Costimulatory molecule CD154 in systemic lupus erythematosus and rheumatoid arthritis. Therapeutic perspectives.

SLE is a systemic autoimmune disease characterized by B cell hyperactivity. Evidence from the last years has shown that B cells play a key role in the development of the immune response. The interaction of CD40 on B cells with its ligand CD154 on activated T cells provides a costimulatory signal that induces T dependent B cell proliferation and differentiation with subsequent antibody production. Moreover, CD154 can act as a cytokine, in addition to its main role to mediate the interactions between T and CD40+ target cells. This review focuses on the multiple roles of CD154 in systemic lupus erythematosus and rheumatoid arthritis and its involvement in the humoral immunity disregulation of patients with these diseases. It also takes in consideration the most recent therapeutic perspectives regarding the use of monoclonal antibodies against CD154, which might be a powerful tool in the treatment of these diseases in the future.

[Autoimmune pancreatitis]. / Autoimmune Pankreatitis.

Over the last years several case reports and articles have been published suggesting that a new form of chronic pancreatitis has been diagnosed and named autoimmune pancreatitis. The present overview scrutinizes the proposed evidence in the light of the current literature and aims to prove whether autoimmune pancreatitis is a special entity of chronic pancreatitis.

Serum soluble IL-2 receptor as a marker of lymphocyte activation in some autoimmune diseases. Effect of immunosuppressive therapy.

Our experience regarding serum soluble interleukin-2 receptor (sIL-2R) measurement as a marker of lymphocyte activation consists of patients with autoimmune disease: 37 with systemic lupus erythematosus (SLE), 23 with autoimmune hepatitis (AIH), 74 with inflammatory bowel disease and six with Wegener's granulomatosis (WG). The influence of immunosuppressive therapy has also been assessed. Serum sIL-2R in SLE is significantly higher than in healthy controls and good correlation is found between sIL-2R and disease activity. Severity of kidney inflammation in lupus nephritis can be reflected by the increased excretion of sIL-2R. It was found that sIL-2R level significantly falls when the disease becomes clinically inactive after immunosuppressive therapy, but in many cases (up to 50%) it does not reach normal levels. The last finding suggests that lymphocyte activation may still be present even though the disease is considered inactive under clinical criteria and support the need of prolonged immunosuppression after the first signs of remission. In AIH the serum levels of sIL-2R are elevated in all patients with active disease; all cases with "highly active" disease have significantly higher concentrations than patients with "mild activity". A good correlation has been demonstrated between elevated serum sIL-2R values and anti-asialoglycoprotein receptor (ASGPR) titer (the specific marker of AIH). The follow-up study showed a significant decrease of both sIL-2R levels and anti-ASGPR titer after 3-9 month immunosuppressive therapy. The findings support that sIL-2R and anti-ASGPR titer could serve as reliable humoral markers for disease-specific activity. Compared with inactive ulcerative colitis (UC) and Crohn's disease (CD), significantly higher levels of sIL-2R were present in the serum of patients with active disease, and in inactive disease than in healthy age-matched controls. Methotrexate (MTX) therapy of patients with refractory UC resulted in sIL-2R decrease at the end of therapeutic period (20 i.m. injections of once a week 25 mg), good responders showing > 50% decrease even at 5-7 weeks of treatment. Serum sIL-2R is elevated in all six patients with WG. Contrary to anti-neutrophil cytoplasmic antibodies (ANCA), sIL-2R remains elevated above cut-off for normal range, despite clinical improvement following immunosuppressive treatment. The last observation suggests that serum sIL-2R is not a good measure of the disease activity and argue for the need of longer immunosuppressive therapy just after the first days of clinical remission.

Anti asialoglycoprotein receptor antibodies and soluble interleukin-2 receptor levels as marker for inflammation in autoimmune hepatitis.

