Protein tyrosine phosphatase non-receptor type 22 gene polymorphism C1858T is not associated with leprosy in Azerbaijan,Northwest Iran

BACKGROUND:

Leprosy (Hansen''s disease) is a human chronic granulomatous infectious disease caused by Mycobacterium leprae. Several types of study support a role for host genetics in susceptibility to leprosy. The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene encodes an intracellular lymphoid protein tyrosine phosphatase that has been shown to play a negative regulatory role in T-cell activation.

AIMS:

The aim of the present study was to find out associating the PTPN22 C1858T (R620W) polymorphism and leprosy in the Azeri population from Northwest Iran.

MATERIALS AND METHODS:

A total of 153 treated leprosy patients and 197 healthy and ethnic matched controls entered this study. We used restriction fragment length polymorphism method to type PTPN22 C1858T polymorphism.

RESULTS:

There was no significant difference in distribution of genotype and allele frequencies of PTPN22 C1858T polymorphism between leprosy patients and controls (P = 0.641 and 0.645; respectively). Moreover, there was no significant association between different clinical findings (karnofsky performance status score, clinical forms and manifestations of leprosy) and PTPN22 C1858T polymorphism. Data showed a low frequency of the minor (T) allele by 2.3% in leprosy and 1.5% in healthy individuals.

CONCLUSIONS:

The PTPN22 C1858T (R620W) is not relevant in susceptibility to leprosy in the Azeri population of Northwest Iran.     

Genetics of cat hemoglobins: A quantitative polymorphism

Blood samples from domestic cats, representing the parents (26) and offspring (91) from 33 matings, were analyzed to determine the proportions of hemoglobins A and B. Evidence is presented that the proportions of the two hemoglobins are genetically determined and that cats may be divided into three groups on the basis of this characteristic. Family data and Hardy-Weinberg analysis support the hypothesis that the three groups represent the possible combinations of an allelic gene pair. In an attempt to explain the observed phenotypic differences, possible points of action of this gene pair are discussed, including effects on rates of synthesis or epigenetic modification of globin chains.     

Association of the solute carrier family 11 member 1 gene polymorphisms with susceptibility to leprosy in a Brazilian sample

Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1gene (Nramp1/Slc11a1) is a gene that controls the susceptibility ofinbred mice to intracellular pathogens. Polymorphisms in the humanSlc11a1/Nramp1 gene have been associated with host susceptibilityto leprosy. This study has evaluated nine polymorphisms of theSlc11a1/Nramp1 gene [(GT)n, 274C/T, 469+14G/C, 577-18G/A, 823C/T,1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19patients had the multibacillary and the paucibacillary clinical forms of the disease,respectively), and 239 healthy controls matched by age, gender, and ethnicity. Thefrequency of allele 2 of the (GT)n polymorphism was higher in leprosy patients [p =0.04, odds ratio (OR) = 1.49], whereas the frequency of allele 3 was higher in thecontrol group (p = 0.03; OR = 0.66). Patients carrying the 274T allele (p= 0.04; OR = 1.49) and TT homozygosis (p = 0.02; OR = 2.46), suchas the 469+14C allele (p = 0.03; OR = 1.53) of the 274C/T and 469+14G/Cpolymorphisms, respectively, were more frequent in the leprosy group. The leprosy andcontrol groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A,1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy,while the allele 2 and 3 of the (GT)n polymorphism in the promoter region wereassociated with susceptibility and protection to leprosy, respectively.     

