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Biomedical subjects

A J Macpherson

Publications and source records attributed to A J Macpherson.

At least 19 recordsLinked to original sources
PubMed2006

IgA adaptation to the presence of commensal bacteria in the intestine.

The lower intestine of mammals is colonised by a dense flora composed mainly of non-pathogenic commensal bacteria. These intestinal bacteria have a wide-ranging impact on host immunity and physiology. One adaptation following intestinal colonisation is increased production and secretion of polyspecific intestinal IgA. In contrast to the strong mucosal immune response to bacterial colonisation, the systemic immune system remains ignorant of these organisms in pathogen-free mice. Small numbers of bacteria can penetrate the epithelial surface overlying Peyer's patches and survive in dendritic cells to induce IgA by T-dependent and T-independent mechanisms. These dendritic cells loaded with live commensal organisms can home to the mesenteric lymph nodes but do not reach systemic secondary lymphoid structures, so induction of mucosal responses is focused in mucosal lymphoid tissues. The secretion of antibodies across the intestinal epithelial surface in turn limits the penetration of commensal organisms, but this is one of many mechanisms which adapt the intestinal mucosa to co-existence with commensal bacteria.

Animals↗
PubMed2002

The functions of mucosal T cells in containing the indigenous commensal flora of the intestine.

There is an immense load of non-pathogenic commensal bacteria in the distal small intestine and the colon of mammals. The physical barrier that prevents penetration (translocation) of these organisms into the body is a simple epithelium comprised of the single enterocyte/colonocyte cell layer with its overlying mucus. In this review, we discuss the roles of intestinal T cells in initiating and regulating innate and adaptive mucosal immune responses of the mucosal immune system that avoid or limit penetration of the commensal intestinal bacteria.

Animals↗
PubMed2002

In siblings with similar genetic susceptibility for inflammatory bowel disease, smokers tend to develop Crohn's disease and non-smokers develop ulcerative colitis.

BACKGROUND AND AIMS: Smoking tobacco has opposite effects on the different forms of inflammatory bowel disease (IBD). It predisposes to the development of Crohn's disease (CD) yet is associated with a reduced incidence of ulcerative colitis (UC). We have studied sib pairs discordant for both smoking and IBD phenotype (UC or CD) to investigate whether smoking determines the type of IBD that develops in individuals with very similar genetic susceptibility. PATIENTS: Smoking habits and disease characteristics were analysed in 242 IBD pedigrees (658 patients). Within this group there were 339 affected sibling pairs of whom 89 were discordant for smoking when diagnosed. RESULTS: Smoking at diagnosis was associated with development of CD (odds ratio (OR) 3.55; 95% confidence limits 2.50-5.02; p<0.001) in all of the familial patients, with increases when analysed for ileocaecal disease, fibrostenosis, and intestinal resection. Smokers were also protected from UC (OR 0.28; 0.2-0.4; p<0.001). Of 89 sibling pairs discordant for smoking at diagnosis, 23 were also discordant for disease type-in 21 of these, CD occurred in the smoker and UC in the non-smoker (OR 10.5; 2.6-92; p<0.0001). CONCLUSIONS: Smoking is a strong environmental risk factor for Crohn's disease and increases the likelihood of needing surgery. However, sib pairs who are discordant for both smoking and IBD type almost always show CD in the smoker and UC in the non-smoker, and so in some cases tobacco consumption acts on IBD genetic predisposition to shift the phenotype from UC towards CD. The explanation of part of the apparent "protective" effect of smoking on sporadic UC may be that the form of IBD that develops in a proportion of smokers is not UC but CD.

Adult↗
PubMed2001

IgA production without mu or delta chain expression in developing B cells.

Surface, membrane-bound, immunoglobulin M (IgM) or IgD expression early in B cell ontogeny is considered essential for the differentiation of antibody-producing cells in mammals; only in IgM+ B cells is the heavy chain locus rearranged to express antibodies of other classes. We show here that IgA is selectively expressed in muMT mice, which lack IgM or IgD expression and have a pro-B cell developmental block. muMT IgA binds proteins of commensal intestinal bacteria and is weakly induced by Salmonella infection, although not through conventional immunization. This muMT IgA pathway requires extrasplenic peripheral lymphoid tissues and may be an evolutionarily primitive system in which immature B cells switch to IgA production at peripheral sites.

Animals↗
PubMed2001

Fine mapping of the chromosome 3p susceptibility locus in inflammatory bowel disease.

