Staphylococcus aureus and Wegener's granulomatosis

Wegener's granulomatosis (WG) is a form of systemic vasculitis. It is characterized by granulomatous inflammation in the upper and lower airways, vasculitis and necrotizing glomerulonephritis, and is strongly associated with antineutrophil cytoplasmic antibodies against proteinase 3. Since the etiology of the disease is not clear, treatment, consisting of corticosteroids and immunosuppressives, is nonspecific and associated with severe side effects. Pinpointing the trigger(s) of the disease would highly improve treatment. Clinical evidence shows that an infectious agent, the bacterium Staphylococcus aureus, is a risk factor for disease relapse, suggesting its involvement in the pathogenesis of WG. Here we review both clinical and experimental data that either indicate or support a role for S. aureus in WG.     

Staphylococcus aureus and Wegener's granulomatosis

Wegener's granulomatosis (WG) is a form of systemic vasculitis. It is characterized by granulomatous inflammation in the upper and lower airways, vasculitis and necrotizing glomerulonephritis, and is strongly associated with antineutrophil cytoplasmic antibodies against proteinase 3. Since the etiology of the disease is not clear, treatment, consisting of corticosteroids and immunosuppressives, is nonspecific and associated with severe side effects. Pinpointing the trigger(s) of the disease would highly improve treatment. Clinical evidence shows that an infectious agent, the bacterium Staphylococcus aureus, is a risk factor for disease relapse, suggesting its involvement in the pathogenesis of WG. Here we review both clinical and experimental data that either indicate or support a role for S. aureus in WG.     

Proteinase-3 as the major autoantigen of c-ANCA is strongly expressed in lung tissue of patients with Wegener's granulomatosis

Proteinase-3 (PR-3) is a neutral serine proteinase present in azurophil granules of human polymorphonuclear leukocytes and serves as the major target antigen of antineutrophil cytoplasmic antibodies with a cytoplasmic staining pattern (c-ANCA) in Wegener's granulomatosis (WG). The WG disease appears as severe vasculitis in different organs (e.g. kidney, nose and lung). Little is known about the expression and distribution of PR-3 in the lung. We found that PR-3 is expressed in normal lung tissue and is upregulated in lung tissue of patients with WG. Interestingly, the parenchymal cells (pneumocytes type I and II) and macrophages, and not the neutrophils, express PR-3 most strongly and may contribute to lung damage in patients with WG via direct interaction with antineutrophil cytoplasmic antobodies (ANCA). These findings suggest that the PR-3 expression in parenchymal cells of lung tissue could be at least one missing link in the etiopathogenesis of pulmonary pathology in ANCA-associated disease.     

Proteinase-3 as the major autoantigen of c-ANCA is strongly expressed in lung tissue of patients with Wegener's granulomatosis

Proteinase-3 (PR-3) is a neutral serine proteinase present in azurophil granules of human polymorphonuclear leukocytes and serves as the major target antigen of antineutrophil cytoplasmic antibodies with a cytoplasmic staining pattern (c-ANCA) in Wegener's granulomatosis (WG). The WG disease appears as severe vasculitis in different organs (e.g. kidney, nose and lung). Little is known about the expression and distribution of PR-3 in the lung. We found that PR-3 is expressed in normal lung tissue and is upregulated in lung tissue of patients with WG. Interestingly, the parenchymal cells (pneumocytes type I and II) and macrophages, and not the neutrophils, express PR-3 most strongly and may contribute to lung damage in patients with WG via direct interaction with antineutrophil cytoplasmic antobodies (ANCA). These findings suggest that the PR-3 expression in parenchymal cells of lung tissue could be at least one missing link in the etiopathogenesis of pulmonary pathology in ANCA-associated disease.     

Alterations in the phenotype of CMV-specific and total CD8+ T-cell populations in Wegener's granulomatosis

Wegener's granulomatosis (WG) is an autoimmune disease of as yet unknown etiology. To date it has remained obscure what causes WG or determines disease progression. Case reports suggest that viral infections such as cytomegalovirus (CMV) reactivation may contribute to disease flares. In this study we found a skewing of the phenotype of CMV-specific CD8+tet(ramer)+ T-cells in WG. A marked proportion of these cells displayed a late differentiated "effector memory" T-cell phenotype with decreased expression of CD28 and CD62L, and heterogeneous CD27 expression, features which were also seen in CD8+tet- T-cells in WG, but not in controls. Our results might reflect profound generalized changes in the CD8+ T-cell compartment also affecting virus-specific T-cell responses in WG.     

