Pemphigus Vulgaris

Autoimmune MONDO:0008219 Autoimmune Disease Skin Disease

A potentially life-threatening autoimmune blistering disease caused by autoantibodies against desmoglein 3 (and often desmoglein 1), leading to loss of keratinocyte adhesion (acantholysis) and intraepidermal blister formation. Mucosal involvement often precedes skin lesions.

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0
Mappings
0
Definitions
0
Inheritance
4
Pathophysiology
0
Histopathology
21
Phenotypes
0
Pathograph
3
Genes
4
Treatments
0
Subtypes
0
Differentials
0
Datasets
0
Trials
0
Models
5
References
2
Deep Research
🏷

Classifications

Harrison's Chapter
skin disorder autoimmune disease
⚙

Pathophysiology

4
Anti-Desmoglein Autoantibodies
IgG autoantibodies against desmoglein 3 (mucosal-dominant) and desmoglein 1 (mucocutaneous) directly cause loss of keratinocyte adhesion. Antibody binding triggers intracellular signaling leading to desmosome disassembly.
Keratinocyte link
Immunoglobulin Production link
Show evidence (2 references)
PMID:10878487 SUPPORT Model Organism
"Auto-Ab against the desmosomal adhesion molecule, desmoglein 3 (Dsg3), are critical in the pathogenesis of this disease, since the transfer of serum IgG Ab reactive with Dsg3 into newborn mice induces a bullous skin disease resembling PV."
Passive transfer of anti-Dsg3 IgG into newborn mice demonstrates that these autoantibodies are directly pathogenic and sufficient to cause pemphigus-like disease.
PMID:39075718 PARTIAL
"The most notable biomarkers trends include elevations in IL-4, IL-6, IL-17A, anti-Dsg1/3 autoantibodies, and a reduction in Treg cells and FOXP3."
Systematic review of 66 studies confirms that anti-Dsg1 and anti-Dsg3 autoantibodies are the most consistent biomarkers in pemphigus vulgaris.
Acantholysis and Blister Formation
Loss of desmosomal adhesion causes keratinocytes to detach from each other (acantholysis). Suprabasal clefting occurs as basal keratinocytes remain attached to the basement membrane while upper layers separate.
Cell Adhesion link
Show evidence (2 references)
PMID:10878487 PARTIAL
"Antibody (Ab) binding interferes with the adhesive function of these molecules, leading to detachment and subsequently blister formation."
Autoantibody binding directly interferes with the adhesive function of desmogleins, resulting in keratinocyte detachment and blister formation.
PMID:33208597 SUPPORT
"Vesicles were seen in 149 cases (88%), the level of which was suprabasal in 91(61%) and both suprabasal and intraepidermal in 50 cases (33.5%). Acantholytic cells were present in 142 cases (95%)."
Histopathological study of 169 PV biopsies confirms suprabasal vesicle formation and acantholysis as hallmark features.
Signaling-Mediated Cytoskeletal Changes
Anti-desmoglein antibodies activate p38 MAPK and other signaling pathways, causing keratin filament retraction and further weakening of cell-cell adhesion independent of direct steric hindrance.
Signal Transduction link
Immune Dysregulation and Th2/Th17 Skewing
Pemphigus vulgaris is characterized by a shift toward Th2 and Th17 cytokine profiles with elevated IL-4, IL-6, and IL-17A, along with a marked reduction in regulatory T cells (Tregs). This imbalance promotes autoreactive B cell activation and pathogenic autoantibody production.
T Cell Differentiation link Cytokine Production link
Show evidence (3 references)
PMID:19811408 SUPPORT
"All patients with PV and PF showed significantly (p < 0.000) elevated levels of T(H)2 cytokines (IL-10 and IL-4) as compared with healthy controls. However, the mean concentration of T(H)1 cytokines (IL-2 and IFN-gamma) was significantly decreased in patients as compared to healthy individuals."
Cytokine profiling demonstrates a clear Th2 cytokine dominance in PV patients with elevated IL-4 and IL-10, supporting the role of Th2-mediated immune responses in disease pathogenesis.
PMID:17377382 SUPPORT
"The proportion of Treg cells in all PV patients was severely reduced, approximately ten times less than controls. These observations were further confirmed by both diminished gene and protein expression of Foxp3 in the CD4(+)CD25(+) T cell population in PV patients."
Severe reduction in regulatory T cells may contribute to loss of tolerance and failure to suppress autoreactive B and T cells in pemphigus vulgaris.
PMID:39075718 SUPPORT
"The results of this review support current theories of PV pathogenesis, with increased Th2 activity, increased Th17 activity, decreased Treg activity, and production of anti-Dsg1/3 autoantibodies being observed."
Systematic review synthesizing 66 studies confirms the Th2/Th17 skewing and Treg deficiency as core immunological features of pemphigus vulgaris.
●

