Bronchoalveolar lavage cell profiles in Wegener's granulomatosis

RESPIRATORY MEDICINE (1999) 93, 498-506

Bronchoalveolar lavage cell profiles in We granulomatosis

A. SCHNABEL”, M. REUTER+, K. GLOECKNER*, J. MUELLER-QUERNHEIM~ AND W. L. GROSS”

‘Poliklinik fiir Rheumatologie, Medizinische Univevsitiit Liibeck and Rhetlmaklinik Bad Bramstedt, Germany ‘Klinik fiiv Radiologische Diagnostik, Universitiit Kiel, Germany ‘Institut fiir Pathologic, Univevsitht Ltibeck, Germany TiMedi.zinische Klinik, Forschungszentvum Borstel, Germany

Pulmonary involvement due to Wegener’s granulomatosis (WG) can present radiologically either as diffuse infiltrates or as nodular and linear opacities. Clinical experience suggests that these radiological patterns are associated with different bronchoalveolar lavage (BAL) cell profiles, but this has not been examined formally.

We compared the BAL cell profile in eight WC patients with diffuse infiltrates on chest X-ray, indicative of highly active pneumonitis, with corresponding findings in 37 patients with nodular, linear and focal low-attenuation infiltrates on high-resolution computed tomography (HRCT) which reflected low-grade, mainly interstitial disease. A control group was composed of 11 patients with pulmonary sarcoidosis.

Diffuse infiltrates occurred in association with high systemic disease activity and featured a neutrophilic BAL profile in the presence of generally normal BAL lymphocytes. HRCT findings suggestive mainly of interstitial disease were associated with either a lymphocytic BAL cell profile or a normal cell pattern. Patients with a lymphocytic cell profile generally had a preferential elevation of CD4+ cells in the BAL in the presence of a normal CD4/CD8 ratio in the blood. This was a common feature of WG and pulmonary sarcoidosis.

In conclusion, highly active pneumonitis and pulmonary disease of low or moderate activity in WG are associated with disparate BAL cell profiles. It remains to be examined whether the preferential elevation of CD4+ cells in the latter condition reflects a common pathogenetic role of this subset of cells in WC and pulmonary sarcoidosis.

RESPIR. MED. (1999) 93, 498-506

Wegener’s granulomatosis (WG) is an inflammatory multi- organ disease of unknown aetiology which almost always affects the respiratory tract (1). Roentgenologically, the two most common disease patterns at the lung are either ill-defined infiltrates or solitary or multiple, cavitating or non-cavitating nodules (2,3). The diffuse infiltrates generally occur in association with high systemic disease activity. The underlying histopathology is either acute parenchymal damage with airspace consolidation and infil- tration mainly by neutrophils, or an infiltrate resulting from diffuse alveolar bleeding (45). A more chronic type of inflammatory infiltration usually underlies the nodular roentgenological infiltrates (4,5). The prototype lesion is the necrotizing granuloma of WG, the prevailing cellular

Received 16 December 1998 and accepted in revised form 17 March 1999. Correspondence should be addressed to: Dr Armin Schnabel, Poliklinik fiir Rheumatologie, Medizinische Universitat Liibeck, Ratzeburger Allee 160, D-23538 Liibeck, Germany. Fax: +49 (0)451-5003650; E-mail: [email protected]

elements of which are histiocytes, lymphocytes and multinucleate giant cells (4-6).

This latter category of roentgenological morphology was recently augmented by high-resolution computed tomogra- phy (HRCT) findings (7-9). This disclosed a range of less obtrusive parenchymal abnormalities consisting of small nodules, septal and non-septal lines and focal low- attenuation opacities, many of which had eluded detection by conventional chest X-ray (CXR) (9). It is our experience that a major proportion of these changes recedes under immunosuppressive treatment, marking them as active inflammatory lesions. Bronchoalveolar lavage @AL) revealed that these changes are commonly associated with a lymphocytic cell profile, whereas previous studies of patients with highly active lung disease due to WG showed mainly neutrophilic cell profiles (2,10,11).

