American Journal of Respiratory and Critical Care Medicine

To investigate the degree and the type of inflammation in the bronchial mucosa in patients with Sjögren's syndrome, we examined lobar bronchial biopsies obtained from 10 patients with Sjögren's syndrome (six with primary and four with secondary) and eight control subjects. Histochemistry with hematoxylin-eosin was performed both to identify the number of mononuclear cells and eosinophils and to measure the thickness of the basement membrane. Immunohistochemistry was performed to identify neutrophils (neutrophil-elastase), macrophages (CD68), and T-lymphocyte subpopulations (CD4 and CD8) in the submucosa. Subjects with Sjögren's syndrome presented a greater number of CD4-positive T-lymphocytes than did the normal control subjects (p = 0.0129). Instead, eosinophils, neutrophils, macrophages, CD8 positive T-lymphocytes, and basement membrane thickness were similar in the two groups. There were no differences in cell counts between patients with primary and those with secondary Sjögren's syndrome and between symptomatic and asymptomatic patients. No correlation was found between cell counts, symptoms, lung volumes, and disease duration. This study has shown that patients with Sjögren's syndrome have an increased number of CD4 positive T-lymphocytes in the bronchial mucosa outside of the bronchial glands, supporting the concept that, in the airways, Sjögren's syndrome involves also extraglandular tissues.

Sjögren's syndrome, a slowly progressing inflammatory autoimmune disease, is the result of lymphocyte-mediated destruction of exocrine glands that leads to diminished or absent glandular secretions and mucosal dryness (1). In about one-third of the patients the lymphocytic infiltrate extends beyond the exocrine glands and affects parenchymal organs such as the thyroid, liver, kidneys, and lungs. Sjögren's syndrome can occur alone (primary Sjögren's syndrome) or in association with almost all of the autoimmune diseases (secondary Sjögren's syndrome) (1), and pulmonary involvement has been reported both in primary (2) and secondary Sjögren's syndrome (3).

Several specific pulmonary complications have been described in patients with Sjögren's syndrome, including interstitial pneumonitis and fibrosis, lymphoma, vasculitis, and airway disease (4-7). The involvement of the airways has been previously reported in different studies (6-11). Indeed, irritating dry cough (6) and mild increase in bronchial responsiveness (8, 9) are common in these patients. Moreover, several studies have found evidence of airway obstruction in patients with Sjögren's syndrome (6, 7, 10, 11). However, we still have little knowledge concerning the morphology of the large airways, especially of the extraglandular tissue, in this disease and no controlled studies have so far been performed on bronchial biopsies.

To investigate the degree and the type of inflammation in the bronchial mucosa in patients with Sjögren's syndrome, we examined lobar bronchial biopsies obtained from 10 patients with Sjögren's syndrome (six with primary and four with secondary) and eight control subjects.

Subjects

The study population was composed of two groups: 10 nonsmoking patients with Sjögen's syndrome (six with primary and four with secondary) and 8 nonsmoking normal control subjects. Diagnosis of Sjögren's syndrome was based on the European criteria (12); for the diagnosis of primary Sjögren's syndrome four of the following six criteria are necessary: (1) subjective complaints of xerophthalmia (specific questionnaire), (2) subjective complaints of xerostomia (specific questionnaire), (3) ocular signs of keratoconjunctivitis (specific questionnaire), (4) histopathologic features in the labial minor salivary gland biopsy compatible with focal sialoadenitis (specific grading), (5) evidence of salivary gland involvement (specific tests), (6) presence of autoantibodies to Ro/SS-A or La/SS-B in the sera of patients. The diagnosis of the secondary form of the disease was based on the coexistence of Sjögren's syndrome with other autoimmune disorders.

All subjects in both groups had no past history of asthma or bronchitis-bronchiectasis and had been free of acute respiratory tract infections in the month preceding the study. None of the patients with Sjögren's syndrome had received oral or inhaled glucocorticoids, antibiotics, or immunosuppressants during the 3 mo preceding the study. The study conformed to the declaration of Helsinki, and informed written consent was obtained for each subject. All subjects underwent interview, clinical examination, chest radiography, ECG, routine and immunologic blood tests, and pulmonary function tests within the week before bronchoscopy.

Pulmonary Function Tests

Pulmonary function tests included measurements of FEV1 and FVC under baseline conditions in all of the subjects examined. The predicted normal values were those from Communite Europeenne du Carbon e de l'Acier (CECA) (13).

