Bullous pemphigoid (BP) is one of the most frequent autoimmune bullous diseases that mainly occurs in the elderly and display no gender predilection. The cumulative incidence of BP is 8.2/million individuals, which is higher in Europe than in Asia (1). Although the incidence is generally low, the risk of developing BP increases with age. Studies have shown that people over 90 years of age have a 300-fold increased risk compared to people under 60 years of age (2). Moreover, compared to the general population of the same age, patients with BP have a 3.6 times increased risk of death (3). Although it is an autoimmune disease, it can be induced by multiple stimuli, including gliptin, COVID-19 vaccines, and programmed cell death-1/programmed cell death ligand-1 inhibitors (4–6), suggesting possible different biological underpinnings in these patients.

BP is predominantly evoked by autoantibodies against two types of hemidesmosomal proteins, BP180 (XVII collagen) and BP230, which are located in the basement membrane zone (BMZ) and responsible for the dermo-epidermal junction (7). During the formation of subepidermal blisters with negative Nikolsky sign, these autoantibodies and immune cells act together to destroy hemidesmosomes in keratinocytes (8). Histopathological examination frequently reveals separation of the dermis and epidermis, and inflammatory cell infiltration, mainly composed of lymphocytes and eosinophils (9).

BP cause a vast array of burdens to patients. Patients with BP usually develop pruritic, tense blisters or bullae locally or widespread on normal skin or erythematous background on the trunk and limbs (10). Some patients present with a non-bullous prodromic phase characterized by eczematous, excoriated, urticaria-like, or nodular lesions that varying in duration (11). Meanwhile, patients often suffer from comorbid health conditions, including neurological disorders, malignancies, and cardiovascular diseases. Specifically, it has been proven that multiple sclerosis, diabetes, hypertension, basal cell carcinoma of the skin, dementia, Parkinson’s disease, epilepsy, stroke, pneumonia, and pulmonary embolism have an increased prevalence among patients with BP (11–15). In addition to physical discomfort, BP could also contribute to decreased quality of life and increased psychological burden, such as anxiety and depression, because of the skin lesions, functional problems, pruritus, and disease chronicity (16, 17).

In terms of therapy, topical or systematic glucocorticosteroids are the primary treatment for BP, which can be supplemented by immunosuppressors such as methotrexate, azathioprine, and mycophenolate mofetil (2). However, long-term systemic use of corticosteroids may cause a variety of side effects, including hypertension, bone fracture, cataract, gastrointestinal discomfort and metabolic conditions, such as weight gain and hyperglycemia (18). Another key fact is that some patients with BP are resistant to traditional treatment. Currently, plasmapheresis, intravenous immunoglobulin, immunoadsorption, and rituximab can be administered to refractory patients (11). It has been demonstrated that more than 90% of patients with moderate-to-severe BP can get complete remission relatively safely using a combination therapy with rituximab and corticosteroids (19). However, some patients with BP are not sensitive to these therapies; thus, there is an urgent need for drugs with fewer side effects and superior efficacy.

Recently, an increasing number of studies have found that the pathogenesis of BP is closely related to type 2 inflammation, and the use of dupilumab, a monoclonal antibody against the type 2 inflammatory factors interleukin 4 (IL-4) and IL-13, seems to have a certain curative effect in patients with BP. Moreover, the European Academy of Dermatology and Venereology considers that dupilumab and omalizumab are optional treatments for refractory BP (20). These results provide a new direction for further exploration of the pathogenesis of BP and the search for more effective treatments. Here, we review the general process of type 2 inflammation, its role in the BP pathogenesis, and potential therapeutic targets and medications related to type 2 inflammation. Our aim is to provide new ideas and research directions for the development of more effective drugs with fewer side effects for the treatment of BP.

Type 2 inflammation is an immune response which exerts an important role in host defense against parasites and is predominantly mediated by group 2 innate lymphoid cells (ILC2s), type 2 T helper (Th2) cells, eosinophils, and relevant cytokines, such as IL-4, IL-5, and IL-13 (21). A large number of stimuli can trigger type 2 inflammation, including helminths, various allergies, certain viral or bacterial infections, and endogenous molecules (22). The process involves both innate and adaptive immune responses.

