Bullous pemphigoid (BP) is an organ-specific
autoantibody-mediated blistering
skin disease that mainly affects the elderly. Typical clinical features include the widespread
blisters, often preceded by and/or associated with itchy urticarial or
eczema-like lesions. BP patients have circulating
autoantibodies against BP180 and/or the plakin family
protein BP230 both of which are components of hemidesmosomes in basal keratinocytes. Most BP
autoantibodies particularly target the
epitopes within the non-collagenous NC16A domain of BP180. Clinical findings and murine models of BP have provided evidence of a pathogenic role of anti-NC16A
autoantibodies. However, it is largely unknown what triggers the breakage of immunotolerance against BP180 in elderly individuals. The incidence of BP has been increased over the past two decades in several countries. Aside from aging populations, the factors behind this phenomenon are still not fully understood.
Neurodegenerative diseases such as
multiple sclerosis,
Parkinson's disease, and certain
dementias are independent risk factors for BP. Recently several case reports have described BP in patients with
diabetes mellitus (DM) patients who have been treated with dipeptidyl peptidase-4 inhibitors (DPP-4i or
gliptins), which are a widely used class of anti-DM drugs. The association between the use of DPP-4is, particularly
vildagliptin, and BP risk has been confirmed by several epidemiological studies. Evidence suggests that cases of
gliptin-associated BP in Japan display certain features that set them apart from cases of "regular" BP. These include a "non-inflammatory" phenotype, targeting by
antibodies of different immunodominant BP180
epitopes, and a specific association with the
human leukocyte antigen (HLA) types. However, recent studies in European populations have found no major differences between the clinical and immunological characteristics of
gliptin-associated BP and "regular" BP. The DPP-4
protein (also known as CD26) is ubiquitously expressed and has multiple functions in various cell types. The different effects of the inhibition of DPP-4/CD26 activity include, for example, tissue modeling and regulation of inflammatory cells such as T lymphocytes. Although the pathomechanism of
gliptin-associated BP is currently largely unknown, investigation of the unique effect of
gliptins in the induction of BP may provide a novel route to better understanding of how immunotolerance against BP180 breaks down in BP.