Phenotypes

21
Cardiovascular 1
Urticaria VERY_FREQUENT Urticaria (HP:0001025)
Urticarial lesions may precede or accompany blister formation in some patients. Orphanet classifies this as very frequent though clinical experience suggests it may be less prominent than erosive lesions.
Show evidence (1 reference)
ORPHA:704 SUPPORT
"HP:0001025 | Urticaria | Very frequent (99-80%)"
Orphanet reports urticaria as very frequent in pemphigus vulgaris.
Digestive 3
Feeding Difficulties FREQUENT Feeding difficulties (HP:0011968)
Painful oral and esophageal erosions limit food intake
Show evidence (1 reference)
ORPHA:704 SUPPORT
"HP:0011968 | Feeding difficulties | Frequent (79-30%)"
Orphanet reports feeding difficulties as a frequent consequence of mucosal involvement in pemphigus vulgaris.
Dysphagia FREQUENT Dysphagia (HP:0002015)
Esophageal involvement with painful swallowing
Show evidence (2 references)
PMID:34630689 SUPPORT
"leading to severe complaints including pain, dysphagia, and fetor"
Review confirms dysphagia as a significant clinical complaint in pemphigus affecting mucosal surfaces.
PMID:31313078 SUPPORT
"severe complaints for the patients including pain, dysphagia, and foetor"
Review of oral lesions in autoimmune bullous diseases confirms dysphagia as a frequent symptom.
Feeding Difficulties in Infancy VERY_FREQUENT Feeding difficulties in infancy (HP:0008872)
Relevant to neonatal pemphigus from transplacental transfer of maternal anti-desmoglein antibodies. Oral erosions in affected neonates impair feeding.
Show evidence (1 reference)
ORPHA:704 SUPPORT
"HP:0008872 | Feeding difficulties in infancy | Very frequent (99-80%)"
Orphanet reports feeding difficulties in infancy as very frequent, reflecting neonatal pemphigus from transplacental antibody transfer.
Head and Neck 1
Oral Mucosal Erosions VERY_FREQUENT Erosion of oral mucosa (HP:0031446)
Often the first manifestation; buccal mucosa most commonly affected
Show evidence (3 references)
ORPHA:704 SUPPORT
"HP:0031446 | Erosion of oral mucosa | Very frequent (99-80%)"
Orphanet reports oral mucosal erosions as very frequent in pemphigus vulgaris.
PMID:31313078 SUPPORT
"The oral mucosa is frequently affected in these diseases, in particular, in mucous membrane pemphigoid, pemphigus vulgaris"
Review confirms the oral mucosa is frequently affected in pemphigus vulgaris.
PMID:34630689 SUPPORT
"Oral mucosal postbullous erosive lesions are frequently the first sign of disease in pemphigus vulgaris"
Comprehensive review confirms oral erosions as the initial presentation in PV.
Immune 3
Recurrent Infections VERY_FREQUENT Recurrent infections (HP:0002719)
Secondary infections of eroded skin; historically a major cause of mortality. Immunosuppressive treatment further increases infection risk.
Show evidence (2 references)
ORPHA:704 SUPPORT
"HP:0002719 | Recurrent infections | Very frequent (99-80%)"
Orphanet reports recurrent infections as very frequent, reflecting loss of skin barrier function and immunosuppressive treatment effects.
PMID:39075718 SUPPORT
"Pemphigus vulgaris (PV) is a rare intraepidermal blistering disease that is potentially life-threatening due to risk of infection and failure of skin barrier function."
Systematic review identifies infection risk from barrier failure as a defining feature of PV morbidity.
Recurrent Cutaneous Abscess Formation VERY_FREQUENT Recurrent cutaneous abscess formation (HP:0100838)
Secondary bacterial infection of eroded skin surfaces
Show evidence (1 reference)
ORPHA:704 SUPPORT
"HP:0100838 | Recurrent cutaneous abscess formation | Very frequent (99-80%)"
Orphanet reports recurrent cutaneous abscess formation as very frequent in pemphigus vulgaris.
Autoimmunity VERY_FREQUENT Autoimmunity (HP:0002960)
Disease is fundamentally autoimmune in nature
Show evidence (1 reference)
ORPHA:704 SUPPORT
"HP:0002960 | Autoimmunity | Very frequent (99-80%)"
Orphanet reports autoimmunity as very frequent, consistent with the autoimmune pathogenesis of pemphigus vulgaris.
Integument 3
Skin Blisters FREQUENT Abnormal blistering of the skin (HP:0008066)
Flaccid blisters that rupture easily leaving erosions
Show evidence (2 references)
ORPHA:704 SUPPORT
"HP:0008066 | Abnormal blistering of the skin | Frequent (79-30%)"
Orphanet classifies abnormal blistering of the skin as frequent, reflecting that mucosal-dominant disease may present without skin blisters.
PMID:34630689 SUPPORT
"Patients may present erythema, blisters, erosions, and ulcers that may affect the skin"
Review describes blisters and erosions as characteristic skin manifestations.
Skin Erosions FREQUENT Skin erosion (HP:0200041)
Positive Nikolsky sign; erosions are often more prominent than intact blisters. HP:0200041 is not directly listed in ORPHA:704 phenotype table; frequency derived from clinical knowledge of skin involvement in PV.
Show evidence (1 reference)
PMID:34630689 SUPPORT
"Patients may present erythema, blisters, erosions, and ulcers that may affect the skin"
Review explicitly describes skin erosions as a characteristic presentation of pemphigus.
Atypical Scarring of Skin VERY_FREQUENT Atypical scarring of skin (HP:0000987)
Post-inflammatory hyperpigmentation and scarring at sites of erosions
Show evidence (1 reference)
ORPHA:704 SUPPORT
"HP:0000987 | Atypical scarring of skin | Very frequent (99-80%)"
Orphanet reports atypical scarring as very frequent in pemphigus vulgaris.
Nervous System 2
Depression FREQUENT Depression (HP:0000716)
Related to chronic disease burden, impact on appearance, social stigmatization, and treatment side effects
Show evidence (2 references)
ORPHA:704 SUPPORT
"HP:0000716 | Depression | Frequent (79-30%)"
Orphanet reports depression as frequent in pemphigus vulgaris.
PMID:37381772 SUPPORT
"30.7% of patients with pemphigus suffered from either anxiety disorder (25%) or depressive disorders (14.3%)."
Clinical study found 14.3% prevalence of depressive disorders in PV cohort, with severity significantly higher than psoriasis controls.
Anxiety FREQUENT Anxiety (HP:0000739)
Associated with chronic disease course and impact on quality of life
Show evidence (2 references)
ORPHA:704 SUPPORT
"HP:0000739 | Anxiety | Frequent (79-30%)"
Orphanet reports anxiety as frequent in pemphigus vulgaris.
PMID:37381772 SUPPORT
"30.7% of patients with pemphigus suffered from either anxiety disorder (25%) or depressive disorders (14.3%)."
25% prevalence of anxiety disorder in a clinical PV cohort.
Constitutional 1
Pain OCCASIONAL Pain (HP:0012531)
Significant pain from mucosal erosions; impacts quality of life
Show evidence (2 references)
ORPHA:704 SUPPORT
"HP:0012531 | Pain | Occasional (29-5%)"
Orphanet classifies pain as occasional in pemphigus vulgaris.
PMID:37381772 SUPPORT
"the Visual Analogue Scale for pain and itching symptoms"
Clinical study includes pain assessment as a standard measure in PV patients.
Growth 1
Weight Loss VERY_FREQUENT Weight loss (HP:0001824)
Due to painful oral erosions impairing food intake
Show evidence (1 reference)
ORPHA:704 SUPPORT
"HP:0001824 | Weight loss | Very frequent (99-80%)"
Orphanet reports weight loss as very frequent, likely secondary to painful oral involvement limiting food intake.
Other 6
Oral Mucosal Blisters VERY_FREQUENT Oral mucosal blisters (HP:0200097)
Fragile blisters that rapidly rupture leaving erosions
Show evidence (2 references)
ORPHA:704 SUPPORT
"HP:0200097 | Oral mucosal blisters | Very frequent (99-80%)"
Orphanet reports oral mucosal blisters as very frequent in pemphigus vulgaris.
ORPHA:704 SUPPORT
"A rare autoimmune bullous skin diseases characterized by painful, flaccid blisters and erosions of the oral mucosa, predominantly involving the buccal area"
Orphanet definition describes painful, flaccid blisters of the oral mucosa as the characterizing feature.
Acantholysis VERY_FREQUENT Acantholysis (HP:0100792)
Loss of keratinocyte adhesion; hallmark histopathological feature
Show evidence (2 references)
ORPHA:704 SUPPORT
"HP:0100792 | Acantholysis | Very frequent (99-80%)"
Orphanet reports acantholysis as very frequent in pemphigus vulgaris.
PMID:33208597 SUPPORT
"Acantholytic cells were present in 142 cases (95%)."
Large histopathological study confirms acantholysis in 95% of PV biopsies.
Suprabasal Cleavage FREQUENT Suprabasal cleavage (HP:0034194)
Characteristic histopathological pattern distinguishing PV from pemphigus foliaceus
Show evidence (2 references)
ORPHA:704 SUPPORT
"HP:0034194 | Suprabasal cleavage | Frequent (79-30%)"
Orphanet reports suprabasal cleavage as a frequent histopathological finding in pemphigus vulgaris.
PMID:33208597 SUPPORT
"Vesicles were seen in 149 cases (88%), the level of which was suprabasal in 91(61%) and both suprabasal and intraepidermal in 50 cases (33.5%)."
Suprabasal clefting observed in 61% of biopsies as the primary pattern.
Alopecia of Scalp OCCASIONAL Alopecia of scalp (HP:0002293)
Non-scarring alopecia from acantholysis in hair follicle outer root sheath; hair regrowth typically occurs with treatment
Show evidence (2 references)
ORPHA:704 SUPPORT
"HP:0002293 | Alopecia of scalp | Occasional (29-5%)"
Orphanet reports scalp alopecia as occasional in pemphigus vulgaris.
PMID:22122058 SUPPORT
"Acantholysis between outer root sheath keratinocytes extending from the infundibulum to suprabalbar level was evident in anagen hair follicles of affected lesions."
Study demonstrates that PV alopecia results from autoantibody-mediated acantholysis in hair follicle outer root sheath keratinocytes.
Anti-Desmoglein-3 Antibody Positivity FREQUENT Anti-desmoglein-3 antibody positivity (HP:4000014)
Primary pathogenic autoantibody; present in virtually all active PV
Show evidence (2 references)
ORPHA:704 SUPPORT
"HP:4000014 | Anti-desmoglein-3 antibody positivity | Frequent (79-30%)"
Orphanet reports anti-desmoglein-3 antibody positivity as a frequent finding in pemphigus vulgaris.
PMID:10878487 SUPPORT
"Auto-Ab against the desmosomal adhesion molecule, desmoglein 3 (Dsg3), are critical in the pathogenesis of this disease"
Anti-Dsg3 autoantibodies are the defining pathogenic autoantibody in pemphigus vulgaris.
Anti-Desmoglein-1 Antibody Positivity FREQUENT Anti-desmoglein-1 antibody positivity (HP:4000013)
Present in mucocutaneous disease; correlates with skin involvement
Show evidence (2 references)
ORPHA:704 SUPPORT
"HP:4000013 | Anti-desmoglein-1 antibody positivity | Frequent (79-30%)"
Orphanet reports anti-desmoglein-1 antibody positivity as a frequent finding in pemphigus vulgaris, particularly in mucocutaneous disease.
PMID:39075718 SUPPORT
"The most notable biomarkers trends include elevations in IL-4, IL-6, IL-17A, anti-Dsg1/3 autoantibodies"
Systematic review confirms anti-Dsg1 autoantibodies as a key biomarker in pemphigus vulgaris.
🧬

Genetic Associations

3
HLA-DRB1*04 (Risk Factor)
Show evidence (2 references)
PMID:10878487 PARTIAL
"The involvement of CD4+ T lymphocytes in PV has been suggested by the strong association with distinct HLA class II alleles."
Strong HLA class II associations support the role of autoreactive CD4+ T cells in recognizing desmoglein epitopes and driving autoantibody production.
PMID:34630689 SUPPORT
"HLA-DR4 (DRB1*0402) and HLA-DRw6 (DQB1*0503) allele more common in patients with pemphigus vulgaris"
Review identifies HLA-DRB1*0402 as a major genetic susceptibility allele for pemphigus vulgaris.
HLA-DRB1*14 (Risk Factor)
HLA-DQB1*0503 (Risk Factor)
Show evidence (1 reference)
PMID:34630689 SUPPORT
"HLA-DR4 (DRB1*0402) and HLA-DRw6 (DQB1*0503) allele more common in patients with pemphigus vulgaris"
Review identifies HLA-DQB1*0503 as a major genetic susceptibility allele for pemphigus vulgaris alongside DRB1*0402.
💊

Treatments

4
Rituximab
Action: pharmacotherapy MAXO:0000058
Agent: rituximab ↗
First-line treatment in combination with low-dose short-term prednisone. The RITUX 3 trial demonstrated superiority over prednisone alone.
Show evidence (1 reference)
PMID:28342637 SUPPORT
"At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone"
Landmark RITUX 3 RCT demonstrates 89% complete remission with first-line rituximab plus short-term prednisone vs 34% with prednisone alone.
Corticosteroids
Action: pharmacotherapy MAXO:0000058
Agent: prednisone ↗
Systemic corticosteroids for induction of remission. Now typically used at lower doses and shorter duration when combined with rituximab.
Show evidence (1 reference)
PMID:28342637 SUPPORT
"prednisone alone, 1·0 or 1·5 mg/kg per day tapered over 12 or 18 months"
RITUX 3 trial documents standard prednisone dosing regimens for PV.
Azathioprine
Action: pharmacotherapy MAXO:0000058
Agent: azathioprine ↗
Steroid-sparing immunosuppressive maintenance agent.
Show evidence (1 reference)
PMID:25655250 SUPPORT
"The interventions which appear promising, but will require further evaluation include adjuvant mycophenolate mofetil (MMF), azathioprine"
Systematic review identifies azathioprine as a promising adjuvant treatment for pemphigus vulgaris.
Mycophenolate Mofetil
Action: pharmacotherapy MAXO:0000058
Agent: mycophenolate mofetil ↗
Alternative steroid-sparing immunosuppressive agent.
Show evidence (1 reference)
PMID:25655250 SUPPORT
"The interventions which appear promising, but will require further evaluation include adjuvant mycophenolate mofetil (MMF), azathioprine"
Systematic review identifies mycophenolate mofetil as a promising adjuvant treatment.
🔬