Bronchoscopy and Bronchial Biopsies

Fiberoptic bronchoscopy was performed as previously described (14). Three to five endobronchial biopsies were taken through a bronchoscope (Olympus BF type 1T10; Olympus Co., Tokyo, Japan) with sterile forceps (FB 15C; Olympus Co.) from the subcarinae of basal segment bronchi of the right middle lobe.

Histochemical and Immunohistochemical Stainings

The two biopsies that macroscopically appeared the most satisfactory were fixed in formaldehyde in 0.1 M phosphate buffer at pH 7.2 and, after dehydration, embedded in paraffin. Serial sections of 6 μm thick were cut, and tissue specimens were oriented for histologic analysis. Two sections at a regular interval of 100 μm were used for each staining. Histochemistry with hematoxylin-eosin was performed for the identification of eosinophils and mononuclear cells, including macrophages and lymphocytes. Mouse monoclonal antibodies were used for identification of neutrophils (antielastase clone NP57; Dako Ltd, High Wycombe, UK) (15, 16), macrophages (anti-CD68 clone KPI; Dako) (14, 16, 17), CD4 positive T-lymphocytes (anti-CD4 clone OPD4; Dako) (16, 18), and CD8 positive T-lymphocytes (anti-CD8 clone C8/144B, Dako) (18). Monoclonal antibody binding was detected with the alkaline phosphatase antialkaline phosphatase method (Dako APAAP kit system k 670) and fast-red substrate. To identify macrophages, tissue sections were pretreated with 0.05% trypsin (Sigma Chemical, St. Louis, MO) in 45 mM calcium chloride and pH 7.8 at 37° C for 10 min. To identify CD8 positive T-lymphocytes, the sections, immerged in citrate buffer 0.5 mM at pH 6.0, were heated in a microwave (M704; Philips, Eindhoven, The Netherlands) at maximal power for 1 h. Control slides were included in each staining run, using human tonsil as a positive control and mouse monoclonal anticytokeratin antibody (M717; Dako) as a negative control. Light microscopic analysis was performed with a Jenamed 30 G 0040 microscope (Aus, Jena, Germany) at magnification ×780. For each section, the number of positive stained cells was counted in several nonoverlapping high power fields until all available area from the reticular basement membrane to a depth of 100 μm was covered. Two sections were counted for each quantification. The results were expressed as the number of cells per square millimeter of tissue examined, and the median value for each subject was obtained. To avoid observer bias, the slides were coded before analysis and read blind.

The thickness of the epithelial basement membrane was assessed in the two sections stained with hematoxylin-eosin and was measured from the base of the bronchial epithelium to the outer limit of the reticular lamina at regular 200-μm intervals along the length of each section, using an eyepiece graticule. The final result was a single value per patient obtained from the average of the measurements performed in each biopsy (19).

Data Analysis

Group data were expressed as means ± SEM or medians and range when appropriate. Differences between groups were assessed using Student's t test for clinical data and the Mann-Whitney U test for morphologic data. Correlation coefficients were calculated using Spearman's rank method. Probability values of p < 0.05 were accepted as significant. The coefficient of repeatability as described by Bland and Altman (20) was used to compare measurements performed on the two sections of the same biopsy. This coefficient was calculated as the standard deviation of the differences between the measurements performed on the two sections of the same biopsy for each cellular quantification. At least three replicate measurements of morphometric parameters were performed by the same observer, and the intraobserver reproducibility was assessed with the coefficient of variation for repeated measurements.

Clinical Findings

The characteristics of the subjects are reported in Table 1. The two groups of subjects were similar with regard to age and sex. Disease duration ranged between 1 and 15 yr with an average value of 3.8 ± 1.3 yr. Respiratory symptoms were present in six patients, predominantly cough and exertional dyspnea. Signs of chest disease on chest auscultation were present in three patients with secondary Sjögren's syndrome (Patients 2, 4, and 7 in Table 1), in the form of fine bilateral basal lung crackles; the same patients had abnormal chest radiographs as well. There was a trend for the value of FEV1 (% of predicted) and to a lesser degree for FVC (% of predicted) to be lower in subjects with Sjögren's syndrome than in normal control subjects, but the difference was not significant. However, when we considered only patients with Sjögren's syndrome, FEV1, and FVC presented significantly lower values in those with secondary Sjögren's syndrome as compared with patients with primary Sjögren's syndrome (p = 0.0082 and p = 0.0038, respectively).

