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Clara Abraham

Publications and source records attributed to Clara Abraham.

9 recordsLinked to original sources
PubMed2007

Inflammatory bowel disease genetics: Nod2.

The inflammatory bowel diseases (IBD) are comprised of two major subphenotypes, Crohn's disease (CD) and ulcerative colitis (UC). A significant role for genetic factors in IBD was established from epidemiologic studies and, more recently, the identification of well-established disease associations, notably the association of Nod2 (CARD15) polymorphisms with CD. The mapping to CD of Nod2 variants that alter protein function represents one of the earliest, most well-established, associations in complex genetic disorders. Since the initial discovery, genotype-phenotype correlations, definition of Nod2 expression and signaling pathways, association studies in other, related disorders, and features of Nod2 deficiency in murine models have been reported. Taken together, the Nod2 association to CD provides an illustrative model of the role of single gene variants in disease pathogenesis for common, complex multigenic disorders. Here we review general aspects of IBD genetics with particular focus on the role of Nod2 in CD.

Genetic Predisposition to Disease↗
PubMed2006

A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.

The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.

Alleles↗
PubMed2006

IFN-gamma-induced TNFR2 expression is required for TNF-dependent intestinal epithelial barrier dysfunction.

BACKGROUND & AIMS: Tumor necrosis factor (TNF) plays a critical role in intestinal disease. In intestinal epithelia, TNF causes tight junction disruption and epithelial barrier loss by up-regulating myosin light chain kinase (MLCK) activity and expression. The aim of this study was to determine the signaling pathways by which TNF causes intestinal epithelial barrier loss. METHODS: Caco-2 cells that were either nontransfected or stably transfected with human TNF receptor 1 (TNFR1) or TNFR2 and mouse colonocytes were used for physiologic, morphologic, and biochemical analyses. RESULTS: Colitis induced in vivo by adoptive transfer of CD4(+)CD45RB(hi) T cells was associated with increased epithelial MLCK expression and myosin II regulatory light chain (MLC) phosphorylation as well as morphologic tight junction disruption. In vitro studies showed that TNF caused similar increases in MLCK expression and MLC phosphorylation, as well as barrier dysfunction, in Caco-2 monolayers only after interferon (IFN)-gamma pretreatment. This reductionist model was therefore used to determine the molecular mechanism by which IFN-gamma and TNF synergize to cause intestinal epithelial barrier loss. IFN-gamma priming increased TNFR1 and TNFR2 expression, and blocking antibody studies showed that TNFR2, but not TNFR1, was required for TNF-induced barrier dysfunction. Transgenic TNFR2, but not TNFR1, expression allowed IFN-gamma-independent TNF responses. CONCLUSIONS: IFN-gamma primes intestinal epithelia to respond to TNF by inducing TNFR2 expression, which in turn mediates TNF-induced MLCK-dependent barrier dysfunction. The data further suggest that epithelial TNFR2 blockade may be a novel approach to restore barrier function in intestinal disease.

Animals↗
PubMed2006

Functional consequences of NOD2 (CARD15) mutations.

Polymorphisms in NOD2 (CARD15) are associated with ileal and ileocolonic Crohn's disease, increased mortality from graft-versus-host disease, and Blau syndrome. NOD2 activation by peptidoglycan components initiates various signaling pathways and CD-associated NOD2 mutations are associated with decreased activation of NF-kappaB. NOD2 may be important for both initial defenses against commensal and pathogenic bacteria and tolerance mechanisms for maintaining controlled activation of the intestinal immune system. Significant progress has been made in defining NOD2 signaling partners and pathways and functional consequences of NOD2 mutations with respect to its activation, expression, signaling, synergistic effects with Toll-like receptor signaling, and antimicrobial effects. However, NOD2 contributions to human intestinal inflammation are complex and incompletely understood. Improved understanding of NOD2-mediated pathways may lead to identification of other molecules that can also contribute to the development of Crohn's disease in humans.

Animals↗
PubMed2005

CD18 is required for optimal development and function of CD4+CD25+ T regulatory cells.

CD4+CD25+ T regulatory (Treg) cells inhibit immunopathology and autoimmune disease in vivo. CD4+CD25+ Treg cells' capacity to inhibit conventional T cells in vitro is dependent upon cell-cell contact; however, the cell surface molecules mediating this cell:cell contact have not yet been identified. LFA-1 (CD11a/CD18) is an adhesion molecule that plays an established role in T cell-mediated cell contact and in T cell activation. Although expressed at high levels on murine CD4+CD25+ Treg cells, the role of LFA-1 in these cells has not been defined previously. We hypothesized that LFA-1 may play a role in murine CD4+CD25+ Treg function. To evaluate this, we analyzed LFA-1-deficient (CD18-/-) CD4+CD25+ T cells. We show that CD18-/- mice demonstrate a propensity to autoimmunity. Absence of CD18 led to diminished CD4+CD25+ T cell numbers and affected both thymic and peripheral development of these cells. LFA-1-deficient CD4+CD25+ T cells were deficient in mediating suppression in vitro and in mediating protection from colitis induced by the transfer of CD4+CD25- T cells into lymphopenic hosts. Therefore, we define a crucial role for CD18 in optimal CD4+CD25+ Treg development and function.

