Meibomian gland dysfunction (MGD) is characterized by insufficient production and/or altered secretion of meibum, predominantly lipids, to the tear film, producing instability, rapid tear evaporation, and dry eye disease (DED) symptoms, including blurry vision, redness, ocular pain, and foreign body sensation [1]. Population and clinical-based studies with varying design, patient characteristics, and definitions report an MGD prevalence of 38.9% in the US, but as high as 69.3% in subjects aged 60 years or older [2]. Despite being one of the most frequent ophthalmic conditions encountered in eye clinics worldwide, treatment is mostly palliative in nature, and currently there are no FDA approved pharmacotherapies indicated for MGD [3].

This unmet medical need can be partially explained by our incomplete understanding around the early triggers which initiate the disease process. The predominating hypothesis is that MGD begins with hyperkeratinization of the meibomian gland duct epithelium. This event, which has been extensively reviewed by other authors [3,4], is thought to lead to obstruction, increased intraglandular pressure, cystic dilation of the duct, acinar cell dysfunction, disuse atrophy, and gland dropout, with subsequent abnormal meibum composition and decreased secretion [[5], [6], [7], [8], [9]]. However, in counter distinction to the obstructive hyperkeratinization hypothesis, a role for ductal hyperplasia, as characterized by ductal thickening and epithelial cell desquamation without orifice hyperkeratinization, has also been proposed in some forms of MGD [2]. Moreover, how these early changes and downstream consequences relate to inflammation that is co-incident with most forms of MGD is poorly understood. In fact, whether immunopathogenesis is necessary and/or sufficient in the disease process is a topic of current debate [10].

The original purpose of this perspective piece was to delineate the distinct perspectives for the role of non-immune versus immune processes in MGD pathobiology. Subsequently, this discussion expanded to encompass a unified perspective that integrates these two seemingly disparate views into a novel, unified framework focused on the interplay between glandular-driven and immune-driven dysfunction. In contrast to the existing ‘vicious cycle’ perspective [1,11,12], which argues a more sequential process in MGD pathogenesis, we postulate a highly fluid model to represent the inter-relationship between certain pathological immune responses and aberrant glandular cell functions – we have likened this interaction to the Yin and Yang of MGD.