Hereditary pancreatitis (HP) is an autosomal dominant disorder with
incomplete penetrance characterized by recurring episodes of severe
abdominal pain often presenting in childhood. Although this disorder has
only been recently described, about 100 families have been documented
worldwide. The pathophysiology of this disorder is unknown. Here, a large
French family of 147 individuals (47 of whom were affected) from a
four-generation kindred with HP has been examined and a genome segregation
analysis of highly informative microsatellite markers has been performed.
Linkage has been found between HP and six chromosome 7q markers. Maximal
two point lod scores between HP and D7S 640, D7S 495, D7S 684, D7S 661, D7S
676 and D7S 688 were 4.00 (theta = 0.143), 5.85 (theta = 0.143), 4.91
(theta = 0.156), 8.58 (theta = 0.077), 8.28 (theta = 0.060), 4.40 (theta =
0.169), respectively. Multipoint linkage data combined with recombinant
haplotype analysis indicated that the most likely order is: D7S 640-D7S
495-D7S 684-D7S 661-D7S 676-D7S 688, with the HP gene situated in the
underlined region. As in all families reported in the literature, the
clinical presentation of the disease is identical to the presentation of
sporadic cases, one could expect that the knowledge of the HP gene could be
a clue to pancreatitis in general. Based on its map position, this is the
first step towards the positional cloning of the Hereditary Pancreatitis
Gene (HPG).
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The Werner's syndrome (WS) is a rare recessive disease characterized by an early onset of geriatric disorders. The Werner's syndrome gene (WRN) recently cloned, encodes for an helicase and therefore plays a role in DNA metabolism and DNA repair. Here, we report the study of a French family with two affected members and numerous cancers. Using the protein truncation test and sequencing, we identified a homozygous mutation in the WRN gene. This mutation generates a frame shift leading to a very short 391 amino acids truncated protein without the helicase motif. A particularly severe phenotype of the affected patient was associated with an unusual vulvar cancer traditionaly observed in elderly patients and therefore likely to be related to the Werner's syndrome. An additional substitution of G for A at nucleotidic position 1392 was also described. We suggest that a relation between genotype and phenotype could exist in the studied family. 相似文献
Killer cell immunoglobulin-like receptors (KIRs) belong to a diverse family of natural killer (NK) cell receptors recognizing human leukocyte antigen (HLA) class I molecules. Due to this functional link, KIR molecules are expected to display a high polymorphism, such as their HLA ligands. Moreover, many studies conducted in mouse and human models have shown that NK-KIR receptors play an important role in haematopoietic stem cell transplantation (HSCT). A beneficial impact of peculiar KIR ligand (HLA) mismatching has been reported suggesting a role to this combinatory HLA-KIR polymorphism. It is thus important to investigate KIR diversity in various human populations. To this end, we used polymerase chain reaction-sequence-specific primers to evaluate KIR gene in five selected populations (France, Guadeloupe, Senegal, Finland and Réunion). Genotypic and haplotypic frequencies were computed, as well as genetic distances and dendrogram (phylip package). These data illustrate the genetic relationship of these five populations through the KIR polymorphism. Results revealed a wide diversity in KIR gene frequencies in Guadeloupe and Réunion, and a high specificity in Senegal. The obtained dendrogram indicated small genetic distances between France, Guadeloupe and Réunion as well as between France and Finland. Senegal showed a distant genetic relationship with the other countries and, interestingly, an inverted ratio of coding/non-coding (KIR2DS4/1D) alleles compared with Caucasians. These data expose the broad diversity in KIR genes worldwide and show that KIR genes are pertinent tools in human population genetics. If the role of KIR donor-recipient incompatibilities is confirmed, KIR diversity according to ethnicity should be taken into account during the selection of HSCT donors. 相似文献