Circulating anti asialoglycoprotein receptor antibodies (anti-ASCPR) and soluble interleukin-2 receptor levels (sIL-2R) were blindly determined in sera of 23 patients with autoimmune hepatitis and compared to 18 healthy individuals. All patients underwent liver biopsy which was blindly staged and graded. 14 of 23 (61%) patients but none of normal controls showed anti-ASCPR positivity. Eleven of twelve (92%) patients with biopsy-proven grade 3 hepatitis were high-titered anti-ASCPR positive compared to three of eleven patients with grade I hepatitis. Mean levels of sIL-2R +/- standard deviation were 1.175 +/- 663 units/ml in the total number of patients with auto-immune hepatitis comparing to 372 +/- 69 units/ml in healthy controls (p < 0.001). Eleven of twelve patients with grade 3 hepatitis had significant higher sIL-2R levels (1,669 +/- 559) than patients with mild disease (635 +/- 113). Chi-square analysis demonstrated a significant correlation between positive anti-ASCPR titer and elevated sIL-2R values. A follow-up analysis of six patients showed a significant decrease of both anti-ASCPR titer and sIL-2R levels after three to nine months of immunosuppressive therapy. These findings suggest that elevated sIL-2R levels and anti-ASCPR titer are associated in patients with autoimmune hepatitis and- as a function of either T or B cell activation, respectively- could serve as reliable humoral marker for disease-specific activity.

A soluble form of the human transferrin receptor is released by activated lymphocytes in vitro.

Soluble transferrin receptors (sTfR) were detected in culture supernatants of activated human peripheral blood mononuclear cells (PBMC) using a sandwich ELISA technique with two non-cross-reacting TfR MoAbs. Mitogenic stimulation of lymphoid cells induced both up-regulation of TfR surface density and release of sTfR to the medium. Peak levels of sTfR in culture supernatants occurred at day 4 after activation, 1 day later than maximum expression of TfR in the plasma membrane. Production of sTfR was independent of proliferation, as demonstrated by measuring sTfR release by PBMC, which had been irradiated with a dose of 20 Gy before activation. In addition to these in vitro experiments, we tested the sera of 85 patients with systemic lupus erythematosus (SLE), an autoimmune disease accompanied by in vivo activation of lymphocytes, for their sTfR levels. No correlation of these data was detectable to serum concentrations of the soluble alpha-chain of the IL-2 receptor, an unequivocal marker of lymphocyte activation. However, they correlated negatively to the haemoglobin content of the patients' erythrocytes, indicating that erythroid progenitors are the predominant source of sTfR in SLE patients' sera.

Enhancement of carcinoembryonic antigen (CEA) expression in colorectal tumors by neuraminidase.

Twelve colorectal carcinomas with transitional mucosa and 10 colorectal adenomas which previously displayed weak or no carcinoembryonic antigen (CEA) expression were selected to verify whether neuraminidase unmasks CEA carbohydrate epitopes and, consequently, enhances the CEA expression. Peroxidase-antiperoxidase (PAP) method was performed on routinely processed tissues, without and with neuraminidase pretreatment of the sections. Lysine, without and with neuraminidase pretreatment of the sections. Lysine, as a modifier of electrostatic charge at cell surface, instead of neuraminidase was used to clarify whether the enzyme yields a specific or non-specific influence on CEA expression. All colorectal tumors exhibited more CEA after neuraminidase pretreatment, while previous negative specimens developed CEA expression. The same effect was observed in some transitional mucosa sections. This has not occurred in normal mucosa, probably owing to a resistant sialylation. The enhancement effect of lysine, although more weakly and not entirely superimposed to that or neuraminidase, suggests non-specific mechanisms of enzyme action. The removal of the negative charge at cell surface, especially due to sialic acid, allows more anti-CEA antibodies to react. The neuraminidase pretreatment of the sections is a useful method to demonstrate the real incidence of CEA in the colorectal tumors.

Effect of cyclophosphamide in active nonviral cirrhosis.