To substantiate the impression that lung disease due to WG is associated with disparate BAL cell patterns depend- ing on disease activity, we recruited two patient groups on the basis of radiological features, A group with high pulmonary disease activity was recruited on the basis of

0954-6111/99/070498 + 09 $12.00/O 0 1999 W. B. SAUNDERS COMPANY LTD

BRONCHOALVEOLARLAVAGECELLPROFILESINWEGENER'SGRANULOMATOSIS 499

ill-defined infiltrates in the CXR in the presence of high systemic disease activity. A second group was recruited on the basis of a normal CXR but nodular or linear infiltrates on HRCT suggestive of moderately active, mainly inter- stitial lung disease. The BAL cell pattern in these two groups was determined morphologically and, in the event of elevated lymphocytes, by immunotyping for CD3’ T cells, CD4’ helper/inducer cells and CD8” suppressor/cytotoxic cells.

Patients and Methods

PATIENTS

The study included 45 consecutive patients (20 women, 25 men; median age 57.0 years, 95% confidence interval 49-64 years) with active WG. WG was diagnosed according to the 1990 American College of Rheumatology criteria (12) and the 1994 Chapel-Hill definition (13). The site of histological confirmation was the upper respiratory tract in 28 patients, the lung in three, the kidney in two, the skin in one and skeletal muscle in one. The patients received a comprehen- sive staging examination, including ophthalmological, otorhinolaryngological and neurological referral, CXR, lung function testing, bronchoscopy and BAL. The range of organ system involvement and the extent of disease was scored using the disease extent index (DEI) (14). Anti- neutrophil cytoplasmic antibodies (ANCA) testing by a standard immunofluorescence test, followed by testing with mono-specific ELISA, resulted in a PR3-ANCA in 39 patients, cANCA of undetermined specificity in one and MPO-ANCA in two (15).

The high disease activity group consisted of eight patients presenting with widespread, ill-defined infiltrates in the CXR in the presence of high systemic disease activity. Excluded were patients with microbiological evidence of infection and patients with clinical or bronchoscopic evi- dence of alveolar bleeding. Four of the eight patients were examined at initial presentation with generalized disease and were untreated. Four patients were examined during a relapse and two of these were on cyclophosphamide. The low disease activity group consisted of 37 patients with active, progressive WG who had pulmonary symptoms (cough, dyspnoea), abnormal lung function tests (vital capacity or CO diffusion capacity below 80% of predicted values) or a history of lung disease due to WG but a normal CXR. These patients were subjected to HRCT and all of them had abnormal parenchymal HRCT findings, which were comprised of septal or non-septal lines, small nodules or low-attenuation opacities. Thirteen of these patients were examined at initial presentation and 24 patients during follow-up. Eighteen patients were untreated, seven were on low-dose prednisolone, six were on cyclophosphamide and six were on low-dose methotrexate.

For comparison, the BAL cell profile and T-cell subsets in BAL and blood were examined in five women and six men with a median age of 35 years (range 2841 years) with pulmonary sarcoidosis. The diagnosis was based on the criteria of Yamamoto and Sharma (16) and all patients had

highly active disease associated with systemic manifesta- tions. The latter were arthralgia or arthritis in 11 patients and erythema nodosum in five.

HRCT, PULMONARY FUNCTION TESTING

Pulmonary HRCT was performed with a Somatom Plus-S device (Siemens, Erlangen, Germany). Thin-section radio- graphs (l-mm section thickness) were taken at maximum inspiration from the apex to the base of the lungs by a table feed of 10 mm. Scans were reconstructed by means of a high spatial frequency reconstruction algorithm and images were documented at window settings appropriate for lung parenchyma (20001-450). Pulmonary function was measured using a MasterLab unit (Jaeger, Wuerzburg, Germany) according to the recommendations of the American Thoracic Society (17). Values for the CO diffu- sion capacity were corrected for haemoglobin and alveolar volume as measured by the helium dilution technique (18).

BRONCHOSCOPY AND TRANSBRONCHIAL BIOPSY

Fibre-optic bronchoscopy was performed after local anaesthesia with lidocaine and premeditation with atropine and a morphine antitussant. BAL was directed at lung areas showing abnormal CXR or HRCT findings. The broncho- scope was wedged into a segmental bronchus and 10 fractions of 20-ml sterile saline 0.9% were instilled and aspirated. The recovered material was examined for con- ventional bacterial pathogens, acid-fast bacteria, Legionella spp, Chlamyclia spp, Mycoplasma spp and Pneumocystis cavinii. Any infected material was omitted from further study. Transbronchial biopsy (TBB) was also directed at radiologically abnormal lung areas. Tissue specimens were transferred into buffered formalin and embedded in paraf- fin. Sections were stained with haematoxylin and eosin and evaluated for inflammatory cells by morphological criteria.