NK‐cell function is regulated by a balance between inhibitory and activating killer cell immunoglobulin‐like receptors (KIR) that specifically recognize HLA class I molecules. Using KIR‐specific mAb to discriminate between KIR2DS1 and KIR2DL1 receptors, we show that KIR2DS1+ NK cells are C2‐alloreactive only from C2? individuals. Moreover, using an in vitro model of NK‐cell expansion, we show here that the frequency of KIR2DL1+ NK cells is significantly higher in the absence of C2 ligand on stimulator EBV‐B cells than in its presence. This observation was made regardless of the presence or absence of the autologous C2 ligand, suggesting that the C2? EBV‐B stimulator cells used in this in vitro model could activate unlicensed KIR2DL1+ NK cells. In the case of KIR2DL1+/S1+ genotyped individuals, KIR2DS1+ NK‐cell frequency was increased after stimulation with C2+ compared with C2? stimulator B cells, but only from C2? individuals. Altogether, these data highlight the C2 alloreactivity of KIR2DS1+ NK cells that is only observed in C2? individuals. These results provide new insights into the way in which NK KIR cell expansion might be regulated in an allogeneic environment. 相似文献
Interleukin 2 (IL-2) has been purified by a protocol using gel filtration high performance liquid chromatography (HPLC) and hydrophobic affinity chromatography with blue-trisacryl M. Peripheral blood lymphocytes or tonsillar lymphocytes were stimulated with phytohemagglutinin (PHA). Serum free conditioned medium (CM) containing IL-2, other lymphokines and residual PHA molecules was analyzed after 3 variations of ammonium sulfate (AS) precipitation: (1) precipitation of CM with 50% AS yielded a precipitate containing most of the residual PHA but also a fraction of IL-2. (2) Precipitation with direct 80% AS of crude CM yielded both IL-2 and residual PHA. (3) A double step procedure (50% AS followed by 80% AS) yielded a precipitate containing IL-2 but free of residual lectin.
HPLC purification of these various AS-precipitated materials or of lyophilized crude CM yielded 2 peaks with mitogenic activity as assayed with the CTLL2 murine clone or IL-2-dependent human Con A-stimulated lymphoblasts. IFN was easily separated from IL-2 and PHA, but BCGF still copurified with IL-2. Peak I (25 kDa) was enriched 400-fold for IL-2 while peak II (68 kDa) contained the residual PHA.
The IL-2-containing fractions eluted from HPLC were further purified by blue-trisacryl M chromatography. The IL-2 eluted with 0.4 M NaCl. The entire protocol (HPLC followed by blue-trisacryl) led routinely to 8000-fold IL-2 enrichment. Preparative HPLC directly applied to lyophilized crude (CM) enriched IL-2 activity 400-fold with yield averaging 60% of the IL-2 input. The final material was free from interferon and IL-1, but BCGF still copurified with IL-2. The 2-step purified material (HPLC and blue-trisacryl) gave 2 bands in SDS-PAGE both of which contained IL-2. 相似文献
Decline in blood CD4+ lymphocytes during primary symptomatic infections
with HIV is usually attributed to viral killing, and has not been
considered in terms of altered lymphocyte migration and sequestration. We
therefore sought to examine whether CD4+ cell loss from blood of macaques
undergoing an acute primary SIV infection might be due to increased
synthesis of cytokines, known to profoundly affect lymphocyte trafficking,
rather than to direct lymphocyte destruction by virus. The findings
indicate that rapid lymphocyte depletion following acute infection is not
selective for CD4+ cells, correlates precisely with increased plasma
IFN-gamma and tumor necrosis factor-alpha levels, and is reversible.
CD4/CD8 ratios in lymph nodes with high viral burdens remain relatively
unchanged despite lymphocyte loss from blood. Levels of cytokine mRNA
measured in lymphoid organs reflect neither cytokine plasma levels nor
their potential to induce sequestration. These results support a model of
cytokine-induced lymphocyte extravasation to account for the acute
HIV/SIV-induced CD4+ cell lymphopenia and raise questions regarding the
extent to which altered lymphocyte migration plays a role in the gradual
CD4+ cell depletion throughout infection.
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