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1.
A Novel ZRS Mutation Leads to Preaxial Polydactyly Type 2 in a Heterozygous Form and Werner Mesomelic Syndrome in a Homozygous Form
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Yuan Xue Donna Daentl Ethylin Wang Jabs William R. Wilcox Nadav Ahituv 《Human mutation》2014,35(8):945-948
Point mutations in the zone of polarizing activity regulatory sequence (ZRS) are known to cause human limb malformations. Although most mutations cause preaxial polydactyly (PPD), triphalangeal thumb (TPT) or both, a mutation in position 404 of the ZRS causes more severe Werner mesomelic syndrome (WMS) for which malformations include the distal arm or leg bones in addition to the hands and/or feet. Of more than 15 reported families with ZRS mutations, only one homozygous individual has been reported, with no change in phenotype compared with heterozygotes. Here, we describe a novel point mutation in the ZRS, 402C>T (AC007097.4:g.105548C>T), that is transmitted through two Mexican families with one homozygous individual. The homozygous phenotype for this mutation, WMS, is more severe than the numerous heterozygous individuals genotyped from both families who have TPT and PPD. A mouse transgenic enhancer assay shows that this mutation causes an expansion of the enhancer's expression domain in the developing mouse limb, confirming its pathogenicity. Combined, our results identify a novel ZRS mutation in the Mexican population, 402C>T, and suggest that a dosage effect exists for this ZRS mutation. 相似文献
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Lymph nodes, spleen and thymus obtained from Lewis rats were examined over the course of experimental autoimmune myasthenia gravis (EAMG) for the distribution and the number of antigen-reactive CD4+ T helper cells which, upon recognition of Torpedo acetylcholine receptor (AChR) or the α, β, γ or δ subunits of Torpedo AChR, responded by secretion of interferon-gamma (IFN-γ). T cells with these specificities were detected in these three immune organs. Numbers were highest in lymph nodes. In spleen and thymus, numbers of antigen-reactive T cells did not differ. T cells reacting against the intact AChR were more frequent than T cells recognizing any of the subunits. The immunogenicity between the four subunits did not differ, with the exception that the α subunit induced a slightly higher T-cell response. No restriction of the T-cell repertoire to the four subunits was detected during early compared to late phases of EAMG. The AChR and subunit-reactive T cells could—via secretion of effector molecules including IFN-γ—play an important role in the initiation and perpetuation of EAMG. and consequently also of human myasthenia gravis. T cells with the same specificities were also detected in control animals injected with adjuvant only, but at much lower numbers which were within the range of T cells recognizing the control antigen myelin basic protein. They could represent naturally occurring autoimmune T cells. 相似文献
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Spontaneous and pokeweed mitogen-induced production of specific autoantibodies were studied in cultures of peripheral blood mononuclear cells from patients with different clinical stages of myasthenia gravis. Receptor antibody-related idiotypes and anti-idiotypic antibodies were defined by binding to mouse monoclonal anti-idiotypic and anti-receptor antibodies, respectively. Patients with severe disease had a more complete spectrum of idiotypes in serum, and cells from such patients spontaneously produced more antibody species and higher concentration of both idiotypes and anti-idiotypes than patients with mild disease. The frequencies of antibody specificities in tissue culture supernatants more closely reflected disease activity than those in serum. Tissue culture for the study of different species of autoantibodies has proved to be a useful tool for monitoring the disease and the effects of treatment. 相似文献
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B. STUHLMÜLLER I. KALIES H. KACHELRIES K.-F. DRUSCHKY J. R. KALDEN 《Scandinavian journal of immunology》1994,39(3):305-313
The autoimmune disease myasthenia gravis (MG), caused by the effect of specific antibodies, directed towards the nicotinic acetylcholine receptor, is triggered by autoantigen-specific T cells. In order to investigate cellular parts of the immune response in MG, the authors investigated the binding of the nicotinic acetylcholine receptor (AChR) to peripheral blood mononuclear cells (PBMC) from MG patients. AChR binding cells were identified by resetting experiments using AChR-coated fluoresceine beads. Applying this technique, a significant percentage of PBMC (21.2 × 7.65%) from MG patients formed rosettes with AChR-coated beads.