BAL CELL ANALYSIS

The lavage material was centrifuged and the cell pellet was resuspended in RPM1 1640 medium (Gibco, Eggenstein, Germany) to a density of lo6 cells ml-‘. Cytospin prep- arations were prepared with a Shandon II cytocentrifuge (Shandon Products, Cheshire, U.K.) and stained according to May-Giemsa-Gruenwald. The cell differential was assessed by counting 300 cells. Normal reference values in this laboratory are < 15% for lymphocytes, I 5% for neutrophils and 5 1% for eosinophils. In the event of an elevated lymphocyte count, BAL and blood lymphocytes were immunophenotyped for T cells and T-cell subsets. BAL cells were suspended in RPM1 1640 containing 0.01% human serum albumin (Sigma, Munich, Germany) and incubated for 30 min with fluorescence-conjugated anti- CD3, anti-CD4, and anti-CD8 (Coulter, Krefeld and Becton Dickinson, Heidelberg, Germany). After a final wash, cells were measured in a Coulter EPICS II flow cytometer. Blood samples were subjected to lysis of

500 A. SCHNABEL ET AL.

TABLE 1. Characteristics of patients with pneumonitis due to Wegener’s granulomatosis (high pulmonary disease activit group)

Patient Current organ involvement

Disease ESR CRP extent index ANCA-titre (mm h - ‘) (mg dl - ‘) Chest X-ray

W.E. female, 71 years

H.D., male, 39 years

K.R., female, 44 years

R.L., male, 58 years

S.D., male, 40 years

F.H., male, 55 years

P.H., female, 65 years

P.W.; male, 61 years

ENT, lung, kidney, heart, B symptoms ENT, lung, kidney, neuropathy, arthritis, B symptoms ENT, eye, lung, arthritis, neuropathy, B symptoms ENT, lung, B symptoms Lung, kidney, arthritis, B symptoms ENT, lung, kidney, skin, central and peripheral nervous system, arthritis, B symptoms Lung, kidney, B symptoms Lung, eye, arthritis, skin, gastrointestinal tract, B symptoms

9 12048 1000

11 1:64 120

11 I:128

5 1:32 135 39.4 Bilateral infiltrates

7 1:256 70 16.7 Bilateral infiltrates

15 1:64 90 5‘9 Bilateral infiltrates

31 I:128

7 1:32

120

100

125

15.8

8.7

24. I Bilateral infiltrates

Il.0

14.0

Bilateral infiltrate5

Bilateral infiltrates

Bilateral infiltrates

Bilateral infiltrates

erythrocytes using the Optilyse (Becton Dickinson) pro- cedure and subsequently incubated with the same fluor- escent antibodies as described above for the BAL cells. Lymphocytes were gated by their light scatter characteris- tics and measured for CD3’/CD4’ and CD3’iCDS’ cells. Results are expressed as percentage of total lymphocytes.

STATISTICS

Clinical characteristics, pulmonary function data and BAL cell data are presented as a median and 25th and 15th percentiles. Values for the BAL cell differential are pre- sented as a percentage of total BAL cells and values for lymphocyte subsets as a percentage of total lymphocytes. Differences in the composition of T-cell subsets in BAL and the blood were tested for statistical significance using the Wilcoxon test for paired data.

Results

HIGH PULMONARY DISEASE ACTIVITY

The eight patients in the high pulmonary disease activity group also had highly active extrapulmonary disease, prominent constitutional symptoms and markedly elevated acute phase reactants. The median ESR was 110 (90-120) mm h- ‘, the C-reactive protein 14.9 (8,7-24,l) mg dl-’ and the median ANCA titre 1:96

(1:31-l :256). Sinusitis and glomerulonephritis were more common than eye: heart, central nervous system, peripheral nervous system, skin or joint involvement, resulting in a median DE1 score of 8 (indicative of current involvement of four organ systems) (Table 1). Microbiological studies of blood, BAL fluid and tracheobronchial secretions were invariably negative and rapid clinical and radiological improvement in response to high-dose prednisolone sup- ported the assessment that the lung disease resulted from the underlying vasculitis and not from infection. Further- more, no patient had haemoptysis and in no case was haemorrhagic fluid recovered by BAL, which by all standards ruled out diffuse alveolar haemorrhage. The consistent BAL abnormality in these patients was an eleva- tion of neutrophils to values between 6 and 61% of total BAL cells (Fig. 1). In four patients a borderline elevation of the eosinophils (l-3%) was also seen, but only one patient had a marginally elevated lymphocyte count.

