62 patients with primary SS and in 400 healthy subjects. These data were assessed for correlations with the concentration of IL-10 in the plasma. The frequency of the IL-10 GCC haplotype (G at position -1082, C at position -819, and C at position -592 of the IL-10 gene) was increased (P < 0.05, odds ratio [OR] 1.90, 95% confidence interval [95% CI] 0.955-3.62) and the frequency of the ACC haplotype decreased (P < 0.05, OR 0.443, 95% CI 0.257-0.764) in primary SS patients compared with healthy controls. Moreover, the frequency of the ATA haplotype was similar in primary SS patients and healthy controls, but the incidence of the GCC/ATA genotype was elevated in the primary SS patients (P < 0.05, OR 2.19, 95% CI 1.19-4.03). The concentration of plasma IL-10 was significantly higher in patients carrying the GCC haplotype than in non-carriers of GCC. These results suggest that the presence of the GCC haplotype or the GCC/ATA genotype and the absence of the ACC haplotype of the IL-10 gene are associated with an increased susceptibility to primary SS. This effect is probably mediated by the increased capability to produce IL-10 among carriers of the GCC haplotype.

Alteration of peripheral blood dendritic cells in patients with primary Sjögren's syndrome.

We recently identified 3 fractions of human peripheral blood (PB) dendritic cells (DC), including the monocyte-associated fractions 1 and 2 (CD1a+,CD11c+ and CD1a-,CD11c+, respectively) and the lymphoid-associated fraction 3 (CD1a-,CD11c-). We attempted to determine whether these fractions were altered in Sjögren's syndrome (SS). We examined 23 patients with primary SS and 22 normal control subjects. DC were purified from PB and analyzed by flow cytometry. Immunohistochemical staining of labial salivary glands of SS patients was performed with monoclonal antibodies against fascin, which is known to be specific for DC. The total numbers of PB DC and fraction 1 DC were decreased in SS. Immunohistochemical staining demonstrated that fascin+,CD11c+,HLA-DR+ mononuclear cells were present and scattered among numerous fascin-hyperfiltrating cells in SS patients. Interferon-gamma (IFNgamma)-producing Th1 cells were shown to be increased in both PB and salivary glands of patients, indicating the presence of general IFNgamma-producing Th1 polarization in SS. Furthermore, numbers of Thl cells were increased when naive T cells were cocultured with fraction 1 DC in vitro. These findings suggest selective trafficking of fraction 1 DC into focal sites of inflammation and subsequent promotion of Th1 balance, suggesting a novel pathogenesis of SS.

Polymorphisms of the Ro52 gene associated with anti-Ro 52-kd autoantibodies in patients with primary Sjögren's syndrome.

To screen for the Ro52 gene encoding the 52-kd Ro autoantigen for possible mutations and polymorphisms associated with primary Sjogren's syndrome (SS). The restriction enzyme fragment-single-strand conformation polymorphism method was used to search for mutations and polymorphisms in the Ro52 gene in 97 patients with primary SS and 72 healthy control subjects. The results were verified by automated DNA sequencing and natural or amplification-created restriction site tests. A single-nucleotide polymorphism (SNP) was discovered in intron 3 (137 bp upstream of exon 4). The C/T genotype was significantly more prevalent among patients who were positive for anti-Ro 52-kd (20 of 38) than among healthy controls (9 of 72) (P = 0.00003); significant differences were not seen in patients who were negative for anti-Ro 52-kd. Furthermore, the frequency of the T allele in this position among groups of anti-Ro 52-kd-positive patients, anti-Ro 52-kd-negative patients, and control subjects was significantly increased in the patients who were positive for anti-Ro 52-kd compared with the controls. We present the results of a complete screening for the Ro52 gene in patients with primary SS and the results of an association study. An SNP in intron 3 was found to be strongly associated with the presence of anti-Ro 52-kd autoantibodies in primary SS. This finding is interesting in light of the fact that an alternative messenger RNA is made by deleting exon 4, which encodes a putative leucine zipper domain, to generate a shorter version of the Ro 52-kd protein.

Primary Sj??gren's Syndrome and Celiac Disease: Causal Association or Serendipity?