TUNEL and limited immunophenotypic analyses of apoptosis in paucibacillary and multibacillary leprosy lesions

Some mycobacterial infections, such as tuberculosis, are characterized by apoptosis of infected or by-stander mononuclear immune cells. For localized (paucibacillary, PB) and disseminated (multibacillary, MB) leprosy, characterized by polarized Th1-like vs. Th2-like immune responses, respectively, little is known about lesional apoptosis. We analyzed sections of paraffin-embedded, untreated leprosy lesions from 21 patients by an indirect immunofluorescent terminal deoxynucleotide-transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assay. Some TUNEL (+) PB sections were then reacted with phycoerythrin-conjugated (red) antibodies against T cells, monocytes, or antigen-presenting (Langerhans) cells. TUNEL (+) bodies were detected in 9 of 16 PB lesions (56%) and in 1 of 5 MB lesions (20%). Some TUNEL (+) bodies in PB disease were CD3+ (T cell), as well as CD4+ (T-helper) or CD8+ (T-cytotoxic). Apoptosis characterizes PB and MB leprosy lesions and may be more frequent in PB disease. In PB disease, some TUNEL (+) bodies may derive from T cells.     

Self-mortification and the stigma of leprosy in northern India

This article examines the biocultural dynamics of social discrimination and physical disfigurement among people with leprosy, or Hansen's disease (HD), in Banaras, northern India. Based on the narratives and observations ofpeople living in colony and street settings, I trace three destructive processes by which the social stigmata of leprosy become physically expressed. First, strategies of concealment further the progression and spread of HD through late detection and undertreatment. Second, the internalization of stigma can lead to bodily dissociation and injury through self-neglect. Finally, some people intentionally seek injuries under conditions of desperate poverty. As a result of such mortification processes, these people came to embody, quite literally, the prejudices that exacerbated their condition in the first place.     

Interaction of TaqI polymorphism at exon 9 of the vitamin D receptor gene with the negative lepromin response may favor the occurrence of leprosy

Controversies over the vitamin D receptor (VDR) acting as a susceptibility factor in Mycobacterium sp. infections may be the result of incorrect population stratification. The risk of leprosy occurrence conditioned by VDR polymorphism was investigated by stratifying the population of a highly endemic Brazilian region into negative and positive Mitsuda responses. Leprosy patients (102) and a group of healthy nonconsanguineous household contacts (68) were genotyped for the VDR TaqI polymorphism (T/t). TT and Tt genotypes were not considered to be risk factors as their odds ratios (OR) were not different from those presented by the negative Mitsuda response individuals. The combination of the tt genotype and the negative Mitsuda test provided an occurrence rate 13 times higher in leprosy patients than in controls with positive Mitsuda responses. This suggests that there is a higher risk of leprosy development when individuals carry this unfavorable combination, and demonstrates a possible synergistic role of these two variables in leprosy susceptibility via effects on cellular immunity.     

组蛋白乙酰化/去乙酰化与基因表达调控

组蛋白是真核生物染色质的主要成分,组蛋白修饰(如甲基化、乙酰化、磷酸化、泛素化等)在真核生物基因表达调控中发挥着重要的作用.在这些修饰中,组蛋白乙酰化/去乙酰化尤为重要.组蛋白乙酰化/去乙酰化可通过改变染色质周围电荷或参与染色质构型重建而影响基因表达;更重要的是组蛋白乙酰化/去乙酰化可形成一种特殊的“密码”,被其它蛋白质识别,影响多种蛋白质因子的活动或与其相互作用,参与到基因表达调控的整个网络中.     

Armadillo leprosy and a failed vaccine

In 1974, scientists at Gulf South Research Institute (GSRI) in New Iberia, Louisiana, showed that armadillos experimentally infected with leprosy could produce 10¹⁴ bacilli per animal within two years. These vast numbers inspired World Health Organization (WHO) to initiate an international program for development of an anti-leprosy vaccine. US Public Health Service (USPHS) staff at Carville, LA, wrongfully accused GSRI of causing a leprosy zoonosis in wild armadillos. As a result, the GSRI program was terminated in 1979. The talisman for obtaining high yields of bacilli was lost, causing productivity to decrease by two to three orders of magnitude. Nevertheless, field trials on the vaccine continued through 1998. Results published in 1992 on 29,000 volunteers in Venezuela showed that the vaccine when used in combination with BCG was no more effective than BCG alone. Laboratory tests published three years later revealed that the vaccine used in Venezuela had little if any immunoreactivity. A report published in 1996 showed that the vaccine was ineffective in field trials on 112,000 volunteers in Malawi. It is possible that the poor quality of these vaccines can be traced to the catastrophic decline in numbers of bacilli produced by armadillos.     

