Ghorai2024 - Autoantibodies in Dengue Pathogenesis Review

Full citation: Ghorai T, Sarkar A, Roy A, Bhowmick B, Nayak D, Das S (2024). Role of auto-antibodies in the mechanisms of dengue pathogenesis and its progression: a comprehensive review. Archives of Microbiology, 206:214. https://doi.org/10.1007/s00203-024-03954-0

Raw file: [[raw/Ghorai2024.pdf]]

Summary

This comprehensive review from the Virology Laboratory, DAC Regional Research Institute, Kolkata, covers auto-antibody-mediated immunopathogenesis in dengue virus infection. It synthesises the existing literature on autoantibodies targeting platelets, endothelial cells, coagulation/fibrinolytic factors, and desmosomal proteins — the last being an angle not previously highlighted in this wiki. The paper proposes that auto-antibodies generated via molecular mimicry between DENV proteins (NS1, prM, E, core) and host self-antigens are a central driver of dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS).

The review organises autoantibody pathology into four mechanistic domains: (1) thrombocytopenia via IgM anti-platelet autoantibodies and platelet-associated immunoglobulins; (2) endothelial dysfunction and vasculopathy via anti-endothelial cell antibodies (AECA), including hepatic endothelial inflammation; (3) haemostasis disruption via cross-reactive anti-coagulation factor and anti-fibrinolytic autoantibodies producing profibrinolysis and hyperfibrinolysis; and (4) pemphigus — autoimmune blistering skin disease via anti-desmoglein (DSG) antibodies causing acantholysis. The paper concludes with future perspectives on auto-antibody biomarkers and therapeutic targets including monoclonal antibodies designed to neutralise DENV without inducing ADE.

Study Design

• Type: Narrative review (no original patient data)
• Sample size: N/A
• Setting: Kolkata, India (Virology Laboratory, DAC Regional Research Institute + CCRH New Delhi + Peerless Hospital and B.K. Roy Research Centre, Kolkata)
• Population: Literature synthesis; draws on dengue patient cohorts from primary sources including Lin2001, Chuang2013/2014, Vo2020, Wan2013, and others

Key Findings

• General mechanism: Molecular mimicry, epitope spreading, polyclonal activation, and bystander activation contribute to auto-antibody generation during DENV infection; at least 12 regions in DENV proteins (core, prM, E, NS1) share amino acid sequence homology with coagulation factors including X, XI, and VII (citing Lin 2011)
• Thrombocytopenia: Anti-platelet IgM (predominant isotype over IgG, Lin 2001) causes complement-mediated platelet lysis; platelet-associated immunoglobulins (PAIgG, PAIgM) are associated with platelet abnormalities and higher clearance rates
• Endothelial dysfunction: Anti-NS1 AECA induce endothelial apoptosis via the NO pathway (NO → p53↑, Bax↑, Bcl-2/Bcl-xL↓ → cytochrome c release → caspase-3 activation); separately, NF-κB activation (via I-κB degradation) by AECA drives IL-1, IL-6, IL-8, MCP-1, TNF-α → ICAM-1, VCAM-1, E-selectin upregulation; endothelial inflammation activates T cells, monocytes, and NK cells
• Hepatic inflammation: Anti-NS1 AECA cross-react with vascular endothelium of central and portal hepatic veins in murine models; passive inoculation with anti-NS1 antibodies causes enhanced mononuclear phagocytic cell infiltration → fatty liver, necrotic body, liver fibrosis, vesicle formation (Lin 2008 murine model)
• Profibrinolysis: Auto-antibodies bind plasminogen and act on fibrinogen → regulated fibrinogen breakdown; prolongs APTT and thrombin time; (Chuang 2013/2014: scFv from NS1-immunised mice cross-reacting with fibrinogen prolongs thrombin time in vitro)
• Hyperfibrinolysis: Auto-antibodies bind the plasminogen complex → excessive fibrin degradation products → increased bleeding risk; in DHF/DSS: decreased fibrinogen and elevated fibrin degradation products documented (Marchi 2009, Sosothikul 2005)
• Pemphigus (novel to this wiki): Dengue patients can develop anti-desmoglein (DSG) autoantibodies → pemphigus vulgaris (PV, anti-DSG-1 + anti-DSG-3) and pemphigus foliaceus (PF, anti-DSG-1); DSG disruption prevents desmosome assembly → keratin filament collapse → acantholytic intra-epidermal blisters; anti-DSG-3 targets N-terminal extracellular domain 1 (EC1) → steric hindrance or P38 MAPK-dependent signalling pathway → keratinocyte dissociation; associated with both DHF and DF
• Complement in DHF vs. DF: DHF patients have increased C3 convertase (C3bBb) complex formation — alternative complement cascade activation; DF patients have reduced Factor H expression; auto-antibodies against Factor H and Factor P identified especially in primary infections (Kouser 2013)
• IgG auto-antibodies and primary infection: DENV-specific IgGs significantly elevated in secondary infections; IgG auto-antibodies more common in primary infections (Vo 2020; Balakrishnan 2011 — polyreactive natural IgG B cells activated in both primary and secondary)
• Low complement/coagulation auto-antibodies in DHF: Low anti-prothrombin IgG, anti-complement C4 IgG, and anti-Factor P IgG correlated with low platelet counts in DHF — consistent with immune complex-mediated consumption (Vo 2020)