Animals↗
PubMed2005

The critical role of LIGHT in promoting intestinal inflammation and Crohn's disease.

Crohn's disease (CD) is a type of inflammatory bowel disease associated with increased Th1 cytokines and unique pathological features. However, its pathogenesis has not been fully understood. Previous studies showed that homologous to lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for HVEM on T cells (LIGHT) transgenic (Tg) mice develop autoimmunity including intestinal inflammation with a variable time course. In this study, we establish an experimental model for CD by adoptive transfer of Tg mesenteric lymph node cells into RAG(-/-) mice. The recipients of Tg lymphocytes rapidly develop a disease strikingly similar to the key pathologic features and cytokine characterization observed in CD. We demonstrate that, as a costimulatory molecule, LIGHT preferentially drives Th1 responses. LIGHT-mediated intestinal disease is dependent on both of its identified signaling receptors, lymphotoxin beta receptor and herpes virus entry mediator, because LIGHT Tg mesenteric lymph node cells do not cause intestinal inflammation when transferred into the lymphotoxin beta receptor-deficient mice, and herpes virus entry mediator on donor T cells is required for the full development of disease. Furthermore, we demonstrated that up-regulation of LIGHT is associated with active CD. These data establish a new mouse model resembling CD and suggest that up-regulation of LIGHT may be an important mediator of CD pathogenesis.

Adoptive Transfer↗
PubMed2004

LFA-1 on CD4+ T cells is required for optimal antigen-dependent activation in vivo.

The leukocyte-specific integrin, LFA-1, plays a critical role in trafficking of T cells to both lymphoid and nonlymphoid tissues. However, the role of LFA-1 in T cell activation in vivo has been less well understood. Although there have been reports describing LFA-1-deficient T cell response defects in vivo, due to impaired migration to lymphoid structures and to sites of effector function in the absence of LFA-1, it has been difficult to assess whether T cells also have a specific activation defect in vivo. We examined the role of LFA-1 in CD4(+) T cell activation in vivo by using a system that allows for segregation of the migration and activation defects through the adoptive transfer of LFA-1-deficient (CD18(-/-)) CD4(+) T cells from DO11.10 Ag-specific TCR transgenic mice into wild-type BALB/c mice. We find that in addition to its role in trafficking to peripheral lymph nodes, LFA-1 is required for optimal CD4(+) T cell priming in vivo upon s.c. immunization. CD18(-/-) DO11.10 CD4(+) T cells primed in the lymph nodes demonstrate defects in IL-2 and IFN-gamma production. In addition, recipient mice adoptively transferred with CD18(-/-) DO11.10 CD4(+) T cells demonstrate a defect in OVA-specific IgG2a production after s.c. immunization. The defect in priming of CD18(-/-) CD4(+) T cells persists even in the presence of proliferating CD18(+/-) CD4(+) T cells and in lymphoid structures to which there is no migration defect. Taken together, these results demonstrate that LFA-1 is required for optimal CD4(+) T cell priming in vivo.

Adoptive Transfer↗
PubMed2004

Regulation of IL-8 and IL-1beta expression in Crohn's disease associated NOD2/CARD15 mutations.

Crohn's disease (CD) is a chronic inflammation affecting the gastrointestinal tract. Three mutations (Arg702Trp, Gly908Arg and Leu1007fsinsC) within the NOD2/CARD15 gene increase CD susceptibility. Here, we define cytokine regulation in primary human mononuclear cells, with muramyl dipeptide (MDP), the minimal NOD2/CARD15 activating component of peptidoglycan. By microarray, MDP induces a broad array of transcripts, including interleukin 1beta (IL-1beta) and interleukin 8 (IL-8). Leu1007fsinsC homozygotes demonstrated decreased transcriptional response to MDP. Electromobility shift assay demonstrated that MDP-induced NF-kappaB activation is mediated via p50 and p65 subunits, but not RelB or c-Rel. In wild-type individuals, MDP-induced IL-8 protein expression with a greater response to high dose (1 micro g/ml) compared with low-dose (10 ng/ml) MDP. At low MDP doses, in all homozygotes, we observed no induction of IL-8 protein. With high doses of MDP, Leu1007fsinsC homozygotes showed no induction. Modest induction of IL-8 protein was observed in Gly908Arg and Arg702Trp homozygotes, indicating varying MDP sensitivity of the CD-associated mutations. In wild-type healthy control, CD and ulcerative colitis individuals, low-dose MDP and TNFalpha alone results in only modest IL-1beta protein induction. With MDP plus TNFalpha, there is a synergistic induction of IL-1beta secretion. In Leu1007fsinsC homozygotes, there is a profound defect in IL-1beta secretion, despite marked induction of IL-1beta mRNA. These findings demonstrate post-transcriptional dependency on the NOD2/CARD15 pathway for IL-1beta secretion with MDP and TNFalpha treatment. Taken together, these studies suggest that a signaling defect of innate immunity to MDP may be an essential underlying defect in the pathogenesis of some CD patients.

Acetylmuramyl-Alanyl-Isoglutamine↗