After exposure of the epithelium to these stimuli, local tissue homeostasis is disrupted, and epithelial cells release IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), which are termed alarmins. In general, epithelial tissues in different parts of the body release various alarmins. For example, in the lung, type 2 alveolar cells are a primary source of TSLP and IL-33 in the lung (23), whereas in the small intestine and skin, tuft cells and keratinocytes are a major source of IL-25, respectively (24, 25). In addition, other non-epithelial cells can also produce alarmins, with airway smooth muscle cells secreting TSLP (26) and fibroblasts producing IL-33 (27). Under the effect of these alarmins, tissue-resident ILC2s are activated and increase the production of cytokines of IL-4, IL-5, IL-9 and IL-13 (28), termed type 2 cytokines. ILC2 can also be mediated by other molecules released after the attack of exogenous stimuli, such as TL1A from TNF-family (29, 30), prostaglandin D2 and cysteinyl leukotriene (31, 32).

Meanwhile, in the presence of stimuli and cytokines produced by ILC2s, dendritic cells (DC) take up and transport parts of the antigens to local draining lymph nodes. Subsequently, the processed antigens induce naïve CD4+ T cells to activate the latter in the lymph nodes. The latter, with high GATA-binding protein 3 expression, can proliferate and differentiate into Th2 cells and subsequently produce type 2 cytokines with the help of DCs and the aforementioned type 2 cytokines, also including IL-33 and TSLP (21, 33, 34). After activation of ILC2s, this process generates as part of adaptive immunity. Furthermore, ILC2s have been shown to modulate the differentiation of naïve T cells into Th2 cells and the degree of Th2 response to a large extent. Once the stimulus is gone, ILC2s will be negatively regulated and decrease the support to Th2 cells, ultimately reducing the inflammation (35–37).

Generally, eosinophils, which develop in the bone marrow and circulate in the peripheral blood, play a vital role in type 2 inflammation. IL-5 is a crucial cytokine for the maturation, survival as well as recruitment of eosinophils and can prevent apoptosis (38). In type 2 inflammation, eosinophils are activated and recruited by IL-5, together with IL-33, TSLP, and eotaxins released by inflamed tissues and other chemoattractants, such as C3a and C5a (39–41). After activation, eosinophils can function as antigen-presenting cells for viral antigens (42) and upregulate associated molecules, including major histocompatibility complex (MHC) II, CD86, and CD40, ultimately leading to T cells activation and differentiation in draining lymph nodes (43). In the meantime, mature eosinophils can secrete IL-4, IL-25, and indoleamine 2,3-dioxygenase (44), which may cause selective differentiation of naïve T cells into Th2 cells instead of Th1 cells. Moreover, eosinophil-derived neurotoxin (EDN) and eosinophil peroxidase (EPO) released by eosinophils could strongly affect the maturation of DCs that migrate to lymph nodes, which can indirectly promote Th2 cell functions (45). Eosinophil-derived IL-25 can also promote the proliferation of and cytokine production by Th2 memory cells after antigen triggering (46). Besides their role as promoter for Th2 response, eosinophils can also act as an effector in type 2 inflammation. After recruitment into peripheral tissues, eosinophils cause tissue damage by releasing eosinophilic cationic protein (ECP), which can prompt cell cytotoxicity; EPO, which can generate oxidative stress; and major basic protein (MBP), which can destroy the lipid bilayer and increase cell permeability to damage the epithelium (43). Additionally, eosinophils are able to modulate classical and alternative pathways of complement activation as well as act through antibody-dependent cellular cytotoxicity against stimuli via their Fc receptors (43).

In the last phase of type 2 inflammation, the presence of stimuli and cytokines produced by both ILC2s and Th2 cells, especially IL-4 and IL-13, can facilitate the humoral immune response, activate B cells and cause rearrangement of the immunoglobulin heavy chain locus thus leading to immunoglobulin E (IgE) synthesis and differentiation into IgE-producing plasma cells (47, 48). IgE can bind to its high affinity receptor, FcϵRI, on basophils and mast cells to sensitize the body. When the body is exposed to the corresponding allergen again, the antigen recognition fragment of IgE binding to the cell surface binds to the allergen, resulting in cross-linking with the IgE-FcϵRI complex and degranulation of mast cells and basophils. The degranulation products, including histamine, proteases, prostaglandins and other cytokines (49, 50), lead to inflammatory reactions that manifest as erythema, itching, and edema on the skin; sneezing; cough; increased mucous secretions and bronchospasm in the respiratory tract; nausea, vomiting, and diarrhea in the digestive tract; and hypotension (49) ( Figure 1 )

