Critical Involvement of Macrophage Infiltration in the Development of Sjögren's Syndrome–Associated Dry Eye

• Published in: The American journal of pathology Vol. 181; no. 3; pp. 753 - 760
• Main Authors: Zhou, Delu, Chen, Ying-Ting, Chen, Feeling, Gallup, Marianne, Vijmasi, Trinka, Bahrami, Ahmad F, Noble, Lisa B, van Rooijen, Nico, McNamara, Nancy A
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.09.2012; American Society for Investigative Pathology
• Subjects: Adoptive Transfer; AIRE Protein; Animals; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; Cell Movement - immunology; Clodronic Acid; Corneal Stroma - pathology; Dry Eye Syndromes - complications; Dry Eye Syndromes - immunology; Eye - immunology; Eye - pathology; Humans; Investigative techniques, diagnostic techniques (general aspects); Limbus Corneae - pathology; Liposomes; Macrophages - immunology; Macrophages - pathology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Knockout; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phenotype; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Short Communication; Sjogren's Syndrome - complications; Sjogren's Syndrome - immunology; Sjogren's Syndrome - pathology; Tears - metabolism; Transcription Factors - deficiency; Transcription Factors - metabolism; Immunopathology; Dry eye syndrome; Eye disease; Anatomic pathology; Stomatology; Dry eye; Systemic disease; Development; Autoimmune disease; Infiltration; Sjögren syndrome; Macrophage
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2012.05.014

Lymphocytic infiltration of the lacrimal gland and ocular surface in autoimmune diseases such as Sjögren's syndrome (SS) causes an aqueous-deficient dry eye that is associated with significant morbidity. Previous studies from our laboratory and others have established autoimmune regulator (Aire)–deficient mice as a useful model to examine exocrinopathy and ocular surface disease associated with SS. Consistent with human SS, autoreactive CD4+ T cells play an indispensible role in the development of exocrine and ocular surface disease in Aire knockout mice. We report that in addition to CD4+ T cells, a large number of macrophages infiltrate the corneal stroma, limbus, and lacrimal glands of diseased mice. Adoptive transfer of autoreactive CD4+ T cells from Aire knockout mice led to local infiltration of macrophages and ocular surface damage in immunodeficient recipients. Depletion of local macrophages, through subconjunctival injection of clodronate liposome, attenuated lissamine green staining and improved ocular phenotype. Alternatively, systemic depletion of macrophages had no effect on ocular phenotype but led to significant improvements in lacrimal gland exocrinopathy and tear secretion. Our results suggested that autoreactive CD4+ T cells provoked macrophage infiltration to the eye and lacrimal gland, where they played a functional role in directing the development of autoimmune dry eye.