Asthma is characterized by airway hyperresponsiveness and increased mucus secretion. This is partly due to an influx of Th2 cells that home to the lung, usually in response to an inhaled environmental Ag. A number of chemokines and chemoattractants have been implicated in attracting these Th2 lymphocytes to the airways, but attempts to dissect out which specific molecules might be responsible have not given clear-cut results. Building on previous evidence that Th2 lymphocyte and eosinophil recruitment to the lung is dependent on STAT6 expression, Medoff et al. (p. 623) used STAT6−/− mice to determine in what locality this transcription factor must be expressed to effect efficient chemotaxis. They found that STAT6 expression in the bone marrow was sufficient for production of CCL17, CCL22, CCL11, and CCL24 chemokines. Bone marrow expression of STAT6 was also sufficient for eosinophil and Th2 lymphocyte recruitment to the airway site. Surprisingly, local expression of STAT6 in the airway epithelia was not responsible for either the chemokine production or the cell recruitment necessary for developing asthmatic Th2-driven responses. CD11b+ myeloid cells were determined to be the source of CCL17 and CCL22 by selective depletion. Thus, CD11b+ myeloid cells coordinate the adaptive immune responses that cause asthma through a mechanism dependent on STAT6 expression in the bone marrow.

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-α 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.

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-γ−/−, perforin−/−, or IFN-γ−/−perforin−/− mice. Lymphocytes isolated from the liver and treated with 20d5 secreted IFN-γ 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 NK1iNKT 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 α-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.

Mast cells (MCs) are known to be important in the development of autoimmune arthritis, as their abundance in the synovial tissues of rheumatoid arthritis (RA) patients indicates. However, what role MCs play in joint inflammation and cartilage loss remains unclear. One possible mechanism involves the mast cell-derived tryptase:heparin complexes that are present in significant amounts in the synovium of RA patients and have demonstrated proinflammatory activity. Using the knowledge that the murine ortholog of tryptase, MC protease-6 (mMCP-6), is present in the synovial fluid of arthritic mice, Shin et al. (p. 647) tested the role of these serine protease:heparin complexes in developing arthritic responses. Mice that lacked these tryptase:heparin complexes displayed attenuated arthritic responses. The authors also confirmed that mMCP-6 was the tryptase responsible for arthritic neutrophil infiltration with a serum transfer model of arthritis in K/BxN mice. The inflammation in this model was dependent on the chemokine receptor CXCR2, and when synovial fibroblasts were cultured in the presence of human tryptase:heparin or mMCP-6:heparin there was increased expression of CXCL1, CXCL5, and CXCL8. mMCP-6-deficient mice also avoided the loss of cartilage-derived proteoglycans. Thus, the authors demonstrate that the tryptase:heparin complexes produced by MCs play an important role in inflammation development and tissue destruction in autoimmune arthritis.

Systemic lupus erythematosus (SLE) is currently treated with nonspecific immunosuppression, a therapy that is characterized by side effects and incomplete responses. The peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ agonists, through an adiponectin-dependent protective mechanism, may provide more specific treatment options against lupus with fewer side effects.

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 CD4CD8 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.

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.

The adaptor protein Rai (ShcC) was originally identified in neuronal cells where it supports cell survival through the PI-3K/Akt pathway. Drawing from data that Rai−/− mice developed splenomegaly, Savino et al. (p. 301) examined the expression of Rai in lymphocytes and found it present in T and B cells. However, contrary to its survival role in neuronal cells, Rai expression correlated with enhanced spontaneous apoptosis in lymphocytes. Compared with wild-type mice, Rai−/− animals demonstrated a reduced number of peripheral T cells and increased numbers of B cells. Rai−/− lymphocytes were hyperproliferative in culture when stimulated through their Ag receptors. This hyperproliferative phenotype was consistent in vivo, where Rai−/− mice showed enhanced responses to a 2,4,6-trinitrochlorobenzene (TNCB2)-DTH assay. Considering these results, it was not surprising that a large proportion of the Rai−/− mice developed autoimmune glomerulonephritis. This syndrome consisted of the afore-mentioned splenomegaly, anti-dsDNA Abs, activated T and B cells, and kidney immune complex deposition. These data demonstrate that, unlike its role in neuronal tissues, Rai acts in lymphocytes as a negative regulator and that loss of this factor leads to hyperreactive lymphocytes and the development of autoimmunity.

Summaries written by Kira R. Gantt, Ph.D.