As previously mentioned, BP is predominantly evoked by autoantibodies against BP180 and BP230. In these patients, BP180 and BP230 are recognized, ingested, processed by antigen presenting cells, and subsequently expressed on the cell surface combined with MHC II. After recognition of the antigen, naïve T cells are activated, differentiate to autoreactive Th2 cells and secrete specific cytokines, which in turn stimulate the differentiation and class-switch recombination of B cells. Plasmocytes produce autoantibodies IgG and IgE, leading to the deposition of autoantibodies in both the peripheral blood and the local basement membrane zone. Therefore, Th2 pathways are considered the primary triggers for antibody production in BP (51). It seems that anti-BP180 antibodies are more common than anti-BP230 antibodies in BP. One study showed that anti-BP180 IgG can be found in 95% of patients with BP, while anti-BP230 was found in 70% of patients in the same group (52). Autoantibody IgG can trigger complement activation, which can be proven by the deposition of complement C3 and C4 found in immunofluorescence examination, multiple immune cells recruitment, and proteases release, which can cause an inflammatory cascade reaction. Furthermore, it can directly target the corresponding antigens, causing hemidesmosome destruction and leading to the loss of adhesion to the BMZ and formation of subepidermal blisters (8). Among these autoantibodies, anti-BP180 antibodies are mainly targeted to the immunodominant region termed NC16A in the extracellular regions (53). These anti-BP180 NC16A IgG are positively correlated with the Autoimmune Bullous Skin Disorder Intensity Score and Bullous Pemphigoid Disease Area Index (BPDAI) in its subcomponents of erosion/blister, urticaria/erythema and pruritus scores, while the level of anti-BP230 IgG is not correlated with these scores, suggesting that anti-BP180 NC16A IgG can be a useful indicator of BP activity (54, 55). The above mechanism can partially explain the formation of blisters but fail to explain the manifestation of itching, erythema, and eosinophilia in BP. Elevated serum IgE levels are found in 70–85% patients with BP (56), and deposition of IgE can be seen in immunofluorescence examination, which is related to degranulation of mast cells and basophils, eosinophil recruitment, and manifestations of itch and blister formation (57). Therefore, abnormal T cell immune responses and autoantibodies together lead to the occurrence of BP. The pathogenesis of BP depends on a variety of immune cells, including Th2 cells and eosinophils; autoimmune antibodies, including IgE; and a variety of cytokines, such as IL-4, IL-5, and IL-13, which are all relevant to type 2 inflammation.

BP is an autoimmune bullous disease that mainly occurs in the elderly, severely affecting their health and quality of life. Previous studies have demonstrated that BP is predominantly evoked by autoantibodies against BP180 and BP230, together with an abnormal T cell immune response, which results in the destruction of hemidesmosomes and local inflammation. Traditional therapies are mainly based on the systemic use of corticosteroids. However, long-term use of corticosteroids results in a series of side effects, such as hypertension, bone fracture, cataract, and hyperglycemia, and some patients are not sensitive to hormone therapy. Therefore, there is an urgent need for new medications with fewer side effects and superior therapeutic benefits. Type 2 inflammation is an immune response mainly mediated by ILC2s, Th2 cells, eosinophils, and inflammatory cytokines, such as IL-4, IL-5 and IL-13. As mentioned above, these immune cells and their related molecules play an essential role in the pathogenesis of BP. To date, a variety of monoclonal antibodies against the above factors have been used in the therapy of type 2 inflammation-related diseases and have achieved good clinical efficacy. From this perspective, these targeted drugs are expected to become a new and superior choice for patients with BP. However, the role and efficacy of these targeted medications in the treatment of BP is not completely clear yet; thus, more studies are needed to explore the efficacy of these targeted drugs on BP in the future to find more effective medications with fewer side effects that can benefit patients with BP.

Under the supervision of XL, the manuscript was written by LZ. ZC and LW provided critical evaluation of written content and contributed to manuscript revision. All authors contributed to the article and approved the submitted version.