Membrane preparations of nycodenz- or percoll-separated monocytes from MG patients or T-cell depleted monocytic subpopulations were applied to SDS-PAGE under reducing conditions. Ligand-blotting studies with biotinylated AChRs revealed two cell-membrane proteins with molecular weights of 58- and 78-kD. In parallel the same results were obtained by affinity chromatography of monocytic membrane proteins using AChR-sepharose. A possible interference of anti-AChR IgG was excluded. The 58- and the 78-kD proteins are detectable under reducing conditions by ligand blotting with AChR-biotin, while under non-reducing conditions only the 58-kD protein can be detected. Furthermore, in experiments using Endoglycosidase-H, the 58-kD protein appears to be non-glycosylated, while the 78-kD protein bears carbohydrates.
These findings suggest that monocytes which bind the AChR via specific membrane proteins on their surface might act as antigen-presenting cells and may lead to an induction of the T-cell response, in the early phase of the disease. 相似文献
Membrane preparations of nycodenz- or percoll-separated monocytes from MG patients or T-cell depleted monocytic subpopulations were applied to SDS-PAGE under reducing conditions. Ligand-blotting studies with biotinylated AChRs revealed two cell-membrane proteins with molecular weights of 58- and 78-kD. In parallel the same results were obtained by affinity chromatography of monocytic membrane proteins using AChR-sepharose. A possible interference of anti-AChR IgG was excluded. The 58- and the 78-kD proteins are detectable under reducing conditions by ligand blotting with AChR-biotin, while under non-reducing conditions only the 58-kD protein can be detected. Furthermore, in experiments using Endoglycosidase-H, the 58-kD protein appears to be non-glycosylated, while the 78-kD protein bears carbohydrates.
These findings suggest that monocytes which bind the AChR via specific membrane proteins on their surface might act as antigen-presenting cells and may lead to an induction of the T-cell response, in the early phase of the disease. 相似文献
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Tsvetana T. Marinova Kamelia K. Velikova Danail B. Petrov Nikolai S. Kutev Ivan S. Stankulov George N. Chaldakov 《Autoimmunity》2013,46(8):587-592
We have previously reported that the thymus of patients affected by myasthenia gravis (MG) is characterized by an elevated level of nerve growth factor (NGF), an endogenous polypeptide which plays a marked role in the cell biology of nervous and immune system. A consistent number of studies has shown altered expression of NGF in diseases associated with inflammatory and/or autoimmune responses. To evaluate the biochemical and molecular mechanisms implicated in NGF action in human myasthenic thymus, it is important to identify the cellular and structural organization of NGF receptors. To address this question, we investigated, both at light and electron microscopic levels, the cellular distribution of immunoreactivity for NGF and its low-affinity receptors, (p75) and its high-affinity receptor (TrkA) in the thymus of patients with MG. The present investigation shows that NGF and NGF receptors are overexpressed in the thymic cells of patients with MG compared to control subjects. 相似文献
