The Journal of Immunology, 2006, 177: 4943-4944.
Copyright © 2006 by The American Association of Immunologists, Inc.
IN THIS ISSUE
New RA Treatment Targets
Serum amyloid A (SAA) is elevated in sera of patients with rheumatoid arthritis (RA), and one of its receptors, formyl peptide receptor-like 1 (FPRL1), is overexpressed in inflamed synovial tissue. However, it is not known if SAA or FPRL1 is involved directly in RA pathology. Incorporation of [3H]thymidine and viability of RA fibroblast-like synoviocytes increased in a dose-dependent fashion after Lee et al. (p. 5585
) treated them with SAA; responses of SAA-treated synoviocytes from patients with osteoarthritis (OA) were less pronounced. SAA also blocked NO- or cycloheximide-induced apoptosis. Both mRNA and protein expression levels of FPRL1, measured by Northern blotting and ligand binding, respectively, were higher in RA than OA synoviocytes. Transfection of RA synoviocytes with a short interfering RNA to FPRL1 resulted in its specific mRNA loss, protein reduction, and diminished proliferation and survival of the cells in response to SAA. Both SAA and a FPRL1 ligand induced greater intracellular release of Ca2+ over baseline values in RA vs OA cells. Increased phosphorylation of several molecules downstream of FPRL1 and increased expression of a cell cycle protein and an antiapoptotic protein were seen in SAA-treated RA cells. SAA-treated HUVECs had greater DNA synthesis, increased migration from a wound, and more differentiation into tube-like structures than untreated cells. Sprouting of endothelial cells from rat aorta rings increased in ex vivo and in vivo Matrigel plug angiogenesis assays in the presence of SAA; hemoglobin content of the in vivo Matrigel plugs was 10-fold higher than control gels. The data indicate that proliferation of RA synoviocytes and angiogenesis of endothelial cells are stimulated by binding of SAA to FPRL1 and mediated by activated Ca2+ and several downstream molecules. The authors propose SAA and FPRL1 as targets for treatment of RA.
Silencing IDO in Tumors
Tumor cells can evade or escape immune detection through production of IDO, an enzyme that catabolizes tryptophan. The result is increased apoptosis and decreased activation and proliferation of T cells, especially CTLs. By transfecting a short interfering RNA (siRNA) against IDO into mouse melanoma cells, Zheng et al. (p. 5639
) shut off IDO mRNA and reduced IDO protein synthesis. Media of melanoma cells treated with IDO-siRNA or a chemical inhibitor of IDO had higher levels of tryptophan and lower levels of its catabolite, kynurenine, than those of untreated tumor cells. Melanoma onset was delayed, and tumor size was significantly decreased in mice injected with IDO-siRNA-silenced tumor cells; tumor growth was partially inhibited by pretreatment of melanoma cells with the chemical inhibitor. Fewer apoptotic spleen and lymph node T cells and a higher percentage of CD8+ T cells were obtained from mice injected intratumorally with IDO-siRNA compared with controls, and the IDO-siRNA-injected tumors grew more slowly. Supernatant from IDO-silenced melanoma cells was less effective than supernatant from untreated tumor cells in suppressing proliferation of T cells activated by anti-CD3 mAb or by IDO-silenced dendritic cells (DCs) in a MLR. CD8+ T cells from tumor-bearing mice exhibited increased tumor-specific lysis of IDO-siRNA-treated vs untreated tumor cells in vitro. Ag-pulsed IDO-silenced DCs presented Ag more effectively to T cells in vivo than DCs expressing IDO. The data indicate that siRNA silencing of IDO in mouse melanoma cells effectively reverses tumor-induced T cell suppression.
CNS Targets in MS
Inflammatory demyelination is considered to be the primary lesion in chronic multiple sclerosis (MS). However, the Qin laboratory recently demonstrated binding of single chain variable fragment (scFv)-Abs derived from B cells in the cerebral spinal fluid of MS patients to axons in MS brain lesions. In a continuation of that work, Kolln et al. (p. 5652
) in the Qin laboratory identified two proteins in normal and MS brain extracts that reacted with Igs from cerebral spinal fluids of MS patients. The proteins were identified as triosephosphate isomerase (TPI) and GAPDH. ELISA detected anti-TPI and anti-GAPDH Abs in the cerebral spinal fluid of MS patients. Elevated levels of anti-TPI Abs were found in patients with clinically isolated syndrome suggestive of MS, with other inflammatory neurological diseases, and with other noninflammatory neurological diseases; levels of anti-GADPH Abs were highest in the MS patients. Simultaneous detection of Abs to both proteins was almost exclusively in MS patients. Elevated levels of the anti-TPI and anti-GAPDH Abs were measured in sera of the four groups of patients and in healthy controls, indicating that only the CNS reaction was MS specific. Axonal-reactive scFv-Abs were generated from clonal B cells in the cerebral spinal fluid of patients with clinically isolated syndrome and from a MS brain lesion. All reacted with TPI and GAPDH on immunoblots, whereas a control scFv-Ab did not. This identification of TPI and GAPDH as targets in MS suggests that Ag-driven B cell clonal expansion in the CNS of MS patients is a major factor in progressive axon loss.
