TLR2 Expression on Leukemic B Cells from Patients with Chronic Lymphocytic Leukemia.

Antigenic stimulation is considered as a possible trigger of neoplastic transformation in chronic lymphocytic leukemia (CLL). B-cell receptor plays a key role in the interactions between the microenvironment and leukemic cells; however, an important role has also been attributed to Toll-like receptors (TLRs). It is believed that disorders of TLR expression may play a part in the pathogenesis of CLL. In this study, we investigated the potential role of TLR2 in CLL by analyzing its expression on leukemic B cells in correlation with clinical and laboratory parameters characterizing disease activity and patients' immune status. We assessed the frequencies of TLR2+/CD19+ cells by the flow cytometry method in peripheral blood of 119 patients with CLL. The percentage of TLR2+/CD19+ cells was significantly lower in patients with CLL as compared to the healthy volunteers. There was also a lower percentage of TLR2+/CD19+ cells in CLL patients with poor prognostic factors, such as ZAP70 and/or CD38 expression, 17p and/or 11q deletion. On the other hand, among patients with del(13q14) associated with favorable prognosis, the percentage of TLR2+/CD19+ cells was higher than among those with del(11q22) and/or del(17p13) as well as in the control group. We found an association between low percentage of CD19+/CD5+/TLR2+ cells and shorter time to treatment. We also demonstrated the relationship between low percentage of CD19+/CD5+ TLR2-positive and overall survival (OS) of CLL patients. CLL patients with a proportion of 1.6% TLR2-positive B CD5+ cells (according to the receiver operating characteristic curve analysis) or more had a longer time to treatment and longer OS than the group with a lower percentage of TLR2 positive cells. To sum up, the results of the study suggest that low TLR2 expression is associated with poor prognosis in CLL patients. The monitoring of CD19+/CD5+/TLR2+ cells number may provide useful information on disease activity. Level of TLR2 expression on leukemic B cells may be an important factor of immunological dysfunction for patients with CLL. Our study suggests that TLR2 could becomes potential biological markers for the clinical outcome in patients with CLL.

Acquired hemophilia in the patient suffering from rheumatoid arthritis: case report.

Acquired hemophilia is a severe bleeding diathesis caused by autoantibodies against a coagulation factor VIII (FVIII inhibitor). Massive bleeding diathesis, often life threatening are observed in almost 90% of patients. In 50-60% of cases, inhibitor emerges spontaneously. However, there are some conditions like pregnancy, puerperium, autoimmune disorders or cancers that seem to induce acquired hemophilia. We report a case of a 49-year-old woman suffering from rheumatoid arthritis (RA) for several years, who was diagnosed with acquired hemophilia in September 2011. The patient had been treated by steroids and leflunomide during the last few months. At the time of diagnosis, diffuse bruising of the forearms and the trunk was observed. The patient was treated with recombinant activated factor VII, and the first-line immunosuppressive therapy was introduced (cyclophosphamide and prednisone). We observed the elimination of symptoms and the disappearance of diathesis. Significant reduction of the titer of inhibitor was achieved, but only partial remission was obtained. It lasted until the beginning of December 2011, when the titer of the inhibitor increased again and massive bleeding to the left lower limb occurred. It was necessary to administer recombinant factor VIIa together with the second-line immunosuppressive therapy based on the Budapest protocol. The rapid reduction of the diathesis and improvement of the patient's general condition was achieved as previously. However, still there was no complete remission. After 2 weeks of treatment, the titer of inhibitor diminished, and factor VIII activity increased slightly. Because of RA, the patient was treated with methylprednisolone in maintenance doses during the next few weeks. Unfortunately, after over a month, the increase of inhibitor titer and the decrease of FVIII level were observed again. Some bruises appeared. It was necessary to increase doses of corticosteroids to therapeutic levels and add cyclophosphamide in low doses to prevent the appearance of more hemorrhagic diathesis. Partial remission was achieved a second time at the end of April 2012. The patient was given methylprednisolone with chloroquine as a maintenance treatment and the control of RA. The titer of the inhibitor increased again in June 2012, but there were no signs of diathesis. In August 2012, some bruises were detected, and we decided to add cyclophosphamide again instead of escalating the doses of methylprednisolone to prevent the occurrence of side-effects of corticosteroids. Cyclophosphamide was given with intervals only depending on activated partial thromboplastin time. No further diathesis was observed in spite of the lack of remission. We were forced to withdrawn cyclophosphamide completely in October 2012 because of signs of hematuria. Fortunately, right nephrolithiasis and urinary tract infection were the cause of that condition. These symptoms vanished after standard supportive treatment. Maintenance doses of corticosteroids and chloroquine were continued as the main treatment. The patient's condition was good, but the titer of inhibitor increased over the value that had been detected at the time of diagnosis, and some bruises appeared again at the end of January 2013. The decision to use rituximab as the next-line therapy was made. This anti-CD20 monoclonal antibody is primarily used in the management of lymphomas. However, it has been successfully applied in the management of various autoimmune conditions. The usual treatment regime involves four separate intravenous infusions of 375 mg/m each, administered at weekly intervals. At the time of admission to the hospital in the second half of February 2013, the titer of inhibitor was dangerously high, almost three times more than the initial level. Fortunately, only a few bruises were observed, and no bypassing agents were needed. The patient was given the whole-planned therapy. Concomitant continuation of maintenance doses of corticosteroids was necessary to enforce the effect of eradication of inhibitor because of high levels of its titer during rituximab administration. It prevented the patient from massive diathesis that might occur. The laboratory tests were improving during the next subsequent weeks after the last dose of rituximab. Over a month later, a significant decrease of the titer of inhibitor and an increase of factor VIII activity was observed. Probably, the laboratory tests will be improving during the next few weeks. The patient is in outpatient care now. She is treated with maintenance doses of corticosteroids and chloroquine as the main treatment of RA. We will try to withdraw corticosteroids unless it is not feasible to achieve complete remission. We will have to introduce another kind of immunosuppressive agent in case of recurrence.

[Isotype switching of produced immunoglobulins in multiple myeloma]. / Przelaczanie klasy produkowanych immunoglobulin w szpiczaku mnogim.

Multiple myeloma is usually characterized by production of a single serum monoclonal protein of constant isotype and light chain restriction. Isotype switching in human lymphomas appears to be an uncommon event. It could be due to altered para-protein production by the malignant plasma cell clone, or oligoclonal Ig production during recovery of B-cell function after chemotherapy. We describe a case of clonal heavy chain isotype switching in a patient with lymphoplasmocytic lymphoma.