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An idiotypic network involving T and B cells bearing complementary structures has been suggested to be important for the regulation of immune response in healthy and disease situations. A previous study by the authors has demonstrated the presence of a relatively higher concentration of anti-idiotypic antibodies than of idiotypic antibodies in early myasthenia gravis (MG), suggesting that the development of an anti-idiotypic immunity is important in early MG. The present study was conducted to examine the cellular components of the idiotypic network in the same situation. T and B cells reactive to acetylcholine receptor (AChR) or to a disease-related idiotype and to an anti-idiotype were analysed in seven patients with early MG at various times after the start of the disease. The results show that a significant increase in the number of idiotype-reactive interferon-γ-secreting T cells and a shift from AChR-reactive to idiotype- and/or anti-idiotype-reactive T cells in the patients at 6 month follow-up were noted. Such changes seem to correlate to a clinical improvement in the patients. The enhanced anti-idiotypic T-cell response and the clinical improvement in the patients may speak in favour of a role for the anti-idiotypic immunity in controlling the autoimmune response in MG, i.e., down-regulating autoantibody-producing B cells and idiotypic (AChR-specific) T cells. Thus, an immune intervention towards the enhancement of the anti-idiotypic immunity in patients might be a rewarding approach. Further studies with regard to cell interactions and immune regulations in the network are warranted. 相似文献
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重症肌无力患者血清非Ig成分对突触前、后膜受体及其相应抗体反应的影响 总被引:1,自引:0,他引:1
利用盐析、免疫亲和吸附及Protein G Fast Flow完全去除20例抗乙酰胆碱受体(AchR)抗体和抗突触前膜受体(PsmR)抗体阳性重症肌无力(MG)、20例抗体阴性MG、15例其它神经科疾病患者和15例正常对照血清的Ig部分。并以ABC-ELISA观察应用上述方法提取的血清非Ig成分对AchR和PsmR抗原抗体反应的影响。结果显示除抗体阴性MG血清经非Ig成分作用后,AchR、PsmR与其各自抗体的反应反而增强外,其余各种血清非Ig成分对AchR和PsmR的抗原抗体反应均五星著抑制作用。其机制目前尚不清楚。推测抗体阴性MG患者的血清非Ig成分中可能存在某种活化抗原抗体反应的物质。 相似文献
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Zhuoan Cheng Shaobo Qiu Lin Jiang Anle Zhang Wenjing Bao Ping Liu Jianwen Liu 《Journal of clinical immunology》2013,33(3):567-576
Myasthenia gravis (MG) are T-cell dependent antibody-mediated autoimmune disorders, microRNAs are important regulators of human autoimmune disease pathogenesis. Here, we investigated the miRNAs expression profiles in MG for the first time and found that miR-320a was significantly downregulated in MG patients compared to normal healthy people. Meanwhile, pro-inflammatory cytokins in MG patients were overexpressed. Furthermore, we identified MAPK1 as a direct target of miR-320a. Downregulation of miR-320a induced the overexpression of pro-inflammatory cytokins through promoting COX-2 expression. This process was modulated by ERK/ NF-κB pathways. Taken together, our findings suggested that miR-320a could play a role in modulation of inflammatory cytokins production. 相似文献
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地塞米松治疗小鼠实验性自身免疫性甲状腺炎的研究 总被引:6,自引:1,他引:6
本文采用细胞培养和免疫学技术研究地塞米松对自身免疫性甲状腺炎小鼠T细胞亚群、细胞因子、甲状腺抗体滴度和甲状腺组织病理形态的影响,结果显示:(1)地塞米松能明显降低EAT小鼠TGAb、TNF和IL-1水平;(2)提高Lyt-2阳性T细胞数,降低L_3T_4/Lyt-2比值;(3)明显逆转自身免疫性甲状腺炎小鼠的病理改变。结果提示地塞米松具有调整T淋巴细胞亚群,抑制细胞因子释放,抑制甲状腺过强的自身免疫反应等作用;局部注射地塞米松治疗桥本氏甲状腺炎是一种简单、有效的好方法。 相似文献
12.
