Impaired TGF-ß signaling in patients with active systemic lupus erythematosus is associated with an overexpression of IL-22.

The mechanisms leading to the disruption of self-tolerance in systemic lupus erythematosus (SLE) remain elusive. Herein, we aimed to decipher the molecular basis of the impaired response of mononuclear cells to TGF-ß1. The Smad3-pathway was explored on CD3+ lymphocytes in either active or non active SLE patients. An impaired transcription of TGF-ß1 target genes was demonstrated in the CD3+ lymphocytes of active SLE patients confirming that the defect involves T cells and pointing to its extrinsic nature. We further demonstrate that the defect did not result from an impaired TGF-ßRII expression or Smad2/3 phosphorylation suggesting that the mechanism lies downstream Smad2/3 translocation. Interestingly, the TGF-1 signaling defect did not correlate with an increased expression of soluble or membrane-bound IL-15. However, it was associated with an overexpression of IL-22. This suggests that an excessive activation of AhR pathway (through UV radiations, infections, etc.) could lead to the inhibition of immunosuppressive actions of TGF-ß thus disrupting immune homeostasis in SLE. Collectively, our data suggest that the impaired response to TGF-ß in SLE patients is associated with disease activity and provide new insights into the pathogenesis of SLE since it could establish the link between the environmental factors and the aberrancies of the immune system usually described in SLE.

Resistance to exogenous TGF-ß effects in patients with systemic lupus erythematosus.

BACKGROUND: The mechanisms underlying the loss of self-tolerance in systemic lupus erythematosus (SLE) are incompletely deciphered. TGF-ß plays a key role in self-tolerance demonstrated by the onset of a fatal autoimmune syndrome associated with lupus autoantibodies in mice lacking a functional TGF-ß receptor. The present work aims to define whether resistance to TGF-ß might contribute to the pathogenesis of SLE. METHODS: Twenty-two patients with active SLE, 16 with other connective tissue diseases, and 10 healthy controls were prospectively included in this study. The effects of exogenous TGF-ß1 on IL-2-dependent T-cell proliferation, IFN-γ secretion, and target gene transcription were analyzed on peripheral blood mononuclear cells. RESULTS: Our results showed that 75% of patients with SLE or other connective tissue diseases were totally or partially resistant to the effects of TGF-ß1. The responses to the anti-proliferative and transcriptional effects of TGF-ß were, however, discordant in a high proportion of our patients. Hence, we distinguish three distinct profiles of resistance to TGF-ß1 and suggest that patients may exhibit different defects affecting distinct points of TGF-ß1 signaling pathways. CONCLUSION: Our data demonstrate the presence of an impaired response of peripheral cells to TGF-ß1 in patients with active SLE that may participate to the pathogenesis of the disease. Further studies will be necessary to delineate the mechanisms underlying the lymphocyte resistance to TGF-ß1 in SLE.

TH17 cells expressing CD146 are significantly increased in patients with Systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disorder characterized by vascular damage, excessive fibrosis and abnormal T cells immune-regulation. CD146 is an adhesion molecule essentially expressed in the vascular system, but also on TH17 lymphocytes. In view of the recently described role of CD146 in SSc, we hypothesized an involvement of CD146 positive TH17 cells in this disease. Compared to healthy controls, we showed that both soluble form of CD146 (sCD146), and IL17A levels were increased in patients with SSc with a positive correlation between both factors. A significant increase in TH17 cells attested by an increase of RORγT, IL17A mRNA and CD4+ IL17A+ cell was observed in patients with SSc. Interestingly, the percentage of TH17 cells expressing CD146 was higher in patients with SSc and inversely correlated with pulmonary fibrosis. In vitro experiments showed an augmentation of the percentage of TH17 cells expressing CD146 after cell treatment with sCD146, suggesting that, in patients the increase of this sub-population could be the consequence of the sCD146 increase in serum. In conclusion, TH17 cells expressing CD146 could represent a new component of the adaptive immune response, opening the way for the generation of new tools for the management of SSc.

[Shulman syndrome. A report of 4 cases and review of the literature]. / Syndrome de Shulman. A propos de 4 cas avec revue de la litterature.

The goal of this study is to report four cases of Shulman syndrome with a literature review. Shulman syndrome is a rare disorder recently considered a systemic disease. Our first case shows woody induration of the buttock and trunk with features of morphea. The diagnosis of eosinophilic fasciitis, suspected on hypereosinophilia, was confirmed by histological findings of muscle biopsy. In the second and the third case, the induration affected arms and legs. Obiouvs streneous exercise was noted in the third patient. Those patients fullfiled the criteria of eosinopfilic fasciitis. Visceral involvement consisted on restrictive lung function defects on the second case and oesophageal hypokinesia in the third case. In the fourth case, there was a scleroderma-like on the extremitis with extension to abdomen. Erythrocyte sedimentation rate was normal. Histological findings confirm the diagnosis of eosinophilic fasciitis. All patients were treated with general steroids at high doses associated to cimetidine in the second patient. Once therapy ended, relapses occur in escond and third cases.

[Hyperprolactinemia in systemic lupus erythematosus. A prospective study of 38 cases]. / L'hyperprolactinemie au cours du lupus erythemateux systemique. Etude prospective à propos de 38 cas.

