Methamphetamine inhibits antigen processing, presentation, and phagocytosis.
Methamphetamine inhibits antigen processing, presentation, and phagocytosis.
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甲基苯丙胺抑制抗原加工，表现和吞噬作用。
DOI：
10.1371/journal.ppat.0040028
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发表时间：
2008-02-08
期刊：
影响因子：
6.7
通讯作者：
Santambrogio, Laura
中科院分区：
文献类型：
--
作者：
Talloczy, Zsolt;Martinez, Jose;Joset, Danielle;Ray, Yonaton;Gacser, Attila;Toussi, Sima;Mizushima, Noboru;Nosanchuk, Josh;Goldstein, Harris;Loike, John;Sulzer, David;Santambrogio, Laura
全球有超过3500万人滥用甲基苯丙胺。长期滥用冰毒对与多名性伴侣进行无保护的性行为的个体尤其具有破坏性，因为它与感染艾滋病毒和相关继发感染的风险增加2倍有关。我们报告了第一个具体的证据，甲基安非他明在药理学浓度对树突状细胞和巨噬细胞有直接的免疫抑制作用。作为弱碱，甲基苯丙胺破坏酸性细胞器的pH梯度，包括溶酶体和相关的自噬细胞器。这反过来又抑制了受体介导的抗体包被颗粒的吞噬，内体-溶酶体途径的MHC II类抗原加工，以及树突状细胞向脾T细胞的抗原呈递。更重要的是，甲基安非他明促进了细胞内复制，并抑制了两种主要的艾滋病相关病原体白色念珠菌和新型隐球菌的细胞内杀伤。甲基苯丙胺具有先前未报道的直接免疫抑制作用，导致感染风险增加并加剧艾滋病病理。有一个新的艾滋病毒阳性男性群体，他们在几个月而不是几年的时间里发展成艾滋病。最近，在男同性恋和双性恋男性中，吸食大量冰毒变得很流行。不安全的性行为加上滥用冰毒被怀疑会导致疾病的快速发展。虽然研究表明艾滋病毒+冰毒滥用者的艾滋病症状加重和疾病进展，但分子机制尚不清楚。据推测，这种疾病的快速发展可能是由于一种极具毒性的艾滋病毒“超级菌株”突变所致，但尚未得到证实。人们还认为，这种药物对行为的影响可能导致不安全的性行为，尽管这并不能解释这种疾病病程更快的原因。我们现在证明了甲基苯丙胺是一种免疫抑制剂的第一个直接证据，并且这种免疫抑制的分子机制是由于免疫系统细胞中酸性细胞器pH值的崩溃，抑制抗原呈递和吞噬的功能。这些影响削弱了对机会性感染和艾滋病毒的免疫反应。这些发现可能对公共卫生产生重大影响，因为全世界有3500多万冰毒滥用者
Methamphetamine (Meth) is abused by over 35 million people worldwide. Chronic Meth abuse may be particularly devastating in individuals who engage in unprotected sex with multiple partners because it is associated with a 2-fold higher risk for obtaining HIV and associated secondary infections. We report the first specific evidence that Meth at pharmacological concentrations exerts a direct immunosuppressive effect on dendritic cells and macrophages. As a weak base, Meth collapses the pH gradient across acidic organelles, including lysosomes and associated autophagic organelles. This in turn inhibits receptor-mediated phagocytosis of antibody-coated particles, MHC class II antigen processing by the endosomal–lysosomal pathway, and antigen presentation to splenic T cells by dendritic cells. More importantly Meth facilitates intracellular replication and inhibits intracellular killing of Candida albicans and Cryptococcus neoformans, two major AIDS-related pathogens. Meth exerts previously unreported direct immunosuppressive effects that contribute to increased risk of infection and exacerbate AIDS pathology. There is a new population of HIV+ men who are developing AIDS over months instead of years as typical. It has recently become popular among gay and bisexual men to consume very high levels of Meth. Unsafe sex together with Meth abuse has been suspected to lead to rapid disease progression. While studies show exacerbated AIDS symptoms and disease progression in HIV+ Meth abusers, the molecular mechanism is yet unknown. It was postulated, yet unproven, that the rapid disease progression might be due to a mutant “superstrain” of HIV that was extremely virulent. It was also assumed that the effects of the drug on behavior may lead to unsafe sex, although this would not explain the more rapid time course of the disease. We now demonstrate the first direct evidence that Meth is an immunosuppressive agent, and that the molecular mechanism of this immunosuppression is due to the collapse of acidic organelle pH in cells of the immune system, inhibiting the functions of antigen presentation, as well as phagocytosis. These effects compromise the immune response to opportunistic infections and HIV. These findings could have a major impact on public health, as there are over 35 million Meth abusers worldwide
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影响因子：
32.4
作者：
CASTELLINO, F;GERMAIN, RN
通讯作者：
GERMAIN, RN
影响因子：
15.9
作者：
Levitz, SM;Harrison, TS;Liu, XP
通讯作者：
Liu, XP
DOI：
10.1073/pnas.0501190102
发表时间：
2005-05-31
影响因子：
11.1
作者：
Dengjel, J;Schoor, O;Stevanovic, S
通讯作者：
Stevanovic, S
影响因子：
17.7
作者：
Chang, L;Ernst, T;Grob, CS
通讯作者：
Grob, CS
DOI：
10.1073/pnas.97.2.680
发表时间：
2000-01-18
影响因子：
11.1
作者：
Cox, D;Lee, DJ;Greenberg, S
通讯作者：
Greenberg, S