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Collagen and eye disease
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2(22kDa)) was identical to aa 385–421 of the -2 chain of bovine type 1 collagen. However, CI-2(22kDa) fragments purified from bovine skin, bovine Achilles tendon and rat tail, or pure intact type 1 collagen, or the -1 and -2 collagen chains from bovine iris and ciliary body did not induce the disease. Only V8 protease-digested -2 chains of type 1 collagen were uveitogenic. Rats immunized with deglycosylated CI-2(22kDa) fragments were unaffected. Draining lymph node cells harvested from rats immunized with glycosylated CI-2(22kDa) at day 14 proliferated in vitro in response to the fragment, and harvested CD4+ T cells stimulated in vitro with CI-2(22kDa) transferred the disease to naive rats. Development of humoral immunity did not correlate with disease onset, and injection of immune sera into naive animals did not induce EEAU. The experiments demonstrate that a tissue-specific collagen is the target autoantigen in uveitis and that partial digestion by protease and glycosylation are required for it to be uveitogenic. Dendritic cell genes controlled by IL-10
Cytokine IL-10 is involved in many aspects of the immune response including differentiation, activation and maturation of dendritic cells (DC). Yet the identity of genes in DC controlled by IL-10 is unknown. Perrier et al. (p. 7031 ) found by microarray analyses that human monocyte-derived DCs exposed to LPS for 2 or 8 h had a pattern of gene expression with limited overlap to the expression pattern in DCs exposed to IL-10 for 2 or 8 h. The transcriptional profile of cells exposed to LPS and IL-10 together only partially overlapped with that of cells treated with LPS alone at either time point. IL-10 superinduced some, and inhibited expression of other, LPS-induced genes. Real-time PCR and Northern and Western blot analyses on some of these genes in three independent donors confirmed the microarray results. IL-10 up-regulated in DC several factors related to B cell differentiation and function, most notably IL-7, SLAM, and pre-B cell colony-enhancing factor. LPS plus IL-10 treatment of plasmacytoid DCs and freshly isolated blood myeloid DCs also highly induced CXCL13 that was shown to be chemotactic for a line of B lymphoma cells. The authors assign the genes regulated by IL-10 alone or in concert with LPS to four groups, including one related to B cell differentiation and function and CXCL13-mediated B cell chemotaxis. The study indicates that IL-10 and DC act together to influence B cell physiology.
Hemokinin uses the neurokinin 1 receptor
The tachykinin neuropeptide, substance P (SP), is found in granulomas induced in mice by the human parasite Schistosoma mansoni. The accompanying inflammation is caused by IFN-
release from CD4+ T cells following the interaction of SP with its neurokinin 1 receptor (NK-1R). Metwali et al. (p. 6528
) looked at the immune functions of hemokinin 1 (HK), a new member of the tachykinin family having 55% homology to SP. mRNA encoding the precursor for HK was detected by PCR analyses of total RNA extracted from gut lamina propria mononuclear cells of normal or colitic wild-type and IL-10-deficient mice. The same HK precursor was found in RNA from schistosome liver granulomas of mice and was detected in T cells and macrophages, but not in mature B cells, purified from the granulomas. The transcript also was found in two immature B cell lines and in splenic B cells. Either an NK-1R inhibitor or HK displaced binding of fluorescent labeled SP to CD4+ and CD8+ T cells from granulomas. Splenic T cells incubated with SP or HK released IFN- at higher levels than T cells incubated with soluble Ags from schistosome eggs, and these effects were blocked by the NK-1R inhibitor. The authors conclude that HK and SP have similar origins and functions in the inflammatory granuloma response.
