Dengue Literature Review

Pemphigus and Acantholysis in Dengue

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Pemphigus and Acantholysis in Dengue

Overview

Pemphigus is a group of autoimmune blistering skin diseases characterised by auto-antibodies targeting desmoglein (DSG) proteins — the cadherin-type glycoproteins that mediate cell-to-cell adhesion in the epidermis via desmosome complexes. Dengue virus (DENV) infection has been associated with the development of anti-DSG auto-antibodies, causing acantholysis (loss of keratinocyte cohesion) and intra-epidermal blister formation. This represents a dermatological axis of dengue-induced autoimmunity that is mechanistically distinct from the platelet and endothelial cell mimicry pathways.

This is a rare and under-characterised complication. Evidence currently rests on case-report and mechanistic studies cited in a secondary review (Ghorai2024); no prospective cohort data on anti-DSG prevalence in dengue patients is available in this wiki.

Key Points from Literature

Desmosome structure and DSG biology

Desmosomes are intercellular adhesion complexes in the epidermis and mucous membranes. Their structural proteins include:

  • DSG (desmoglein) and DSC (desmocollin) — transmembrane cadherins mediating homophilic and heterophilic adhesion between keratinocytes
  • DP (desmoplakin) — intracellular linker protein that connects DSG/DSC tails to keratin filaments
  • PKP (plakophilin) and PG (plakoglobin) — adaptor proteins linking DP to DSG/DSC intracellular tails

DSG isoforms in the epidermis are: DSG1, DSG2, DSG3, and DSG4. DSC isoforms are DSC1–3. PKP isoforms are PKP1–3.

Dengue-associated pemphigus types

Two major pemphigus phenotypes are associated with dengue infection:

Pemphigus typeTarget auto-antibodiesPrimary lesions
Pemphigus vulgaris (PV)Anti-DSG-1 + anti-DSG-3Mucous membranes + skin
Pemphigus foliaceus (PF)Anti-DSG-1 onlySkin only (superficial layers)

Both have been documented in association with DHF and DF patients (citing Furue et al. 2017 and Saito et al. 2012 via Ghorai2024). DENV-infected patients developed epidermal blisters following passive transfer of anti-DSG antibodies to neonatal mice — the canonical experimental model for confirming anti-DSG pathogenicity (Spindler et al. 2013, cited via Ghorai2024).

Viral triggers for pemphigus are established more broadly: EBV, CMV, HSV-1/2, and DENV have all been associated with triggering or exacerbating pemphigus.

Mechanism of acantholysis

Two mechanistically distinct pathways are described:

Signalling-dependent pathway (P38 MAPK): Anti-DSG-3 auto-antibodies bind the N-terminal extracellular domain 1 (EC1) of DSG-3, which is essential for trans-adhesive interaction of DSG. This binding induces clustering and endocytosis of DSG-3 via a P38 mitogen-activated protein kinase (P38 MAPK)-dependent signalling cascade → DSG-3 internalisation → keratin filament breakdown → desmosome complex internalisation into cytoplasm → loss of cell adhesion. Inhibitors of P38 MAPK prevent auto-antibody-mediated clustering and DSG-3 endocytosis.

Signalling-independent pathway (steric hindrance): Anti-DSG auto-antibodies targeting EC1 also cause steric hindrance — physically blocking the trans-interaction of DSG between adjacent keratinocytes without requiring P38 MAPK activation or DSG clustering. Keratinocytes separate without need for cellular signalling, solely through interruption of the adhesive DSG-DSG bridge.

Both pathways operate in human PV; dengue-associated acantholysis likely involves both, as established for PV generally (Spindler 2013, Saito 2012 via Ghorai2024).

Additionally, cholesterol rafts on the keratinocyte cell surface are involved in depleting cell surface DSG-3, and calcium-dependent epitopes of DSG-3 may be specifically targeted by more pathogenic anti-DSG antibodies.

Pathogenicity spectrum

Polyclonal PV auto-antibodies vary in pathogenicity:

  • Low pathogenicity anti-DSG-3 → mucosal erosions only
  • High pathogenicity anti-DSG-3 → extensive mucosal involvement even at low levels of DSG-3 assembly

The IgG fractions from PV sera cause blistering; immune adsorption of pathological auto-antibodies against the complete extracellular domains of DSG-1 and DSG-3 eliminates the blister-inducing capacity.

Relationship to molecular mimicry

Ghorai2024 frames dengue-associated pemphigus within the broader molecular mimicry/autoimmune trigger paradigm of DENV infection. Whether dengue generates anti-DSG antibodies through direct molecular mimicry between DENV proteins and DSG sequences, through bystander activation during the inflammatory response, or through viral-induced failure of self-tolerance is not specified in the available sources. The precise dengue protein epitopes responsible for triggering anti-DSG responses (if molecular mimicry is the mechanism) have not been identified.

Contradictions & Debates

  • Evidence level: The dengue-pemphigus association rests on case reports and experimental models (passive neonatal mouse transfer studies) rather than systematic prospective cohort data. The incidence of pemphigus or acantholysis in unselected dengue patient cohorts is unknown.
  • Causal direction: Whether dengue triggers de novo anti-DSG autoantibody production or unmasks pre-existing subclinical pemphigus susceptibility in genetically predisposed individuals cannot be determined from case-report evidence alone.
  • Mechanism specificity: The dengue-specific mechanism triggering anti-DSG autoantibodies (molecular mimicry vs. bystander activation vs. pre-existing genetic susceptibility) is not established. The aetiology of pemphigus generally involves both genetic and environmental/viral factors.

Sources

  • Ghorai2024 - Autoantibodies in Dengue Pathogenesis Review (comprehensive review covering anti-DSG autoantibodies in dengue; acantholysis mechanism; PV and PF in DHF/DF patients; passive transfer neonatal mouse model; P38 MAPK and steric hindrance pathways; DSG-3 EC1 domain as primary anti-DSG target; Kolkata India review — secondary source synthesising case reports and mechanistic literature)

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