Lipid Acetylation Reactions and the Metabolism of Platelet-Activating Factor

In this review properties of lipid acetyltransferase enzymes are outlined. The three activities of interest are lyso PAF acetyltransferase (acetyl CoA: 1-alkyl-sn-glycero-3-phosphocholine acetyltransferase), AGP acetyltransferase (acetyl CoA: 1-alkyl sn-glycero-3-phosphate acetyltransferase) and a transacetylase activity that can transfer acetyl groups from PAF to lipid acceptors in the formation of 1-alkenyl-2-acetyl-sn-glycero-3-phosphoethanolamine and N-acetyl sphingosine (C₂ ceramide). This review focuses on the role of acetyltransferases and transacetylases within the metabolism of platelet-activating factor and specifically addresses characteristics of the enzymes, including subcellular localization, substrate selectivity, and enzymatic regulation     

乙酰化修饰降低Ku蛋白的DNA结合活性

【目的】研究乙酰化修饰对Ku蛋白活性的影响。【方法】利用耻垢分枝杆菌为表达菌株,转入Ku蛋白表达质粒,纯化具有乙酰化修饰的Ku蛋白和无乙酰化的Ku蛋白突变体,比较两类蛋白的生化活性;分析氧化压力和酸性环境下耻垢分枝杆菌细胞内Ku蛋白乙酰化水平的变化。【结果】Ku蛋白过量表达的耻垢分枝杆菌比转入空质粒的对照菌株生长缓慢;乙酰化Ku蛋白比未发生乙酰化Ku蛋白修复断裂DNA的活性降低、DNA结合活性降低;氧化压力和酸性压力环境下,耻垢分枝杆菌细胞内Ku蛋白数量降低,乙酰化Ku蛋白数量变化不大。【结论】乙酰化修饰能够调节Ku蛋白的DNA结合活性,从而调节非同源末端连接修复系统的活性;Ku蛋白乙酰化程度升高是耻垢分枝杆菌对不良生长环境的反应。     

组蛋白乙酰化/去乙酰化在真核基因转录调控中的作用

真核生物中 ,染色质的基本单位是核小体。核小体由H2 A ,H2 B ,H3 ,H4构成的核心组蛋白八聚体及缠绕于其上的DNA构成。最近的研究结果表明 ,核心组蛋白的乙酰化 去乙酰化过程是调控基因活性的一个关键步骤[1] 。而含有组蛋白去乙酰化酶活性的分子有两类 :一类是与酵母RPD3同源的分子 ,另一类是与RPD3不同源的分子。它们各有其不同的来源 ,存在于各自的复合物中 ,催化不完全相同的组蛋白或其他蛋白质去乙酰化 ;这些去乙酰化酶与基因转录的调控存在着密切的关系 ,主要是介导基因转录的抑制。     

Superoxide production from macrophages of leprosy patients after stimulation withMycobacterium leprae

The macrophages from peripheral blood of normal healthy individuals respond to live or killedMycobacterium leprae by producing superoxide. On the other hand, the macrophages from bacteriologically positive (B +LL) or long term treated bacteriologically negative (B -LL) and tuberculoid leprosy patients are unable to produce superoxide when stimulated with liveMycobacterium leprae. While killedMycobacterium leprae induce superoxide with the cells from tuberculoid andB(-)LL patients, cells fromB(+)LL patients fail to respond. The deficiency inB(-)LL patients to produce superoxide appears to be specific withMycobacterium leprae and the defect can be counteracted by the addition of colchicine. These observations indicate a preexisting membrane disposition which does not favour superoxide production. A similar situation is seen in the cells from tuberculoid leprosy patients. Thus it appears that both cured and active lepromatous leprosy patients have defective macrophages, unable to respond to liveMycobacterium leprae to produce superoxide anion, in contrast to the situation with the cells from normal healthy individuals.     