Table 1. CHARACTERISTICS OF PATIENTS WITH SJÖGREN'S SYNDROME AND CONTROL SUBJECTS

Subject No.SexAge (yr)DiagnosisDisease duration (yr)FEV1(% pred)FVC (% pred)Chest RadiographSymptoms
 1F36pSs 1100 98NormalCough
 2M66sSs (RA) 1 74 66InterstitialCough, ex. dyspnea
 3F62pSs 1140131NormalNone
 4M70sSs (SS) 5 31 45InterstitialCough, ex. dyspnea
 5F54pSs14 89114NormalNone
 6F57pSs 5107114NormalNone
 7F51sSs (PM) 1 67 63InterstitialCough, ex. dyspnea
 8F49pSs 3 87 94NormalNone
 9F71sSs (CREST) 6 83 96NormalCough
10F48pSs 1117115NormalCough
Mean56 4 86 94
SEM 3 1  8  9
11F54Control 95 97
12F46Control126116
13F65Control 97 95
14M62Control 99102
15F22Control110114
16F48Control113107
17F59Control111131
18M34Control 94 87
Mean49106106
SEM 5  4  5

Definition of abbreviations: pSs = primary Sjögren's syndrome; sSs = secondary Sjögren's syndrome; RA = rheumatoid arthritis; SS = systemic sclerosis; PM = polymyositis; CREST = calcinosis, Raynaud's phenomenon, esophageal dysmotility, teleangiectasia; ex = exertional.

Biopsy Findings

Bronchoscopy was well tolerated and macroscopically showed normal airways in all subjects and no evidence of inflammatory bronchitis or bronchial infection; satisfactory endobronchial biopsies were obtained in all cases. The results of morphometric measurements are reported in Table 2 and Figure 1. The mean coefficient of variation for the three repeated measurements by the same observer ranged from 11.8 to 14.1% for the cells studied; it was 8.3% for thickness of the total basement membrane. The coefficients of repeatability for measurements performed on the two sections of each biopsy were 239, 3, 28, 46, 41, and 19 cells/mm2 for mononuclear cells, eosinophils, neutrophils, macrophages, and CD4 and CD8 positive T-lymphocytes, respectively. Among all the inflammatory cells, mononuclear cells were the most represented cells both in patients and control subjects, whereas eosinophils were virtually absent in both groups (Table 2). Subjects with Sjögren's syndrome presented a greater number of CD4 positive T-lymphocytes in the bronchial submucosa than did normal control subjects (p = 0.0129) (Figure 1 and Figure 2, panel a). No significant differences in the number of eosinophils, neutrophils, macrophages, CD8 positive T-lymphocytes (Table 2, Figure 1, and Figure 2, panel b) and in the thickness of the basement membrane (4.51 ± 0.38 μm versus 5.3 ± 0.60 μm, p = 0.33) were observed between patients and normal control subjects. There were no differences in cell counts between patients with primary and those with secondary Sjögren's syndrome and between symptomatic and asymptomatic patients. When all subjects were considered together no significant correlations were found between cell counts, symptoms, lung volumes, and disease duration.

Table 2. INDIVIDUAL COUNTS FOR INFLAMMATORY CELLS 100  μ m DEEP  TO THE BASEMENT MEMBRANE OF PATIENTS WITH  SJÖGREN'S SYNDROME AND CONTROL SUBJECTS

Subject No.Mononuclear Cells (cells/mm2 )Eosinophils (cells/mm2 )
 11,4550
 28724
 36060
 41,2650
 57440
 68172
 76900
 89300
 94800
101,3730
Mean9231
SEM1051
Control subjects
 18467
 26120
 36300
 47476
 56800
 63620
 76700
 88530
Mean6752
SEM551

This study has shown that patients with Sjögren's syndrome have an increased number of CD4 positive T-lymphocytes in the bronchial mucosa, outside of the bronchial glands, supporting the concept that in the airways, Sjögren's syndrome involves also extraglandular tissues.