Biochemical Markers

2
Anti-Desmoglein 3 Antibodies (Elevated)
Context: Present in all active PV
Anti-Desmoglein 1 Antibodies (Variable)
Context: Present in mucocutaneous disease
{ }

Source YAML

click to show 
name: Pemphigus Vulgaris
creation_date: '2025-12-19T01:12:52Z'
updated_date: '2026-04-30T18:00:00Z'
category: Autoimmune
parents:
- Autoimmune Disease
- Skin Disease
disease_term:
  preferred_term: Pemphigus Vulgaris
  term:
    id: MONDO:0008219
    label: pemphigus vulgaris
description: >-
  A potentially life-threatening autoimmune blistering disease caused by
  autoantibodies against desmoglein 3 (and often desmoglein 1), leading to
  loss of keratinocyte adhesion (acantholysis) and intraepidermal blister
  formation. Mucosal involvement often precedes skin lesions.
prevalence:
- population: Worldwide
  percentage: 0.1-0.5 per 100,000 per year
  notes: >-
    Incidence varies geographically with higher rates in populations of
    Middle Eastern, South Asian, and Mediterranean descent.
  evidence:
  - reference: PMID:38289514
    supports: SUPPORT
    snippet: >-
      only two countries, Iran (18.87%) and South Korea (11.43%), accounted
      for approximately a third of the reported PV cases
    explanation: >-
      Global epidemiological review demonstrates geographic clustering of
      pemphigus vulgaris with disproportionate burden in certain populations.
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: >-
      A rare autoimmune bullous skin diseases characterized by painful, flaccid
      blisters and erosions of the oral mucosa, predominantly involving the
      buccal area
    explanation: >-
      Orphanet definition confirms pemphigus vulgaris is a rare autoimmune
      disease, consistent with low worldwide prevalence.
pathophysiology:
- name: Anti-Desmoglein Autoantibodies
  description: >-
    IgG autoantibodies against desmoglein 3 (mucosal-dominant) and desmoglein 1
    (mucocutaneous) directly cause loss of keratinocyte adhesion. Antibody
    binding triggers intracellular signaling leading to desmosome disassembly.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: Immunoglobulin Production
    term:
      id: GO:0002377
      label: immunoglobulin production
  evidence:
  - reference: PMID:10878487
    reference_title: "Humoral and cellular autoimmunity in autoimmune bullous skin disorders."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Auto-Ab against the desmosomal adhesion molecule, desmoglein 3 (Dsg3),
      are critical in the pathogenesis of this disease, since the transfer of
      serum IgG Ab reactive with Dsg3 into newborn mice induces a bullous skin
      disease resembling PV.
    explanation: >-
      Passive transfer of anti-Dsg3 IgG into newborn mice demonstrates that
      these autoantibodies are directly pathogenic and sufficient to cause
      pemphigus-like disease.
  - reference: PMID:39075718
    reference_title: "Biomarkers in Pemphigus Vulgaris: A Systematic Review."
    supports: PARTIAL
    snippet: >-
      The most notable biomarkers trends include elevations in IL-4, IL-6,
      IL-17A, anti-Dsg1/3 autoantibodies, and a reduction in Treg cells and
      FOXP3.
    explanation: >-
      Systematic review of 66 studies confirms that anti-Dsg1 and anti-Dsg3
      autoantibodies are the most consistent biomarkers in pemphigus vulgaris.
- name: Acantholysis and Blister Formation
  description: >-
    Loss of desmosomal adhesion causes keratinocytes to detach from each other
    (acantholysis). Suprabasal clefting occurs as basal keratinocytes remain
    attached to the basement membrane while upper layers separate.
  biological_processes:
  - preferred_term: Cell Adhesion
    term:
      id: GO:0007155
      label: cell adhesion
  evidence:
  - reference: PMID:10878487
    reference_title: "Humoral and cellular autoimmunity in autoimmune bullous skin disorders."
    supports: PARTIAL
    snippet: >-
      Antibody (Ab) binding interferes with the adhesive function of these
      molecules, leading to detachment and subsequently blister formation.
    explanation: >-
      Autoantibody binding directly interferes with the adhesive function of
      desmogleins, resulting in keratinocyte detachment and blister formation.
  - reference: PMID:33208597
    supports: SUPPORT
    snippet: >-
      Vesicles were seen in 149 cases (88%), the level of which was suprabasal in
      91(61%) and both suprabasal and intraepidermal in 50 cases (33.5%).
      Acantholytic cells were present in 142 cases (95%).
    explanation: >-
      Histopathological study of 169 PV biopsies confirms suprabasal vesicle
      formation and acantholysis as hallmark features.
- name: Signaling-Mediated Cytoskeletal Changes
  description: >-
    Anti-desmoglein antibodies activate p38 MAPK and other signaling pathways,
    causing keratin filament retraction and further weakening of cell-cell
    adhesion independent of direct steric hindrance.
  biological_processes:
  - preferred_term: Signal Transduction
    term:
      id: GO:0007165
      label: signal transduction
- name: Immune Dysregulation and Th2/Th17 Skewing
  description: >-
    Pemphigus vulgaris is characterized by a shift toward Th2 and Th17 cytokine
    profiles with elevated IL-4, IL-6, and IL-17A, along with a marked reduction
    in regulatory T cells (Tregs). This imbalance promotes autoreactive B cell
    activation and pathogenic autoantibody production.
  biological_processes:
  - preferred_term: T Cell Differentiation
    term:
      id: GO:0030217
      label: T cell differentiation
  - preferred_term: Cytokine Production
    term:
      id: GO:0001816
      label: cytokine production
  evidence:
  - reference: PMID:19811408
    reference_title: "Involvement of T(H)1/T(H)2 cytokines in the pathogenesis of autoimmune skin disease-Pemphigus vulgaris."
    supports: SUPPORT
    snippet: >-
      All patients with PV and PF showed significantly (p < 0.000) elevated
      levels of T(H)2 cytokines (IL-10 and IL-4) as compared with healthy
      controls. However, the mean concentration of T(H)1 cytokines (IL-2 and
      IFN-gamma) was significantly decreased in patients as compared to healthy
      individuals.
    explanation: >-
      Cytokine profiling demonstrates a clear Th2 cytokine dominance in PV
      patients with elevated IL-4 and IL-10, supporting the role of Th2-mediated
      immune responses in disease pathogenesis.
  - reference: PMID:17377382
    reference_title: "CD4+CD25high regulatory T cells are markedly decreased in blood of patients with pemphigus vulgaris."
    supports: SUPPORT
    snippet: >-
      The proportion of Treg cells in all PV patients was severely reduced,
      approximately ten times less than controls. These observations were further
      confirmed by both diminished gene and protein expression of Foxp3 in the
      CD4(+)CD25(+) T cell population in PV patients.
    explanation: >-
      Severe reduction in regulatory T cells may contribute to loss of tolerance
      and failure to suppress autoreactive B and T cells in pemphigus vulgaris.
  - reference: PMID:39075718
    reference_title: "Biomarkers in Pemphigus Vulgaris: A Systematic Review."
    supports: SUPPORT
    snippet: >-
      The results of this review support current theories of PV pathogenesis,
      with increased Th2 activity, increased Th17 activity, decreased Treg
      activity, and production of anti-Dsg1/3 autoantibodies being observed.
    explanation: >-
      Systematic review synthesizing 66 studies confirms the Th2/Th17 skewing
      and Treg deficiency as core immunological features of pemphigus vulgaris.
phenotypes:
- name: Oral Mucosal Erosions
  category: Oral
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Erosion of Oral Mucosa
    term:
      id: HP:0031446
      label: Erosion of oral mucosa
  notes: Often the first manifestation; buccal mucosa most commonly affected
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0031446 | Erosion of oral mucosa | Very frequent (99-80%)"
    explanation: >-
      Orphanet reports oral mucosal erosions as very frequent in pemphigus
      vulgaris.
  - reference: PMID:31313078
    supports: SUPPORT
    snippet: >-
      The oral mucosa is frequently affected in these
      diseases, in particular, in mucous membrane pemphigoid, pemphigus vulgaris
    explanation: >-
      Review confirms the oral mucosa is frequently affected in pemphigus
      vulgaris.
  - reference: PMID:34630689
    supports: SUPPORT
    snippet: >-
      Oral mucosal postbullous erosive lesions are frequently the first sign
      of disease in pemphigus vulgaris
    explanation: >-
      Comprehensive review confirms oral erosions as the initial
      presentation in PV.
- name: Oral Mucosal Blisters
  category: Oral
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Oral Mucosal Blisters
    term:
      id: HP:0200097
      label: Oral mucosal blisters
  notes: Fragile blisters that rapidly rupture leaving erosions
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0200097 | Oral mucosal blisters | Very frequent (99-80%)"
    explanation: >-
      Orphanet reports oral mucosal blisters as very frequent in pemphigus
      vulgaris.
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: >-
      A rare autoimmune bullous skin diseases characterized by painful, flaccid
      blisters and erosions of the oral mucosa, predominantly involving the
      buccal area
    explanation: >-
      Orphanet definition describes painful, flaccid blisters of the oral
      mucosa as the characterizing feature.
- name: Skin Blisters
  category: Dermatological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal Blistering of the Skin
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  notes: Flaccid blisters that rupture easily leaving erosions
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0008066 | Abnormal blistering of the skin | Frequent (79-30%)"
    explanation: >-
      Orphanet classifies abnormal blistering of the skin as frequent,
      reflecting that mucosal-dominant disease may present without skin blisters.
  - reference: PMID:34630689
    supports: SUPPORT
    snippet: >-
      Patients may present erythema, blisters,
      erosions, and ulcers that may affect the skin
    explanation: >-
      Review describes blisters and erosions as characteristic skin
      manifestations.
- name: Skin Erosions
  category: Dermatological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Skin Erosion
    term:
      id: HP:0200041
      label: Skin erosion
  notes: >-
    Positive Nikolsky sign; erosions are often more prominent than intact
    blisters. HP:0200041 is not directly listed in ORPHA:704 phenotype table;
    frequency derived from clinical knowledge of skin involvement in PV.
  evidence:
  - reference: PMID:34630689
    supports: SUPPORT
    snippet: >-
      Patients may present erythema, blisters,
      erosions, and ulcers that may affect the skin
    explanation: >-
      Review explicitly describes skin erosions as a characteristic
      presentation of pemphigus.
- name: Atypical Scarring of Skin
  category: Dermatological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Atypical Scarring of Skin
    term:
      id: HP:0000987
      label: Atypical scarring of skin
  notes: Post-inflammatory hyperpigmentation and scarring at sites of erosions
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0000987 | Atypical scarring of skin | Very frequent (99-80%)"
    explanation: >-
      Orphanet reports atypical scarring as very frequent in pemphigus vulgaris.
- name: Acantholysis
  category: Histopathological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Acantholysis
    term:
      id: HP:0100792
      label: Acantholysis
  notes: Loss of keratinocyte adhesion; hallmark histopathological feature
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0100792 | Acantholysis | Very frequent (99-80%)"
    explanation: >-
      Orphanet reports acantholysis as very frequent in pemphigus vulgaris.
  - reference: PMID:33208597
    supports: SUPPORT
    snippet: >-
      Acantholytic cells were present in 142 cases (95%).
    explanation: >-
      Large histopathological study confirms acantholysis in 95% of PV biopsies.
- name: Suprabasal Cleavage
  category: Histopathological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Suprabasal Cleavage
    term:
      id: HP:0034194
      label: Suprabasal cleavage
  notes: Characteristic histopathological pattern distinguishing PV from pemphigus foliaceus
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0034194 | Suprabasal cleavage | Frequent (79-30%)"
    explanation: >-
      Orphanet reports suprabasal cleavage as a frequent histopathological
      finding in pemphigus vulgaris.
  - reference: PMID:33208597
    supports: SUPPORT
    snippet: >-
      Vesicles were seen in 149 cases (88%), the level of which was suprabasal in
      91(61%) and both suprabasal and intraepidermal in 50 cases (33.5%).
    explanation: >-
      Suprabasal clefting observed in 61% of biopsies as the primary pattern.
- name: Weight Loss
  category: Constitutional
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Weight Loss
    term:
      id: HP:0001824
      label: Weight loss
  notes: Due to painful oral erosions impairing food intake
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0001824 | Weight loss | Very frequent (99-80%)"
    explanation: >-
      Orphanet reports weight loss as very frequent, likely secondary to
      painful oral involvement limiting food intake.
- name: Feeding Difficulties
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Feeding Difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  notes: Painful oral and esophageal erosions limit food intake
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0011968 | Feeding difficulties | Frequent (79-30%)"
    explanation: >-
      Orphanet reports feeding difficulties as a frequent consequence of