Primary Sjögren's syndrome (pSS) is an autoimmune disease associated with other autoimmune diseases like thymoma, hypothyroidism or mucosa-associated lymphoid tissue lymphomas. Celiac disease (CD) is a gluten sensitive enteropathy that causes small bowel mucosal damage in genetically susceptible individuals. Several immunologic alterations and immune-associated diseases, for example, insulin dependent diabetes mellitus, autoimmune thyroid disease, and connective tissue disorders, have been described in CD. We report 3 of 141 pSS patients who also had CD and review literature that suggests that CD is increased in patients with pSS. Successful treatment of CD did not relieve sicca symptoms or signs; thus, the two diseases must be treated independently. Although intestinal inflammation can occur in patients with pSS, diarrhea should be evaluated for CD and other causes. Because of the occasional severity of CD, clinicians must be aware of the possible association with pSS.

Immunoglobulin variable genes and epitope recognition of human monoclonal anti-Ro 52-kd in primary Sjögren's syndrome.

To clone and characterize human anti-Ro/SSA autoantibodies from a patient with primary Sjögren's syndrome (pSS). Monoclonal antibodies (mAb) were raised from the peripheral blood of a patient with pSS using Epstein-Barr virus transformation and a hybridoma technique. Specificity was determined using cell extracts, recombinant Ro 52-kd, Ro 60-kd, and La proteins as well as Ro 52-kd peptides in enzyme-linked immunosorbent assay (ELISA) and Western blot. The immunofluorescence pattern was analyzed using cultured human and mouse cell lines. Complementary DNA was amplified by polymerase chain reaction, and Ig variable (V)-region genes were directly sequenced. Two human anti-Ro 52-kd mAb of IgM isotype, denoted SG1 and SG3, were cloned from the peripheral blood of a patient with pSS. The 2 mAb reacted with the Ro 52-kd antigen in cell extracts of human cell lines and mouse cell lines, and with purified human recombinant Ro 52-kd protein in ELISA and Western blot. SG1 reacted specifically with 1 peptide, amino acids 136-156, of the Ro 52-kd protein, and SG3 was mapped to react with a recombinant fragment representing amino acids 136-292. Immunofluorescence studies revealed cytoplasmic staining with both mAb. Both were encoded by V(H)3-family genes. SG1 was highly homologous to the DP-77 germ-line gene, with 2 replacement mutations and 1 silent. It utilized the DPL-11 germ-line gene from the Vlambda2-family gene, with 1 silent mutation. SG3 was 100% homologous to the DP-47 germ-line gene, combined with a Vkappa1-family gene that was 100% homologous to the A30 germ-line gene. Two human mAb were demonstrated to be specific for the Ro 52-kd protein and to be directed against 2 different epitopes, 1 linear and 1 conformation-dependent, within a region previously described to be immunodominant. Somatic hypermutation appeared to be of minor importance in generating these 2 specificities.

Correlation of increased susceptibility to apoptosis of CD4+ T cells with lymphocyte activation and activity of disease in patients with primary Sjögren's syndrome.

To investigate whether a change in the CD95-related apoptosis of T lymphocytes might have a share in the development of the disease in patients with primary Sjögren's syndrome (SS). Two-color cytometric analysis was used to study the phenotype of freshly separated mononuclear cells, while Western blotting was used to detect CD95 ligand (CD95L) expression in total homogenates of isolated CD4+ T lymphocytes. The ability of various subpopulations of T cells to undergo apoptosis was investigated in 1-day cultures in medium alone or following various (anti-CD3, anti-CD95 monoclonal antibody, calcium ionophore) treatments. Apoptosis was detected using 7-aminoactinomycin D dye. Compared with the findings in healthy controls, the number of CD4+ T lymphocytes was decreased, while their expression of CD95, HLA-DR, and CD45RO was significantly increased in patients with primary SS. A positive correlation was found between the activity of disease, the decrease in the CD4+ T cell number, and the increase in the expression of CD95, CD95L, HLA-DR, and CD45RO molecules within the CD4+ T cell subset. An increased rate of spontaneous, anti-CD3-, or anti-CD95-induced apoptosis was found in the T cells of SS patients, and this was more pronounced in the CD4+ T cell population, correlated with the decreased CD4+ T cell number, increased CD45RO expression, and activity of disease, and concerned mainly the CD95+ cells. These observations indicate that the increased susceptibility to apoptosis of peripheral CD4+ T cells from SS patients correlates with disease activity. These findings support the hypothesis that the chronic activation of the immune system that occurs in this autoimmune disease is the primary mechanism responsible for this cell-deletion process.