LOW PULMONARY DISEASE ACTIVITY

The 37 patients in the low pulmonary disease activity group had a median DE1 score of 4 (&6), a median erythrocyte sedimentation rate of 32 (18-71) mm h-l, a C-reactive protein of 0.5 (0.4-1.8) mg dl - 1 and an ANCA titer of 1:64 (O-l: 128) which reflected moderate systemic disease activity (Table 2). Twenty-five patients had concurrent disease activity in the upper respiratory tract, 12 had urine

BRONCHOALVEOLAR LAVAGE CELL PROFILES IN WEGENEWS GRANULOMATOSIS 501

(a)

-e l

0

Low High activity activity

WG SARC

(b)

r 30

20

0 Low High LOW

--. . High

activity activity activity activity WG smc WG SAW

60

0

100

80 L

i

l

activity activity WG SARC

FIG. 1. BAL cell profile in Wegener’s granulomatosis (WG) and pulmonary sarcoidosis (SARC). Shaded areas represent the normal range.

abnormalities suggestive of glomerulonephritis, 10 had ous disease and one cutaneous vasculitis. Pulmonary com- peripheral neuropathy, six had ophthalmic disease, six plaints were non-productive cough in 16 patients and arthralgia or arthritis, two heart disease, one central nerv- exertional dyspnoea in seven patients. Nine patients had a

502 A. SCHNABEL ETAL.

TABLE 2. Characteristics of patients with low pulmonary disease activity due to Wegener’s granulomatosis

Women/men (n) Age (years) Duration of disease (months) ESR (mm h-i) C-reactive protein (mg dl - ‘) ANCA titre (reciprocal) Disease extent index Extrapulmonary organ involvement (n)

Ear, nose, throat Kidney Peripheral nervous system Eye Arthralgialarthritis Heart Central nervous system Skin

VCIN (% of predicted) FEV,/ VCIN (%) TLCOcI VA (% of predicted) Arterial PO, (mmHg) Arterial PCO, (mmHG)

17120 62 (49-67) 18 (7-75) 32 (18-71)

0.5 (0.4-18) 64 (O-128) 4 (4-6)

25 12 10 6 6 2 1 1

100 (86-107) 74 (64-82) 99 (85-l 10) 89 (81-98) 36 (34-38)

ANCA: anti-neutrophil cytoplasmic antibodies; VCIN: inspiratory vital capacity; FEV,: forced expiratory volume in 1 set; 7XOcIVA: transfer factor for CO corrected for haemoglobin and alveolar volume.

low-grade restrictive ventilatory defect or impaired CO diffusion capacity but the medians for these parameters were within the normal range. The most prevalent HRCT abnormalities were small nodules, occurring singly or multiply, which were seen in 22 patients [Fig. 2(a)]. Septal or non-septal lines were seen in 20 patients [Fig. 2(a)]. They were focal in distribution and in no case was an extended reticular or honeycombing pattern seen. Focal low- attenuation (ground-glass) opacities were seen in seven patients [Fig. 2(b)]. Twenty-six of these patients had an abnormal BAL cell profile (Fig. 1). The most common abnormality, found in 25 patients, was an elevation of the lymphocytes to a median of 40% (2147%) of the total BAL cells. These patients also had an elevated total cell count in BAL (193 x lo3 cells ml- ‘) which also resulted in an elevated absolute lymphocyte count. Two patients had low-grade elevation of the BAL neutrophils and two patients had low-grade elevation of the eosinophils.

IMMUNOTYPING OF BAL AND BLOOD LYMPHOCYTES

Immunotyping was performed in the 25 low disease activity patients with a lymphocytic BAL profile. A median of 92% (85-94%) of the BAL lymphocytes were CD3’ T cells compared with 75% (68-82%) in the blood (Fig. 3, Table 3). In the BAL a median 69% of (58-78%) lymphocytes were CD4+ and 19% (ll-29%) were CD8+; corresponding values in the blood were 44% (33-50%) CD4’ cells and 3 1%

FIG. 2. High-resolution computed tomography in Wegener’s granulomatosis with low pulmonary disease activity. (a) Subcarinal section showing septal and non- septal lines, a nodular lesion and pleural irregularities. (b) Subcarinal section showing focal low-attenuation opacities in the upper lobes.