      mucosal involvement in pemphigus vulgaris.
- name: Dysphagia
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  notes: Esophageal involvement with painful swallowing
  evidence:
  - reference: PMID:34630689
    supports: SUPPORT
    snippet: >-
      leading to severe complaints including pain,
      dysphagia, and fetor
    explanation: >-
      Review confirms dysphagia as a significant clinical complaint in
      pemphigus affecting mucosal surfaces.
  - reference: PMID:31313078
    supports: SUPPORT
    snippet: >-
      severe complaints for the patients including pain,
      dysphagia, and foetor
    explanation: >-
      Review of oral lesions in autoimmune bullous diseases confirms
      dysphagia as a frequent symptom.
- name: Recurrent Infections
  category: Immunological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent Infections
    term:
      id: HP:0002719
      label: Recurrent infections
  notes: >-
    Secondary infections of eroded skin; historically a major cause of
    mortality. Immunosuppressive treatment further increases infection risk.
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0002719 | Recurrent infections | Very frequent (99-80%)"
    explanation: >-
      Orphanet reports recurrent infections as very frequent, reflecting
      loss of skin barrier function and immunosuppressive treatment effects.
  - reference: PMID:39075718
    supports: SUPPORT
    snippet: >-
      Pemphigus vulgaris (PV) is a rare intraepidermal blistering
      disease that is potentially life-threatening due to risk of infection and
      failure of skin barrier function.
    explanation: >-
      Systematic review identifies infection risk from barrier failure as
      a defining feature of PV morbidity.
- name: Recurrent Cutaneous Abscess Formation
  category: Dermatological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent Cutaneous Abscess Formation
    term:
      id: HP:0100838
      label: Recurrent cutaneous abscess formation
  notes: Secondary bacterial infection of eroded skin surfaces
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0100838 | Recurrent cutaneous abscess formation | Very frequent (99-80%)"
    explanation: >-
      Orphanet reports recurrent cutaneous abscess formation as very frequent
      in pemphigus vulgaris.
- name: Pain
  category: Constitutional
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pain
    term:
      id: HP:0012531
      label: Pain
  notes: Significant pain from mucosal erosions; impacts quality of life
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0012531 | Pain | Occasional (29-5%)"
    explanation: >-
      Orphanet classifies pain as occasional in pemphigus vulgaris.
  - reference: PMID:37381772
    supports: SUPPORT
    snippet: >-
      the Visual Analogue Scale for pain and itching symptoms
    explanation: >-
      Clinical study includes pain assessment as a standard measure in PV
      patients.
- name: Depression
  category: Neuropsychiatric
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  notes: >-
    Related to chronic disease burden, impact on appearance, social
    stigmatization, and treatment side effects
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0000716 | Depression | Frequent (79-30%)"
    explanation: >-
      Orphanet reports depression as frequent in pemphigus vulgaris.
  - reference: PMID:37381772
    supports: SUPPORT
    snippet: >-
      30.7% of patients with pemphigus suffered from either anxiety disorder
      (25%) or depressive disorders (14.3%).
    explanation: >-
      Clinical study found 14.3% prevalence of depressive disorders in PV
      cohort, with severity significantly higher than psoriasis controls.
- name: Anxiety
  category: Neuropsychiatric
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  notes: Associated with chronic disease course and impact on quality of life
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0000739 | Anxiety | Frequent (79-30%)"
    explanation: >-
      Orphanet reports anxiety as frequent in pemphigus vulgaris.
  - reference: PMID:37381772
    supports: SUPPORT
    snippet: >-
      30.7% of patients with pemphigus suffered from either anxiety disorder
      (25%) or depressive disorders (14.3%).
    explanation: >-
      25% prevalence of anxiety disorder in a clinical PV cohort.
- name: Alopecia of Scalp
  category: Dermatological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Alopecia of Scalp
    term:
      id: HP:0002293
      label: Alopecia of scalp
  notes: >-
    Non-scarring alopecia from acantholysis in hair follicle outer root sheath;
    hair regrowth typically occurs with treatment
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0002293 | Alopecia of scalp | Occasional (29-5%)"
    explanation: >-
      Orphanet reports scalp alopecia as occasional in pemphigus vulgaris.
  - reference: PMID:22122058
    supports: SUPPORT
    snippet: >-
      Acantholysis between outer root sheath keratinocytes
      extending from the infundibulum to suprabalbar level was evident in anagen hair
      follicles of affected lesions.
    explanation: >-
      Study demonstrates that PV alopecia results from autoantibody-mediated
      acantholysis in hair follicle outer root sheath keratinocytes.
- name: Anti-Desmoglein-3 Antibody Positivity
  category: Laboratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Anti-Desmoglein-3 Antibody Positivity
    term:
      id: HP:4000014
      label: Anti-desmoglein-3 antibody positivity
  notes: Primary pathogenic autoantibody; present in virtually all active PV
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:4000014 | Anti-desmoglein-3 antibody positivity | Frequent (79-30%)"
    explanation: >-
      Orphanet reports anti-desmoglein-3 antibody positivity as a frequent
      finding in pemphigus vulgaris.
  - reference: PMID:10878487
    supports: SUPPORT
    snippet: >-
      Auto-Ab against the desmosomal adhesion molecule, desmoglein 3 (Dsg3),
      are critical in the pathogenesis of this disease
    explanation: >-
      Anti-Dsg3 autoantibodies are the defining pathogenic autoantibody
      in pemphigus vulgaris.
- name: Anti-Desmoglein-1 Antibody Positivity
  category: Laboratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Anti-Desmoglein-1 Antibody Positivity
    term:
      id: HP:4000013
      label: Anti-desmoglein-1 antibody positivity
  notes: Present in mucocutaneous disease; correlates with skin involvement
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:4000013 | Anti-desmoglein-1 antibody positivity | Frequent (79-30%)"
    explanation: >-
      Orphanet reports anti-desmoglein-1 antibody positivity as a frequent
      finding in pemphigus vulgaris, particularly in mucocutaneous disease.
  - reference: PMID:39075718
    supports: SUPPORT
    snippet: >-
      The most notable biomarkers trends include elevations in IL-4, IL-6,
      IL-17A, anti-Dsg1/3 autoantibodies
    explanation: >-
      Systematic review confirms anti-Dsg1 autoantibodies as a key biomarker
      in pemphigus vulgaris.
- name: Urticaria
  category: Dermatological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Urticaria
    term:
      id: HP:0001025
      label: Urticaria
  notes: >-
    Urticarial lesions may precede or accompany blister formation in some
    patients. Orphanet classifies this as very frequent though clinical
    experience suggests it may be less prominent than erosive lesions.
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0001025 | Urticaria | Very frequent (99-80%)"
    explanation: >-
      Orphanet reports urticaria as very frequent in pemphigus vulgaris.
- name: Feeding Difficulties in Infancy
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Feeding Difficulties in Infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  notes: >-
    Relevant to neonatal pemphigus from transplacental transfer of maternal
    anti-desmoglein antibodies. Oral erosions in affected neonates impair
    feeding.
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0008872 | Feeding difficulties in infancy | Very frequent (99-80%)"
    explanation: >-
      Orphanet reports feeding difficulties in infancy as very frequent,
      reflecting neonatal pemphigus from transplacental antibody transfer.
- name: Autoimmunity
  category: Immunological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  notes: Disease is fundamentally autoimmune in nature
  evidence:
  - reference: ORPHA:704
    supports: SUPPORT
    snippet: "HP:0002960 | Autoimmunity | Very frequent (99-80%)"
    explanation: >-
      Orphanet reports autoimmunity as very frequent, consistent with
      the autoimmune pathogenesis of pemphigus vulgaris.
biochemical:
- name: Anti-Desmoglein 3 Antibodies
  presence: Elevated
  context: Present in all active PV
- name: Anti-Desmoglein 1 Antibodies
  presence: Variable
  context: Present in mucocutaneous disease
genetic:
- name: HLA-DRB1*04
  association: Risk Factor
  evidence:
  - reference: PMID:10878487
    reference_title: "Humoral and cellular autoimmunity in autoimmune bullous skin disorders."
    supports: PARTIAL
    snippet: >-
      The involvement of CD4+ T lymphocytes in PV has been suggested by the
      strong association with distinct HLA class II alleles.
    explanation: >-
      Strong HLA class II associations support the role of autoreactive CD4+ T
      cells in recognizing desmoglein epitopes and driving autoantibody production.
  - reference: PMID:34630689
    supports: SUPPORT
    snippet: >-
      HLA-DR4 (DRB1*0402) and HLA-DRw6 (DQB1*0503) allele more
      common in patients with pemphigus vulgaris
    explanation: >-
      Review identifies HLA-DRB1*0402 as a major genetic susceptibility
      allele for pemphigus vulgaris.
- name: HLA-DRB1*14
  association: Risk Factor
  notes: >-
    HLA-DRB1*14 has been reported in some PV cohorts (particularly Japanese
    and Iranian populations) but the primary literature evidence links it
    more strongly to pemphigus foliaceus. No PV-specific abstract snippet
    available at this time.
- name: HLA-DQB1*0503
  association: Risk Factor
  notes: >-
    HLA-DQB1*0503 (HLA-DRw6) is a major susceptibility allele for pemphigus
    vulgaris, particularly in non-Jewish populations.
  evidence:
  - reference: PMID:34630689
    supports: SUPPORT
    snippet: >-
      HLA-DR4 (DRB1*0402) and HLA-DRw6 (DQB1*0503) allele more
      common in patients with pemphigus vulgaris
    explanation: >-
      Review identifies HLA-DQB1*0503 as a major genetic susceptibility
      allele for pemphigus vulgaris alongside DRB1*0402.
treatments:
- name: Rituximab
  description: >-
    First-line treatment in combination with low-dose short-term prednisone.
    The RITUX 3 trial demonstrated superiority over prednisone alone.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  evidence:
  - reference: PMID:28342637
    supports: SUPPORT
    snippet: >-
      At month 24, 41 (89%) of 46 patients assigned to
      rituximab plus short-term prednisone were in complete remission off-therapy
      versus 15 (34%) of 44 assigned to prednisone alone
    explanation: >-
      Landmark RITUX 3 RCT demonstrates 89% complete remission with
      first-line rituximab plus short-term prednisone vs 34% with prednisone alone.
- name: Corticosteroids
  description: >-
    Systemic corticosteroids for induction of remission. Now typically used
    at lower doses and shorter duration when combined with rituximab.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  evidence:
  - reference: PMID:28342637
    supports: SUPPORT
    snippet: >-
      prednisone alone, 1·0 or 1·5 mg/kg per day tapered over 12 or 18 months
    explanation: >-
      RITUX 3 trial documents standard prednisone dosing regimens for PV.
- name: Azathioprine
  description: Steroid-sparing immunosuppressive maintenance agent.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: azathioprine
      term:
        id: CHEBI:2948
        label: azathioprine
  evidence:
  - reference: PMID:25655250
    supports: SUPPORT
    snippet: >-
      The interventions which appear promising, but will require further
      evaluation include adjuvant mycophenolate mofetil (MMF), azathioprine
    explanation: >-
      Systematic review identifies azathioprine as a promising adjuvant
      treatment for pemphigus vulgaris.
- name: Mycophenolate Mofetil
  description: Alternative steroid-sparing immunosuppressive agent.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: mycophenolate mofetil
      term:
        id: CHEBI:8764
        label: mycophenolate mofetil
  evidence:
  - reference: PMID:25655250
    supports: SUPPORT
    snippet: >-
      The interventions which appear promising, but will require further
      evaluation include adjuvant mycophenolate mofetil (MMF), azathioprine
    explanation: >-
      Systematic review identifies mycophenolate mofetil as a promising
      adjuvant treatment.
classifications:
  harrisons_chapter:
  - classification_value: skin disorder
  - classification_value: autoimmune disease
references:
- reference: DOI:10.1101/2025.02.10.637416
  title: In pemphigus, cell detachment, but not autoantibody binding, induces cell-wide, long-lasting transcriptomic and proteomic changes
  findings: []
- reference: DOI:10.1177/12034754241266136
  title: 'Biomarkers in Pemphigus Vulgaris: A Systematic Review'
  findings: []
- reference: DOI:10.1186/s12865-023-00582-z
  title: Tacrolimus reverses pemphigus vulgaris serum-induced depletion of desmoglein in HaCaT cells via inhibition of heat shock protein 27 phosphorylation
  findings: []
- reference: DOI:10.3389/fimmu.2023.1169947
  title: 'Mouse models of pemphigus: valuable tools to investigate pathomechanisms and novel therapeutic interventions'
  findings: []
- reference: DOI:10.3389/fimmu.2024.1500231
  title: Cytokine profiling reveals HLA-linked Th2 and Th17 driven immune activation in pemphigus vulgaris patients and genetically susceptible healthy controls
  findings: []
📚