Wegener's granulomatosis: clinico-radiological finding at initial presentation

Diagnosis of Wegener's granulomatosis at the early stage is difficult because of the nonspecific symptoms which mimic other disorders. The aim of this paper is to describe clinical and radiological features of Wegener's granulomatosis (WG) in a Serbian population at initial presentation. A retrospective review of 37 patient's case records was carried out. All those patients were diagnosed with WG and they attended the Institute for lung diseases in Belgrade over the period of 15 years. There were 20 males and 17 females, ranging in age from 18 to 73 years (mean age 46.2 years). The mean period from the onset of the first symptoms to diagnosis of WG was 4.59 +/- 6.15 months. The criteria of American College of Rheumatology were fulfilled in all patients. Twenty-five of 37 patients had systemic, generalized form of WG and while 12 of them had a limited involvement of upper and lower respiratory system. The frequency of different system involvement was: upper respiratory tract 64.8%, lower respiratory tract 100%, kidneys 67.5%, musculoskeletal system 40.5%, skin 27.2%, eyes 8.1%, and nervous system two patients. ANCA (antineutrophil cytoplasmic antibodies) test was positive in 32 ((86.5%) patients, and negative in 5 (13.5%). All patients were ANA negative. Histological evidence of granulomatous vasculitis was obtained in 34 (91.9%), whereas in three patients the diagnosis was based on clinical manifestations and positive c-ANCA test. There are minor variations in our data when compared with those reported in literature.     

Atypical squamous cells as a diagnostic pitfall in pulmonary Wegener's granulomatosis. A case report

BACKGROUND: Wegener's granulomatosis (WG) is characterized by systemic, necrotizing, granulomatous inflammation accompanied by vasculitis. It classically involves the triad of the upper respiratory tract, lungs and kidneys. Isolated pulmonary lesions of WG may present in some patients as pulmonary masses, simulating neoplasms. The features of WG can be suggested by cytologic study. Atypical epithelial cells associated with WG have previously been reported as a cause of a false positive diagnosis of bronchoalveolar carcinoma. CASE: In this case the cytologic findings included atypical squamous cells in a background of acute, chronic and granulomatous inflammation. In several respiratory specimens the atypical squamous cells were incorrectly interpreted as diagnostic of squamous cell carcinoma. The correct diagnosis of WG was confirmed with open lung biopsy, which demonstrated necrotizing granulomatous inflammation with geographic necrosis and associated vasculitis. CONCLUSION: Markedly atypical squamous cells mimicking squamous cell carcinoma can be found accompanying the inflammatory process associated with WG and are a possible diagnostic pitfall. The possibility of WG as well as other inflammatory processes should always be considered in the differential diagnosis of squamous cell carcinoma of the lung. This case is the only reported case of WG in which atypical squamous cells were a diagnostic pitfall, initially suggesting a diagnosis of squamous cell carcinoma.     

Differential glycosylation of polyclonal IgG, IgG-Fc and IgG-Fab isolated from the sera of patients with ANCA-associated systemic vasculitis

Post-translational modifications (PTMs) of proteins produced in vivo may be tissue, developmentally and/or disease specific. PTMs impact on the stability and function of proteins and offer a challenge to the commercial production of protein biotherapeutics. We have previously reported a marked deficit in galactosylation of oligosaccharides released from polyclonal IgG isolated from sera of patients with the anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitides; Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA). Whilst normal polyclonal IgG molecules are glycosylated within the IgG-Fc region, approximately 20% of molecules also bear oligosaccharides attached to the variable regions of the light or heavy chain IgG-Fab. It is of interest, therefore to compare profiles of oligosaccharides released from the IgG-Fc and IgG-Fab of normal IgG with that isolated from the sera of patients with WG or MPA. This study shows that whilst the oligosaccharides released from ANCA IgG-Fc are hypogalactosylated those released from IgG-Fab are galactosylated and sialylated. These results show that hypogalactosylation of IgG-Fc is not due to a defect in the glycosylation or processing machinery. It rather suggests a subtle change in IgG-Fc conformation that influences the addition of galactose. Remarkably, this influence is exerted on all plasma cells. Interestingly, a licensed monoclonal antibody therapeutic, produced in Sp2/0 cells, is also shown to be hypogalactosylated in its IgG-Fc but fully galactosylated in its IgG-Fab.     