Detection of Heterozygous Mutation in the Retinoblastoma Gene in a Human Pituitary Adenoma Using PCR-SSCP Analysis and Direct Sequencing 总被引:1,自引:0,他引:1
Genomic deoxyribonucleic acid from surgical specimens of 25 pituitary adenomas was screened for the presence of mutations
in the tumor suppressor gene, retinoblastoma gene, using polymerase chain reaction and single-strand conformation polymorphism
analysis, followed by direct deoxyribonucleic acid sequencing. Mutation causing an amino acid change was found in one of the
25 pituitary adenomas. The mutation site was in exon 19 (codon 621) of the retinoblastoma gene. In addition, there were three
types of silent mutations in introns of the gene. The patient in whom the retinoblastoma mutation was identified had a tumor
with high clinical malignancy, a high percentage of c-myc protein-labeled cells, and a diagnosis of plurihormonal pituitary adenoma based on the presence of cells immunoreactive for
five pituitary hormones. This article suggests that point mutation of retinoblastoma gene is rare in human pituitary adenomas
but may provide a marker for aggressive pituitary adenoma. 相似文献
13.
Myasthenia gravis (MG) patients may have circulating autoantibodies against titin. In this study, we have stimulated T cells from MG patients with a recombinant polypeptide containing the main immunogenic region of titin, MGT-30 (myasthenia gravis titin-30 kDa). In an ELISpot assay, MGT-30 reactive interferon (IFN)-γ secreting cells (Th1 cells) were detected in six of 10 titin antibody positive MG patients. Such cells were not detected in any of the five titin antibody negative MG patients or in the seven blood donors. In three patients, the stimulated number of cells decreased when total remission of MG symptoms was achieved after thymectomy or following a period of intensive immunosuppressive medication. We detected MGT-30 interleukin (IL)-4 secreting cells (Th2 cells) in two of five titin antibody positive MG patients, but not in the two titin antibody negative patients or the five blood donors examined. We conclude that titin antibody positive MG patients have a combined Th1/Th2 cell mediated immunity against the muscle protein titin. 相似文献
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Abdulrahman N. Alodayani Abdulnasir M. Al-Otaibi Caroline Deswarte Husn Habib Frayha Matthieu Bouaziz Maryam AlHelale Tom Le Voyer Alejandro Nieto-Patlan Vimel Rattina Mofareh AlZahrani Rabih Halwani Fahad Al Sohime Hamoud Al-Mousa Saleh Al-Muhsen Sami H. Alhajjar Nabil S. Dhayhi Laurent Abel Jean-Laurent Casanova May S. AlBarrak Suliman A. Al-Jumaah Jacinta Bustamante 《Journal of clinical immunology》2018,38(3):278-282
Purpose
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing congenitally affected individuals to diseases caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccine strains and environmental mycobacteria. IL-12p40 deficiency is a genetic etiology of MSMD resulting in impaired IL-12- and IL-23-dependent IFN-γ immunity. Most of the reported patients with IL-12p40 deficiency originate from Saudi Arabia (30 of 52) and carry the recurrent IL12B mutation c.315insA (27 of 30).Methods
Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain.Results
Genetic analysis revealed a homozygous mutation, p.W60X, in exon 3 of the IL12B gene, resulting in complete IL12p40 deficiency. This mutation is recurrent due to a new founder effect.Conclusions
This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.15.