BACKGROUND AND AIMS: Genetic predisposition for inflammatory bowel disease (IBD) has been demonstrated by epidemiological and genetic linkage studies. Genetic linkage of IBD to chromosome 3 has been observed previously. A high density analysis of chromosome 3p was performed to confirm prior linkages and elucidate potential genetic associations. METHODS: Forty three microsatellite markers on chromosome 3 were genotyped in 353 affected sibling pairs of North European Caucasian extraction (average marker density 2 cM in the linkage interval). Marker order was defined by genetic and radiation hybrid techniques. RESULTS: The maximum single point logarithm of odds (LOD) score was observed for Crohn's disease at D3S3591. Peak multipoint LOD scores of 1.65 and 1.40 for the IBD phenotype were observed near D3S1304 (distal 3p) and near D3S1283 in the linkage region previously reported. Crohn's disease contributed predominantly to the linkage. The transmission disequilibrium test showed significant evidence of association (p=0.009) between allele 4 of D3S1076 and the IBD phenotype (51 transmitted v 28 non-transmitted). Two known polymorphisms in the CCR2 and CCR5 genes were analysed, neither of which showed significant association with IBD. Additional haplotype associations were observed in the vicinity of D3S1076. CONCLUSIONS: This study provides confirmatory linkage evidence for an IBD susceptibility locus on chromosome 3p and suggests that CCR2 and CCR5 are unlikely to be major susceptibility loci for IBD. The association findings in this region warrant further investigation.

Alleles↗
PubMed2000

A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria.

The immunoglobulin A (IgA) is produced to defend mucosal surfaces from environmental organisms, but host defenses against the very heavy load of intestinal commensal microorganisms are poorly understood. The IgA against intestinal commensal bacterial antigens was analyzed; it was not simply "natural antibody" but was specifically induced and responded to antigenic changes within an established gut flora. In contrast to IgA responses against exotoxins, a significant proportion of this specific anti-commensal IgA induction was through a pathway that was independent of T cell help and of follicular lymphoid tissue organization, which may reflect an evolutionarily primitive form of specific immune defense.

Animals↗
PubMed1999

A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort.

Inflammatory bowel disease (IBD) is characterized by a chronic relapsing intestinal inflammation, typically starting in early adulthood. IBD is subdivided into two subtypes, on the basis of clinical and histologic features: Crohn disease and ulcerative colitis (UC). Previous genomewide searches identified regions harboring susceptibility loci on chromosomes 1, 3, 4, 7, 12, and 16. To expand our understanding of the genetic risk profile, we performed a 9-cM genomewide search for susceptibility loci in 268 families containing 353 affected sibling pairs. Previous linkages on chromosomes 12 and 16 were replicated, and the chromosome 4 linkage was extended in this sample. New suggestive evidence for autosomal linkages was observed on chromosomes 1, 6, 10, and 22, with LOD scores of 2.08, 2.07, 2.30, and 1.52, respectively. A maximum LOD score of 1.76 was observed on the X chromosome, for UC, which is consistent with the clinical association of IBD with Ullrich-Turner syndrome. The linkage finding on chromosome 6p is of interest, given the possible contribution of human leukocyte antigen and tumor necrosis-factor genes in IBD. This genomewide linkage scan, done with a large family cohort, has confirmed three previous IBD linkages and has provided evidence for five additional regions that may harbor IBD predisposition genes.

Cohort Studies↗
PubMed1999

Why children with inflammatory bowel disease are diagnosed at a younger age than their affected parent.

BACKGROUND: Genetic anticipation has been proposed to explain observed age differences at diagnosis of Crohn's disease in affected parents and offspring. AIMS: To compare affected parent-child pairs with Crohn's disease and ulcerative colitis with a control group of non-familial patients with inflammatory bowel disease (IBD) in order to quantify whether ascertainment bias could account for this effect. METHODS: 137 affected parent-child pairs from 96 families and 214 patients with sporadic IBD were studied. Age at onset of symptoms and diagnosis were ascertained by interview and disease confirmed from clinical records. RESULTS: Of the 137 affected parent-child pairs, 50 had Crohn's disease only, 51 had ulcerative colitis only, and in 36, one had Crohn's disease and the other ulcerative colitis. The median age of parents at diagnosis was 17.5 years older, 16 years older, and 18 years older in the Crohn's disease, ulcerative colitis, and mixed disease families respectively (p<0.001 in each case). These observed age differences were compatible with those predicted from the regression lines of years of birth against age at diagnosis for the non-familial IBD patients. No evidence was found for an effect of parental sex on age at diagnosis or disease extent in offspring. CONCLUSIONS: There was no evidence of genetic anticipation or genomic imprinting of age at diagnosis in this sample of IBD families. Ascertainment bias is responsible for the age differences at diagnosis between affected parents and children.

