Independent and Opposing Roles For Btk and Lyn in B and Myeloid Signaling Pathways

Transphosphorylation by Src family kinases is required for the activation of Bruton's tyrosine kinase (Btk). Differences in the phenotypes of Btk−/− and lyn−/− mice suggest that these kinases may also have independent or opposing functions. B cell development and function were examined in Btk−/−lyn−/− mice to better understand the functional interaction of Btk and Lyn in vivo. The antigen-independent phase of B lymphopoiesis was normal in Btk−/−lyn−/− mice. However, Btk−/−lyn−/− animals had a more severe immunodeficiency than Btk−/− mice. B cell numbers and response to T cell–dependent antigens were reduced. Btk and Lyn therefore play independent or partially redundant roles in the maintenance and function of peripheral B cells. Autoimmunity, hypersensitivity to B cell receptor (BCR) cross-linking, and splenomegaly caused by myeloerythroid hyperplasia were alleviated by Btk deficiency in lyn−/− mice. A transgene expressing Btk at ∼25% of endogenous levels (Btklo) was crossed onto Btk−/− and Btk−/−lyn−/− backgrounds to demonstrate that Btk is limiting for BCR signaling in the presence but not in the absence of Lyn. These observations indicate that the net outcome of Lyn function in vivo is to inhibit Btk-dependent pathways in B and myeloid cells, and that Btklo mice are a useful sensitized system to identify regulatory components of Btk signaling pathways

Osteonecrosis of the femoral head in patients with type 1 human immunodeficiency virus infection: clinical analysis and review

Osteonecrosis of the femoral head (ONFH) typically affects relatively young, active patients and frequently follows an unrelenting course resulting in considerable loss of function. In human immunodeficiency virus-infected patients, ONFH is a growing problem. Etiology, pathogenesis, and treatment of ONFH in these patients remain controversial. We analyzed retrospectively patients with ONFH in a series of 815 patients followed in our AIDS reference center. Six patients out of the 815 were affected by ONFH (0.74%). The sex ratio was 1. Two of the six patients (33.3%) had no evidence of risk factor, whereas four patients (66.6%) had risk factors. One patient had three cumulated risk factors which were corticosteroids, chemotherapy, and radiotherapy. For this patient, the onset time for ONFH was shorter (36 months). It is difficult to attribute the effect to any single class of antiretroviral agents because combination therapy is standard of care, and a change in therapies is common. All classes of antiretroviral drugs have been used: protease inhibitors (mean use duration of 15.2 months before the ONFH onset), non-nucleoside reverse transcriptase inhibitors (12 months), and nucleoside reverse transcriptase inhibitors (40.5 months). ONFH was bilateral in four cases (66.6%) and unilateral in two cases (33.3%). One patient had other osteonecrosis location (both shoulders). ONFH was classified on plain radiography stage IV in five patients and stage III in one patient. All patients received initial medical treatment. It consisted of painkillers and non-weight bearing of the hip. All were finally operated on by total hip arthroplasty (THA). The average interval between ONFH diagnosis and the first THA was 10.3 months for the six patients. A controlateral THA was performed for three patients after a mean interval of 23.3 months after ONFH diagnosis. Of the nine implanted prostheses, four were cemented, four were cementless, and one was resurfacing prosthesis