Showing papers by "Jo Spencer published in 2011"

Bench-to-bedside review: Immunoglobulin therapy for sepsis - biological plausibility from a critical care perspective

Abstract: Sepsis represents a dysregulated host response to infection, the extent of which determines the severity of organ dysfunction and subsequent outcome. All trialled immunomodulatory strategies to date have resulted in either outright failure or inconsistent degrees of success. Intravenous immunoglobulin (IVIg) therapy falls into the latter category with opinion still divided as to its utility. This article provides a narrative review of the biological rationale for using IVIg in sepsis. A literature search was conducted using the PubMed database (1966 to February 2011). The strategy included the following text terms and combinations of these: IVIg, intravenous immune globulin, intravenous immunoglobulin, immunoglobulin, immunoglobulin therapy, pentaglobin, sepsis, inflammation, immune modulation, apoptosis. Preclinical and extrapolated clinical data of IVIg therapy in sepsis suggests improved bacterial clearance, inhibitory effects upon upstream mediators of the host response (for example, the nuclear factor kappa B (NF-κB) transcription factor), scavenging of downstream inflammatory mediators (for example, cytokines), direct anti-inflammatory effects mediated via Fcγ receptors, and a potential ability to attenuate lymphocyte apoptosis and thus sepsis-related immunosuppression. Characterizing the trajectory of change in immunoglobulin levels during sepsis, understanding mechanisms contributing to these changes, and undertaking IVIg dose-finding studies should be performed prior to further large-scale interventional trials to enhance the likelihood of a successful outcome.

Pivotal Advance: CD45RB glycosylation is specifically regulated during human peripheral B cell differentiation

Abstract: A screen of cell surface markers differentially expressed during peripheral B cell differentiation identified that the CD45RB epitope detected by the mAb MEM-55 was highly expressed on CD27(+) memory B cells and absent on CD27(-) naive B cells. IgG(+)CD27(-) memory and a previously unacknowledged CD27(-) population in blood also expressed high levels of CD45RB(MEM55). Naive and memory B cells from tonsils followed the pattern observed in blood, and CD38(high) B cells had a bimodal expression pattern when analyzed using flow cytometry. No CD38(high) GC B cells, however, expressed the CD45RB(MEM55) epitope when assayed using immunohistochemistry. Rather, CD38(high)CD45RB(MEM55high) B cells had a distinct cellular phenotype and were localized outside of GCs. CD45RB epitopes, detected by other antibody clones, were expressed at high levels through B cell differentiation, and no changes in splicing of the CD45RB exon were observed during B cell differentiation. Instead, B cells regulated their expression of the CD45RB(MEM55) epitope through site-specific modifications of an O-linked glycochain. CD4(+) T cells differentially spliced CD45 but did not vary the glycosylation of the CD45RB(MEM55) epitope, and CD8(+) cells modified CD45RB(MEM55) expression in a similar manner as B cells. Monocytes expressed the CD45RB exon but not the CD45RB(MEM55) epitope. As CD45 is a highly expressed tyrosine phosphatase that regulates antigen receptor signaling strength in lymphocytes, we conclude that regulated O-linked glycosylation of CD45RB can be used to follow B cell differentiation and that this regulation may be involved in fine-tuning antigen signaling in the cell.

Transitional B cells: how well are the checkpoints for specificity understood?

Abstract: It is crucial for the immune system to minimise the number of circulating mature self-reactive B cells, in order to reduce the potential for the development of autoantibody-related autoimmune diseases. Studies of animal models have identified two major checkpoints that ensure that such cells do not contribute to the naive B cell repertoire. The first is in the bone marrow as B cells develop and the second is in the spleen; B cells that are released from the bone marrow as transitional B cells go through more stringent selection in the spleen before they develop into mature naive B cells. Transitional B cells and their maturation have mostly been studied in mice. However, recent studies characterised human transitional B cells and found considerable differences to current models. In this review, we will consider these differences alongside known differences in mouse and human splenic function and ask whether human transitional B cells might develop along a different pathway.