A role for altered phagosome maturation in the long-term persistence of Helicobacter pylori infection.

The vigorous host immune response that is mounted against Helicobacter pylori is unable to eliminate this pathogenic bacterium from its niche in the human gastric mucosa. This results in chronic inflammation, which can develop into gastric or duodenal ulcers in 10% of infected individuals and gastric cancer in 1% of infections. The determinants for these more severe pathologies include host (e.g., high IL-1ß expression polymorphisms), bacterial [e.g., cytotoxicity-associated gene (cag) pathogenicity island], and environmental (e.g., dietary nitrites) factors. However, it is the failure of host immune effector cells to eliminate H. pylori that underlies its persistence and the subsequent H. pylori-associated disease. Here we discuss the mechanisms used by H. pylori to survive the host immune response and, in particular, the role played by altered phagosome maturation.

Lysosomal storage disease: revealing lysosomal function and physiology.

The discovery over five decades ago of the lysosome, as a degradative organelle and its dysfunction in lysosomal storage disorder patients, was both insightful and simple in concept. Here, we review some of the history and pathophysiology of lysosomal storage disorders to show how they have impacted on our knowledge of lysosomal biology. Although a significant amount of information has been accrued on the molecular genetics and biochemistry of lysosomal storage disorders, we still do not fully understand the mechanistic link between the storage material and disease pathogenesis. However, the accumulation of undegraded substrate(s) can disrupt other lysosomal degradation processes, vesicular traffic, and lysosomal biogenesis to evoke the diverse pathophysiology that is evident in this complex set of disorders.

Genetic and gene expression analyses of the polycystic ovary syndrome candidate gene fibrillin-3 and other fibrillin family members in human ovaries.

Several studies have demonstrated an association between polycystic ovary syndrome (PCOS) and the dinucleotide repeat microsatellite marker D19S884, which is located in intron 55 of the fibrillin-3 (FBN3) gene. Fibrillins, including FBN1 and 2, interact with latent transforming growth factor (TGF)-beta-binding proteins (LTBP) and thereby control the bioactivity of TGFbetas. TGFbetas stimulate fibroblast replication and collagen production. The PCOS ovarian phenotype includes increased stromal collagen and expansion of the ovarian cortex, features feasibly influenced by abnormal fibrillin expression. To examine a possible role of fibrillins in PCOS, particularly FBN3, we undertook tagging and functional single nucleotide polymorphism (SNP) analysis (32 SNPs including 10 that generate non-synonymous amino acid changes) using DNA from 173 PCOS patients and 194 controls. No SNP showed a significant association with PCOS and alleles of most SNPs showed almost identical population frequencies between PCOS and control subjects. No significant differences were observed for microsatellite D19S884. In human PCO stroma/cortex (n = 4) and non-PCO ovarian stroma (n = 9), follicles (n = 3) and corpora lutea (n = 3) and in human ovarian cancer cell lines (KGN, SKOV-3, OVCAR-3, OVCAR-5), FBN1 mRNA levels were approximately 100 times greater than FBN2 and 200-1000-fold greater than FBN3. Expression of LTBP-1 mRNA was 3-fold greater than LTBP-2. We conclude that FBN3 appears to have little involvement in PCOS but cannot rule out that other markers in the region of chromosome 19p13.2 are associated with PCOS or that FBN3 expression occurs in other organs and that this may be influencing the PCOS phenotype.

Fibrillins and latent TGFbeta binding proteins in bovine ovaries of offspring following high or low protein diets during pregnancy of dams.

The microsatellite D19S884, located in intron 55 of fibrillin-3 (FBN3) gene, associates with polycystic ovary syndrome (PCOS) in familial studies. The family of fibrillin proteins (FBN1-3), which includes latent TGF-beta binding proteins (LTBP-1 to -4), are extracellular matrix proteins. We localized and examined the expression of these proteins in the adult bovine ovaries (n=7-10 per group, average age 681 days) born to mothers fed high (13% protein per total dry weight) or a low protein diet (5%) in each of the first and second trimesters of pregnancy (n=4 groups). FBN1 and LTBP-1 and -2 were the major members expressed in the mature ovary. Each protein had a unique localization pattern but all were associated with stromal tissue including the tunica albuginea (FBN1 and LTBP-2 near surface, and FBN1 and LTBP-1 deeper in the tunica), cortical stroma (FBN1 and LTBP-1) and follicular thecal layers (FBN1 in theca interna, LTBP-1 in the inner regions of the theca externa, and LTBP-2 in the outer regions of the theca externa). No significant (P>0.05) effects of maternal diet were observed on either the localization or the levels of mRNA of any of these proteins in the tunica. Expression levels of all three FBNs were positively correlated with each other, and FBN1 and 2 were positively correlated with LTBP-2, suggesting some level of co-ordinate regulation. This is the first study to investigate the expression and localization of these genes affecting TGFbeta bioavailability in the ovary.