The hallmark of gonorrhea is an intense inflammatory response that is characterized by polymorphonuclear leukocytes (PMNs) with intracellular gonococci. A redundancy of defenses may protect Neisseria gonorrhoeae from phagocyte-derived reactive oxygen species. Here we showed that a gonococcal catalase (kat) mutant in strain MS11 was more sensitive to H2O2 than mutants in cytochrome c peroxidase (ccp), methionine sulfoxide reductase (msrA), or the metal-binding protein (mntC) of the MntABC transporter. kat ccp and kat ccp mntC mutants were significantly more sensitive to H2O2 than mutants in any single factor. None of the mutants showed increased susceptibility to murine PMNs. Recovery of the mntC and kat ccp mntC mutants from the lower genital tract of BALB/c mice, but not the kat or kat ccp mutants, was significantly reduced relative to wild-type bacteria. Interestingly, unlike the MS11 kat mutant, a kat mutant of strain FA1090 was attenuated during competitive infection with wild-type FA1090 bacteria. The FA1090 kat mutant and MS11 mntC mutant were also attenuated in mice that are unable to generate a phagocytic respiratory burst. We conclude that inactivation of three well-characterized antioxidant genes (kat, ccp, and mntC) does not increase gonococcal susceptibility to the phagocytic respiratory burst during infection and that gonococcal catalase and the MntC protein confer an unidentified advantage in vivo. In the case of catalase, this advantage is strain specific. Finally, we also showed that an msrA mutant of strain MS11 demonstrated delayed attenuation in BALB/c but not C57BL/6 mice. Therefore, MsrA/B also appears to play a role in infection that is dependent on host genetic background.Neisseria gonorrhoeae is a facultative anaerobic bacterium with no environmental or animal reservoir outside of humans. N. gonorrhoeae is maintained in the human population on mucosal surfaces, including the urethra, cervix, pharynx, and rectum. Tissues of the upper reproductive tract of both males and females can also be infected. As is typical of the pyogenic cocci, N. gonorrhoeae induces an intense inflammatory response during symptomatic infections that is characterized by numerous polymorphonuclear leukocytes (PMNs) with intracellular gram-negative diplococci (21).The mechanism(s) by which the gonococcus evades oxidative killing by phagocytes is of particular interest based on evidence that a proportion of intracellular gonococci survives and even multiplies within the PMNs (5, 6, 34, 42, 54, 55) despite the induction of an intracellular respiratory burst (42, 58). Several factors protect N. gonorrhoeae from exposure to oxidative stress in vitro (reviewed in reference 43). A nonenzymatic quenching mechanism that is based on the accumulation of intracellular manganese through the MntABC transporter protects N. gonorrhoeae from H2O2 and superoxide anion (52), and high levels of catalase protect gonococci from H2O2 and exposure to paraquat (20, 25, 47). Cytochrome c peroxidase (Ccp) also increases gonococcal resistance to H2O2 (53), and methionine sulfoxide reductase (MsrA/B), which repairs methionine sulfoxide residues on oxidatively damaged proteins, confers increased resistance to H2O2 and extracellularly generated reactive oxygen species (ROS) (45). Several other gonococcal factors that detoxify H2O2 and/or ROS have been identified (8, 41, 50, 59).Many physiological factors can affect interactions between N. gonorrhoeae and PMNs. These factors include iron concentration, O2 tension, pH (17), lactate (3), and the presence of CMP neuraminic acid (18, 38, 58). Environmental factors also regulate the expression of genes that protect N. gonorrhoeae from H2O2 and ROS in vitro (43). The balance of these physiological factors is difficult to reproduce in vitro. Infection of estradiol-treated BALB/c mice with N. gonorrhoeae causes a localized inflammatory response as evidenced by elevated numbers of PMNs and macrophages in vaginal and cervical tissue from infected mice (48). We recently reported that a catalase (kat) mutant of N. gonorrhoeae strain FA1090 can establish experimental murine infection despite the induction of a vigorous PMN response. High numbers of catalase-deficient gonococci were seen within PMNs and there was no significant difference in the number of wild-type or kat mutant gonococci recovered (46). That report was the first demonstration that catalase-deficient gonococci can persist during periods of inflammation in an in vivo system. We did not use the sensitive method of competitive infection to assess colonization of the kat mutant, however, or test the possibility that functionally redundant factors may mask any attenuation due to the absence of catalase.Here we examined the contribution of four well-characterized antioxidant factors toward N. gonorrhoeae resistance to oxidative killing by phagocytes in the mouse infection model. To this end, we constructed single, double, and triple mutants in the kat, ccp, msrA, and/or mntC genes in the same strain background. Mutants that showed the most sensitivity to H2O2 in vitro were tested for the capacity to colonize BALB/c mice during competitive infection with the wild-type parent strain. Mutants that were attenuated in BALB/c mice were tested in mice that are deficient in the Phox91 subunit of the NADPH oxidase complex to determine if evasion of phagocytic respiratory burst was the basis of the attenuation. 相似文献
16.
