Objective. CD22 is a surface molecule exclusively expressed on B cells that regulates adhesion and B cell receptor (BCR) signaling as an inhibitory coreceptor of the BCR. Central downstream signaling molecules that are activated upon BCR engagement include spleen tyrosine kinase (Syk) and, subsequently, phospholipase C␥2 (PLC␥2), which results in calcium (Ca 2؉ ) mobilization. The humanized anti-CD22 monoclonal antibody epratuzumab is currently being tested in clinical trials. This study was undertaken to determine the potential mechanism by which this drug regulates B cell activation.Methods. Purified B cells were preincubated with epratuzumab, and the colocalization of CD22 and CD79␣, without BCR engagement, was assessed by confocal microscopy. Conclusion. These findings are consistent with the concept of targeting CD22 to raise the threshold of BCR activation, which could offer therapeutic benefit in patients with autoimmune diseases.Antigen binding to the cognate B cell receptor (BCR) induces intracellular activation signals, usually resulting in differentiation, proliferation, or, alternatively, apoptosis of B cells. An intact BCR is a requirement for differentiation of naive and, in part, memory B cells into plasma cells, based on BCR engagement together with costimulatory activation. This pathway also results in immunoglobulin class switching and somatic hypermutation, characteristics known to establish B cell memory. Furthermore, an intact antigen receptor signal is an essential precondition for B cell maturation from pre-B cells to the immature stage, and for the survival of mature B cells (1,2).CD22 is an inhibitory coreceptor of the BCR that is exclusively expressed on B cells (3). It plays a key role in setting the threshold of the BCR response (3-5). Engagement of CD22 initiates its phosphorylation, which subsequently activates SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1) and leads to attenuation of BCR signaling via dephosphorylation of Supported by the DFG (Collaborative Research Centre grant 650/TP16 and DFG grant 491/7-1) and in part by UCB

Summary:Purpose: The aim of this study was to determine the long-term case fatality of patients with a first episode of status epilepticus (SE group) of cerebrovascular etiology, as compared with that in acute stroke patients without SE (AS group).Methods: Patients with SE who had been prospectively admitted to an epidemiologic study were retrospectively compared with a cohort of patients from the local stroke registry. The main outcome end point was overall survival. Survival curves were generated according to the Kaplan-Meier method and compared by using the log-rank test. An extended Cox model was used to examine the impact of patient group on the risk of death. Covariates considered potential confounders included age at diagnosis, sex, type of stroke, affected hemisphere, and localization of lesions.Results: Of 166 patients who entered the study, 93 patients were in the SE group, and 73 patients were in the AS group; 53 SE patients and 35 AS patients died during the study. Patient group (SE vs. AS) showed no significant impact on survival (p = 0.0832) in univariate analysis. In contrast, the results from a multivariable analysis suggest that after 6 months, patients with SE were at about twice the risk of death as were patients with AS [hazard ratio of 2.12 with 95% confidence interval, 1.04-4.32, p = 0.0392].Conclusions: The occurrence of SE in patients with cerebrovascular disease indicates a high risk of death within 3 years. In contrast, the case fatality risk attributable to recurrent status or seizures is lower. Key Words: Long-term mortality-Case fatality-Risk factors-Causes of death-Status epilepticus.Status epilepticus (SE) is a major neurologic emergency with an incidence of ∼20/100,000 for the white population in industrialized countries. Several studies have described determinants of mortality among patients with SE (Lowenstein and Alldredge, 1998). Most of these studies have investigated mortality after SE up to a maximum follow-up period of <1 year, mostly up to 30 days or to discharge from hospital (Aminoff and Simon, 1980;Barry and Hauser, 1993;Scholtes et al., 1994;Towne et al., 1994;Logroscino et al., 1997).SE was associated with short-term mortality rates of ∼20% (Hauser, 1990;DeLorenzo et al., 1995;Logroscino et al., 1997;Lowenstein and Alldredge, 1998;Knake et al., 2001;Rosenow et al., 2002;Wu et al., 2002). Patient age at diagnosis, etiology of SE (especially anoxia), severity of the underlying disease. and duration of SE were main predictors of increased short-term mortality (Hauser, 1990;Lowenstein and Alldredge, 1998;Wu et al., 2002 In contrast, available reports examining long-term mortality after SE are sparse. Only one recent study systematically analyzed mortality at more than 10 years after the first episode of SE and found an increased long-term mortality of 43%, significantly associated with older age, status duration >24 h, acute symptomatic etiology including stroke, and myoclonic SE caused by hypoxic brain injury (Logroscino et al., 2002).The authors concluded that SE alone...

Objective. Systemic lupus erythematosus (SLE) is characterized by B cell hyperactivity and autoantibody production. As spleen tyrosine kinase (Syk) is pivotal in B cell activation, these experiments aimed to examine the extent to which Syk was abnormally expressed in SLE B cells and the nature of the B cell subset that differently expressed Syk.Methods. B cells from healthy donors and SLE patients were analyzed by flow cytometry to assess basal expression of Syk and phosphorylated Syk. B cell subsets expressing higher levels of Syk were found, and their detailed phenotype, in vitro differentiation into plasmablasts/plasma cells, and Syk induction by cytokines were determined. Conclusion. SLE patients exhibit an increased frequency of hitherto unknown CD27؊Syk؉؉ memorylike B cells, indicating that intracellular Syk density could distinguish CD27؊ memory B cells from truly naive B cell subsets. Furthermore, the CD27؊Syk؉؉ subset is a candidate for a source of increased plasma cells in SLE.B cell activation is a complex process involving different soluble and cellular components and, most importantly, if antigen-dependent, binding of the antigen to the B cell receptor (BCR). After BCR ligation, reorganization of autoregulatory BCR clusters with recruitment of intracellular kinases and subsequent internalization of the cognate antigen (1) initiate an intracellular signaling cascade by phosphorylation of the associated BCR molecules CD79␣ and CD79␤. In this process, other signaling molecules, such as Lyn, spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (BTK), and phospholipase C␥2 (PLC␥2) are recruited and activated in an ordered manner to fine-tune BCR signaling. After BCR engagement, Syk becomes phosphorylated (tyrosine residues Y 348 and Y 352 ), induced by immunoreceptor tyrosine-based activation motifs (ITAMs) on the cytosolic tail of the BCRϪCD79 complex (2).Several studies have linked the development of murine lupus to abnormalities of BCR-associated signalSupported by the DFG (SFB650 project TP16, SFB633 A14, SPP ImmunoBone DFG Do491/8-2, and DFG project Do491/7-3).