Age-Specific Schistosoma Responses
Schistosomiasis, which occurs with high frequency in a large number of countries, is treated successfully with the drug praziquantel. However, posttreatment susceptibility to reinfection by cercariae of the nematode Schistosoma is highest among children vs adults. To determine the immunological basis for this difference in reinfection rates, Walter et al. (p. 5490
) looked at pretreatment and 7-wkposttreatment Ig responses to S. mansoni soluble egg Ag, soluble worm Ag, and worm tegument Ag among individuals in a Ugandan fishing community. Pre- and posttreatment Ig responses to soluble egg Ag did not change much with age, except for the IgE response, which increased posttreatment only among 13–16 year olds. In contrast, pretreatment IgG1, IgG2, IgG4, and IgE responses to soluble worm Ag increased with age. Posttreatment increases in IgA, IgG4, and IgE responses to soluble worm Ag were restricted to patients older than 15 years, and the IgE levels correlated negatively with pretreatment infection levels. Posttreatment increases in IgG1, IgG4, and IgE to worm tegument Ag were seen only in patients older than 13 years. With regard to cytokine responses in children, both pre- and posttreatment antisoluble worm Ag IgE levels strongly correlated with pretreatment IL-5 levels as measured by response of whole blood cultures to soluble worm Ag. Pretreatment IL-5 and/or IL-13 levels also positively correlated with posttreatment levels of various Ig subclasses against soluble worm Ag and worm tegument Ag among adults. The authors propose that the relative resistance of adults and greater susceptibility of children to posttreatment reinfection with S. mansoni is due, in part, to greater pretreatment IL-5 responses and treatment-induced antiworm-specific IgE responses within the population older than 15 years.
RANTES and RA Inflammation
Data from the Pope laboratory show that induced arthritis in rodents is alleviated by inhibition of RANTES, abundant in joints of patients with rheumatoid arthritis (RA), before but not after onset of disease. These results suggest a role for RANTES beyond monocyte chemotaxis. Shahrara et al. (p. 5077
) found that incubation of human peripheral blood monocytes with RANTES before LPS stimulation reduced IL-6 and TNF-
secretion by 40%; p38 MAPK phosphorylation was induced. LPS-induced p38 activation was increased, and IL-6 but not TNF- mRNA synthesis was suppressed by RANTES. Preincubation of the cells with anti-CCR1 plus anti-CCR5 Abs, with a RANTES antagonist, or with anti-IL-10 Ab reversed the RANTES-induced cytokine suppression. IL-10 was not released from cells treated with RANTES alone or from LPS-stimulated RANTES-treated cells transfected with a short interfering p38 MAPK RNA. Although LPS induced IL-6 secretion from RA synovial fibroblasts, pretreatment with RANTES had no effect. RANTES induced and increased LPS-induced p38 MAPK phosphorylation in RA synovial fibroblasts, but LPS did not induce IL-10 release in the absence or presence of RANTES. Ab neutralization of RANTES in RA synovial fluids in vitro resulted in induction of TNF- from monocytes without LPS stimulation, in increased LPS-induced TNF-, and in reduced LPS-induced IL-10 production. The authors show that RANTES suppression of LPS-induced IL-6 and TNF- secretion from human monocytes and RA synovial fibroblasts is mediated through CCR1 and CCR5, p38 MAPK, and IL-10.
Carping about the Lectin Pathway
Homologs of mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs), components of the lectin pathway of C activation, are found in arthropods, coral, and cartilaginous and bony fish. However, evidence for evolution of the lectin pathway from the minimum prototype in invertebrates to the mammalian system is lacking. Nakao et al. (p. 5471
) looked for a functional lectin pathway in a bony fish, the common carp (Cyprinus carpio). They purified from carp serum a MBL-like lectin, with an oligosaccharide-binding spectrum identical with that of human MBL, and a galactose-binding lectin (GalBL). Both lectins were associated with a MASP2/C1s-like serine protease that cleaved native C4. Carp MBL1 and MBL2 were cloned by 3'- and 5'-RACE and were found by amino acid sequencing to contain the typical MBL domain organization with 37% identity to human MBL. Phylogenetically, the MBLs form a cluster in the bony fish clade separate from that of GalBLs, indicating that GalBLs evolved after divergence of bony fish from a common ancestor. The carp MASP, identified by two-dimensional SDS-PAGE, was highly homologous at the amino acid level to human MASP2 and retained its domain structure. MBL and GalBL were detected as single copies and MASP2 as a double copy in the carp genome. This study shows that a bony fish, the carp, evolved a functional lectin pathway consisting of MBL and GalBL that associate with MASP2 to activate C4.
Biomarker for MS
The clinical course of multiple sclerosis (MS) varies greatly among individuals and is highly unpredictable. In searching for an MS biomarker, Aranami et al. (p. 5659
) looked at the distribution of a population of NK cells expressing the dendritic cell (DC) marker, CD11c, among 10 healthy individuals and 25 MS patients in clinical remission. Almost all NK cells in MS patients were CD11c+ compared with 20–80% in the controls; however, the mean fluorescence index of CD11c expression on CD11c+ cells was considerably higher in the MS patients. The patients were divided into two groups, expressing either a high or a low level of CD11c+. NK and CD4+ T cells from the CD11chigh group had higher surface levels of HLA-DR, but NK cells from the CD11clow group had higher levels of IL-5 and GATA-3 mRNA than those from the CD11clow group or healthy controls. NK cells from healthy individuals cultured with IL-15 or IL-12 plus IL-18 up-regulated CD11c expression. Relapse of CD11chigh MS patients in remission occurred at a higher frequency than CD11clow MS patients (60 vs 15%) over a 120-day period; earlier relapse was seen for CD11chigh patients younger than 38.5 years and for females. Relapse was characterized by a decline in CD11c expression on NK cells, with the highest relapse rate occurring among patients whose cells were CD95highCD11chigh. The authors propose that a high level of CD11c expression on peripheral NK cells in MS patients in clinical remission is an indicator for relapse.
Summaries written by Dorothy L. Buchhagen, Ph.D.
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