Etiology of Chronic Pneumonia in Rats and a Study of the Experimental Disease in Mice 总被引:2,自引:0,他引:2
The lungs of conventional rats with chronic pneumonia contained Streptobacillus moniliformis and Mycoplasma pulmonis. These organisms singly and in combination failed to produce lung disease when inoculated into specific pathogen-free rats. On the other hand, diseased lung homogenate not containing cultivable organisms caused a chronic pneumonia when inoculated into specific pathogen-free rats. The organism involved was seen by electron microscopy and is morphologically indistinguishable from the grey lung agent of Andrewes and Glover and Nelson's enzootic bronchiectasis "virus." All of these agents have morphological and biological properties which indicate close relationship to the mycoplasmas. However, we failed to culture them either in tissue cultures or on inanimate media and conclude that a group of highly fastidious mycoplasma-like agents are a cause of chronic pneumonia in rodents. 相似文献
17.
Muhammad Farooq Atsushi Fujimoto Hiroki Fujikawa Ossama Abbas Georges Nemer Jessica Saliba Rima Sleiman Mona Tofaili Abdul‐Ghani Kibbi Masaaki Ito Yutaka Shimomura 《Human mutation》2013,34(4):578-581
Pure hair and nail ectodermal dysplasia (PHNED) is a rare genetic disorder characterized by hypotrichosis or complete alopecia, as well as nail dystrophy. Mutations in the type II hair keratin gene KRT85 and the HOXC13 gene on chromosome 12q have recently been identified in families with autosomal‐recessive PHNED. In the present study, we have analyzed a consanguineous Syrian family with an affected girl having complete alopecia and nail dystrophy since birth. The family clearly showed linkage to chromosome 12q13.13–12q14.3, which excluded the KRT85 gene. Sequencing of another candidate gene HOXC13 within the linkage interval identified a homozygous frameshift mutation (c.355delC; p.Leu119Trpfs*20). Expression studies in cultured cells revealed that the mutant HOXC13 protein mislocalized within the cytoplasm, and failed to upregulate the promoter activities of its target genes. Our results strongly suggest crucial roles of the HOXC13 gene in the development of hair and nails in humans. 相似文献
18.
Takayuki Kanai Yoshiko Nomura Masaya Segawa Katsumasa Takagi Satoru Senju Sho Matsushita Yasuharu Nishimura 《Human immunology》1997,56(1-2)
ABSTRACT: Infant-onset myasthenia gravis, an autoimmune disease specific to Asians predominantly affects neuromuscular junctions in ocular muscles. An AChRα peptide (p71–91) specific autoreactive CD4+αβ T cell clone was established by stimulating PBMC from a patient heterozygous for two disease-susceptible HLA-DR9-DQ9 and DR13-DQ6 haplotypes with a mixture of overlapping peptides covering AChRα. The T cell clone recognized the AChRα peptide in the context of the HLA-DQ6 molecule and produced a large amount of IFN-γ and a trace amount of IL-4. A part (p75–83) of the core epitope of the autoantigenic peptide (p75–87) is encoded for by an exon P3A of the AChRα gene which can be alternatively spliced. The T cell clone responded to the recombinant AChRα protein with a P3A exon product, but not without a P3A exon product. We investigated responses of the T cell clone to 114 analogue peptides carrying single residue substitutions of the core AChRα peptide. The majority of analogues substituted at residues Phe-77, Leu-80 and Asn-82 stimulated proliferation of the T cell clone. Conversely, the majority of analogue peptides substituted at either Gln-81 or Glu-83 did not stimulate proliferative responses, and all exhibited strong or intermediate inhibitory effects on proliferative responses of the T cell clone to the wild type peptide, possibly by TCR antagonism. Thus, an HLA class II allele specific to Asians may directly control susceptibility to the Asians-specific type of myasthenia gravis. Analogues of the auto-antigenic AChRα peptide may prove effective for new immunosuppressive therapy. 相似文献
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