#Dengue #ImmuneResponse #Immunity #NKCells
#TCells
Dengue is an arboviral disease endemic in over
100 countries and poses a major public health threat. While most cases are
mild, severe forms—
severe dengue (SD) or dengue hemorrhagic fever—are marked by
vascular hyperpermeability, hypovolemic shock, and a risk of death. Notably,
these severe manifestations are often the result of an
exacerbated immune
response rather than viral replication itself.
Current treatments are
exclusively symptomatic.
No specific antiviral or validated immunomodulatory therapy is currently
available. This lack of targeted therapy is largely due to the
complexity of
the immune responses involved and the
insufficient understanding of the
underlying cellular mechanisms.
One of the main challenges lies in
understanding how certain immune responses, which are supposed to protect the
host, can instead contribute to the clinical severity of dengue. This review
aims to identify the key immune cell players and the mechanisms of
dysregulation involved, taking into account viral serotype variability and
prior exposure history.
Who loses control?
This review analyzes selected clinical, animal, and in vitro studies that
specifically examine cellular immune responses involved in severe dengue. The
activation, dysregulation, and functions of major immune cells—NK cells,
monocytes/macrophages, dendritic cells, T and B lymphocytes—are evaluated in
response to various dengue virus serotypes. Particular attention is given to
the mechanisms promoting hyperinflammation and to the role of
antibody-dependent enhancement (ADE) in disease worsening. Immune profiles
observed in mild cases are compared with those in severe cases to identify
cellular signatures associated with pathological progression.
The review highlights several major alterations
in immune response during severe dengue.
NK cells and monocytes/macrophages are
strongly activated by the infection and
massively secrete pro-inflammatory
cytokines such as IL-6, TNF-α, and IFN-γ, contributing to a cytokine storm
responsible for vascular leakage.
Dendritic cells show impaired activation,
disrupting coordination between innate and adaptive responses.
CD4+ and CD8+ T
cells exhibit
intense activation and
excessive cytotoxic responses, with high granzyme
B and perforin production, directly linked to symptom severity.
B cells play an
ambivalent role. While they offer protection through neutralizing antibodies,
they may also contribute to pathogenesis via ADE. In previously exposed
individuals,
secondary memory responses can paradoxically worsen the infection
by facilitating viral entry into target cells through non-neutralizing
antibodies.
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When immunity goes haywire
Severe dengue is characterized by a dysregulated immune response in which both
innate and adaptive cells actively contribute to the breakdown of vascular
barriers and clinical worsening. The main challenges are to finely distinguish
protective from pathogenic responses, identify predictive biomarkers, and
develop therapies targeting immune regulation. This review sought to explore
immune dysfunctions in severe dengue to better identify potential therapeutic
targets.
Current data underscore the importance of
targeted immunomodulation to prevent severe complications. However, this review
is limited by data heterogeneity, the lack of strict correlation between
cellular activation levels and clinical symptoms, and the scarcity of robust
longitudinal studies. Future work should include the development of therapeutic
strategies to
limit excessive immune cell activation, vaccine designs that
consider ADE risks, and better integration of immunological profiles in risk
stratification of patients.
Read next: Dengue and the Mind: The Silent Storm
