Giovanna Rotondo Dottore1, Liborio Torregrossa2, Patrizio Caturegli3, Ilaria Ionni1, Angela Sframeli4, Elena Sabini1, Francesca Menconi1, Paolo Piaggi5, Stefano Sellari-Franceschini6, Marco Nardi4, Francesco Latrofa1, Paolo Vitti1, Claudio Marcocci7, Fulvio Basolo2, Michele Marinò1. 1. Department of Clinical and Experimental Medicine, Endocrinology Unit I, University of Pisa and University Hospital of Pisa, Pisa, Italy. 2. Department of Surgical, Medical and Molecular Pathology, Pathology Unit, University of Pisa and University Hospital of Pisa, Pisa, Italy. 3. Department of Pathology, Division of Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland. 4. Department of Surgical, Medical and Molecular Pathology, Ophthalmopathy Unit I, University of Pisa and University Hospital of Pisa, Pisa, Italy. 5. Obesity and Diabetes Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona. 6. Department of Surgical, Medical and Molecular Pathology, Endocrinology Unit I, University of Pisa and University Hospital of Pisa, Pisa, Italy. 7. Department of Clinical and Experimental Medicine, Endocrinology Unit II, University of Pisa and University Hospital of Pisa, Pisa, Italy.
Abstract
Importance: Graves orbitopathy (GO) responds to immunosuppressive treatments when clinically active but poorly when inactive. In other autoimmune diseases, response has been ascribed to a reduction in lymphocytes infiltrating the target organ. It is not known whether active vs inactive GO differs in this regard, which would help in understanding the link between GO immunologic features and clinical behavior. Objective: To investigate the association between orbital lymphocytic infiltrate and GO clinical features. Design, Setting, and Participants: A cohort study aimed at assessing the extent and immunohistochemical phenotype of orbital lymphocytes and associating it with the ophthalmologic features of GO, especially its clinical activity score (CAS), was conducted at a tertiary referral center. Twenty consecutive patients with GO who underwent orbital decompression were included. The study was conducted from January 1 to May 31, 2017. Exposures: Orbital tissue histology and immunohistochemistry testing as well as ophthalmologic evaluation. Main Outcomes and Measures: Association between CAS and orbital lymphocytes, analyzed as total number of lymphocytes and main lymphoid subsets. Results: The patient population included 8 men and 12 women, all of white race, with a mean (SD) age of 46 (13) years. With an established cutoff value of 300 lymphoid cells per tissue sample, lymphocytes above this value were found in orbital tissues of 9 of 20 patients (45%), often organized into distinct foci. The lymphocytes comprised a mixture of T (CD3-positive) and B (CD20-positive) cells, suggesting a mature, polyclonal autoimmune response. In a simple linear regression model, the total number of lymphocytes, as well as the number of CD3- and CD20-positive subsets, correlated with CAS (R = 0.63; 95% CI, 0.27-0.84; P = .003; R = 0.59; 95% CI, 0.20-0.82; P = .006; and R = 0.65; 95% CI, 0.30-0.85; P = .002, respectively). In a multiple linear regression model, lymphocytes maintained their effect on CAS when adjusted for 2 additional variables that were correlated with CAS-smoking and GO duration-highlighting even more the important role of orbital lymphocytes in affecting CAS (total number: R = 0.58; 95% CI, 0.18-0.82; P = .01; CD3-positive: R = 0.58; 95% CI, 0.17-0.82; P = .01; and CD20-positive: R = 0.59; 95% CI, 0.19-0.83; P = .01). Conclusions and Relevance: This study shows a correlation between T and B lymphocytes infiltrating orbital tissues and the activity of GO, possibly enhancing our understanding of the association between GO immunologic features and clinical expression.
Importance: Graves orbitopathy (GO) responds to immunosuppressive treatments when clinically active but poorly when inactive. In other autoimmune diseases, response has been ascribed to a reduction in lymphocytes infiltrating the target organ. It is not known whether active vs inactive GO differs in this regard, which would help in understanding the link between GO immunologic features and clinical behavior. Objective: To investigate the association between orbital lymphocytic infiltrate and GO clinical features. Design, Setting, and Participants: A cohort study aimed at assessing the extent and immunohistochemical phenotype of orbital lymphocytes and associating it with the ophthalmologic features of GO, especially its clinical activity score (CAS), was conducted at a tertiary referral center. Twenty consecutive patients with GO who underwent orbital decompression were included. The study was conducted from January 1 to May 31, 2017. Exposures: Orbital tissue histology and immunohistochemistry testing as well as ophthalmologic evaluation. Main Outcomes and Measures: Association between CAS and orbital lymphocytes, analyzed as total number of lymphocytes and main lymphoid subsets. Results: The patient population included 8 men and 12 women, all of white race, with a mean (SD) age of 46 (13) years. With an established cutoff value of 300 lymphoid cells per tissue sample, lymphocytes above this value were found in orbital tissues of 9 of 20 patients (45%), often organized into distinct foci. The lymphocytes comprised a mixture of T (CD3-positive) and B (CD20-positive) cells, suggesting a mature, polyclonal autoimmune response. In a simple linear regression model, the total number of lymphocytes, as well as the number of CD3- and CD20-positive subsets, correlated with CAS (R = 0.63; 95% CI, 0.27-0.84; P = .003; R = 0.59; 95% CI, 0.20-0.82; P = .006; and R = 0.65; 95% CI, 0.30-0.85; P = .002, respectively). In a multiple linear regression model, lymphocytes maintained their effect on CAS when adjusted for 2 additional variables that were correlated with CAS-smoking and GO duration-highlighting even more the important role of orbital lymphocytes in affecting CAS (total number: R = 0.58; 95% CI, 0.18-0.82; P = .01; CD3-positive: R = 0.58; 95% CI, 0.17-0.82; P = .01; and CD20-positive: R = 0.59; 95% CI, 0.19-0.83; P = .01). Conclusions and Relevance: This study shows a correlation between T and B lymphocytes infiltrating orbital tissues and the activity of GO, possibly enhancing our understanding of the association between GO immunologic features and clinical expression.
Authors: Sefina Arif; Pia Leete; Vy Nguyen; Katherine Marks; Nurhanani Mohamed Nor; Megan Estorninho; Deborah Kronenberg-Versteeg; Polly J Bingley; John A Todd; Catherine Guy; David B Dunger; Jake Powrie; Abby Willcox; Alan K Foulis; Sarah J Richardson; Emanuele de Rinaldis; Noel G Morgan; Anna Lorenc; Mark Peakman Journal: Diabetes Date: 2014-06-17 Impact factor: 9.461
Authors: Peter N Taylor; Lei Zhang; George J Kahaly; Marian Ludgate; Richard W J Lee; Ilaria Muller; Daniel G Ezra; Colin M Dayan Journal: Nat Rev Endocrinol Date: 2019-12-30 Impact factor: 43.330