Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome

The hyperimmunoglobulinemia D and periodic fever (hyper-IgD) syndrome is typified by recurrent febrile attacks with abdominal distress, joint involvement (arthralgias/arthritis), headache, skin lesions, and an elevated serum IgD level (> 100 U/mL). This familial disorder has been diagnosed in 59 patients, mainly from Europe. The pathogenesis of this febrile disorder is unknown, but attacks are joined by an acute-phase response. Because this response is considered to be mediated by cytokines, we measured the acute-phase proteins C-reactive protein (CRP) and soluble type-II phospholipase A2 (PLA2) together with circulating concentrations and ex vivo production of the proinflammatory cytokines interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF alpha) and the inhibitory compounds IL-1 receptor antagonist (IL-1ra), IL-10, and the soluble TNF receptors p55 (sTNFr p55) and p75 (sTNFr p75) in 22 patients with the hyper-IgD syndrome during attacks and remission. Serum CRP and PLA2 concentrations were elevated during attacks (mean, 213 mg/L and 1,452 ng/mL, respectively) and decreased between attacks. Plasma concentrations of IL-1 alpha, IL-1 beta, or IL-10 were not increased during attacks. TNF alpha concentrations were slightly, but significantly, higher with attacks (104 v 117 pg/mL). Circulating IL-6 values increased with attacks (19.7 v 147.9 pg/mL) and correlated with CRP and PLA2 values during the febrile attacks. The values of the antiinflammatory compounds IL-1ra, sTNFr p55, and sTNFr p75 were significantly higher with attacks than between attacks, and there was a significant positive correlation between each. The ex-vivo production of TNF alpha, IL-1 beta, and IL-1ra was significantly higher with attacks, suggesting that the monocytes/macrophages were already primed in vivo to produce increased amounts of these cytokines. These findings point to an activation of the cytokine network, and this suggests that these inflammatory mediators may contribute to the symptoms of the hyper-IgD syndrome.     

Anti-Scl-70 antibodies detected by immunoblotting in progressive systemic sclerosis: specificity and clinical correlations.

One hundred and forty five serum samples from patients with a connective tissue disease and 30 serum samples from healthy blood donors were analysed by immunoblotting. The presence of anti-Scl-70, which seems to discriminate between progressive systemic sclerosis (PSS) and the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) syndrome, was found in 31/64 (48%) patients with PSS, in 6/55 (11%) patients with systemic lupus erythematosus, in 2/26 (8%) patients with mixed connective tissue disease, and in none of 30 healthy blood donors. These data resulted in a specificity of 93% for this antibody in systemic sclerosis. For patients with PSS the duration of disease was significantly shorter in those with anti-Scl-70 antibodies than in those without, whereas the presence of anti-Scl-70 did not correlate with severity of disease. An 82% prevalence of anticentromere antibodies in patients with the CREST variant compared with a 4% prevalence in patients with PSS or with overlap syndrome confirms the high diagnostic value of this autoantibody for the CREST variant of PSS.     

Hepatitis C virus replication in 'autoimmune' chronic hepatitis.

Both high and low anti-hepatitis C virus antibody (anti-HCV) prevalence has been reported in autoimmune chronic active hepatitis. Therefore, we studied 15 consecutive HBsAg-negative, ELISA anti-HCV-positive, autoantibody-positive patients with biopsy proven chronic active hepatitis in order to confirm ELISA specificity by immunoblot test (RIBA-HCV), and to evaluate HCV replication by serum HCV-RNA. Nine patients were anti-nuclear, three type 1 anti-liver-kidney microsomal and three anti-smooth muscle antibody positive. None had associated autoimmune disease. All cases showed mild clinical disease and only moderate necroinflammatory activity. Response to prednisone was poor. RIBA-HCV confirmed ELISA results in all patients. HCV-RNA was found in the serum from 10 patients. Institution of alpha-interferon treatment in three steroid non-responsive patients was followed by prompt normalization of transaminases. Thus, a subgroup of autoantibody-positive chronic active hepatitis can be recognized as HCV-related and should be clinically and etiologically distinguished from autoimmune chronic active hepatitis. Trials of alpha-interferon treatment are worthwhile in this condition.     

T cells from patients with Hodgkin's disease have a defective T-cell receptor zeta chain expression that is reversible by T-cell stimulation with CD3 and CD28

To investigate the mechanisms underlying the deficiency of T lymphocytes from patients with Hodgkin's disease, we investigated the expression of the T-cell receptor (TCR) zeta chain in patients with Hodgkin's disease. By flow cytometry using an anti-zeta chain monoclonal antibody, peripheral blood T lymphocytes from patients with untreated Hodgkin's disease were shown to express decreased levels of the TCR zeta chain. After stimulation by combined CD3 and CD28 cross- linking, T cells from Hodgkin's disease patients upregulated zeta chain protein expression to normal values within 48 hours and achieved a cytolytic potential and levels of interleukin (IL)-2 secretion that were not different from T cells obtained from healthy controls. These results show that downregulation of the TCR zeta chain in Hodgkin's T lymphocytes is a reversible event. Costimulation of CD3 and CD28 is a novel approach for overcoming the T-cell deficiency in Hodgkin's disease and might be exploited clinically. As upregulation of the zeta chain can also be achieved using bispecific monoclonal antibodies (BI- MoAbs) with specificity for tumor antigens and CD3 and CD28, respectively, an immunotherapy with CD3/CD30 and CD28/CD30 Bi-MoAbs may overcome and should therefore, not be jeopardized by the inherent T- cell deficiency in patients with Hodgkin's disease.     