Pitfalls in the diagnosis of Wegener''s granulomatosis on fine needle aspiration cytology

OBJECTIVE: To review the clinical and pathological findings in six suspected cases of Wegener's granulomatosis (WG) and highlight the diagnostic difficulties faced by the cytopathologist. METHODS: Retrospective review of records of the Cytopathology Department to identify patients who underwent image-guided transthoracic pulmonary fine needle aspiration cytology (FNAC) for pulmonary lesions of suspected WG and those who were subsequently confirmed to have WG. Detailed evaluation of cytomorphological features was carried out. RESULTS: A total of six cases were identified in whom the initial procedure to obtain a pathological diagnosis was transthoracic FNAC. In one case, atypical squamous cells on cytology initially suggested a diagnosis of squamous cell carcinoma while in another a diagnosis of WG was made on cytology; however, a subsequent lung biopsy revealed silicosis. CONCLUSION: Acute inflammation and necrosis are the most consistent cytopathological findings in WG. In selected cases FNAC can provide supportive pathological evidence to establish a diagnosis of WG.     

Clinical utility of fine needle aspiration biopsy in the diagnosis of Wegener's granulomatosis. A report of two cases.

In two patients, pulmonary lesions of Wegener's granulomatosis (WG) were sampled by fine needle aspiration biopsy: one with the clinical diagnosis of primary pulmonary malignancy and the other with a clinical suspicion of WG. In the latter case the smears showed distinctive eosinophilic, collagen necrosis (pathergic necrosis), poorly formed granulomata composed of loose aggregates of elongated, often palisading epithelioid histiocytes, and multinucleate histiocytes. A cell block preparation in this case contained minute tissue fragments illustrating the distinctive, pathergic-type necrosis. In the former case, many of these features were present, but additionally there were several groups, atypical bronchial epithelial cells that, in light of the clinical impression, initially led to an incorrect diagnosis of bronchoalveolar carcinoma. Subsequent review of this case led to the diagnosis of WG. Antineutrophil cytoplasmic antibody (ANCA) serology was later obtained, confirming the diagnosis of WG in both cases. In our experience, the cytomorphologic findings of granular collagen necrosis, granulomata and multinucleate cells, although not specific, should alert the cytopathologist to consider the diagnosis of WG, especially when special stains for microorganisms are negative. A recommendation for ANCA serology testing early in the disease process, particularly in the limited forms of the disease, may lead to early recognition of WG, resulting in prompt institution of immunosuppressive therapy, greatly improving the patient's prognosis.     

What you should know about PR3-ANCA: Evidence for the role of T cells in the pathogenesis of systemic vasculitis

The pathogenesis of systemic vasculitis is complex and is likely to involve many mechanisms. There is a growing body of evidence that T cells may contribute to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Predominantly, T cells and monocytes are found in inflammatory infiltrates in patients with Wegener's granulomatosis (WG). The production of ANCA appears to be T-cell-dependent. T lymphocytes from the peripheral blood of patients with ANCA-associated vasculitis have been shown to proliferate in response to proteinase 3 (PR3). These and other findings outlined in this review indicate T-cell involvement, although further studies are still needed to elucidate the exact contribution of T cells to the pathogenesis of systemic vasculitis.     

Transthoracic needle aspiration biopsy in Wegener's granulomatosis. Morphologic findings in five cases

Percutaneous needle aspiration biopsies of the lung from five patients with Wegener's granulomatosis were reviewed. Three of the patients presented with the generalized form of the disease while two presented with the limited pulmonary form; one of the latter subsequently developed disseminated disease. The morphologic findings in the pulmonary aspirates were similar in all cases. The cytologic preparations contained neutrophils entrapped within necrotic debris plus scattered but prominent histiocytic giant cells, which often had nuclei arranged in rings or horseshoes, in a background of lymphocytes, epithelioid histiocytes and reactive pneumocytes. Cell block preparations showed discrete areas of necrosis containing a neutrophilic infiltrate and focally palisaded by epithelioid histiocytes. The intervening viable tissue contained prominent histiocytic giant cells and chronic inflammatory cells enmeshed in a fibrous matrix. One cell block contained a small artery with a small focus of possible granulomatous arteritis. While an open lung biopsy is generally required for a definitive diagnosis, the pathologist may encounter unsuspected Wegener's granulomatosis in a needle aspirate. Recognition of the findings observed in these cases should alert the pathologist to the possibility of Wegener's granulomatosis so that an open lung biopsy can be performed if clinically indicated and cytotoxic therapy can be promptly instituted if the diagnosis of this entity is confirmed.     

What you should know about PR3-ANCA. Evidence for the role of T cells in the pathogenesis of systemic vasculitis

The pathogenesis of systemic vasculitis is complex and is likely to involve many mechanisms. There is a growing body of evidence that T cells may contribute to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Predominantly, T cells and monocytes are found in inflammatory infiltrates in patients with Wegener's granulomatosis (WG). The production of ANCA appears to be T-cell-dependent. T lymphocytes from the peripheral blood of patients with ANCA-associated vasculitis have been shown to proliferate in response to proteinase 3 (PR3). These and other findings outlined in this review indicate T-cell involvement, although further studies are still needed to elucidate the exact contribution of T cells to the pathogenesis of systemic vasculitis.     