References & Deep Research

References

5
DOI:10.1101/2025.02.10.637416
In pemphigus, cell detachment, but not autoantibody binding, induces cell-wide, long-lasting transcriptomic and proteomic changes
No top-level findings curated for this source.
DOI:10.1177/12034754241266136
Biomarkers in Pemphigus Vulgaris: A Systematic Review
No top-level findings curated for this source.
DOI:10.1186/s12865-023-00582-z
Tacrolimus reverses pemphigus vulgaris serum-induced depletion of desmoglein in HaCaT cells via inhibition of heat shock protein 27 phosphorylation
No top-level findings curated for this source.
DOI:10.3389/fimmu.2023.1169947
Mouse models of pemphigus: valuable tools to investigate pathomechanisms and novel therapeutic interventions
No top-level findings curated for this source.
DOI:10.3389/fimmu.2024.1500231
Cytokine profiling reveals HLA-linked Th2 and Th17 driven immune activation in pemphigus vulgaris patients and genetically susceptible healthy controls
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Pemphigus Vulgaris
  • Category: Autoimmune
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 12

Key Pathophysiology Nodes

  • Anti-Desmoglein Autoantibodies
  • Acantholysis and Blister Formation
  • Signaling-Mediated Cytoskeletal Changes
  • Immune Dysregulation and Th2/Th17 Skewing
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1101/2025.02.10.637416
  • DOI:10.1177/12034754241266136
  • DOI:10.1186/s12865-023-00582-z
  • DOI:10.3389/fimmu.2023.1169947
  • DOI:10.3389/fimmu.2024.1500231
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 24 citations 2025-12-18T09:56:25.205788

Disease Pathophysiology Research Report

Target Disease - Disease Name: Pemphigus Vulgaris (PV) - MONDO ID: MONDO:0008691 (autoimmune blistering disease) - Category: Autoimmune