TIMs and autoimmunity in humans
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production from these cells. Conversely, stimulated Th2 cells secreted low levels of IFN-, high levels of IL-13, and had higher expression of TIM-1 mRNA than TIM-3 mRNA. No difference in TIM-1 and TIM-3 expression was seen in PBMCs of multiple sclerosis (MS) patients compared with normal controls. However, TIM-1 mRNA was expressed in mononuclear cells isolated from the cerebral spinal fluid of 85% of MS patients compared with 37% of controls. TIM-1 mRNA levels were higher in cells from patients in remission than in patients who had clinically relapsed. TIM-3 mRNA levels did not differ with disease or status vs controls. Expression of TIM-1 mRNA was highest in CD4+ T, CD8+ T, NK, and NKT cells sorted by flow cytometry, whereas TIM-3 mRNA was highest in NK and NKT cells. In vivo expression patterns of Th cytokines and TIMs were similar to the in vitro patterns. The data indicate that differential expression of TIM-1 and TIM-3 correlated with Th1 and Th2 cytokine expression and disease states in MS. Protecting neurons in Alzheimer’s disease
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amyloid peptide (A42) accumulates in the brains of Alzheimer’s patients and activates mononuclear phagocytes through the G-protein-coupled formylpeptide receptor-like molecule, FPRL1. Humanin (HN), a 24-aa peptide isolated from the occipital lobe, that is rarely affected in these patients, rescues neuronal cells from apoptosis induced by exposure to A42. The actions of A42 and HN are the focus of research presented by Ying et al. (p. 7078
). HN-induced human monocyte chemotaxis and Ca2+ mobilization were abolished or reduced by pretreatment of the cells with the bacterial chemotactic peptide fMLF or specific FPRL1 agonists. Agonists for FPRL1 desensitized HEK293 cells transfected with FPRL1 to chemotaxis induced by HN. HN and A42 cross-desensitized each other’s signaling in the FPRL1 transfected cells. Similar chemotactic and desensitization results were seen for HEK293 cells transfected with FPR2, the murine counterpart of human FPRL1. Treatment of the cells with HN or A42 led to down-regulation and internalization of FPR2. HN-mediated down-regulation of FPRL1 receptor on human macrophages prevented entry and intracellular aggregation of A42. Neuroblastoma cell lines were found by RT-PCR to express FPRL1, and Gi proteins were phosphorylated in response to both HN and A42. Pre-exposure of the cells to HN reduced cytotoxicity induced by A42. The authors suggest that HN blocks FPRL1 to prevent A42 entry, thereby protecting the cell from an apoptotic signaling cascade. HLA pathway targeting of tumor Ags in dendritic cells
Optimization of cancer immunotherapy includes dendritic cell (DC) presentation of epitopes derived from both HLA class I- and class II-restricted tumor-associated Ags. Bonehill et al. (p. 6649
) electroporated immature and mature DCs with constructs of melanoma Ag (MAGE-3) mRNA containing one of three different HLA class II pathway targeting sequences. The sequences were the transmembrane and cytoplasmic domains from endosomal-localized invariant chain, lysosome-associated membrane protein-1 (LAMP1), or LAMP specific to mature DCs (DC.LAMP). Electroporated fluorescent-tagged mRNAs were degraded by 24 h in nontreated DCs but not in DCs treated with the lysosomal degradation inhibitor chloroquine. DCs that received MAGE-A3 mRNA linked to any of the sorting signals could stimulate HLA class II restricted MAGE-A3-specific T cells. DCs that received unlinked MAGE-A3 mRNA could activate HLA class I restricted MAGE-3-specific T cells, but attaching a sorting signal enhanced the activation. DCs receiving MAGE-A3 mRNA linked to the DC.LAMP targeting sequence were more efficient in stimulating the HLA class II-specific T cells than DCs receiving MAGE-A3 mRNA linked to the LAMP1 sequence; DCs receiving MAGE-3 mRNA linked to the invariant chain sequence were least efficient. Electroporation of mature DCs led to greater T cell stimulatory activity than electroporation of immature DCs. The overall T cell stimulatory capacity of DCs electroporated with MAGE-3 mRNA constructs was 
80% that of peptide pulsed DCs. The experiments demonstrate that coupling an HLA class II sorting signal to a tumor associated Ag enhances the effectiveness of DC-mediated immunotherapy.
OX40 and peripheral tolerance
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spontaneously in vitro and at high levels in response to PMA/ionomycin stimulation. Purified TCR transgenic T cells from transgenic animals treated with anti-OX40 Ab were anergic to stimulation with peptide and fresh APC in vitro, but they proliferated vigorously when given IL-2 and produced high levels of IFN- when given IL-12 plus IL-18. The authors conclude that in their system OX40 enhances tolerant T cell differentiation in the presence of specific Ag and that the process involves an inflammatory cytokine positive feedback loop. Summaries written by Dorothy L. Buchhagen, Ph.D.
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