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Pax5 and osteoclast development
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IL-19 in asthma
Interleukin-19 is a new member of the IL-10 family. Although IL-10 plays an inhibitory role in allergic asthma, the involvement of IL-19 in the disease has not been explored. Liao et al. (p. 6712
) found that the average serum level of IL-19 in asthmatic pediatric patients was twice that of healthy controls, whereas levels of IL-4 and IL-13 were elevated 100-fold. In a murine model of the disease, asthmatic mice had higher levels of serum IL-19 and IL-19 mRNA in lung tissue than healthy controls. Healthy mice injected with a plasmid expressing IL-19 had increased serum levels of IL-19, IL-4, IL-5, and IL-10 vs vector-injected controls; levels of IL-13, in addition to the other Th2 cytokines, were elevated only in IL-19 plasmid-injected asthmatic mice. Injection of IL-19 plasmid further increased already high serum IgE levels in asthmatic mice. In vitro-activated mouse splenic CD4+ T cells released higher levels of all the Th2 cytokines after treatment with IL-19; IL-19 inhibited IFN-
production in in vitro-activated Th1-polarized CD4+ T cells. Similar studies on Jurkat T cells showed that IL-19 could increase IL-13 mRNA levels only in activated cells. The data suggest that IL-19 up-regulates Th2 cytokines and induces IL-13 production from activated T cells in asthmatics.
Peptide modulation of experimental autoimmune encephalomyelitis
Blocking the action of axonal regrowth inhibitors, such as the myelin protein Nogo-A, is one route to treating experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. Fontoura et al. (p. 6981
) found that following EAE-induction, Nogo-A/B/C knockout mice had reduced mortality compared with wild-type C57BL/6 controls. Peptides derived from the common C-terminal region of Nogo (Nogo-66)-induced clinical disease in wild-type mice; the most reactive peptides were Nogo1–22 and Nogo45–66 in SJL/J and Nogo1–22 and Nogo23–44 in C57BL/6 mice. Sera from immunized animals incubated with microarrays containing EAE-relevant targets demonstrated a spreading of the Ab response from the immunizing Nogo peptide to other myelin proteins and peptides. This spreading was most pronounced in SJL/J mice immunized with Nogo45–66. In contrast, Nogo-specific T cell lines developed from SJL/J animals reacted only with the immunizing peptide and not with other myelin autoantigens, and naive SJL/J mice adoptively transferred with purified Nogo-specific T cells did not develop clinical EAE. Nogo-specific T cell recipients immunized with an unrelated encephalitogenic myelin Ag had reduced clinical severity of EAE and the transferred T cells entered the CNS. Nogo45–66-specific T cells were found by in vitro cytokine assays to produce IL-4 and IL-10, whereas Nogo1–22-specific T cells produced IFN-. The authors conclude that immunization with Nogo peptides, that induce humoral and cell-mediated immunity, can both activate and ameliorate EAE.
Development of infectious memory
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Natural protection against type 1 diabetes
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cell autoimmunity is unknown. You et al. (p. 6777
) combined tetramer technology and GAD65 peptide p221 expansion of CD4+ T cells to isolate GAD-reactive T cells from unimmunized naive NOD mice. The p221/tetramer stained 14% of naive NOD spleen cells that had divided in vitro in response to stimulation for 10 days with p221 and irradiated APCs, but p221/tetramer stained only 1.5% unstimulated NOD cells and no cells incubated with a control peptide. The expanded p221+ cells expressed high levels of activation markers and secreted IL-2, IL-10, IFN-, and several other cytokines, but little IL-4 and no TGF-, in response to p221 stimulation. The cells had low avidity for p221. The p221+ cells inhibited proliferation and IFN- production of cells responding to a different peptide; addition of p221 enhanced the inhibitory effect. Transwell experiments showed that inhibition did not require cell-cell contact. IL-10 production by unactivated p221+ cells was increased by the activated target cells or by IL-2 alone. Addition of anti-IL-10 and anti-IL-10R Abs abrogated the p221+ cell-induced inhibition of proliferation. Approximately 50% of NOD/scid mice adoptively transferred with p221+ cells plus NOD splenocytes remained free of diabetes compared with no mice receiving NOD splenocytes or p221+ cells alone. The data show that spleens of naive NOD mice harbor a small population of GAD-specific, IL-10-producing regulatory CD4+ T cells that protect against type 1 diabetes. Nitric oxide mast cell cytokines
Mast cell activation and degranuation are suppressed by NO. However, it is not known whether NO has any effect on cytokine production by mast cells. Davis et al. (p. 6914
) found that several NO donors inhibited IgE/Ag-induced synthesis of IL-4, IL-6, and TNF mRNAs and cytokine release in an established mast cell line and in primary cultured bone marrow mast cells (BMMCs). Mast cell degranulation was partially inhibited in BMMCs, and phosphorylation of phospholipase C kinase-1 was significantly inhibited. Incubation of the cells with one NO donor without Ag challenge increased phosphorylation of p38 MAPK and CREB but reduced Ag-induced phosphorylation of c-Jun. NO treatment of BMMCs abrogated Ag-induced DNA binding activity of phosphorylated c-Jun, JunB, JunD, FosB, and c-Fos, and partially abrogated DNA binding activity of NFAT. However, incubation of nuclear proteins with the NO donor did not alter DNA binding activities of transcription factors. The data demonstrate that cytokine production is inhibited in mast cells exposed to NO before IgE/Ag activation and that this inhibition occurs by preventing activation of components of the AP-1 transcription factor complex involved in cytokine expression.
Cys67 of HLA-B27
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2-microglobulin, one of several 9-aa peptides and recombinant HLA-B27 H chains containing either wild-type cysteine at aa 67 (Cys67) or mutant serine at aa 67 (Ser67) in the B pocket. HLA-B27 molecules, containing either Cys67 or Ser67, refolded with several different peptides and linked to streptavidin (tetramers) bound to indicator cells. However, the thermal stability of HLA-B27.Ser67 tetramers containing a human aggrecan-derived peptide was considerably lower than HLA-B27.Cys67 tetramers, as was staining of in vitro aggrecan peptide-stimulated CD8+ T cells from spleens of HLA-B27 transgenic mice immunized with the same peptide. Ser67 substitution had no affect on the ability of the HLA-B27/EBV peptide tetramers to stain CD8+ T cells from EBV-infected mice. HLA-B27.Cys67/aggrecan tetramers detected aggrecan peptide-specific CD8+ T cells in situ in spleen sections from aggrecan peptide-immunized HLA-B27 transgenic mice, whereas the tetramers containing the Ser67 mutation did not. The authors conclude that Cys67 in the B pocket of the H chain is required for stability of the HLA-B27/peptide complex and its proper recognition by the peptide-specific CD8+ T cell. Summaries written by Dorothy L. Buchhagen, Ph.D.
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