(21-340/b) CDS+ cells. This resulted in a CD4/CD8 ratio of 4.1 (2.0-5.8) in BAL, which was significantly higher than the ratio of 1.4 (1.1-2.1) in the blood (P<O.OOl). The WG patients had the compartmentalized elevation of the CD4+ cells in the lung in common with the sarcoidosis patients (Table 3). In the latter patients 82% (65-89%) of the BAL lymphocytes were CD4+ and 7% (6-18%) were CD&+. Corresponding values in the blood were 45% (42-57%) CD4’ cells and 20% (18-28) CD8’ cells; the CD4/CD8 ratios were 12.6 (5.0-15.3) in BAL and 2.2 (1.5-2.3) in blood (P=O.O03).

HISTOPATHOLOGY

TBB in the 37 patients in the low pulmonary disease activity group gave adequate material in 32 patients. The most common findings were mononuclear cell infiltrates of low or moderate density mainly consisting of lymphoid cells, while histiocytes were less common, Neutrophils and eosinophils were seen only occasionally (Table 4). Only five

BRONCHOALVEOLAR LAVAGE CELL PROFILES IN WEGENEWS GRANULOMATOSIS 503

100 -

80 -

s 60 [II 1 8 + m

8 40 -

20 -

80 -

8 60- *

3 u +x2 e

40 -

20 -

O-

WG smc

WG SARC WG SARC

100

80

20

0 -

0

WG SAFtC

12

1

0 24 0 22 0

0 0

0.

31

0 0 0

0

0

0

0 0

0% t 0

FIG. 3. T cells and T-cell subsets in BAL in Wegener’s granulomatosis (WG) and pulmonary sarcoidosis (SARC) Shaded areas represent the normal range.

504 A. SCHNABEL ET AL.

TABLE 3. Lymphocyte subsets in Wegener’s granulomatosis with elevated BAL lymphocytes and in pulmonary sarcoidosis. Values represent percentage of the total BAL lymphocytes

BAL Blood BAL vs blood

Wegener’s granulomatosis (n =25) CD3’ CD4’ CD8+ CD4/CD8

Sarcoidosis (n = 11) CD3 + CD4’ CD8’ CD41CD8

92 (85-94) 69 (58-78) 19 (11-29)

4.1 (2.0-5.8)

95 (82-96) 82 (65-89)

7 (6-18) 12.6 (5.0-15.3)

75 (68-82) 44 (33-50) 31 (21-34)

I.4 (1.1-2.1)

72 (66-78) 45 (42-57) 20 (18-28)

2.2 (1.5-2.3)

P<O.OOl P<O.OOl P=O.O14 P<O.OOl

P=O.O04 P=O.O03 P=O.O05 P=O.O03

patients had granulomatous lesions and three patients had scattered giant cells.

Discussion

This study demonstrates that pulmonary disease due to WG can be associated with two disparate BAL cell patterns. Patients with high pulmonary disease activity, characterized by extensive infiltrates in the CXR in the presence of high systemic disease activity, invariably had elevated BAL neutrophils, whereas patients with low pul- monary disease activity and mainly interstitial or nodular changes in the HRCT had elevated BAL lymphocytes or a normal cell profile. The lymphocytic BAL cell profile in the latter condition correlated with tissue infiltration by mainly mononuclear cells and a granulomatous histopathology. Immunotyping of the lymphocytes in these patients dis- closed a preferential elevation of the CD4’ cells in BAL which was not reflected in the blood.