Executive Summary Pemphigus vulgaris is an IgG autoantibody-mediated desmosomal disorder characterized by loss of keratinocyte cohesion (acantholysis) with prominent involvement of oral mucosa and skin. Core mechanisms integrate: (i) pathogenic anti-desmoglein-3 (DSG3) and anti-desmoglein-1 (DSG1) binding with epitope/subclass specificity; (ii) keratinocyte signaling cascades downstream of desmosome perturbation (notably p38 MAPK, Src, EGFR, PLC/PKC, AKT, and HSP27); (iii) desmosome ultrastructural reduction/disassembly and keratin cytoskeletal retraction; (iv) immune dysregulation centered on HLA class II risk alleles (DRB104:02; DQB105:03), T follicular helper (Tfh) and Th17/Th2 axes (with IL-21 as a key B-cell helper cytokine); and (v) translation to therapies targeting B cells and IgG (rituximab, BTK inhibitors, FcRn antagonists) and antigen-specific CAAR-T. Recent 2023–2024 studies corroborate HLA-linked immune activation (even in healthy carriers) and refine keratinocyte signaling nodes and rescue strategies. (emtenani2023mousemodelsof pages 9-9, schwartz2024cytokineprofilingreveals pages 1-2, xie2023tacrolimusreversespemphigus pages 1-2, hartmann2025inpemphiguscell pages 32-34, hartmann2025inpemphiguscell pages 28-32, geng2024biomarkersinpemphigus pages 2-4)

  1. Core Pathophysiology
  2. Primary mechanism: Pathogenic IgG autoantibodies against desmosomal cadherins DSG3 (mucosal-dominant) and DSG1 (skin involvement) are sufficient to cause acantholysis in passive transfer models and with epitope-validated monoclonals. “Patient autoantibodies are directly pathogenic in passive-transfer and neonatal mouse models” and epitope-specific anti-DSG3 antibodies targeting the adhesive interface induce PV phenotypes (2023 review of mouse models). (emtenani2023mousemodelsof pages 9-9)
  3. Keratinocyte signaling: Autoantibody binding triggers pathways including p38 MAPK, Src, EGFR, PLC/PKC, AKT, and HSP27 phosphorylation, promoting desmosome disassembly and cytoskeletal retraction. In vitro PV-sera rapidly deplete Dsg3 and convert linear to granular desmosomal staining; FK506 restores adhesion by “decreas[ing] PV serum-induced phosphorylation of HSP27” without altering p38 phosphorylation (BMC Immunology 2023). (xie2023tacrolimusreversespemphigus pages 1-2)
  4. Desmosome ultrastructure: High-resolution imaging shows PV-IgG reduces desmosome number and size, increases plaque distance/thickness, and causes keratin retraction; inhibition of p38 MAPK or PLC fully rescues ultrastructural parameters in experimental systems (Frontiers in Immunology 2025). (hartmann2025inpemphiguscell pages 32-34)
  5. Complement and cell death: Complement involvement has been evaluated in murine pemphigus models; apoptosis is considered secondary (“biphasic p38 activation links apoptosis as a downstream event”), and pyroptosis has been proposed, but direct human PV evidence remains limited and context-dependent (2023 review). (emtenani2023mousemodelsof pages 9-9)

  6. Immune dysregulation and HLA: PV shows strong HLA-II associations (DRB104:02; DQB105:03). A 2024 study of 116 PV patients and HLA-matched/unmatched controls found “PV patients display an activated cytokine and chemokine immune response… [and] healthy individuals that carry the PV susceptibility alleles… show an upregulation of certain pro-inflammatory, Th2, and Th17 mediators,” with IL-10 and IL-15 reduced in HLA-matched controls, implying HLA-linked baseline immune activation and counter-regulation. (schwartz2024cytokineprofilingreveals pages 1-2)

  7. Key Molecular Players

  8. Genes/Proteins (HGNC): DSG3, DSG1, EGFR, SRC, MAPK14 (p38), PLCG1, PRKCA, AKT1, HSPB1 (HSP27), FCGRT (FcRn), BTK, CD19. Roles summarized in embedded artifact table. (emtenani2023mousemodelsof pages 9-9, xie2023tacrolimusreversespemphigus pages 1-2, hartmann2025inpemphiguscell pages 32-34, starr2025insightsintopathomechanismsa pages 81-83)
  9. Chemical Entities (CHEBI): Pathogenic IgG; therapeutics: rituximab (anti-CD20), efgartigimod (FcRn antagonist), rilzabrutinib (BTK inhibitor), experimental DSG3-CAART. (emtenani2023mousemodelsof pages 9-9, xie2023tacrolimusreversespemphigus pages 1-2)
  10. Cell Types (CL): Keratinocytes (signal transduction, adhesion machinery), B cells/plasma cells (autoantibodies), Tfh (IL-21), Th17 and Th2 (inflammatory milieu). (schwartz2024cytokineprofilingreveals pages 1-2, geng2024biomarkersinpemphigus pages 2-4)

  11. Anatomical Locations (UBERON): Skin epidermis and oral mucosa (oral often earliest site due to DSG3 expression dominance). (emtenani2023mousemodelsof pages 9-9, geng2024biomarkersinpemphigus pages 2-4)

  12. Biological Processes (GO annotations)

  13. Cell–cell adhesion and desmosome organization: loss of desmosomal adhesion and desmosome number/size changes underpin acantholysis. (hartmann2025inpemphiguscell pages 32-34)
  14. MAPK cascade and keratinocyte differentiation: p38 MAPK is a central node; keratinocyte stress responses and differentiation programs are perturbed after detachment. (emtenani2023mousemodelsof pages 9-9, hartmann2025inpemphiguscell pages 28-32)

  15. B-cell activation and T-cell help: Tfh/Th17 skewing with IL-21 supports autoreactive B cells and plasma-cell differentiation. (schwartz2024cytokineprofilingreveals pages 1-2, geng2024biomarkersinpemphigus pages 2-4)

  16. Cellular Components

  17. Desmosomes and plasma membrane: DSG1/3 cluster in desmosomal plaques linked to keratin intermediate filaments; ultrastructurally reduced/desynchronized after PV-IgG. (hartmann2025inpemphiguscell pages 32-34)
  18. Cytoskeleton (keratin/actin) and signaling complexes: HSP27-mediated actin remodeling and keratin retraction accompany adhesion loss. (xie2023tacrolimusreversespemphigus pages 1-2)

  19. Endoplasmic reticulum stress–desmosome signaling crosstalk has been suggested in pemphigus models. (starr2025insightsintopathomechanismsa pages 81-83)

  20. Disease Progression

  21. Sequence of events (canonical): Genetic susceptibility (HLA-DRB104:02, DQB105:03) + triggers → autoreactive Tfh/Th17 help → anti-DSG3±DSG1 IgG production → direct inhibition of DSG transinteraction and induction of keratinocyte signaling (p38, Src, EGFR, PLC/PKC, AKT, HSP27) → desmosome disassembly/ultrastructural reduction → keratin retraction and acantholysis → erosions/blisters; inflammation and transcriptomic reprogramming are accentuated after mechanical detachment. (emtenani2023mousemodelsof pages 9-9, schwartz2024cytokineprofilingreveals pages 1-2, hartmann2025inpemphiguscell pages 32-34, hartmann2025inpemphiguscell pages 28-32)

  22. Stages: Prodromal mucosal phase (DSG3-dominant) often precedes cutaneous involvement; phenotype can reflect antibody profile (DSG3 vs DSG1 co-reactivity). (geng2024biomarkersinpemphigus pages 2-4)

  23. Phenotypic Manifestations (HP terms)

  24. Oral mucosal erosions and flaccid cutaneous blisters due to suprabasal acantholysis; Nikolsky sign; chronic relapsing course. Molecular correlate is desmosomal failure in suprabasal layers. (emtenani2023mousemodelsof pages 9-9, geng2024biomarkersinpemphigus pages 2-4)

  25. Recent Developments (2023–2024)

  26. HLA-linked cytokine activation: Large cohort demonstrates “Th2 and Th17 driven immune activation” in PV patients and HLA-risk healthy individuals; IL-10/IL-15 downregulated in HLA-matched controls. (Dec 2024; Frontiers in Immunology; https://doi.org/10.3389/fimmu.2024.1500231) (schwartz2024cytokineprofilingreveals pages 1-2)
  27. HSP27 as a targetable node: FK506 counteracts PV-sera–induced Dsg3 depletion and restores adhesion by inhibiting HSP27 phosphorylation in keratinocytes. (Nov 2023; BMC Immunology; https://doi.org/10.1186/s12865-023-00582-z) (xie2023tacrolimusreversespemphigus pages 1-2)
  28. Desmosome ultrastructure rescue: Experimental inhibition of p38 MAPK or PLC rescues desmosome number and plaque geometry; EGFR/Src pathways modulate desmosomal remodeling. (2025 preprint referencing 2024 work; bioRxiv; https://doi.org/10.1101/2025.02.10.637416) (hartmann2025inpemphiguscell pages 32-34)

  29. Biomarker synthesis: Systematic review across 2,463 patients highlights elevations in IL‑4, IL‑6, IL‑17A, anti‑Dsg1/3, and “reduction in Treg cells and FOXP3,” supporting Th2/Th17 and Treg deficiency in PV pathogenesis. (Jul 2024; J Cutaneous Medicine and Surgery; https://doi.org/10.1177/12034754241266136) (geng2024biomarkersinpemphigus pages 2-4)

  30. Current Applications and Real-world Implementations

  31. Anti-CD20 B-cell depletion (rituximab): Now a first-line biologic in many guidelines; mechanistically reduces anti-DSG autoantibody production (supporting evidence from models and clinical experience). (emtenani2023mousemodelsof pages 9-9)
  32. FcRn antagonism (e.g., efgartigimod): FcRn blockade “stabilizes keratinocyte monolayer integrity in the presence of anti‑DSG3 antibodies” and lowers circulating pathogenic IgG, offering a mechanistically rational option in IgG-mediated PV. (emtenani2023mousemodelsof pages 9-9)
  33. BTK inhibitors (rilzabrutinib): Target BCR signaling and myeloid FcγR pathways to reduce autoantibody production/inflammation; development is ongoing with disease-specific trials. (starr2025insightsintopathomechanismsa pages 81-83)

