Molecular Basis for Global Incidence of Pemphigoid Diseases and Differences in Phenotypes

Molecular Basis for Global Incidence of Pemphigoid Diseases and Differences in Phenotypes

A. Razzaque Ahmed1*, Sarah Anwar2 and Pedro A. Reche3

1 Department of Dermatology, Center for Blistering Diseases, Tufts University School of Medicine, Boston, MA, United States, 2 Tufts University School of Medicine, Boston, MA, United States, 3 Department of Immunology & O2, Faculty of Medicine, University Complutense of Madrid, Madrid, Spain


Pemphigoid (Pg) diseases are a group of potentially fatal autoimmune mucocutaneous diseases. They have different clinical phenotypes, involving only the skin or multiple mucous membranes. They occur globally and frequently affect the elderly. The common marker among all variants is the presence of autoantibodies targeting the dermalepidermal or mucosal-submucosal junctions, or basement membrane zone (BMZ). Four target antigens in the BMZ were studied. These included BPAG1, BPAG2 and subunits of a6 and b4 human integrins. Our objective was to find a molecular basis for the global incidence of Pg diseases and a mechanism that will explain the vast differences in clinical phenotypes and outcomes. All the variants of Pg that were analyzed had a statistically significant association with HLA-DQb1*03:01 in ten countries on four continents. This explains the reason for global incidence. Prediction models discovered multiple peptides in each of the four antigens that serve as T cell epitopes. These T cell epitopes were shown to bind to HLA-DQb1*03:01. In addition, structure modelling demonstrated the peptide-HLA complex bound to the T cell receptor. These autoreactive T cells would stimulate B cells to produce specific anti-BMZ autoantibodies. Anti-BMZ autoantibodies with different specificities will produce different phenotypes, which will account for involvement of different tissues and organs in different molecules. The contribution this study makes is that it provides a molecular basis of why a similar disease occurs in different racial groups. Furthermore, it provides the basis for the production of autoantibodies with different specificities, which resultantly produces different phenotypes.


 Pemphigoid (Pg) is a group of autoimmune blistering diseases that can affect the skin and multiple mucous membranes (1). They can be fatal, difficult to diagnose, and treatment can be delayed. Data presented in this manuscript suggests that they are a good model to study autoimmunity.
The lesions in bullous pemphigoid (BP) are vesicles and bullae of variable sizes, in an acral or generalized distribution (2). In some patients mucous membranes may be involved. The most common cause of death in these patients is opportunistic infection due to prolonged iatrogenic immune suppression (3). BP affects predominantly the elderly, which is of particular relevance as the aging population is increasing globally (4). The mortality rate increases with each increasing decade of life (5). BP occurs between 2.4 to 23 cases per million in the general population worldwide (5).
Mucous membrane pemphigoid (MMP) predominantly affects multiple mucosae and not infrequently the skin. As the blisters heal, they cause scarring, which is the reason for its former name, cicatricial pemphigoid. In most patients, this scarring produces sequelae that are catastrophic and severely impact the quality of life (1, 6). Of special note are two subsets of MMP, ocular MMP and oral MMP. Other clinical entities such as anti-laminin-332 pemphigoid (7) and anti-p200 pemphigoid (8), are not included in this study. There is a general absence of data on these two disease entities, which is central to the hypothesis of this study.
The most common feature among pemphigoid diseases is that the blisters appear at the junction of the epidermis and dermis or mucosa and submucosa. Using direct immunofluorescence, the immunopathologic features include deposition of IgG and complement at the dermal-epidermal junction or basement membrane zone (BMZ) in the perilesional tissues (1). This is the standard test for diagnosis. Autoantibodies to BMZ proteins can be detected by indirect immunofluorescence using human skin or monkey esophagus as substrate (9). In some cases, ELISAs have been developed (1). In several studies anti-BMZ autoantibodies have been purified from plasma of patients with active pemphigoid diseases. When these purified human anti-BMZ autoantibodies are cultured with human tissue in vitro, they bind to the BMZ, when studied by histology and immunopathology. When injected into laboratory animals, they produce blisters in vivo (1, 10). Such studies confirm their role in the pathogenesis. In addition, multiple cells of the immune and inflammatory pathways, play a pivotal and essential role in the phenotypic presentation of pemphigoid diseases.
The pathognomonic and unique feature of MMP is that it causes scarring as it heals, except in the oral cavity (6). Scarring does not occur in BP. In the conjunctiva, the scarring leads to blindness in approximately 25% of patients (11). In the larynx, abrupt closure can result in sudden asphyxiation (6). Esophageal strictures can cause esophageal rupture and can result in fatal mediastinitis (12). Vaginal involvement can result in severe vaginal stenosis (12). Anal involvement can result in constant fecal leakage and the need for adult diapers for most of the patient’slife(12). MMP is more rare with an incidence of 1-2 cases per million (13).
In BP, the anti-BMZ autoantibodies are directed against BP antigen 1 (BPAG1 or BP230) and BP antigen 2 (BPAG2 or BP180) (14, 15). In a large cohort of patients from Germany, in a recent study, the most frequently targeted antigen was BP180 (15). Their injection produces blisters in the skin of neonatal mice (16, 17). In MMP, the antigens are a subunit of human integrins b4 and a6. Antibodies from patients’ sera against b4 produced subepidermal blisters in neonatal mice (18). When normal human oral mucosa was incubated with antibodies to subunit of human a6 integrin from sera of patients with oral pemphigoid, separation of the mucosa from the submucosa has been observed (19).
Earlier studies from our group demonstrated that patients with BP, MMP, and its subsets had a strong correlation with the HLA-DQb1*03:01 allele, in spite of strikingly different clinical presentations, courses and prognoses (20–22).
Recently, a new group of drugs has been added to the treatment of type II diabetes mellitus, known as dipeptidyl peptidase-4 inhibitors (DPP4-is). Many patients treated with these drugs have been reported to develop pemphigoid (23).
The purpose of this study was to determine the global presence of pemphigoid diseases. Furthermore, to investigate the molecular basis for the global presence and simultaneously to study what mechanisms might explain such striking differences in clinical profiles and clinical outcomes, and the reasons for production of autoantibodies to diverse proteins in the BMZ.

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