A Rare Case of Anti‐Integrin β4 IgG‐Positive Bullous Pemphigoid Lacking Mucosal Lesions

Dear Editor,

1.

Autoimmune bullous diseases (AIBDs) clinically and histopathologically show mucocutaneous blistering lesions [1]. AIBDs are classified into two groups, pemphigus and pemphigoid diseases [2]. Bullous pemphigoid (BP) is the major subtype of pemphigoid diseases, clinically presenting various cutaneous lesions with or without mucosal lesions. In addition to the clinical features, the most important diagnostic element is to detect circulating autoantibodies against BP180 and/or BP230 [2]. It is well known that BP sera mainly reacted with the NC16a domain of BP180, while mucous membrane pemphigoid (MMP) sera mainly reacted with LAD‐1/C‐terminal domain of BP180 [3].

A 90‐year‐old male, presenting with pruritus and wide cutaneous lesions such as erythema, ulcer, and blister, visited our hospital at day 0 (Figure 1A). Skin lesions started 3 months ago, with exacerbation recently. No mucosal lesions, including conjunctival lesions, were observed. Gastrointestinal symptoms, such as abdominal pain or diarrhea, were absent. The Bullous Pemphigoid Disease Area Index (BPDAI) is 23. Histopathology of the biopsy of skin tissue showed subepidermal blister and eosinophils' infiltration (Figure 1B). Direct immunofluorescence (DIF) indicated linear IgG and C3 deposition at the basement membrane zone (BMZ). Indirect immunofluorescence using normal human skin (IIF) showed positive IgG staining at the BMZ (Figure 1C). Indirect immunofluorescence using 1 M NaCl‐split normal human skin (ssIIF) showed positive IgG staining at the epidermal side (Figure 1D). Immunoblotting (IB) of epidermal extract detected IgG anti‐BP180 autoantibody in patient serum collected at Day 0, but not at Day 16 (Figure 1E). IB of LAD‐1 recombinant protein (RP) detected IgG anti‐LAD‐1 autoantibody in patient serum collected at Day 0, but not at Day 16 (Figure 1F). By ELISAs, IgG antibodies against BP180 NC16a, LAD‐1, BP230, and integrin β4 extracellular domain (ECD) were detected in patient serum collected at Day 0, and all their titers decreased at Day 16 (Figure 1G). All diagnostic tests and corresponding results were summarized in Figure 1H.

FIGURE 1.

Clinical, histopathological and immunological features of this patient. (A) Skin lesions with widespread erythema and ulceration. (B) Histopathological features with subepidermal blister and eosinophil infiltration (H&E staining). (C) Indirect immunofluorescence using normal human skin (IIF) showed linear IgG staining at basement membrane zone (BMZ). (D) Indirect immunofluorescence using 1 M NaCl‐split normal human skin (ssIIF) showed IgG staining at the epidermal side. (E) Immunoblotting of epidermal extract showed positive IgG autoantibodies against BP180 for patient serum collected at day 0. (F) Immunoblotting of LAD‐1 recombinant protein (RP) showed positive IgG autoantibodies against LAD‐1 for patient serum collected at day 0. (G) Detection of IgG and IgA autoantibodies against indicated autoantigens in the patient sera collected at day 0 and 16, by ELISAs using in house kits. Dot line indicates the cutoff value. (H) Summary of the results of diagnostic tests. BMZ, basement membrane zone; DIF, direct immunofluorescence; Dsg, desmoglein; ECD, extracellular domain; ICD, intracellular domain; IIF, indirect immunofluorescence using normal human skin; LM, laminin; ssIIF, indirect immunofluorescence using 1 M NaCl‐split normal human skin.

Based on the above clinical, histopathological, and immunological findings, this patient was diagnosed as BP with additional IgG antibody against integrin β4. Oral prednisone 40 mg daily was administered. At Day 16, clinical symptoms improved significantly, and no new skin lesions developed.

LAD‐1 is the common autoantigen epitope of MMP, while our BP patient serum could react with both BP180 NC16a and LAD‐1, indicating the circulating anti‐BP180 antibodies may recognize more wide antigen epitopes of BP180.

Integrin β4 is the major autoantigen of ocular MMP [1, 4], indicating its possible contribution to mucosal lesions. In the present study, the IgG anti‐integrin β4 ECD antibody is positive, and its titer decreased with the therapy and improvement of clinical symptoms, although there are no mucosal lesions involved in this patient. In the literature, antibodies against integrin α6β4 ECD were found in a drug‐induced BP patient, who had no mucosal lesions, too [5]. The correlation between anti‐integrin β4 antibody and cutaneous lesions in AIBDs deserves deeper investigations.

Finally, the observed concurrent decline of the four antibodies during treatment, while clinically suggestive, does not constitute sufficient evidence that each autoantibody independently possesses cutaneous lesion capacity.

Funding

This work was supported by the Scientific Research Project of Heilongjiang Provincial Health Commission (No. 20250404120105 and 20250404120493). The work was also supported by the Introduction of Talent and Research Start‐up Funds of Jinan Central Hospital (No. YJRC2023020) and the Science and Technology Development Program of Jinan Municipal Health Commission (No. 2024305003).

Ethics Statement

This study was performed according to the Declaration of Helsinki and approved by the ethics committee of Daqing Oilfield General Hospital. Informed consent of this patient was obtained.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding authors.