  34. Antigen-specific cellular therapy (DSG3‑CAART/CD19 CAR‑T): A Phase 1/2 open-label study in active PV is “RECRUITING” (RESET‑PV; NCT04422912; sponsor Cabaletta Bio), aiming to delete DSG3‑specific B cells or broadly deplete B cells. (NCT04422912)

  35. Expert Opinions and Mechanistic Quotes

  36. “Patient autoantibodies are directly pathogenic in passive‑transfer and neonatal mouse models,” and “multiple studies implicate p38 MAPK as a central downstream signaling node” whose inhibition prevents IgG‑induced reorganization and disease (Frontiers in Immunology 2023). (emtenani2023mousemodelsof pages 9-9)
  37. “PV patients display an activated cytokine and chemokine immune response… [and] healthy individuals that carry the PV susceptibility alleles… show an upregulation of certain pro‑inflammatory, Th2, and Th17 mediators,” while “IL‑10 and IL‑15 were… downregulated in the HLA‑matched control group,” suggesting HLA-linked immune activation with counter-regulation (Frontiers in Immunology 2024). (schwartz2024cytokineprofilingreveals pages 1-2)
  38. “FK506 reverses PV‑IgG induced‑Dsg depletion and desmosomal dissociation… by inhibiting HSP27 phosphorylation” (BMC Immunology 2023). (xie2023tacrolimusreversespemphigus pages 1-2)

  39. Desmosome-focused imaging shows PV‑IgG “reduced desmosome number, decreased desmosome size, increased plaque distance and thickness” and that “inhibition of p38MAPK or PLC completely rescued all parameters” (Frontiers in Immunology 2025; referencing experimental models). (hartmann2025inpemphiguscell pages 32-34)

  40. Relevant Statistics and Data

  41. Cohort size and analytes: 116 PV patients vs 29 controls profiled across 20 cytokines/chemokines showed Th2/Th17 skewing and HLA-linked activation in healthy carriers (Frontiers in Immunology 2024). (schwartz2024cytokineprofilingreveals pages 1-2)
  42. Biomarker synthesis: 66 studies, 2,463 patients; most notable trends include elevations in IL‑4, IL‑6, IL‑17A and anti‑Dsg1/3; reduced Treg/FOXP3 (systematic review 2024). (geng2024biomarkersinpemphigus pages 2-4)
  43. Cellular rescue: In keratinocytes, PV sera downregulated Dsg3 within 1 h and up to 24 h; FK506 restored adhesion and decreased HSP27 phosphorylation (BMC Immunology 2023). (xie2023tacrolimusreversespemphigus pages 1-2)

Ontology-linked Annotations for Knowledge-Base - HGNC: DSG3, DSG1, EGFR, SRC, MAPK14, PLCG1, PRKCA, AKT1, HSPB1, FCGRT, BTK, CD19. - GO: cell–cell adhesion; desmosome organization; MAPK cascade; keratinocyte differentiation; B cell activation; T cell help. - CL: keratinocyte; B cell; T follicular helper cell; Th17 cell. - UBERON: skin epidermis; oral mucosa. - HP: oral mucosal erosions; suprabasal acantholysis; flaccid blisters; positive Nikolsky sign. - CHEBI: IgG; rituximab; efgartigimod; rilzabrutinib.

Embedded resource summarizing entities and evidence: | Category | Entity Name | Ontology ID (source) | Mechanistic role in PV (1–2 sentences) | Key pathway linkage | Evidence (Year; journal) | URL/DOI | Citation Context ID | |---|---|---|---|---|---|---|---| | Gene/Protein | DSG3 | HGNC:DSG3 | Primary mucocutaneous autoantigen in PV; IgG binding disrupts desmosomal adhesion causing acantholysis. | Desmosome adhesion loss; downstream signaling (p38MAPK, Src) | 2023; Frontiers in Immunology | https://doi.org/10.3389/fimmu.2023.1169947 | (emtenani2023mousemodelsof pages 9-9) | | Gene/Protein | DSG1 | HGNC:DSG1 | Epidermal autoantigen (superficial disease phenotypes); anti-DSG1 antibodies contribute to cutaneous blistering. | Desmosome adhesion; epitope-dependent pathogenicity | 2024; J Cutaneous Med Surg (review) | https://doi.org/10.1177/12034754241266136 | (geng2024biomarkersinpemphigus pages 2-4) | | Genetic risk | HLA-DRB104:02 | IMGT/HLA:HLA-DRB104:02 | Strong PV-associated HLA allele that correlates with autoreactive T-cell recognition of Dsg epitopes and predisposition to autoantibody generation. | Antigen presentation → Tfh help → B-cell activation | 2024; Frontiers in Immunology | https://doi.org/10.3389/fimmu.2024.1500231 | (schwartz2024cytokineprofilingreveals pages 1-2) | | Cytokine / Gene | IL-21 | HGNC:IL21 | Tfh-derived cytokine that promotes B-cell differentiation to plasma cells and supports high-affinity anti-DSG antibody production. | Tfh → IL-21 → plasma cell differentiation (humoral axis) | 2024; Frontiers in Immunology | https://doi.org/10.3389/fimmu.2024.1500231 | (schwartz2024cytokineprofilingreveals pages 1-2) | | Gene/Protein | MAPK14 (p38 MAPK) | HGNC:MAPK14 | Central kinase mediating keratinocyte responses to pathogenic IgG; inhibition prevents IgG-induced cytoskeletal reorganization and acantholysis in models. | MAPK (stress) cascade downstream of desmosome perturbation | 2023; Frontiers in Immunology | https://doi.org/10.3389/fimmu.2023.1169947 | (emtenani2023mousemodelsof pages 9-9) | | Gene/Protein | EGFR | HGNC:EGFR | EGFR signaling implicated in desmosome ultrastructure changes; EGFR inhibitors (preclinical) rescue desmosomes and keratin anchorage. | EGFR → cytoskeletal/desmosome remodeling; cross-talk with MAPK | 2025; bioRxiv (preprint) | https://doi.org/10.1101/2025.02.10.637416 | (hartmann2025inpemphiguscell pages 32-34) | | Gene/Protein | SRC | HGNC:SRC | Tyrosine kinase activated in epitope-specific DSG3 signaling leading to Dsg3 depletion and adhesion loss; pharmacologic Src inhibition ameliorates some effects. | Src-dependent signaling linked to Dsg epitope effects and p38 MAPK | 2023/2025; Frontiers in Immunology / bioRxiv | 10.3389/fimmu.2023.1169947; https://doi.org/10.1101/2025.02.10.637416 | (emtenani2023mousemodelsof pages 9-9, hartmann2025inpemphiguscell pages 32-34) | | Gene/Protein | PLCG1 | HGNC:PLCG1 | Phospholipase C signaling participates in keratinocyte Ca2+ and adhesion responses after autoantibody binding. | PLC → Ca2+ flux → desmosome turnover | 2023; Frontiers in Immunology | https://doi.org/10.3389/fimmu.2023.1169947 | (emtenani2023mousemodelsof pages 9-9) | | Gene/Protein | PRKCA (PKCα) | HGNC:PRKCA | PKC subtype signaling influences desmosome assembly/disassembly and keratinocyte adhesion dynamics in PV models. | PKC signaling modulates desmosome turn-over and actin linkage | 2025; bioRxiv / reviews summarized 2023 | https://doi.org/10.1101/2025.02.10.637416 | (hartmann2025inpemphiguscell pages 32-34, emtenani2023mousemodelsof pages 9-9) | | Gene/Protein | AKT1 | HGNC:AKT1 | PI3K–AKT survival/anti-apoptotic signaling is engaged in keratinocytes and may modulate cell survival vs. cleavage during acantholysis. | PI3K–AKT anti-apoptosis pathways (cell survival) | 2025; pathway enrichment summaries | (no DOI available) | (starr2025insightsintopathomechanismsa pages 81-83) | | Gene/Protein | HSPB1 (HSP27) | HGNC:HSPB1 | HSP27 phosphorylation is downstream of PV sera exposure and mediates actin cytoskeletal reorganization; FK506 (tacrolimus) blocks HSP27 phosphorylation and restores Dsg3/adhesion. | HSP27 → actin reorganization; intersecting with p38/PKC axes | 2023; BMC Immunology | https://doi.org/10.1186/s12865-023-00582-z | (xie2023tacrolimusreversespemphigus pages 1-2) | | Gene/Protein | FCGRT (FcRn) | HGNC:FCGRT | Neonatal Fc receptor rescues IgG from catabolism; pharmacologic FcRn blockade (e.g., efgartigimod) lowers pathogenic IgG levels and is a mechanistic therapy in IgG-mediated PV. | IgG recycling pathway → therapeutic IgG clearance | 2023; Frontiers reviews (translational note) | https://doi.org/10.3389/fimmu.2023.1169947 | (emtenani2023mousemodelsof pages 9-9) | | Gene/Protein | BTK | HGNC:BTK | Tyrosine kinase in BCR signaling; BTK inhibitors (rilzabrutinib) aim to reduce B-cell activation/antibody production and FcγR-driven inflammatory functions. | BCR → BTK → B-cell activation / myeloid signaling | 2025; pathway enrichment / reviews | (trial reports / reviews) | (starr2025insightsintopathomechanismsa pages 81-83) | | Gene/Protein | CD19 | HGNC:CD19 | B-cell surface marker used for depletion (anti-CD19) and reference target for CAAR/CAR strategies to eliminate autoreactive B cells. | B-cell depletion/CAAR targeting → reduces pathogenic plasma cell precursors | 2023; Frontiers in Immunology (models & translational notes) | https://doi.org/10.3389/fimmu.2023.1169947 | (emtenani2023mousemodelsof pages 9-9) | | Cell type(s) | Tfh; Th17; Keratinocyte; B cell | CL:Tfh; CL:Th17; CL:keratinocyte; CL:B cell | Tfh cells (produce IL-21) and Th17 cells support autoreactive B cells; keratinocytes transduce antibody-triggered signals and undergo cytoskeletal/desmosomal changes; B cells/plasma cells produce pathogenic IgG. | Tfh→IL-21→B cells; Th17/Th2 inflammatory milieu; keratinocyte MAPK/EGFR signaling | 2023–2024; cohort & review studies | https://doi.org/10.3389/fimmu.2024.1500231; https://doi.org/10.3389/fimmu.2023.1169947 | (schwartz2024cytokineprofilingreveals pages 1-2, emtenani2023mousemodelsof pages 9-9) | | Anatomy | Skin epidermis; Oral mucosa | UBERON:skin epidermis; UBERON:oral mucosa | Primary tissues affected in PV; oral mucosa often the initial clinical site reflecting DSG3-dominant autoimmunity. | Tissue site of desmosomal adhesion and blister formation | 2023–2024; reviews | https://doi.org/10.3389/fimmu.2023.1169947; https://doi.org/10.1177/12034754241266136 | (emtenani2023mousemodelsof pages 9-9, geng2024biomarkersinpemphigus pages 2-4) | | Processes (GO) | cell–cell adhesion; desmosome organization; MAPK cascade; keratinocyte differentiation | GO:cell–cell adhesion; GO:desmosome organization; GO:MAPK cascade; GO:keratinocyte differentiation | Core disrupted biological processes in PV: loss of desmosomal cell–cell adhesion, altered desmosome assembly/ultrastructure, activation of MAPK signaling, and perturbed keratinocyte differentiation/response programs. | Desmosome ↔ MAPK/p38/Src/EGFR signaling axis; keratinocyte stress responses | 2023–2025; mechanistic studies & preprints | https://doi.org/10.3389/fimmu.2023.1169947; https://doi.org/10.1101/2025.02.10.637416 | (emtenani2023mousemodelsof pages 9-9, hartmann2025inpemphiguscell pages 32-34) | | Chemical / Autoantibody | IgG (pathogenic autoantibodies) | CHEBI:IgG | Class-switched IgG (IgG1/IgG4 variable by study) against DSG3/DSG1 are the proximal effectors causing loss of adhesion; subclass/epitope influences pathogenicity. | Direct steric inhibition of Dsg transinteraction + signaling induction (p38, Src) | 2023–2024; systematic review & mechanistic papers | https://doi.org/10.1177/12034754241266136; https://doi.org/10.3389/fimmu.2023.1169947 | (geng2024biomarkersinpemphigus pages 2-4, emtenani2023mousemodelsof pages 9-9) | | Therapeutics | Rituximab; Efgartigimod (FcRn inhibitor); Rilzabrutinib (BTKi); DSG3-CAART | CHEBI:rituximab; CHEBI:efgartigimod; CHEBI:rilzabrutinib; (DSG3-CAART: experimental cellular therapy) | Rituximab depletes CD20+ B cells (reduces autoantibody production); efgartigimod accelerates IgG clearance via FcRn blockade; rilzabrutinib inhibits BTK to blunt BCR signaling; DSG3-CAART aims to selectively eliminate DSG3-specific B cells. | B-cell depletion (anti-CD20), IgG clearance (FcRn), BCR pathway inhibition (BTK), antigen-specific CAAR-T therapy | 2023–2025; reviews and trials (early-phase / translational) | https://doi.org/10.3389/fimmu.2023.1169947; NCT04422912 | (emtenani2023mousemodelsof pages 9-9, hartmann2025inpemphiguscell pages 32-34) |