Using bronchoalveolar lavage (BAL), previous studies have detected increased number of T-lymphocytes in patients with Sjögren's syndrome (21-24). Hatron and coworkers (21) reported subclinical lymphocytic alveolitis in a high proportion of patients with primary Sjögren's syndrome. Most of the T-cells found in BAL had the CD4 phenotype (22). Dalavanga and coworkers (23) reported that activated helper T-cell alveolitis is quite common in primary Sjögren's syndrome, and the higher levels of BAL lymphocytosis were observed in those patients with high grading of lymphocytic infiltration in the minor lip biopsy. Moreover, Breit and coworkers (24) reported that in patients with other autoimmune disorders the major determinant for BAL lymphocytosis appears to be the coexpression of Sjögren's syndrome.

Relatively few patients have been studied histologically in vivo, and there is a lack of data in the literature regarding the morphologic status of the airways in patients with Sjögren's syndrome. The histologic studies available have been focused on the small airways and/or on lung interstitium (6, 10, 25, 26), whereas no studies have been performed so far on bronchial biopsies. Constantopoulos and coworkers (6) performed transbronchial lung biopsy in five patients with primary Sjögren's syndrome and detected both peribronchiolar and interstitial inflammation. Newball and Brahim (10) performed open lung biopsies in two patients with primary Sjögren's syndrome and disclosed narrowed small airways with thickened walls infiltrated with mononuclear leukocytes. Gardiner and coworkers (25) investigated by transbronchial biopsy 16 dyspneic patients with Sjögren's syndrome and detected, by histochemical techniques, peribronchiolar lymphocytic infiltrates in five patients and interstitial changes in six patients.

Sjögren's syndrome presents with a wide spectrum: from exocrinopathy to extraglandular systemic disease and finally to B-cell neoplasia (1). The common lesion of all organs affected in patients with Sjögren's syndrome is a potentially progressive lymphocytic infiltration. Indeed, previous studies on renal (27) and liver (28) biopsies of patients with Sjögren's syndrome disclosed lymphocytic infiltrates around tubules and cholangial ducts, respectively.

Moutsopoulos and Kordossis (29) have advanced the hypothesis that the above-mentioned extraglandular manifestations in Sjögren's syndrome might be related to the attraction of immune effector cells by different ion-transporting epithelial tissues such as renal tubules, bronchi, and cholangial ducts. These organs, which at least in part perform also “excretory function,” share a common antigen, carbonic anhydrase II, a basic metalloenzyme important for the regulation of acid-base status (30, 31). Evidence of cellular and humoral immune responses against this molecule has been reported in a subset of patients with Sjögren's syndrome (32-34). Although the hypothesis of Moutsopoulos and Kordossis (29) is very intriguing, further studies are necessary to clarify the detailed pathogenetic mechanisms of extraglandular manifestations in Sjögren's syndrome and the relationship between various sites of involvement.

We took advantage of the heterogeneity of our study population with respect to clinical variants to examine a wide spectrum of Sjögren's syndrome. Because the cell profile in bronchial submucosa was similar in primary and secondary Sjögren's syndrome, we believe that the observed increase in CD4 positive T-lymphocytes is an expression of Sjögren's syndrome and not of the associated autoimmune disorder. Previous studies have suggested a link between bronchial inflammation and dry cough through the destruction of the submucosal glands. Nevertheless, a recent study on six autopsied patients with Sjögren's syndrome (two with primary and four with secondary Sjögren's syndrome) reported hyperplasia of airway secretory cells and submucosal glands (35), suggesting that factors different from exocrine gland destruction may be related to the presence of dry cough in these patients. In the present study we were not able to demonstrate a difference in the submucosal inflammatory changes between symptomatic and asymptomatic patients. Properly designed studies need to be performed to clarify the relationship between airway inflammation and symptoms in Sjögren's syndrome.

In conclusion, the present study, by showing an increased number of CD4 positive T-lymphocytes in the bronchial mucosa of patients with Sjögren's syndrome, provides evidence that in the airways this disease involves also extraglandular tissue.

The writers thank Tiziano Bertin for graphic assistance, Luigi Zedda for technical assistance, and Marissa Galliani for revising the manuscript.

Supported by the Italian Ministry of University and Research, by the European Commission (Project Grant ENFUMOSA, no. BMH4-CT96-1471), and a Special Annual Grant (1997) from the Azienda Ospedale/Università di Ferrara.

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Correspondence and requests for reprints should be addressed to Alfredo Potena, M.D., Sezione di Fisipatologia Respiratoria, Arcispedale S. Anna, via Corso Giovecca 203, 44100 Ferrara, Italy.

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