Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastric lesions in primary constitutive immune deficiencies include multifocal atrophic gastritis, erosive pangastritis, and a pattern of gastric lesions reminiscent of graft-versus-host disease. We describe the genetic anomalies in 2 monozygotic twins with an X-linked lymphoproliferative disease (XLP; MIM 308240), a rare familial setting of high susceptibility to Epstein-Barr virus (EBV). Since early childhood, both twin brothers exhibited a severe chronic active atrophic pangastritis. A germline screening of the SH2D1A (MIM 300490) and BIRC4 (MIM 300079) genes was performed, and also a high-resolution whole-genome SNP profiling (Infinium Sentrix Human-1 Genotyping BeadChip, Illumina). A 3 Megabase deletion in the Xq25 region, encompassing the SH2D1A gene, was defined by SNP array genotyping. Histologic analysis of yearly or twice yearly gastric biopsies in both children showed a Helicobacter pylori-negative, Epstein-Barr virus-negative chronic active atrophic pangastritis, with superficial ulcer formation, foveolar hyperplasia, glandular dilatation and ultimately pseudopyloric and intestinal metaplasia. No such chronic active inflammatory gastric lesions have been reported to date in XLP. The similarities between XLP and common variable immunodeficiency (MIM 240500) underscore the need for early recognition and close monitoring of these gastric lesions, with special regard to their neoplastic potential. No infectious cause was determined. We favor a dysimmune mechanism in the development of this chronic atrophic gastritis, presenting a striking similarity to the recently described atrophic autoimmune pangastritis.
 ...
PMID:Chronic active gastritis in X-linked lymphoproliferative disease. 1822 36

Inhibitors of apoptosis proteins (IAPs) regulate apoptosis, but little is known about the role of IAPs in the regulation of immunity. Development of IAP inhibition by second mitochondria-derived activator of caspase (SMAC) mimetics is emerging as a novel therapeutic strategy to treat malignancies. We explored the role of IAPs in allogeneic immunity with 2 distinct yet complementary strategies, namely, chemical and genetic approaches, in clinically relevant models of experimental bone marrow transplantation (BMT). The small-molecule pan-IAP inhibitor SMAC mimetic AT-406 aggravated gastrointestinal graft-versus-host disease (GVHD) in multiple models. The role of specific IAPs in various host and donor cellular compartments was explored by utilizing X-linked IAP (XIAP)- and cellular IAP (cIAP)-deficient animals as donors or recipients. Donor T cells from C57BL/6 cIAP1-/- or XIAP-/- animals demonstrated equivalent GVHD severity and allogeneic responses, both in vivo and in vitro, when compared with B6 wild-type (B6-WT) T cells. By contrast, when used as recipient animals, both XIAP-/- and cIAP1-/- animals demonstrated increased mortality from GVHD when compared with B6-WT animals. BM chimera studies revealed that cIAP and XIAP deficiency in host nonhematopoietic target cells, but not in host hematopoietic-derived cells, is critical for exacerbation of GVHD. Intestinal epithelial cells from IAP-deficient animals showed reduced levels of antiapoptotic proteins as well as autophagy-related protein LC3 after allogeneic BMT. Collectively, our data highlight a novel immune cell-independent but target tissue-intrinsic role for IAPs in the regulation of gastrointestinal damage from GVHD.
 ...
PMID:IAPs protect host target tissues from graft-versus-host disease in mice. 2929 93

Patients with X-linked lymphoproliferative syndrome type 2 (XLP-2) (BIRC4 deficiency) suffer from hyperinflammation often observed during the conditioning regimen prior to allogeneic bone marrow transplant. This article shows that in mice hematopoietic recipient cells contribute to graft-versus-host disease by the secretion of elevated levels of proinflammatory cytokines during engraftment when BIRC4 is absent.
 ...
PMID:XIAP deficiency in hematopoietic recipient cells drives donor T-cell activation and GvHD in mice. 3058 20