Failure to detect human papillomavirus in primary Sjögren's syndrome.

Failure to detect human papillomavirus in primary Sjögren's syndrome.

Autoantibodies in primary Sjögren's syndrome are directed against proteasomal subunits of the alpha and beta type.

The proteasome subunit HC9 (alpha3) has recently been identified as a major target of the humoral autoimmune response in patients with autoimmune myositis and systemic lupus erythematosus. Since B cell hyperreactivity is a common feature of systemic autoimmune diseases, patients with primary Sjögren's syndrome (SS) and other control groups were investigated to evaluate the significance of autoantibodies against the proteasome. Analyses of autoantibodies directed against the 20S proteasome were performed using enzyme-linked immunosorbent assay, immunoblot, and 2-dimensional electrophoresis. Forty-three patients with primary SS, 47 patients with rheumatoid arthritis including 9 with secondary SS, 19 patients with gastrointestinal tumors, and 80 healthy controls were tested for antiproteasome antibodies. Antiproteasome antibodies were detected in 39% of patients (17 of 43) with primary SS. In contrast, only 1 of 47 patients with rheumatoid arthritis showed positive reactivity (P < 0.001). Serum samples from 19 tumor patients (P < 0.003) and 80 healthy controls (P < 0.001) were serologically negative. Moreover, immunoblotting and 2-dimensional analysis of the antiproteasome response revealed a polyspecific recognition pattern in 7 patients with primary SS. Different proteasomal subunits of the alpha and beta type, including subunits that carried the proteolytic active sites, were recognized by the patients' sera. The humoral antiproteasome response in primary SS, in contrast to its secondary form, is characterized by an extensive recognition pattern of several subunits, indicating a polyspecific B cell activation against the 20S proteasome. Moreover, proteolytically active beta-type subunits, which are important for the generation of major histocompatibility complex class I-restricted antigens, appear to be targets of the autoimmune response. The data indicate that the proteasome itself may stand on a cross point of pathways that links mechanisms of the immune defense with features of systemic autoimmunity.

Serum soluble Fas/APO-1 is increased in patients with primary Sjögren's syndrome.

The aim of the study was to elucidate the involvement of Fas antigen in human autoimmune disease, by analysing serum levels of soluble Fas/APO-1 protein in patients with various autoimmune diseases, including system lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), Behçet's syndrome and Sjögren's syndrome (SjS). The levels of soluble Fas/APO-1 in sera were quantitated by a sandwich enzyme-linked immunosorbent assay. Soluble Fas/APO-1 levels were significantly increased in serum from patients with primary Sjögren's syndrome (primary SjS) compared with control subjects. However, no significant differences in soluble Fas/APO-1 levels were noted in patients with secondary Sjögren's syndrome (secondary SjS) nor in patients with any of the other autoimmune diseases. The soluble Fas/APO-1 level in primary SjS patients with extraglandular diseases was significantly higher than that in patients without extraglandular diseases. These results suggest that soluble Fas/APO-1 protein may play an important role in the pathogenesis of primary SS.

A novel NOD-derived murine model of primary Sjögren's syndrome.

