Background/Purpose: IgG4-Related Disease (IgG4-RD) is characterized by inflammation and fibrosis of various organ systems. Its diverse clinical presentations include autoimmune pancreatitis, retroperitoneal fibrosis, sialadenitis, and dacryoadenitis. The etiology and pathogenesis are not well understood; however, the role of regulatory T cells (Treg) has been suggested. We evaluated the phenotype and function of Tregs in IgG4-RD patients with lacrimal and salivary gland involvement.

Methods: Three untreated IgG4-RD patients with chronic lacrimal and salivary gland enlargement underwent clinical evaluation at the Los Angeles County Medical Center Rheumatology clinic. Peripheral blood mononuclear cells were obtained from healthy controls and the untreated IgG4-RD patients. Treg subsets were identified with a combination of monoclonal antibodies (anti-CD4, -CD25, -CD45RA, -Foxp3, -CCR7) conjugated to different fluorochromes. Intracellular cytokine production (IL-2, IL-4, IL-5, IL-17A, IFN-g) was assessed in T cells by flow cytometry after PMA/Ionomycin stimulation in vitro. Statistical analysis was performed using Mann-Whitney or Wilcoxon tests.

Results: The patients, initially referred to rheumatology for Sjogren’s Syndrome, had clinical and histopathologic features consistent with IgG4-RD. Patient 1 was a 50-year-old Caucasian female with submandibular and lacrimal gland swelling for 3 years. She also had an enlarged right submandibular gland excised in 1989. Patient 2 was a 60-year-old African American female with bilateral parotid and lacrimal gland swelling since 2007. Patient 3 was a 33-year-old Filipino male with a history of hemimandibulectomy for ameloblastoma in 1989 who presented with painless enlargement of the lacrimal and parotid glands for 18 months. All patients underwent PET-CT scan, which showed diffuse lymphadenopathy and metabolically active, enlarged lacrimal and salivary glands. Excisional biopsies were performed. Histopathologic evaluation excluded lymphoma but revealed diffuse fibrosis, lymphocytic infiltration, and elevated IgG4/IgG plasma cell staining ratio (>50%) consistent with the diagnosis of IgG4-RD. Serum IgG4 levels were elevated in two patients.

Compared to healthy controls, the frequency of Treg (CD4+CD25+FOXP3+) cells was remarkably decreased in IgG4-RD patients, whereas naïve Treg cells (population with naïve phenotype, CCR7+CD45RA+) were increased.  IgG4-RD patients were also characterized by increased circulating Th2 (including CD4+IL-4+, CD4+IL-5+) cells compared to healthy controls, while Th1 (CD4+IFN-g) and Th17 (CD4+IL17+) cells did not differ significantly.

Conclusion: IgG4-related sclerosing dacryoadenitis and sialadenitis may mimic Sjogren’s Syndrome, prompting referral to rheumatologists. Histopathologic evaluation is essential for diagnosis. Untreated IgG4-RD patients were found to have a higher percentage of Th2 and a lower percentage of Treg, suggesting that correcting the balance of Treg/Th2 cells may be a potential therapeutic approach.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/regulatory-t-cells-in-igg4-related-disease-patients-presenting-with-sclerosing-sialadenitis-and-dacryoadenitis/