OBJECTIVE: To study prospectively the serum prolactin concentrations among patients with systemic lupus erythematosus and their possible relationship to disease activity and manifestations. METHODS: Serum prolactin levels were measured by radioimmunoassay in 38 patients with systemic lupus erythematosus and 22 age matched controls. Patients with known secondary causes for hyperprolactinaemia, such as pregnancy, lactation, prolactinoma and taking medications known to induce prolactin secretion, were excluded from the study. Demographic, clinical and laboratory features of the patients were obtained. Patients were divided into two subgroups according to their disease activity. Mean prolactin levels from both groups were compared using student test, and prolactin from patients with systemic lupus erythematosus was correlated with variables of disease activity, including the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). RESULTS: Mean prolactin levels were higher in patients with systemic lupus erythematosus (15.4) than healthy controls (9.83); however, the difference did not reach statistical significance (p=). Hyperprolactinemia was found in 24 patients with systemic lupus erythematosus and 5 controls. The frequency of hyperprolactinaemia in systemic lupus erythematosus group was higher than healthy controls. No significant difference in mean prolactin levels was found between patients with active versus inactive disease (18.9 vs 18.5). CONCLUSION: Hyperprolactinaemia occurred significantly in patients with systemic lupus erythematosus, but did not correlate with disease activity.

Comparison of clinical features of Behcet disease according to age in a Tunisian cohort.

Behcet's disease (BD) is a multisystemic inflammatory disease that occurs most often between the second and fourth decade of life. Patients have been reported during the first months of life and after 70 years. Our objective was to determine the clinical, paraclinical and genetic characteristics of BD in patients aged < 20 and > 40 years. We conducted a comparative retrospective study including patients with BD (Criteria of International Study Group on BD). Patients were divided into two groups: those < 20 years (Group one) and those > 40 years (Group two). The clinical, paraclinical and genetic (HLA) characteristics were determined and compared in the two groups. The data were compiled and analyzed using SPSS 11.0. Thirty totals of 430 patients were included. Group one included 81 patients (55 men and 26 women). Group two included 68 patients (45 men and 23 women). Cutaneous involvement (88.9 versus 76.5%; P=0.043), pseudofolliculitis (84 versus 64.5%; P=0.004) and vena cava thrombosis (11.11 vs 0%; P=0.004) were significantly more frequent in group one while joint involvements were more common in group two (57.4 versus 40.7%; P= 0.043). The frequency of erythema nodosum as well as ocular, vascular and neurological disorders was comparable between the two groups. Few studies in the literature have compared the clinical, paraclinical and genetic characteristics of BD, who had first symptom onset after 40 years of age. Late-onset BD, usually, affects both genders equally. According to present results, the frequency of severe organ involvement is equal regardless of age, except for vena cava thrombosis.

[Current and upcoming treatments for Behçet disease]. / Traitements actuels et perspectives thérapeutiques dans la maladie de Behçet.

Behçet disease is a multisystem inflammatory disorder, the cause of which remains unclear. Vasculitis is its predominant histopathological feature. It remains a source of significant morbidity in affected patients, many of whom become blind. Treatment of its various manifestations remains controversial today because of the paucity of randomized controlled trials and the absence of standardized outcome measures for this disease. The preferred treatment modalities combine different drugs, including topical therapies as well as systemic corticosteroids, NSAIDs, colchicine, and immunosuppressive and cytotoxic agents. The principal objectives are always relief of symptoms, control of inflammatory eye disease, suppression of systemic inflammation and vasculitis and prevention of recurrences and thus of irreversible damage. Although the prognosis of various manifestations of Behçet disease has improved, many patients still have refractory disease that requires treatment with combinations of various immunosuppressants, cytotoxic agents, and corticosteroids, which may lead to serious infections or secondary malignancy. Recent improvements in our understanding of the pathogenic mechanisms of Behçet disease, especially its molecular basis, have led to a new generation of potential treatments with improved side-effect profiles and more specific immune targeting. These include new immunosuppressants, biologic medicines, tolerizing agents and immunoablation techniques. Until randomized controlled studies with these agents are conducted, however, no final judgment about their usefulness is possible.

Hyperhomocysteinaemia is associated with uveitis but not with deep venous thrombosis in Behcet's disease.

Plasma homocysteine was assessed in Behcet's disease (BD) patients in order to determine the prevalence of hyperhomocysteinaemia in BD and to test its association with clinical manifestations of the disease. The study included 59 patients with BD and 118 age- and sex-matched healthy subjects. Plasma homocysteine, vitamin B(12) and folate were assessed by automated immunoassay methods. Hyperhomo-cysteinaemia was defined as plasma homocysteine >15 micromol/l. Plasma homocysteine concentrations and the prevalence of hyperhomocysteinaemia were significantly higher in BD patients than in controls [median (5th-95th percentile), 11.3 (6.6-28.1) vs. 10.6 (6.6-17.1) micromol/l, and 25.4% vs. 9.3%, respectively]. In BD patients, hyperhomocysteinaemia was related to male gender, disease severity and uveitis [odds ratio (OR), 5.32; 95% confidence interval (CI), 1.43-21.61; p = 0.008], but not to age, smoking, disease activity, deep venous thrombosis, arthritis or neurological involvement. The association between uveitis and hyperhomocysteinaemia persisted (multi-adjusted OR, 7.46; 95% CI, 1.03-54.3; p = 0.05) after adjusting for gender, age, disease activity and duration, smoking, deep venous thrombosis, and serum concentrations of creatinine, vitamin B(12) and folate. Plasma homocysteine should be measured in patients with BD, and the effect of B-vitamin supplementation should be tested in those with hyperhomo-cysteinaemia.