T(H)2 adjuvants: implications for food allergy

A persistent question for immunologists studying allergic disease has been to define the characteristics of a molecule that make it allergenic. There has been substantial progress elucidating mechanisms of innate priming of T(H)2 immunity in the past several years. These accumulating data demonstrate that T(H)2 immunity is actively induced by an array of molecules, many of which were first discovered in the context of antihelminthic immune responses. Similar intrinsic or associated activities are now known to account for the T(H)2 immunogenicity of some allergens, and may prove to play a role for many more. In this review, we discuss what has been discovered regarding molecules that induce innate immune activation and the pathways that promote T(H)2-polarized immune responses generally, and specifically what role these mechanisms may play in food allergy from models of food allergy and the study of T(H)2 gastrointestinal adjuvants.     

SLAM and DC-SIGN measles receptor polymorphisms and their impact on antibody and cytokine responses to measles vaccine

Background

Despite the use of measles vaccine, measles virus continues to circulate and cause severe disease. Immune responses to the measles vaccine are variable between individuals, with up to 10% failing to produce a sufficient protective response post-vaccination. Signaling lymphocyte activation molecule (SLAM) and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN; CD209) are specific measles receptors: SLAM binds and permits entry of the virus into the cell, DC-SIGN acts as an attachment receptor, increasing viral binding efficiency and transmission. Genetic variations in these receptor genes may alter measles vaccine antibody and cellular responses.

Methods

In 12-month-old infants from Perth, Western Australia after their first measles vaccine dose as part of the combination measles-mumps-rubella (MMR) vaccine, 7 SLAM and DC-SIGN polymorphisms were genotyped and associations were investigated with measles IgG antibody levels and in vitro measles cytokine responses.

Results

The DC-SIGN promoter variant −336C/T was associated with overall IFN-γ responses after measles stimulation (P = 0.002) and three DC-SIGN polymorphisms (−336C/T, −139C/T and −871C/T) were associated with the proportion of cytokine non-responders to measles (P = 0.001, P = 0.021 and P = 0.036, respectively). However, no associations were found between the DC-SIGN or SLAM polymorphisms and measles IgG antibody levels.

Conclusions

The results suggest that DC-SIGN −139C/T, −336C/T and −871C/T polymorphisms may modulate cytokine (but not antibody) responses to the measles component of MMR vaccine. Furthermore, contrasting previous studies, SLAM polymorphisms do not appear to affect measles antibody or cytokine responses in this cohort.     

DC-SIGN和DC-SIGNR外显子4在中国结核患者中的遗传多态性

目的探讨DC-SIGN和DC-SIGNR外显子4在中国结核患者中是否存在遗传易感性。方法采用PCR结合DNA测序对227例结核患者和520例健康人群的DC-SIGN和DC-SIGNR外显子4重复序列多态性进行基因分型和测序分析。结果 DC-SIGN外显子4基因型与等位基因频率在结核患者和健康人群间差异无统计学意义（P〉0.05）;DC-SIGNR外显子4等位基因的频率差异也无计学意义（P〉0.05）;但6/6基因型分布频率在结核患者和健康人群间的差异有统计学意义（P〈0.05）。结论 DC-SIGN外显子4遗传多态性与结核感染易感性无明显相关;6/6基因型DC-SIGNR外显子4在结核患者中的分布频率较高,可能与结核感染的易感性相关,值得进一步研究。     

DC-SIGN在树突状细胞传播HIV-1中作用的实验研究

目的探讨DC—SIGN在树突状细胞（DC）传播HIV-1中的作用。方法用M嗜性或T嗜性HIV-1原代分离株分别刺激未成熟DC（immature DC，iDC））和成熟DC（mature DC，mDC），数量与DC相同的CD4^T细胞作为对照组，与活化的CD4^＋T细胞共培养，用ELISA方法定量检测第4、7、10、14天共培养上清中p24抗原，观察Dc在传播HIV-1的作用。预先加入抗DC—SIGNMcAb和，或抗ICAM-3McAb，观察抗DC-SIGNMcAb和抗ICAM-3McAb对DC传播HIV-1作用的影响。结果用M嗜性HIV-1刺激的iDC以及用M和T嗜性HIV-1刺激的mDC的共培养上清中p24含量均随培养时间延长逐渐增加，显著高于对照组（P=0．001）。加入抗DC．SIGNMcAb后，共培养上清p24抗原明显降低；加入抗ICAM-3McAb后上清中p24抗原并不减少。用T嗜性HIV-1刺激的iDC共培养上清中p24含量不随培养时间延长逐渐增加，与对照组相比差异无统计学意义。结论iDC具有传播M嗜性HIV-1的作用，但不具有传播T嗜性HIV-1的作用；mDC既能将M嗜性也能将T嗜性HIV-1传播给CD4^T细胞。抗DC-SIGN McAb能够抑制DC传播HIV-1的作用，提示DC-SIGN在DC向T细胞播散HIV-1过程中可能发挥重要作用。     

Raji B cells, misidentified as THP-1 cells, stimulate DC-SIGN-mediated HIV transmission

A number of studies examining interactions of dendritic cell (DC)-specific ICAM-3 grabbing nonintegrin (DC-SIGN) with viral pathogens have relied on monocytic transfectants as models for primary DCs. Here we show that the presumed "THP-1" monocytic cells used in these studies are instead Raji B cells. Moreover, we demonstrate that true THP-1 cells do not support DC-SIGN-mediated HIV-1 transmission, whereas human B cell lines efficiently enhance this process. These data indicate that there are features common to B cells and DCs that facilitate transmission of HIV-1 and provide new insights toward the mechanism of DC-SIGN-mediated HIV-1 transmission.     

SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2

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Branched oligosaccharide structures on HBV prevent interaction with both DC-SIGN and L-SIGN

Summary.  Hepatitis B virus (HBV) is a DNA virus that infects the liver as primary target. Currently, a high affinity receptor for HBV is still unknown. The dendritic cell specific C-type lectin DC-SIGN is involved in pathogen recognition through mannose and fucose containing carbohydrates leading to the induction of an anti-viral immune response. Many glycosylated viruses subvert this immune surveillance function and exploit DC-SIGN as a port of entry and for trans -infection of target cells. The glycosylation pattern on HBV surface antigens (HBsAg) together with the tissue distribution of HBV would allow interaction between HBV and DC-SIGN and its liver-expressed homologue L-SIGN. Therefore, a detailed study to investigate the binding of HBV to DC-SIGN and L-SIGN was performed. For HCV, both DC-SIGN and L-SIGN are known to bind envelope glycoproteins E1 and E2. Soluble DC-SIGN and L-SIGN specifically bound HCV virus-like particles, but no interaction with either HBsAg or HepG2.2.15-derived HBV was detected. Also, neither DC-SIGN nor L-SIGN transfected Raji cells bound HBsAg. In contrast, highly mannosylated HBV, obtained by treating HBV producing HepG2.2.15 cells with the α-mannosidase I inhibitor kifunensine, is recognized by DC-SIGN. The α-mannosidase I trimming of N-linked oligosaccharide structures thus prevents recognition by DC-SIGN. On the basis of these findings, it is tempting to speculate that HBV exploits mannose trimming as a way to escape recognition by DC-SIGN and thereby subvert a possible immune activation response.     

暗娼人群DC-SIGN及DC-SIGNR基因多态性初步研究

目的分析中国暗娼人群中DC-SIGN及DC-SIGNR基因多态性的分布,比较不同研究人群等位基因频率分布。方法PCR检测234例HIV阴性暗娼DC-SIGN及DC-SIGNR基因多态性。结果DC-SIGN基因型在234例中发现4例突变杂合子。DC-SIGNR等位基因频率以7次重复最为常见(65.2%),其次为5次重复(18.4%)和9次重复(11.9%),其基因频率分布与国外报道差异有统计学意义。结论DC-SIGN基因具有多态性,而DC-SIGNR基因多态性分布同国外报道比较存在差异。     

Methamphetamine Modulates DC-SIGN Expression by Mature Dendritic Cells

We report that methamphetamine (meth) may act as cofactor in human immunodeficiency virus (HIV)-1 pathogenesis by increasing dendritic cell (DC)-specific intercellular adhesion molecule-3 (ICAM-3) grabbing non-integrin (DC-SIGN) expression on DCs. Mature DCs (MDCs), obtained from normal subjects, cultured with meth show an up-regulation of DC-SIGN gene and protein expression as analyzed by real-time quantitative polymerase chain reaction and fluorescence-activated cell-sorting analyses, respectively. Furthermore, these meth-induced effects were reversed by a dopamine D1 receptor antagonist (SCH 23390) and small interfering RNA specific to the D1 receptor (D1R) demonstrating that meth-induced effects are mediated through these receptors. Furthermore, meth in synergy with the HIV-1 peptide gp120 up-regulates DC-SIGN gene expression by MDCs. These data are the first evidence that meth up-regulates the expression of DC-SIGN on MDCs. A better understanding of the role of DC-SIGN in HIV-1 infection may help to design novel therapeutic strategies against the progression of HIV-1 disease in the drug-using population.     

Antiviral agents targeting glycans on dengue virus E-glycoprotein

Evaluation of: Alen MMF, De Burghgraeve T, Kaptein SJF et al. Broad antiviral activity of carbohydrate-binding agents against the four serotypes of dengue virus in monocyte-derived dendritic cells. PLoS ONE 6(6), e21658 (2011).

The molecular recognition of dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) with arthropod-derived N-glycans on E-glycoprotein is essential for dengue virus (DENV) infection in humans. Therefore, the specific interaction of DC-SIGN with N-glycans on E-glycoprotein is a promising target for development of virus replication inhibitors. This article discusses the findings of a recent report describing antiviral activities of carbohydrate-binding agents, such as lectins and a small molecular weight compound against DENV infection of monocyte-derived dendritic cells. Several plant lectins and the small molecular weight compound Pladimicin-S showed potent inhibition of cellular infection by four DENV serotypes.