The immunologic effects of cyclophosphamide were studied in 16 patients with active nonviral liver cirrhosis with a view to improving the pathogenetic treatment of these diseases. After months of cyclophosphamide administration first in doses of 100 mg/day (for 14 days) then in doses of 200 mg per week, the hypergammaglobulinemia present at entry was reduced significantly from 2.55 +/- 0.35 g/dl to 1.71 +/- 0.17 g/dl concomitantly with the proportional increase of the active suppressor T lymphocytes, from 29.3 +/- 3.59% to 38.0 +/- 2.1%. The use of smaller doses of cyclophosphamide, i.e., 200 mg/week, allowed the maintenance of its immunosuppressive properties and prevented its side effects.

The role of transvaginal sonography as compared with endorectal sonography in the evaluation of rectal cancer: preliminary study.

We carried out a preliminary study on the efficacy of endovaginal sonography (EVS) in the evaluation of rectal cancer. The study included 12 women with endoscopically documented rectal cancer, 10 of which were treated surgically. We found that EVS evidenced metastasized lymph nodes (7/9) and infiltration of the rectovaginal space more clearly; moreover, this technique can also be performed in cases of stenosing cancer. Endorectal sonography (ERS) evidenced infiltration of the rectal wall but was less accurate both in detecting metastasized lymph nodes (6/9) and for exploration of the rectovaginal space. We concluded that the two methods complement one another and improve ultrasonographic staging of rectal cancer.

Immunostimulating effect of an oxygen-free radical scavenger on E-rosette forming cells.

The influence of an oxygen-free radical scavenger, Epurox (containing superoxide dismutase, catalase and mannitol) on E-rosette forming cells (E-RFC) obtained from 40 healthy subjects, was studied using a standard method. The preincubation of lymphocytes with Epurox increased the E-rosette forming in 80% of the subjects. The mean E-rosette count after preincubation with Epurox (64.17 +/- 6.95) was greater (p less than 0.01) as compared with that obtained without scavenger addition. The stimulating effect of Epurox may be due to the inhibition of cAMP synthesis. This assumption is supported by our study regarding the antagonistic effect of Epurox on E-rosette inhibition induced by histamine, a powerful stimulator of adenylate cyclase.

[The etiopathogenesis of chronic hepatitis in children]. / Studiu privind etiopatogenia hepatitelor cronice la copil.

The authors study the etiology of chronic hepatitis, with emphasis on the high frequency of the infection with virus B, with a chronization rate of 15-20%. Taking into account the mother fetus, transmission and the increased number of AgHBs chronic carriers, with serious consequences on hepatic affection, the authors insist on the necessity of antiviral vaccination and of the therapy for virus elimination. At the same time, pathogenetic investigations are made for the presence of nonspecific antibodies and antibodies against hepatocytic membrane, elements which prove the permanent character of the hepatic lesions by immune mechanism, induced by the virus B persistence.

[The value and limits of endorectal sonography in the preoperative stage classification of rectal cancer]. / Wert und Grenzen der endorektalen Sonographie in der präoperativen Stadieneinteilung des Rektumkarzinoms.

The article deals with the valuation of endorectal and abdominal sonography in preoperative staging of rectal carcinoma. Data processing of 40 patients suffering from tumours of the rectum examined rectoscopically, by biopsy and via sonography showed that endorectal sonography can achieve preoperative staging (T) with a sensitivity of 89%, a specificity of 100%, a positive predictive value of 89% and a negative predictive value of 100%, the overall accuracy being 81%. Identification of pararectal adenopathies can be performed with a sensitivity of 16% and a specificity of 100%. Liver metastases were determined with a sensitivity and specificity of 100%. Hence, endorectal sonography is a valuable method for preoperative staging of carcinoma of the rectum.

Oxygen free radicals and duodenal ulcer pain. Preliminary data.

Starting from the hypothesis that duodenal ulcer pain is induced by oxygen free radicals, a process demonstrated in other types of bacterial or nonbacterial inflammations, we used a powerful scavenger of human origin in local periulcerous injections performed through endoscope in 12 patients with duodenal ulcer and active lasting pain. Pain subsided in all patients for a variable period of time. The results obtained plead for the involvement of oxygen free radicals in the mechanism of ulcer pain.