Kegg Pathway: Antigen processing and presentation

Cell Cycle. 2008 May 11; 7(14):
Dabrowska M, Skoneczny M, Zielinski Z, Rode W

Nurse cell (NC), formed from skeletal muscle cells upon infection with parasitic nematode trichina, presents a rare system of long-term suspension in the cell cycle. Signaling pathways and general biological functions of Trichinella spiralis NC, inferred from network analysis of competitive expression microarray data (NC vs. C2C12 myoblasts and myotubes), performed in Ingenuity Pathways Analysis (IPA) software and confirmed by Real-Time PCR, are presented. Assuming 4N DNA content in NC nuclei, its cell cycle arrest is identified herein as a hypermitogenic of G(1)-like type, accompanied by induction of senescence, underpinned by increased expression of p15, p16 and p57 cell cycle inhibitors, as well as overexpression of senescence-associated, beta-galactosidase and numerous secretory factors. Growth factor signaling, with predominant role of EGF, cytokine signaling and G-protein-coupled receptor signaling, are suggested as dominant NC signal transduction pathways. Fos, FosB, STAT6, CREBL2, ID4 and retinoic acid dependent nuclear receptors appear to be the main factors determining NC specific gene transcription. Antigen presentation, complement signaling and beta-amyloid processing pathways are also identified as operating in NC. In general, NC pathology is found to pertain to cancer, as well as other, including immunological and neurological, disorders.

Dev Biol (Basel). 2008; 131: 73-81
Weihe E, Bette M, Preuss MA, Faber M, Schäfer MK, Rehnelt J, Schnell MJ, Dietzschold B

Rabies virus (RABV) infection is characterized by the rapid neuronal spread of RABV into the CNS before a protective immune response is raised. Therefore, a typical feature of RABV infection is the paucity of inflammatory reactions in the brain. Here we examined whether the induction of immunosuppressive neuropeptides, in particular CGRP, may contribute to the ability of RABV to evade immune responses. RABV infection of mice caused a strong induction of calcitonin gene-related peptide (CGRP) in neurons and fibres in the neocortex as well as in the dentate gyrus and CA1 region of the hippocampus although RABV did not infect neurons in which CGRP expression was upregulated. Neuropeptide Y (NPY) or vasoactive intestinal peptide (VIP) expressing neurons also were not infected by RABV. In contrast, somatostatin neurons were infected by RABV. There was evidence for an RABV-induced increase of VIP and somatostatin but not of NPY. To test how CGRP expression is related to TNFalpha-induced enhancement of CNS innate and adaptive immunity during RABV infection, we used recombinant RABVs that contained either an active (SPBN-TNFalpha(+)) or an inactive (SPBN-TNFalpha(-)) TNFalpha gene. As compared to SPBN-TNFalpha(-), infection with SPBN-TNFalpha(+) attenuated the induction of CGRP but simultaneously enhanced induction of the invariant chain of MHC II, microglial activation and T cell infiltration. In conclusion, distinct neuropeptidergic neurons in the brain are remarkably spared from RABV infection suggesting a pivotal role of neuropeptides during CNS virus infection. Given the inhibitory effect of CGRP on Antigen presentation, we propose that the strong RABV-induced upregulation of CGRP in the brain may contribute to the mechanism by which RABV escapes immune detection. Targeting the expression of neuropeptides, in particular CGRP, that are induced during RABV infection may open a new avenue for therapeutic intervention in human rabies.

J Zoo Wildl Med. 2008 Jun; 39(2): 236-43
Swenson J, Carpenter JW, Janardhan KS, Ketz-Riley C, Brinkman E