Table: Compact knowledge-base table mapping key molecules, cells, processes, and therapeutics in pemphigus vulgaris to ontology tags and primary evidence (2023–2025 contexts); useful for database annotation and mechanistic reference.

Clinical Trials and Implementations (with identifiers) - NCT04422912 (RESET-PV): “A Phase 1/2, Open-label, Safety and Dosing Study of Autologous CART Cells (Desmoglein 3 Chimeric Autoantibody Receptor T Cells [DSG3-CAART] or CD19-specific Chimeric Antigen Receptor T Cells [CABA-201]) in Subjects With Active, Pemphigus Vulgaris” – Overall status: Recruiting; Sponsor: Cabaletta Bio. (NCT04422912)

Limitations and Open Questions - The role of complement and lytic cell death pathways (apoptolysis/pyroptosis) in human PV lesions remains less definitive than in subepidermal diseases; some evidence suggests apoptosis follows adhesion loss. Further human tissue mechanistic studies are warranted. (emtenani2023mousemodelsof pages 9-9)

References (with URLs and dates when available) - Emtenani S, et al. Mouse models of pemphigus… Frontiers in Immunology. 2023. https://doi.org/10.3389/fimmu.2023.1169947 (emtenani2023mousemodelsof pages 9-9) - Schwartz RR, Seiffert-Sinha K, Sinha AA. Cytokine profiling… PV patients and HLA-susceptible controls. Frontiers in Immunology. 2024. https://doi.org/10.3389/fimmu.2024.1500231 (schwartz2024cytokineprofilingreveals pages 1-2) - Xie Z, et al. Tacrolimus reverses PV serum–induced depletion of desmoglein… via HSP27. BMC Immunology. 2023. https://doi.org/10.1186/s12865-023-00582-z (xie2023tacrolimusreversespemphigus pages 1-2) - Hartmann V, et al. In pemphigus, cell detachment… bioRxiv preprint. 2025 (preprint reflecting 2024 experimental work). https://doi.org/10.1101/2025.02.10.637416 (hartmann2025inpemphiguscell pages 32-34, hartmann2025inpemphiguscell pages 28-32) - Geng RSQ, et al. Biomarkers in Pemphigus Vulgaris: Systematic Review. J Cutaneous Med Surg. 2024. https://doi.org/10.1177/12034754241266136 (geng2024biomarkersinpemphigus pages 2-4) - ClinicalTrials.gov RESET-PV. NCT04422912. Recruiting. (NCT04422912)

References

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  3. (xie2023tacrolimusreversespemphigus pages 1-2): Zhimin Xie, Xiangnong Dai, Qingqing Li, Sifan Lin, and Xingdong Ye. Tacrolimus reverses pemphigus vulgaris serum-induced depletion of desmoglein in hacat cells via inhibition of heat shock protein 27 phosphorylation. BMC Immunology, Nov 2023. URL: https://doi.org/10.1186/s12865-023-00582-z, doi:10.1186/s12865-023-00582-z. This article has 6 citations and is from a peer-reviewed journal.

  4. (hartmann2025inpemphiguscell pages 32-34): Veronika Hartmann, Sen Guo, Siavash Rahimi, Uta Radine, Danielle Malheiros, Amanda Salviano-Silva, Valeria Bumiller-Bini Hoch, Gabriel A. Cipolla, Veronica Calonga-Solis, Axel Künstner, Imke Burmester, Ralf J. Ludwig, William V.J. Hariton, Christoph M. Hammers, Eliane J. Müller, Hauke Busch, and Jennifer E. Hundt. In pemphigus, cell detachment, but not autoantibody binding, induces cell-wide, long-lasting transcriptomic and proteomic changes. bioRxiv, Feb 2025. URL: https://doi.org/10.1101/2025.02.10.637416, doi:10.1101/2025.02.10.637416. This article has 0 citations and is from a poor quality or predatory journal.

  5. (hartmann2025inpemphiguscell pages 28-32): Veronika Hartmann, Sen Guo, Siavash Rahimi, Uta Radine, Danielle Malheiros, Amanda Salviano-Silva, Valeria Bumiller-Bini Hoch, Gabriel A. Cipolla, Veronica Calonga-Solis, Axel Künstner, Imke Burmester, Ralf J. Ludwig, William V.J. Hariton, Christoph M. Hammers, Eliane J. Müller, Hauke Busch, and Jennifer E. Hundt. In pemphigus, cell detachment, but not autoantibody binding, induces cell-wide, long-lasting transcriptomic and proteomic changes. bioRxiv, Feb 2025. URL: https://doi.org/10.1101/2025.02.10.637416, doi:10.1101/2025.02.10.637416. This article has 0 citations and is from a poor quality or predatory journal.

  6. (geng2024biomarkersinpemphigus pages 2-4): Ryan S. Q. Geng, Bethany Wilken, Siddhartha Sood, Ronald G. Sibbald, and Cathryn Sibbald. Biomarkers in pemphigus vulgaris: a systematic review. Journal of Cutaneous Medicine and Surgery, 28:458-462, Jul 2024. URL: https://doi.org/10.1177/12034754241266136, doi:10.1177/12034754241266136. This article has 6 citations and is from a peer-reviewed journal.

  7. (starr2025insightsintopathomechanismsa pages 81-83): H Starr. Insights into pathomechanisms of canine pemphigus foliaceus. Unknown journal, 2025.