An indomethacin sensitive suppressor factor released by macrophages of leprosy patients

Reduction inF _c receptor expression as assayed by ‘erythrocyte’ rosetting of macrophage cultures from long term treated lepromatous leprosy patients (bactereologically negative) was seen in the presence of viableMycobacterium leprae. Macrophages with and without intracellular bacilli demonstrated this reduction. On the basis of this observation the conditioned medium ofMycobacterium leprae infected macrophage cultures of lepromatous patients, were tested on macrophages from normal individuals for [³H]-leucine incorporation and antigen specific physical interaction with lymphocytes. Both these parameters showed decreased values as compared to the controls which were not exposed to this conditioned medium. Lymphocyte transformation toMycobacterium leprae in leucocyte cultures of normal individuals was also reduced in the presence of the conditioned medium from lepromatous patients’ macrophages. The indication that this factor may be a prostaglandin was suggested by the observation that its synthesis was inhibited by indomethacin. Its importance in the non-specific depression in cell-mediated immunity seen in lepromatous patients is discussed.     

Polymorphic arylamine N-acetyltransferase encoding gene (NAT2) from homozygous rapid and slow acetylator congenic Syrian hamsters

The nucleotide (nt) and deduced amino acid (aa) sequences were determined for polymorphic arylamine N-acetyl-transferase (NAT2) and its gene, NAT2, from homozygous rapid and slow acetylator congenic Syrian hamsters. The slow acetylator (NAT2^s) allele contained three point mutations which differed from the rapid acetylator allele (NAT2^r); two mutations were silent, and the third mutation resulted in a premature stop codon. The NAT2^r allele contained a truncated open reading frame of 726 nt encoding a 242-aa protein, which is 48-aa shorter than NAT2^r.     

乙酰化修饰调控结核杆菌异柠檬酸裂合酶的研究

目的:探索结核杆菌异柠檬酸裂合酶(ICL)蛋白322位点赖氨酸(Lys322)的乙酰化修饰对蛋白功能的调控作用。方法:构建结核杆菌ICL蛋白原核表达载体p ET28a-icl,并对Lys322位点进行定点突变为精氨酸(Arg,R)和谷氨酰胺(Glu,Q),体外表达纯化获得重组蛋白ICLWT、ICL322R和ICL322Q。通过Western blotting和酶活性测定来揭示Lys322位点突变前后对蛋白的乙酰化修饰水平及蛋白功能的影响。结果:Western blotting检测发现大肠杆菌表达体系获得的ICLWT、ICL322R和ICL322Q蛋白均有较高水平的蛋白赖氨酸乙酰化修饰信号,较ICLWT,ICL322R和ICL322Q突变蛋白的酶活性分别下降了大约50%和70%。结论:在大肠杆菌的表达体系中,ICL蛋白可以获得乙酰化修饰。ICL322Q突变蛋白酶活性的显著下降,揭示Lys322位点乙酰化修饰对ICL蛋白的功能存在负向调控。为未来深入探索赖氨酸乙酰化修饰对结核杆菌代谢,潜伏感染的调控作用奠定了基础。     

p300乙酰化在卡介苗感染中的作用

研究p300乙酰化在卡介苗(bacillus Calmette Guérin,BCG)感染中的作用。构建THP-1巨噬细胞模型,比较BCG感染前后p300蛋白表达水平和组蛋白H3乙酰化水平的改变,加入p300特异性抑制剂Delphinidin,观察细胞内组蛋白H3乙酰化水平的变化。结果表明,在分化成熟的THP-1细胞系中,BCG感染能够上调p300蛋白表达水平和组蛋白H3乙酰化水平,加入p300特异性抑制剂Delphinidin后,组蛋白H3乙酰化水平降低。BCG感染通过p300途径导致蛋白质乙酰化水平发生改变。