A 10-yr-old male intact Asian small clawed otter (Aonyx cinerus) was presumptively diagnosed by histopathology and immunohistochemistry with lymphangiosarcoma after bony destruction of the ischium and spinal column from local tumor invasion had caused progressive signs of hind limb lameness and paresis/paralysis, which led to humane euthanasia. At necropsy, the primary tumor was identified as a flocculent mass present under the caudal lumbar vertebrae. Multiple nerves were seen to run from the spinal cord into the wall of the mass. This mass had locally invaded the surrounding muscle, vertebral column, and spinal cord, which led to the clinical signs noted at presentation. Bony destruction was severe with almost complete obliteration of the right ischium and osteolysis of L6, exposing the spinal cord beneath. The tumor had metastasized to at least two different sites within the spleen. The abdominal tumor was confirmed to be of endothelial origin by the use of immunohistochemical staining for factor VIII-related Antigen and was confirmed as lymphatic origin versus vascular origin because of the lack of red blood cells within the vessels. The length of time from initial presentation with hind limb lameness to euthanasia because of hind limb paralysis was 4 mo. This is the first report of lymphangiosarcoma, an uncommon malignant neoplasm of lymphatic origin, in a mustelid and the first report of neoplastic disease in an Asian small clawed otter. In addition, the presentation of hind limb paresis associated with bony lysis because of local tumor invasion has not been previously reported with lymphangiosarcoma in humans, domestic animals, or nondomestic animals.

J Leukoc Biol. 2008 Jul 16;
Zapata-Gonzalez F, Rueda F, Petriz J, Domingo P, Villarroya F, Diaz-Delfin J, de Madariaga MA, Domingo JC

There is accumulating evidence that omega-3 fatty acids may modulate immune responses. When monocytes were differentiated to dendritic cells (DCs) in the presence of docosahexaenoic acid (DHA), the expression of costimulatory and Antigen presentation markers was altered in a concentration-dependent way, positively or negatively, depending on the markers tested and the maturation stage of the DCs. Changes induced by eicosapentaenoic acid and linoleic acid were similar but less intense than those of DHA, whereas oleic acid had almost no effect. DHA-treated, mature DCs showed inhibition of IL-6 expression and IL-10 and IL-12 secretion, and their lymphoproliferative stimulation capacity was impaired. The phenotypic alterations of DCs induced by DHA were similar to those already reported for Rosiglitazone (Rosi), a peroxisome proliferator-activated receptor gamma (PPARgamma) activator, and the retinoid 9-cis-retinoic acid (9cRA), a retinoid X receptor (RXR) activator. Moreover, DHA induced the expression of PPARgamma target genes pyruvate dehydrogenase kinase-4 and aP-2 in immature DCs. The combination of DHA with Rosi or 9cRA produced additive effects. Furthermore, when DCs were cultured in the presence of a specific PPARgamma inhibitor, all of the changes induced by DHA were blocked. Together, these results strongly suggest that the PPARgamma:RXR heterodimer is the pathway component activated by DHA to induce its immunomodulatory effect on DCs.

FASEB J. 2008 Jul 16;
Brown K, Sacks SH, Wong W

Intercellular transfer of surface molecules has been demonstrated in vitro, or in vivo under artificial situations. Transplantation is a unique clinical situation in which foreign major histocompatibility complex (MHC) molecules are deliberately introduced. This provides a model to study intercellular MHC transfer because donor MHC molecules can easily be tracked. Here we describe the bidirectional transfer of MHC class II molecules between donor and recipient cells after transplantation of vascularized kidney and cardiac allografts in mice. Cells that are positive for both donor and recipient MHC class II accounted for up to 30% of the donor MHC class II(+) population, suggesting that they play a significant role in the Antigen presentation process. The majority of these cells were dendritic cells, but macrophages and B cells were also able to acquire foreign MHC molecules. Most double-positive cells were also positive for costimulatory molecules, indicating a capability to elicit a T-cell response. This transfer of MHC molecules between donor and recipient cells provides a link between the direct and indirect pathways of alloAntigen presentation and suggests that MHC transfer is also likely to occur under normal physiological conditions, which has implications in the fields of infection, vaccination, and tumor immunology.-Brown, K., Sacks, S. H., Wong, W. Extensive and bidirectional transfer of major histocompatibility complex class II molecules between donor and recipient cells in vivo following solid organ transplantation.

Inflamm Bowel Dis. 2008 Jul 14;
Ng SC, Hart AL, Kamm MA, Stagg AJ, Knight SC

The intestinal microbiota plays a fundamental role in maintaining immune homeostasis. In controlled clinical trials probiotic bacteria have demonstrated a benefit in treating gastrointestinal diseases, including infectious diarrhea in children, recurrent Clostridium difficile-induced infection, and some inflammatory bowel diseases. This evidence has led to the proof of principl