The appearance of autoimmune diabetes prior to autoimmune exocrinopathy in the NOD mouse suggests that it is an excellent model of secondary, but not primary, autoimmune sicca complications. Since the unique major histocompatibility complex (MHC) I-A(g7) expression in NOD mice is essential for the development of insulitis and diabetes in these animals, we investigated exocrine gland function in NOD.B10.H2b mice, which have an MHC congenic to NOD, as a potential model for primary Sjögren's syndrome (SS). Histopathologic manifestations of lymphocytic infiltrates into the pancreas and exocrine tissues were examined by light microscopy. Sera were evaluated for the presence of antinuclear antibodies. Saliva, tears, and gland lysates were evaluated for total volume and protein concentration, the aberrant expression and processing of parotid secretory protein, and cysteine protease activity. NOD.B10.H2b mice exhibited the exocrine gland lymphocytic infiltration typical of the SS-like disease and dysfunction observed in NOD mice, but without the insulitis and diabetes. These mice additionally expressed elevated levels of cysteine protease activity (a measure of apoptotic activity) and abnormal expression and cleavage of parotid secretory protein in the submandibular tissues. The results of this study suggest that the unique NOD MHC I-A(g7) is not essential for exocrine tissue autoimmunity. Furthermore, the findings indicate that sicca syndrome occurs independently of autoimmune diabetes and that the congenic NOD.B10.H2b mouse represents a novel murine model of primary SS.

Ocular surface lesions due to keratoconjunctivitis sicca: in primary Sjögren's syndrome.

Keratoconjunctivitis sicca is usually part of Sjögren's syndrome (SS) which is systemic disease. Ocular surface lesions are ascribed either to the reduction, or to to the low quality of tears. To address this question, ocular surface lesions were evaluated in 20 SS patients by the rose bengal test (RBT). The results were compared to those obtained in 20 normal volunteers and collated with the quality (estimated by the break-up-time) and the quantity of tears (estimated by the shirmer's I test and the level of lacrimal lactoferrin, LF). The RBT scores did not correlate with the shirmer's test results, neither did they with the break-up times. This is consistent with the view that Schirmer's I Test and break-up-time cannot make any distinction between patients from controls. In contrast, the RBT scores correlated well with the levels lacrimal LF and paralleled to serological abnormalities.

Primary Sj�gren's syndrome from the viewpoint of an internal physician

The characteristics of primary Sjögren's syndrome are described on the basis of the follow-up of 65 patients with extraglandular symptoms at the onset and during the disease. The mean age of the patients at onset was 41.8 years and at the time of definite diagnosis was 45.8 years. Articular (32 cases), lacrimal (30 cases) and salivary (30 cases) manifestations were the most frequent initial symptoms. In only 22 of the 65 patients could Sjögren's syndrome be diagnosed at the onset. In most cases, the articular symptoms observed observed in 56 patients during the course corresponded to true polyarthritis, as verified by joint scintigraphy. Most frequently the wrists and ankles were affected. Chronic atrophic gastritis was found in 35 patients. In the young patients (13 cases), both the antrum and the corpus were affected more frequently than in the controls. In middle-aged patients (21 cases), atrophy of the antrum, and in the elderly (10 cases) atrophy of the corpus was more frequent than in the controls. All three types of chronic atrophic gastritis occurred in the disease. The decreased gastric acid secretion was characteristic of types A and AB gastritis, but the hypergastrinaemia only of type A. It was verified that chronic duodenitis and jejunitis occur in the disease. The pancreatic lesions were mild. Renal involvement was detected in 15 patients, vascular symptoms in 22 and lower-airway changes in 21. The variety of the different symptoms proved that primary Sjögren's syndrome can involve many organs.

Epidermal cell surface-associated IgG in patients with primary Sj�gren's syndrome: in vitro evidence for immune complex binding

In vivo deposits of IgG have previously been demonstrated in the epidermal intercellular area of clinically unaffected skin from 68% of patients with primary Sjögren's syndrome (primary SS). This study compared circulating IgG from patients with primary SS with that from secondary SS in their ability to bind normal human epidermal cells in vitro. We observed a granular pattern of IgG binding to the normal epidermal cell surfaces with 9 of 18 sera from patients with primary SS (50%), 3 of 19 sera from patients with SS secondary to rheumatoid arthritis (16%) (p = 0.025), and none of 24 normal control sera (p less than 0.001). In a subsequent analysis of polyethylene glycol separated sera from two normal controls and two primary SS patients, the epidermal IgG binding capacity was found only in the precipitates of the patients. These findings support our previous hypothesis that the in vivo intraepithelial IgG deposits in primary SS patients are due, at least in part, to cell surface-bound immune complexes.