Could specific antibodies be the cause of hemorrhagic fever in secondary dengue infections?

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Researchers from the Rockefeller University (NY, USA) have identified a subclass of antibody that could shed light on why some individuals are more vulnerable to dangerous secondary infections of dengue. The findings could allow better identification of which patients are most at risk and also lead to improved treatments and vaccines.

Secondary dengue infection can trigger haemorrhagic fever, a critical and sometimes fatal condition, in a small number of individuals. It has previously been thought that progression to severe dengue was due to antibody-dependent enhancement; however, this doesn’t explain why only less than 15% develop severe complications.

Past work by this group has suggested that differences in antibodies between patients with mild and severe dengue could account for why only some individuals are at risk. In their most recent study, published recently in Science, the team looked more closely at the Fc regions of antibodies taken from the blood of patients with mild and severe dengue.

The researchers discovered that all of the patients they assessed were still producing antibodies as a result of primary infection; however, the structure of the antibodies varied between individuals. The team observed that patients with severe secondary dengue had high levels of a specific subclass of antibody, IgG1, which lacks fucosyl residues on the Fc region.

These antibodies are known to strongly activate immune cells, and in the case of severe secondary dengue, it was demonstrated that IgG1 appeared to cross-react with platelet antigens, leading to the destruction of platelets and therefore causing the thrombocytopenia seen in dengue haemorrhagic fever.

Senior author Jeffrey Ravetch, from the Rockefeller University, explained: “Patients with severe secondary disease have high levels of a particular type of antibody that triggers a forceful immune response. This distinctive signature did not show up in patients with more mild illness,”

“Our work sheds new light on the way in which the dengue virus co-opts antibodies produced as a result of the previous infection, using them to inflict more damage the second time around.”

The researchers suggested that therapeutics and vaccines targeting the production of these antibodies during an infection may help to prevent severe secondary infections.

Ravetch commented: “Because we now know what to look for, it may become possible to identify patients at risk of severe illness, so they can receive intensive, supportive care early on,”

“It could also aid in the development of safe dengue vaccines that stimulate the immune system without triggering a secondary, potentially harmful, response and of new drugs designed to help patients recover by blocking the antibody signalling.”

In addition, the findings could have implications for related viruses, such as the Zika virus. Ravtech concluded: “It will be important to consider the possibility that other, related viruses employ a similar strategy, and that infection with one may affect the subsequent response to another.”

Source: Wang TT, Sewatanon J, Memoli MJ et al. IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity, Science, 355 (6323), 395-398 http://newswire.rockefeller.edu/2017/01/31/discovery-helps-explain-why-only-some-people-develop-life-threatening-dengue-infections/

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  1. One of intrigued scenarios that have been argued for more than 40 years in dengue field is the secondary infection is more vulnerable to hemorrhagic in affected subjects. Recent advancement in the field shows that the frequency of primary infection developing hemorrhagic in naive travelers to the dengue endemic regions is at the same rate as citizen habituating in dengue prone countries. As such, other unknown factors appear to play much more significant role than the current hypothesis.

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