ABSTRACT
BACKGROUND: Anti-citrullinated protein antibodies have been detected with high specificity in serum of patients with rheumatoid arthritis (RA), and citrullination of proteins may play a key role in the pathogenesis of RA. We therefore investigated the presence of citrullination in two extra-articular manifestations of RA, interstitial pneumonia (IP) and rheumatoid nodules. METHODS: Open-lung biopsy specimens from patients with RA-associated IP (n = 18), idiopathic IP (n = 20) and controls (n = 10), as well as specimens of rheumatoid nodules from 26 patients, were examined. All sections were incubated with an anti-modified citrulline antibody. Masked scoring of stained sections and analysis of results by stratification according to demographic and clinical characteristics was performed. RESULTS: Presence of citrulline could be detected in eight lung specimens of patients with RA-associated IP (44%) and nine patients with idiopathic IP (46%). Conversely, lung tissue from control patients showed weak extracellular citrullination in only two cases (20%). Citrullination did not show any significant associations with demographic or clinical characteristics such as age, gender, smoking habits, disease severity, histological subtype, degree of inflammation or steroid use. Rheumatoid nodules were citrulline positive in a majority of cases (70%). CONCLUSION: Citrullination is present in extra-articular manifestations of RA such as IP and nodules. In contrast to the high specificity of anti-citrulline antibodies in RA, citrullination is not only restricted to RA but can also be observed in idiopathic IP. Whether citrullination significantly contributes to the initiation or perpetuation of autoimmunity or merely reflects ongoing inflammation remains to be clarified.
Subject(s)
Arthritis, Rheumatoid/complications , Citrulline/analysis , Lung Diseases, Interstitial/metabolism , Aged , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/metabolism , Arthritis, Rheumatoid/metabolism , Biopsy , Collagen , Female , Humans , Immunoenzyme Techniques , Lung/chemistry , Lung Diseases, Interstitial/etiology , Lung Diseases, Interstitial/pathology , Male , Mice , Mice, Inbred DBA , Middle Aged , Rheumatoid Nodule/etiology , Rheumatoid Nodule/metabolism , Rheumatoid Nodule/pathology , Severity of Illness IndexABSTRACT
BACKGROUND: The role of mast cells in extra-articular manifestations of rheumatoid arthritis (RA) has not been studied so far. OBJECTIVE: To characterise and quantify mast cells in RA associated interstitial pneumonia (IP) by an immunohistological study. METHODS: Lung biopsy specimens from 15 patients with RA associated IP, 12 patients with idiopathic IP, and 5 control patients were stained with antibodies directed against tryptase (mast cell marker). Morphological characterisation of stained specimens was carried out and staining was quantified by computer assisted image analysis. RESULTS: Tryptase staining showed the marked presence of mast cells in idiopathic IP and in RA associated IP. A significant difference in stained tissue area was found between RA associated IP (2.6%, IQR 2.0-3.2%, p = 0.015) and idiopathic IP (3.1%, IQR 1.8-3.7%, p = 0.003) compared with control tissue specimens (1.0%, IQR 0.7-1.5%). The extent of mast cell infiltration correlated well and inversely with pulmonary function variables. CONCLUSIONS: Mast cell infiltrates are present in RA associated IP and idiopathic IP. The observed correlation of pulmonary function and mast cell numbers would be consistent with the proposed role of mast cell mediators in the promotion of fibrogenesis. The findings provide a rationale for studying functional aspects of mast cell involvement in the pathogenesis of RA associated lung disease.
