<i>HFE</i>, the MHC and hemochromatosis: Paradigm for an extended function for MHC class I

Cardoso, Carla; Sousa, Maria de

doi:10.1034/j.1399-0039.2003.00065.x

Cited by 43 publications

(49 citation statements)

References 100 publications

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“…For example, in mice, the class Ib locus M molecules can present peptides with NH 2 -formylated amino termini from infectious organisms, such as Listeria monocytogenes (52). However, other MHC class Ib loci (HLA-A) have functions unrelated to the immune system such as iron metabolism and uptake in the intestinal tract (10). Unfortunately, the specificity of the MHC class Ib locus Aw2, downregulated with Clamoxyl, is unknown.…”

Section: Discussionmentioning

confidence: 99%

Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome

Schumann

Nutten²,

Donnicola³

et al. 2005

Physiological Genomics

141

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The postnatal maturation of the gut, partially modulated by bacterial colonization, ends up in the establishment of an efficient barrier to luminal antigens and bacteria. The use of broad-spectrum antibiotics in pediatric practices alters the gut bacterial colonization and, consequently, may impair the maturation of the gut barrier function. To test this hypothesis, suckling Sprague-Dawley rats received a daily intragastric gavage of antibiotic (Clamoxyl; an amoxicillin-based commercial preparation) or saline solution from postnatal day 7 (d7) until d17 or d21. Luminal microbiota composition and global gene expression profile were analyzed on samples from small intestine and colon of each group. The treatment with Clamoxyl resulted in the almost-complete eradication of Lactobacillus in the whole intestine and in a drastic reduction of colonic total aerobic and anaerobic bacteria, in particular Enterobacteriacae and Enterococcus. The global gene expression analysis revealed that Clamoxyl affects the maturation process of 249 and 149 Affymetrix probe sets in the proximal and distal small intestine, respectively, and 163 probe sets in the colon. The expression of genes coding for Paneth cell products (defensins, matrilysin, and phospholipase A2) was significantly downregulated by the Clamoxyl treatment. A significant downregulation of major histocompatibility complex (MHC) class Ib and II genes, involved in antigen presentation, was also observed. Conversely, mast cell proteases expression was upregulated. These results suggest that early treatment with a largespectrum antibiotic deeply affects the gut barrier function at the suckling-weaning interface, a period during which the gut is challenged by an array of novel food-borne antigens. innate immunity; antigen presentation; mast cell THE GASTROINTESTINAL (GI) mucosa is in constant contact with a luminal environment that contains not only nutrients but also a huge array of potentially harmful microorganisms and toxins. A healthy GI mucosa is able to handle this massive collection of antigens and modulate the immune response according to the level of hazard related to each antigen. This capacity of the GI tract is defined as gut barrier function. In infants, the intestine remains immature and relatively permeable to antigens during the first weeks of life (3,18,50). Subsequently, the postnatal maturation of the mucosal barrier reduces drastically such transfer, so that in healthy adults, only small amounts of dietary antigens can reach the circulation (22). The maturation of the intestinal barrier is the consequence of morphological and functional changes of the mucosa, which occur under genetic and endocrine control (6). However, the onset of weaning and the impact of bacterial colonization have been shown to modulate this process (11, 28). The comparison of germ-free vs. conventional microbiota animals has brought interesting clues to further our understanding of the impact of the gut microbiota on the different mechanisms involved in the gut barrier function. In...

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Section: Discussionmentioning

confidence: 99%

Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome

Schumann

Nutten²,

Donnicola³

et al. 2005

Physiological Genomics

141

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“…Surprisingly, no correlation between serum Trf levels and CD4 + or total lymphocyte numbers was seen. Such a result brings to light once more the involvement of MHC class I in this disorder [10,28,33]. CD8 + but not CD4 + T lymphocytes are activated and proliferate in the context of MHC class I molecules (reviewed in [17]).…”

Section: Discussionmentioning

confidence: 99%

Low serum transferrin levels in HFE C282Y homozygous subjects are associated with low CD8+ T lymphocyte numbers

Macedo

Cruz

Lacerda

et al. 2005

Blood Cells, Molecules, and Diseases

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Hereditary hemochromatosis (HH) is a genetic iron overload disease, in the majority of cases associated with homozygosity for the C282Y mutation of the HFE gene. In spite of this genetic homogeneity, there is a great clinical heterogeneity among HH patients. Low CD8 + lymphocyte numbers have been associated with a more severe expression of iron overload in HH patients, and in experimental models of iron overload. HH patients present low serum transferrin levels. Transferrin is an indispensable resource for lymphopoiesis. Lymphocyte homeostasis follows general ecology rules of population dynamics that involve competition for limiting resources. In the present study, we questioned whether transferrin levels could be associated with the anomalies seen previously in lymphocyte subset numbers in HH patients. Transferrin levels, total and subset T lymphocyte counts were done in 426 apparently healthy subjects genotyped for HFE. All HFE C282Y carriers presented significantly lower serum transferrin levels than the wild type group, a difference that could not be explained solely by the degree of iron overload. Significant differences were also seen in transferrin levels between males and females, with females presenting higher average serum Transferrin levels. In the population of subjects with Transferrin levels lower than 248 mg/dl, a positive correlation was seen between the peripheral CD8 + lymphocyte numbers and serum transferrin levels (R 2 = 2.41; r = 0.16; P = 0.018). To test the possible limiting resource effect of transferrin, the correlation between transferrin levels and CD8 + lymphocyte numbers was scrutinized in 34 HH patients, homozygous for the C282Y mutation. In the homozygous males, where the lowest average transferrin levels were seen, another highly significant correlation was observed between Transferrin levels and CD8 + numbers. This correlation points to a possible role of transferrin as a limiting resource for MHC class I dependent lymphocyte proliferation, an effect that was not observed in C282Y homozygous female patients. D

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“…6) that do not have any immune basis, let alone antigen presentation; (6) The antigen presentation paradigm does not offer a plausible explanation for allele-dose impact on disease susceptibility and severity, nor can it explain allele-dose effects on concordance rates in genetically susceptible monozygotic twins. 7 MHC and MHC-like molecules can perform other functions besides antigen presentation, including regulation of iron metabolism, 8 olfaction, 9 transport of immunoglobulins, 10 activation of innate immune signaling (certain HLA-DR and class I MHC molecules, reviewed in ref. 11) and more.…”

Section: Beyond the Groovementioning

confidence: 99%

MHC molecules in health and disease: At the cusp of a paradigm shift

Almeida¹,

Holoshitz²

2011

Self/Nonself

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HFE, the MHC and hemochromatosis: Paradigm for an extended function for MHC class I

Cited by 43 publications

References 100 publications

Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome

Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome

Low serum transferrin levels in HFE C282Y homozygous subjects are associated with low CD8+ T lymphocyte numbers

MHC molecules in health and disease: At the cusp of a paradigm shift

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