Methods Used

Review paper synthesising published experimental and clinical literature; no original methods. Primary methods described in cited sources include NS1 Antigen Detection, RT-PCR, ELISA, flow cytometry assays for anti-platelet/anti-endothelial autoantibodies, recombinant single-chain variable fragment (scFv) assays for coagulation interference.

Entities Mentioned

• NS1 Protein
• E Protein
• prM Protein
• DENV-1, DENV-2, DENV-3, DENV-4

Concepts Addressed

• Autoimmunity in Dengue
• NS1 Molecular Mimicry in Dengue
• Dengue Pathophysiology
• Infection-Triggered Autoimmunity
• Cross-Reactive Antibodies
• Cytokine Storm
• Coagulation and Fibrinolysis in Dengue
• Pemphigus and Acantholysis in Dengue

Relevance & Notes

This review is a secondary source — it synthesises findings from primary papers already in this wiki (Lin2001, Saito2004, Oishi2003, Vo2020, Wan2012, Bhatt2020, and others) alongside additional primary literature not currently in the wiki (Chuang 2013/2014 on scFv coagulation interference; Lin 2008 on anti-NS1 hepatic inflammation murine model). Its primary contributions to this wiki are:

1. Coagulation/fibrinolysis mechanism — the profibrinolysis/hyperfibrinolysis dual mechanism (auto-antibodies binding plasminogen and plasminogen complex with distinct downstream effects) is the most detailed mechanistic account in this wiki of DENV-associated coagulopathy from the auto-antibody angle, extending the existing WGNGCG/E protein coagulation homology coverage.

2. Pemphigus and acantholysis — introduces the anti-DSG autoantibody and skin blistering mechanism as a dengue complication not previously covered in this wiki.

3. Hepatic inflammation via anti-NS1 AECA — provides explicit murine-model details (fatty liver, necrotic body, liver fibrosis, mononuclear infiltration pattern) for the anti-NS1 hepatic damage pathway, extending the existing Lin2006 reference in the wiki (which mentions hepatitis-like effects but less mechanistic detail).

4. Institutional context: From the same city (Kolkata) as Chatterjee2024 but from a different institution (DAC Regional Research Institute / Peerless Hospital vs. ICMR-NICED). Reflects the density of dengue research infrastructure in Kolkata.

Epistemic note: As a narrative review without systematic search methodology or PRISMA reporting, this paper’s comprehensiveness cannot be verified. The pemphigus association with dengue cites case report-level evidence (Saito et al. 2012; Spindler et al. 2013) rather than cohort data. The coagulation mechanism detail draws heavily on the Chuang group’s in vitro scFv studies — not validated in patient cohorts. The DENV-5 mention (Malaysia 2013) reflects established virology.

Questions Raised

• Chuang 2013/2014 scFv coagulation experiments — do serum-level anti-plasminogen autoantibodies in natural dengue infection achieve concentrations sufficient to produce the profibrinolysis/hyperfibrinolysis effects demonstrated with isolated scFv? A study measuring anti-plasminogen antibody titres in dengue patient sera alongside fibrinogen, D-dimer, and thrombin time would directly test this.
• Pemphigus-dengue incidence — how commonly is pemphigus-like acantholysis documented in dengue? The Ghorai2024 review cites case-report-level evidence; systematic surveillance data on dengue-associated skin blistering in endemic populations would clarify whether this is a rare complication or under-diagnosed.
• Anti-DSG detection in dengue patient sera — have anti-DSG1/DSG3 antibodies been systematically measured in dengue cohorts? If so, is their prevalence infection-order dependent (like anti-EC IgG isotype shift)? Measurement by ELISA in a prospective cohort would test whether anti-DSG is a genuine autoantibody response or limited to rare susceptible individuals.
• Lin 2008 hepatic model in humans — anti-NS1 antibodies cause hepatic histopathological changes in mice. Whether analogous autoantibody-mediated hepatic pathology occurs in human dengue (vs. direct viral hepatocyte infection and apoptosis, which is the Guzman2016-cited mechanism) is not established. A liver biopsy study with anti-NS1 immunostaining and histopathological characterisation in fatal DHF with liver involvement would test this.