The Yin and Yang of non-immune and immune responses in meibomian gland dysfunction

Abstract

Meibomian gland dysfunction (MGD) is a leading cause of dry eye disease and one of the most common ophthalmic conditions encountered in eye clinics worldwide. These holocrine glands are situated in the eyelid, where they produce specialized lipids, or meibum, needed to lubricate the eye surface and slow tear film evaporation - functions which are critical to preserving high-resolution vision. MGD results in tear instability, rapid tear evaporation, changes in local microflora, and dry eye disease, amongst other pathological entities. While studies identifying the mechanisms of MGD have generally focused on gland obstruction, we now know that age is a major risk factor for MGD that is associated with abnormal cell differentiation and renewal. It is also now appreciated that immune-inflammatory disorders, such as certain autoimmune diseases and atopy, may trigger MGD, as demonstrated through a T cell-driven neutrophil response. Here, we independently discuss the underlying roles of gland and immune related factors in MGD, as well as the integration of these two distinct mechanisms into a unified perspective that may aid future studies. From this unique standpoint, we propose a revised model in which glandular dysfunction and immunopathogenic pathways are not primary versus secondary contributors in MGD, but are fluid, interactive, and dynamic, which we likened to the Yin and Yang of MGD.

Figure 1.. The healthy meibomian gland.

A) The meibomian glands (dashed lines) can be seen as a row of white structures embedded in the distal eyelid that extend from the eyelid margin and are comprised of clusters of small round acini. B) H&E-stained tissue section of eyelid from a normal wild-type mouse showing the meibomian gland underlying the orbicularis muscle. The gland has a blind ended central duct (Duct) connecting acini to the gland orifice (Arrowhead) at the junction between the skin and conjunctiva.

Figure 2.. Potential mechanism controlling meibocyte differentiation and acinar atrophy.

Meibocyte differentiation requires binding of lipid sensitive nuclear receptor, PPARγ, and RXRα to the PPARγ DNA binding domain. Activation of FOXO1 by isotretinoin (Accutane), inflammatory cytokines, TLRs, or PAMPs leads to replacement of PPARγ from the DNA binding site and the inhibition of meibocyte differentiation. Growth factor signaling leading to phosphorylation of FoxO1 leads to the nuclear exit of FoxO1 and facilitates downstream PPARγ signaling. Abbreviations: PPARγ, peroxisome proliferator activated receptor gamma; RXRα, retinoid; ATRA, all-trans retinoic acid; TLR, toll-like receptor; PAMPs, pathogen-associated molecular patterns; FOXO1, forkhead box protein O1; Akt, protein kinase B; PI3K, phosphoinositide 3-kinases.

Figure 3.. Immune-mediated MGD is driven by type 3 immune responses.

Similar to other type 3 responses, immune mediated MGD appears to rely on conjunctival IL-17A production leading to downstream neutrophil recruitment, which induces glandular dysfunction through mechanisms that are still being studied. NET formation is a leading hypothesis, but the specific mechanism requires further study. Abbreviations: AED, allergic eye disease; IL, interleukin; Th, T helper; MGD, Meibomian gland dysfunction; NET, neutrophil extracellular traps.

Figure 4.. The Yin and Yang of MGD: Dynamics of immune and non-immune contributions to the MGD disease process.

The Yin and Yang analogy captures the 3 points we argued regarding the need for a more fluid and dynamic model to represent the disease process. These points are: (1) that the early initiators of MGD can either be immune-driven or glandular-driven pathologic pathways; (2) that both pathways can interact in the disease process; and (3) that some pathologic stimuli may trigger both pathways simultaneously. The level of contribution from each pathway can change depending on the etiology and disease state, but both compartments must be considered to holistically understand MGD pathogenesis. Abbreviations: MGD, Meibomian gland dysfunction.