In the news: Inflammatory marker HLA-DR In Dry Eye Disease: New Findings

Background: HLA-DR, an Inflammatory Marker

It’s widely recognized that inflammation plays a prominent role in the development and progression of dry eye disease (DED). Tear film instability and hyperosmolarity can induce ocular surface damage and initiate an inflammatory cascade that generates innate and adaptive immune responses. These immuno-inflammatory responses lead to further ocular surface damage and a self-perpetuating inflammmatory cycle.

Human leukocyte antigen-DR (HLA-DR) is a biomarker of inflammation, which is normally expressed on most immune-competent cells. HLA-DR molecules are upregulated in response to signaling, reflecting immune activation. HLA-DR, for example, serves as a dendritic cell activation (maturation) marker that increases when exposed to inflammatory cytokines.

The expression of HLA-DR has been associated with many immune disorders, inflammatory processes, and ocular surface diseases such as DED. The results of several new clinical investigations suggest that HLA-DR is a useful tool in evaluating DED.

HLA-DR & DED Signs, Symptoms

In the first report (1), researchers from the Institute of Vision, Sorbonne Universities collected baseline data from three large, phase III randomized clinical trials conducted on moderate to severe DED patients. Measures of DED, at baseline and after treatment with cyclosporine (1 mg/mL) and placebo (in two of the three studies), were analyzed and correlations performed in 311 patients. HLA-DR was quantified by flow cytometry in impression cytology specimens.

The investigators found that HLA-DR significantly increased with the diagnosis of Sjögren's syndrome and meibomian gland disease (p<0.0001, p=0.02 respectively). The strongest significant correlation was seen with HLA-DR and corneal fluorescein staining (r =0.30, p<0.0001), to a lesser extent with Schirmer’s test, and weakly with TBUT and symptom reporting questionnaires. Importantly, HLA-DR was significantly reduced after cyclosporine treatment compared to placebo (p=0.02 in both studies).

Dry eye signs and symptoms are often inconsistent. The expression of HLA-DR in conjunctival cells has the potential to bridge the gap between signs and symptoms, according to the paper’s authors.

HLA-DR & DED Severity, Goblet Cell Loss

The second report comes from Baylor College of Medicine, where researchers examined whether clinical severity and goblet cell loss is correlated with dendritic cell maturation markers HLA-DR and CD86 in the conjunctiva of aqueous tear deficient patients (2).

Compared to the control group, the percentages of dendritic cell activation markers (HLA-DR+, CD86+ and others) were found to be higher in the conjunctiva of the aqueous tear deficient group. Clinical severity negatively correlated with goblet cell density (r = -0.54, P<0.05) and positively correlated with percentage of CD45+HLA-DR+ cells (r = 0.71, P<0.05). Goblet cell density negatively correlated with percentage of CD45+HLA-DR+ cells (r = -0.61, P<0.05).

In short, a greater percentage of activated (mature) dendritic cells were found in the conjunctiva of aqueous tear deficient patients, and that increased presence of mature dendritic cells was consistent with greater clinical severity and the loss of goblet cells.

Evaluating HLA-DR expression by impression cytology is emerging as an effective and reliable way to assess conjunctival inflammation in DED patients and as a useful means to monitor the effectiveness of anti-inflammatory treatments in DED. In a long-term, controlled trial of postmenopausal women with DED, for example, supplementation with the fatty acids GLA, EPA and DHA, prevented the increase in HLA-DR seen in placebo-treated patients (3).

References

1. Brignole-Baudouin F, et al. Correlation between the inflammatory marker HLA-DR and signs and symptoms in moderate to severe dry eye disease. Cornea. Invest Ophthalol Vis Sci 58:2436-48, 2017.
2. Pflugfelder S, et al. Conjunctival dendritic cell maturation and goblet cell density in aqueous tear deficiency. HLA-DR Program Number 3754, ARVO Annual Meeting, Baltimore, May 7-11, 2017.
3. Sheppard J, et al. Long-term supplementation with n-6 and n-3 PUFAs improves moderate-to-severe kerato-conjunctivitis: A randomized double-blind clinical trial. Cornea. 32:1297-304, 2013.