Anti-oxidized low-density-lipoprotein (OxLDL) antibodies in systemic lupus erythematosus with and without antiphospholipid syndrome

The aim of this study was to examine potential links between antiOxLDL antibodies and the clinical and biological features of secondary antiphospholipid syndrome (II APLS) associated with systemic lupus erythematosus (SLE). A cohort study was done of 98 SLE patients followed-up for 1 y, including 18 with definite II APLS and 13 patients with definite primary APLS (I APLS). IgG anticardiolipin, IgG anti beta2 GPI, lupus anticoagulant, VDRL and IgG antiOxLDL were measured in all 98 study subjects. High antiOxLDL titers were found in seven (39%) of the 18 patients with II APLS vs 10 (12.5%) of the 80 patients without APLS (P < 0.01; OR = 4.45; 95% CI = 1.4-14.1) and none of the 13 patients with I APLS (P < 0.02). The mean antiOxLDL titer was not significantly higher in the SLE patients with than without II APLS (P > 0.05). A high antiOxLDL titer was correlated with deep venous thrombosis (P < 0.01; OR = 5.77; 95% CI = 0.54-61) but not with arterial thrombosis (P > 0.05; OR = 1; 95% CI = 0.29-3.09), thrombocytopenia, central nervous system involvement, livedo reticularis, or a positive Coombs test. The antiOxLDL antibody titer was correlated with the IgG anticardiolipin antibody titer (r = 0.235; P = 0.02) and with the IgG anti-beta2 GPI antibody titer (r = 0.224; P = 0.026). AntiOxLDL elevation was found in 17% of SLE patients and was significantly associated with II APLS and venous thrombosis. We found no evidence suggesting that antiOxLDL may be associated with atherosclerosis.     

Outcome after surgical resection of intraductal papillary and mucinous tumors of the pancreas

OBJECTIVE: Treatment of intraductal papillary and mucinous tumors of pancreas (IPMT) usually requires surgery. The objective of this study was to evaluate the risk of recurrence in patients after surgery according to the histological nature of the neoplasm and the type of surgery. METHODS: The outcome of 45 patients who underwent partial pancreatectomy (n = 35) or total pancreatectomy (n = 10) for IPMT was studied according to the nature of the neoplasm (invasive carcinoma or noninvasive neoplasm), type of surgery (partial or total pancreatectomy), and lymph nodes status. RESULTS: The overall 3-yr actuarial survival rate was 83%. Death occurred in seven of 20 (35%) patients with invasive carcinoma and in one of 26 (4%) patients with noninvasive tumors (p<0.05). There were two recurrences in the seven patients with noninvasive neoplasm who underwent partial pancreatectomy with involved resection margins, and none in the 13 patients with disease-free margins. In patients with invasive carcinoma, there was one recurrence after total pancreatectomy, six after partial pancreatectomy with disease-free margins and six after partial pancreatectomy with involved margins. In patients with invasive carcinoma, total pancreatectomy and the absence of lymph nodes involvement were independently associated with a low risk of recurrence. CONCLUSIONS: IPMT may be managed as follows: 1) in patients with noninvasive neoplasms, partial pancreatic resection should be guided by frozen section examination until disease-free margins are obtained; and 2) in patients with invasive carcinoma, total pancreatectomy seems most likely to cure the patient, but should be discussed according to the general status and the age.     

High-dose intravenous gammaglobulin in alloimmunized platelet transfusion recipients

High-dose intravenous gammaglobulin (polyvalent immunoglobulin G) has been shown to be of benefit in some patients with immune thrombocytopenic purpura (ITP), possibly by producing reticuloendothelial system blockade. We studied this approach in patients refractory to random donor platelet transfusion using an IV IgG preparation manufactured by the Swiss Red Cross. Eleven adult patients with acute leukemia received either 0.4 g IgG/kg/d intravenously X five days (four patients) or 0.6 g/kg/d X five days (seven patients). All patients had high levels of lymphocytotoxic antibody and poor responses to random donor platelets. Except for mild headaches in two patients, there were no side effects related to the IgG infusions. All patients had significant elevations of serum IgG on the day after completion of treatment. Either random donor or partially HLA-matched platelet transfusions were administered the day after and, in some cases, during the IgG therapy. No patient had an improvement in one hour posttransfusion platelet count increments. Two additional patients received pooled platelet concentrates incubated for 30 minutes at 37 degrees C with IgG at a final concentration of 3 g% prior to transfusions. These results indicate that high-dose IgG, an extremely expensive treatment, cannot be recommended for alloimmunized adults with leukemia.     

High incidence of monoclonal proteins in the serum and urine of chronic lymphocytic leukemia patients

Chronic lymphocytic leukemia (CLL) is generally considered a nonsecretory B cell immunoproliferative disorder. Conventional electrophoretic and immunoelectrophoretic methods have revealed serum monoclonal proteins in less than 10% of these patients. However, there is increasing experimental evidence from in vitro studies demonstrating that CLL cells may secrete immunoglobulins, particularly free light chains. We examined the serum and urine of 36 consecutive CLL patients for monoclonal proteins using sensitive immunochemical methods (high resolution agarose gel electrophoresis combined with immunofixation). The results obtained were correlated with the Rai stage, quantitative immunoglobulin levels, and lymphocyte membrane immunoglobulin phenotype of the leukemic cells. Twenty-three monoclonal proteins were identified in the serum or urine of 22 patients, an incidence of 61%. Six patients had serum monoclonal proteins, seven had only urinary monoclonal proteins, and nine had monoclonal proteins in serum and urine. In every instance the monoclonal protein was the same light chain type as expressed on the leukemic cells. Our findings suggest that the monoclonal proteins observed in the serum or urine of CLL patients are secretory products of the tumor cells and that their discovery is a function of the sensitivity of the method used for their detection.