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Finding the STAT6 Highway
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Adjuvants Made Simple
The mycobacterial cell wall components in CFA and the Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine have long been known to have a strong immunostimulatory effect. This is due to the mycobacterial components’ ability to directly stimulate APCs. However, the specific mycobacterial lipid that might be causing this stimulation has yet to be identified. Andersen et al. (p. 424
) used human primary dendritic cells to determine that a very simple monomycolated glycerol (MMG) lipid derived from BCG was responsible for potent stimulation of APCs. Treatment of human dendritic cells with this nonpolar lipid caused up-regulation of CD86, CD40, and HLA-DR surface expression and subsequent secretion of TNF-
and IL-6. By comparison, polar lipids isolated from BCG did not elicit the same response. A 32-carbon synthetic analog of MMG with shorter fatty acids was found to elicit a comparable dendritic cell response to that of MMG. A strong Th1 response was elicited from mice that were immunized with a cationic liposome preparation that included MMG or the 32-carbon synthetic analog with the mycobacterial vaccine Ag Ag85B-ESAT-6. With this simple nonpolar lipid, the authors have potentially identified a new class of vaccine adjuvants for use against infectious agents.
Controlling iNKT cells
Concanavalin A-induced hepatitis is considered to be dependent on the activation of invariant natural killer T (iNKT) cells, which are preferentially found in the liver. However, what role NK cell receptors play in this activation is still under investigation. Kawamura et al. (p. 250
) used the antagonistic mAb 20d5 to block signaling through the inhibitory NK cell receptor NKG2A that is preferentially expressed on iNKT cells. Treatment with 20d5 exacerbated Con A-induced hepatitis in normal, gld, and IL-4–/– mice. This increase in disease was found even with NK and CD8+ T cell depletion. 20d5 treatment did not exacerbate Con A-induced hepatitis in IFN-
–/–, perforin–/–, or IFN-–/–perforin–/– mice. Lymphocytes isolated from the liver and treated with 20d5 secreted IFN- and had increased perforin-mediated cytotoxicity, although the exposure to Ab had no effect on FasL/Fas-mediated killing. After Con A injection, activated iNKT cells were observed to disappear from the liver, but NK1–iNKT cells expressing CD94/NKG2A remained. However, pretreatment with 20d5 facilitated the disappearance of iNKT cells from the liver, including the NK1– iNKTs. When CD94/NKG2A–/– mice were treated with Con A or -galactosylceramide they developed a more severe form of hepatitis than mice that expressed CD94/NKG2A. Thus, signals mediated through the NKG2A inhibitory receptor negatively regulate injury in hepatitis and iNKT cell activation.
Arthritic Mast Cells in Mice and Men
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Good for Diabetes and Lupus
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(PPAR) agonist rosiglitazone, used for the treatment of diabetes mellitus, also up-regulates the production of adiponectin. In the search for a more specific and effective SLE treatment, Aprahamian et al. (p. 340
) built on previous data that administering adiponectin ameliorated lupus in a mouse model and examined the action of rosiglitazone in these animals. The authors found that administering rosiglitazone reduced atherosclerosis, kidney disease, and autoantibody production in murine models of SLE. In lupus-susceptible mice deficient in adiponectin, rosiglitazone had no effect. Further evidence that adiponectin protected against SLE was found as lupus-susceptible mice deficient in adiponectin suffered from more severe disease than mice that expressed adiponectin. Adenovirus expressing adiponectin was able to reverse this defect and mice subsequently showed reduced levels of antinuclear Abs and glomerular infiltrate. These data suggest that the use of PPAR agonists, through an adiponectin-dependent protective mechanism, may provide more specific treatment options against lupus with fewer side effects. Defining cTEC
Interactions between immature thymocytes and thymic epithelial cells (TECs) are vital for the selection of self-tolerant T cells that have the correct MHC restriction. However, the mechanism by which cortical TECs (cTECs) originate and develop has been largely unknown. Shakib et al. (p. 130 ) exhaustively tracked the development of EpCAM1+CD205+ cTECs from embryonic day 12 (E12) when these cells arose from multipotent progenitors expressing EpCAM1. Gene expression analysis of the EpCAM1+CD205+ cTECs revealed that at E12, CD205 expression correlated with the expression of a cTEC-specific proteosome subunit β5t. Nude mice lacking FoxN1 failed to develop the CD205-, β5t-expressing cTEC population in the thymus, indicating that the existence of cTECs is dependent on the presence of FoxN1. The authors also looked at the expression of CD40 and MHCII on cTECs and found that MHCII was found on the surface of these cells before CD40 expression. The expression of these two markers that help define cTEC maturation was determined by the presence of CD4–CD8– thymocytes. However, CD205+ cTECs were able to proliferate to some extent without the presence of these double negative thymocytes. Thus, normal development of thymic cortical epithelial cells and accrual of the correct maturation markers depend on the presence of FoxN1 and double negative thymocytes.
MFG-E8 Dependence on CD14
Without normal phagocytosis of apoptotic material, dying cells release a host of inflammatory and antigenic materials that can lead to diverse negative effects. Sepsis, caused by infection, leads to widespread release of proinflammatory cytokines, apoptosis of lymphocytes, and subsequent immunosuppression as the body attempts to adapt. The milk fat globule epidermal growth factor-factor VIII (MFG-E8) is homologous to human lactadherin and partially constitutes milk fat globules. MFG-E8 also plays an important role in promoting the phagocytosis of apoptotic cells and improving sepsis survival. The expression of MFG-E8 is down-regulated in the presence of LPS. Knowing that LPS is elevated in sepsis, Komura et al. (p. 581 ) tested the hypothesis that MGF-E8 down-regulation occurs through CD14. With a polymicrobial sepsis model of cecal ligation and puncture (CLP) or peritoneal administration of endotoxin, the authors analyzed CD14–/–, TLR4-mutated, and wild-type (WT) mice. WT mice had a 49% suppression of MFG-E8 mRNA and a 33% suppression of MFG-E8 protein during sepsis. CLP treatment of WT mice caused a 30% reduction in the phagocytic ability of peritoneal macrophages, an effect not seen in similarly treated CD14–/– mice. LPS administration reduced MFG-E8 mRNA in a dose-dependent fashion. Neither CD14–/– nor TLR4-mutated mice had CLP-dependent MFG-E8 suppression, indicating a dependence on the CD14 pathway. The number of apoptotic cells in WT mice treated with CLP was increased over that of CLP-treated CD14–/– mice. Thus, sepsis leads to down-regulated MFG-E8 through a CD14-dependent mechanism, and subsequent phagocytosis of apoptotic cells is diminished.
"Rai"-sing Autoimmunity
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Summaries written by Kira R. Gantt, Ph.D.
Related articles in The JI:
Agonist Rosiglitazone Ameliorates Murine Lupus by Induction of Adiponectin
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