Adolescent↗
PubMed1998

Genetic analysis of inflammatory bowel disease in a large European cohort supports linkage to chromosomes 12 and 16.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a complex disorder of unknown etiology. Epidemiological investigations suggest a genetic basis for IBD. Recent genetic studies have identified several IBD linkages. The significance of these linkages will be determined by studies in large patient collections. The aim of this study was to replicate IBD linkages on chromosomes 12 and 16 in a large European cohort. METHODS: Three hundred fifty-nine affected sibling pairs from 274 kindreds were genotyped using microsatellite markers spanning chromosomes 12 and 16. Affection status of the sibling pairs was defined as Crohn's disease (CD) or ulcerative colitis (UC). RESULTS: Nonparametric statistical analyses showed linkage for both chromosomes. Two-point results for chromosome 12 peaked at D12S303 (logarithm of odds [LOD], 2.15; P = 0.003) for CD and at D12S75 (LOD, 0.92; P = 0.03) for UC. Multipoint analyses produced a peak LOD of 1.8 for CD. Chromosome 16 showed linkage for CD at marker D16S415 (LOD, 1.52; P = 0.007). Multipoint support peaked above markers D16S409 and D16S411 (LOD, 1.7). CONCLUSIONS: These data are consistent with linkage of IBD to chromosomes 12 and 16. The replication of genetic risk loci in a large independent family collection indicates important and common susceptibility genes in these regions and will facilitate identification of genes involved in IBD.

Chromosomes, Human, Pair 12↗
PubMed1997

CD4+ T cell down-regulation in human intestinal mucosa: evidence for intestinal tolerance to luminal bacterial antigens.

T cells from the intestinal mucosal proliferate poorly in vitro, and the contribution of Ag-specific recognition to this hyporesponsiveness is unclear, since the Ag repertoire of intestinal mucosal T cells is unknown. In this study, T cell proliferation in response to Ag-prepulsed autologous peripheral blood-derived APC was examined. Whereas T cells from peripheral blood proliferated to inner membrane and cytoplasmic Escherichia coli proteins, T cells from intestinal mucosa responded only to purified component Ags of these proteins and not to their combination. This suggests that the lack of proliferation in response to these Ags presented as a mixture is not due to the absence of E. coli-specific T cells in the mucosa, but, rather, to down-regulation after T cell recognition. Down-regulation was assayed by measuring the inhibition of autologous peripheral blood T cell proliferation in response to Ag-prepulsed APC. Coculture with leukocytes from intestinal mucosa and not from mesenteric lymph nodes, inhibited autologous peripheral blood T cell proliferation in response to E. coli proteins, but not to tetanus toxoid, PHA, or IL-2. Inhibition was independent of cell contact, provided APC were available to the mucosal cell population, and was reversible by neutralization of IL-10 or TGF-beta with mAb or depletion of mucosal CD4+ T cells. Taken together, the data suggest that mucosal T cell unresponsiveness to luminal Ags is mediated by production of inhibitory cytokines after specific Ag recognition by CD4+ T cells.

Aged↗
PubMed1995

Mitochondrial gene expression in small intestinal epithelial cells.

Most mitochondrial genes are transcribed as a single large transcript from the heavy strand of mitochondrial DNA, and are subsequently processed into the proximal mitochondrial (mt) 12 S and 16 S rRNAs, and the more distal tRNAs and mRNAs. We have shown that in intestinal epithelial biopsies the steady-state levels of mt 12 S and 16 S rRNA are an order of magnitude greater than those of mt mRNAs. Fractionation of rat small intestinal epithelial cells on the basis of their maturity has shown that the greatest ratios of 12 S mt rRNA/cytochrome b mt mRNA or 12 S mt rRNA/cytochrome oxidase I mt mRNA are found in the surface mature enterocytes, with a progressive decrease towards the crypt immature enteroblasts. Cytochrome b and cytochrome oxidase I mt mRNA levels are relatively uniform along the crypt-villus axis, but fractionation experiments showed increased levels in the crypt base. The levels of human mitochondrial transcription factor A are also greater in immature crypt enteroblasts compared with mature villus enterocytes. These results show that the relative levels of mt rRNA and mRNA are distinctly regulated in intestinal epithelial cells according to the crypt-villus position and differentiation status of the cells, and that there are higher mt mRNA and mt TFA levels in the crypts, consistent with increased transcriptional activity during mitochondrial biogenesis in the immature enteroblasts.

Adult↗