The finding of a neutrophilic BAL cell pattern in patients with high pulmonary disease activity agrees with a previous study which reported this finding in six WC patients with highly active multi-system disease (10). In another study of 14 WG patients, a predominantly granulocytic pattern was found in association with high disease activity, while the proportion of neutrophils and lymphocytes were variable in the patients with moderate disease activity (11). In a

TABLE 4. Inflammatory cells in transbronchial biopsies in low pulmonary disease activity due to WG (n=33). Num- bers of patients showing tissue infiltration with specific cell types are shown

Mononuclear cells Lymphoid cells Histiocytes

Scattered giant cells Granuloma Granulocytes No inflammatory cells

27 (82%) 25 (76%) 20 (61%)

3 (9%) 5 (15%) 3 (9%) 5 (15%)

nationwide collection of WG patients in France, granulo- cyte elevation in BAL also prevailed over lymphocyte elevation but these results were not formally related to clinical or roentgenological findings (2). Of these three studies only that of Barth et al. (11) included a sizable proportion of patients with elevated BAL lymphocytes and these patients had mainly moderate to severe disease.

To substantiate the impression that a lymphocytic BAL cell pattern is a reflection of low or moderate pulmonary disease activity, we recruited a group of patients character- ized by a normal CXR but with HRCT findings indicating low-grade, mainly interstitial disease due to WG (7-9). HRCT abnormalities included small nodules, septal and non-septal lines and focal low-attenuation opacities. Pul- monary function was generally normal in these patients; only a minority had marginally depressed values for vital capacity and CO diffusion capacity. TBB confirmed the presence of low-grade inflammatory infiltration in the majority of these patients. In contrast to the findings in high pulmonary disease activity, the most common BAL abnor- mality in low disease activity was an elevated lymphocyte count.

The existence of disparate BAL patterns in WG becomes plausible when these patterns are related to the documented histopathology of this disorder. In highly active or ‘fulmi- nant’ lesions the infiltrate is dominated by neutrophils which pervade the alveolar septa and accumulate in the alveoli (4,6). Infiltration mainly by neutrophils is also seen in the capillaritis underlying diffuse alveolar haemorrhage, which is a particularly severe form of pulmonary vasculitis (6,19). In contrast, mononuclear cells generally dominate the tissue infiltrate of subacute WG (4-6). Both the char- acteristic necrotizing granuloma and the septal infiltrate in the surroundings of granulomas are composed mainly of histiocytes and lymphocytic cells, with a variable admixture of multinucleate giant cells but few neutrophils (5,6,20). The latter features were also found in the low pul- monary disease activity group in this study. Obviously the lymphocytic BAL pattern in these patients reflects the predominance of mononuclear cells in the tissue.

The preferential elevation of CD4’ cells in WG patients with a lymphocytic BAL cell profile is as yet unreported.

BRONCHOALVEOLAR LAVAGE CELL PROFILES IN WEGENER’S GRANULOMATOSIS 505

Immunohistological studies of the composition of the lym- phocytic infiltrate in respiratory tract lesions in WG appear to be limited to a case report and a series of upper respiratory tract biopsies. An open lung biopsy specimen from a WG patient showed infiltration by lymphocytes and giant cells (21). The lymphocytes were mainly CD3’ T cells, with a slight preponderance of CD4’ over CD8+ cells. Rasmussen et al. found a mixed infiltrate consisting of macrophages, lymphocytes and granulocytes in upper res- piratory tract biopsies from seven WG patients (22). The lymphocytes were mainly CD2’ and CD3’ T cells, with CD4+ cells exceeding CD8+ cells in five of the seven cases. These few data leave it unclear whether the unbalanced CD4’ cell elevation in BAL reflects the distribution of the T-cell subsets in the tissue. Unfortunately, the present study does not resolve this question as the number of lymphocytes in the TBB specimens of these patients was too low to allow a meaningful assessment of T-cell subsets.

The preferential elevation of the CD4’ cells in BAL in the presence of a normal CD41CD8 ratio in the blood appears to be a common feature of WG patients with low-grade pulmonary disease and patients with pulmonary sarcoidosis (23). In sarcoidosis, which is also a chronic inflammatory disease with a proclivity for lung involve- ment, the pulmonary CD4+ cells are thought to be inti- mately involved in the pathogenesis of the granulomatous disease by receiving stimulatory signals from activated macrophages and by secreting a THl pattern of cytokines, which enhances the activational state of the macrophages (24,25). A recent study of blood cells suggested that a disordered interaction between T cells and circulating monocytes is also involved in WG and that this includes secretion of a THl type pattern of cytokines from activated CD4’ but not CD8’ cells (26). In addition to these findings, one might speculate that the expanded pulmonary CD4’ cell component plays a similar role in WG as in sarcoidosis, but this needs to be substantiated by functional studies.

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