Wegener's granulomatosis: current and upcoming therapies

Wegener's granulomatosis is a complex multisystem disease that can be associated with morbidity and mortality. The introduction of cyclophosphamide and glucocorticoids brought about the potential for long-term survival and provided the opportunity and impetus to explore treatment options that can reduce the toxicity of therapy and lessen the likelihood of relapse. With the growth of knowledge regarding disease pathophysiology and the increasing ability to selectively target the immune system, the potential options for therapeutic investigation have continued to expand. Careful study of new agents through rigorously designed trials is essential to answering questions of safety and efficacy in Wegener's granulomatosis.     

Antineutrophil cytoplasmic autoantibodies in Wegener's granulomatosis recognize conformational epitope(s) on proteinase 3.

Although proteinase 3 (PR3) has been identified as a major autoantigen in Wegener's granulomatosis, the precise antibody specificity(ies) and requirements for epitope recognition have not been characterized. We analyzed 11 sera containing antineutrophil cytoplasmic antibodies (cANCA) for binding to azurophilic granule proteins extracted from neutrophils under various conditions and for binding to native or rPR3. Ten of 11 (91%) of the cANCA sera bound to PR3 extracted by nonionic detergents when tested by immunoprecipitation or by IEF followed by capillary immunoblotting. Antibody binding to PR3 was retained when IEF was performed under dissociating conditions (8 M urea) indicating that PR3 is the major autoantigen in azurophilic granules and that association with other proteins is not required for antigenicity. In contrast, antigenicity was totally destroyed by exposure of PR3 to reducing agents or to low pH (less than 3.0) and was either lost or considerably diminished after boiling in SDS. cANCA sera also showed little or no binding to rPR3 expressed as a fusion protein in Escherichia coli or synthesized by wheat germ ribosomes in vitro. Inasmuch as PR3 enzymatic activity was partially retained after acid extraction, these findings indicate that cANCA bind to a limited number of conformational epitopes on PR3. In addition, IEF followed by capillary immunoblotting appears to be a sensitive and specific method to detect anti-PR3 antibodies in Wegener's granulomatosis.     

The protein tyrosine phosphatase nonreceptor 22 C1858T polymorphism and vasculitis: a meta-analysis

The aim of this study was to determine whether the functional protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism (rs2476601) confers susceptibility to vasculitis. A meta-analysis was conducted on the PTPN22 C1858T polymorphism across nine comparative studies containing 1,922 vasculitis patients and 11,505 normal control subjects. Meta-analysis showed no association between the T allele and vasculitis in all subjects [odds ratio (OR) 1.046, 95 % confidence interval (CI) 0.755-1.1.451, p = 0.786], and analysis after stratification by ethnicity indicated that the T allele was not associated with vasculitis in Europeans (OR 1.104, 95 % CI 0.798-1.528, p = 0.551). However, meta-analysis showed a significant association between the T allele and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) (OR 1.415, 95 % CI 1.228-1.630, p = 1.59 × 10(-6)) and Wegener's granulomatosis (WG) (OR 1.829, 95 % CI 1.377-2.431, p = 3.09 × 10(-5)). In addition, meta-analysis showed an association between the T allele and WG in ANCA-positive subjects (OR 2.042, 95 % CI 1.534-2.719, p = 1.02 × 10(-6)), but not in ANCA-negative WG patients (OR 0.595, 95 % CI 0.199-1.781, p = 0.353). This meta-analysis does not show that the PTPN22 C1858T polymorphism is associated with vasculitis susceptibility, but does show that this polymorphism is associated with susceptibility to AAV, WG, and ANCA status in WG.     

Interaction of antibodies to proteinase 3 (classic anti-neutrophil cytoplasmic antibody) with human renal tubular epithelial cells: impact on signaling events and inflammatory mediator generation

Among the anti-neutrophil cytoplasmic Abs (ANCA), those targeting proteinase 3 (PR3) have a high sensitivity and specificity for Wegener's granulomatosis (WG). A pathogenetic role for these autoantibodies has been proposed due to their capacity of activating neutrophils in vitro. Recently, PR3 was also detected in human renal tubular epithelial cells (TEC). In the present study, the effect of murine monoclonal anti-PR3 Abs (anti-PR3) and purified c-ANCA targeting PR3 from WG serum on isolated human renal tubular cell signaling and inflammatory mediator release was characterized. Priming of TEC with TNF-alpha resulted in surface expression of PR3, as quantified in immunofluorescence studies and by flow cytometry. Moreover, PR3 was immunoprecipitated on surface-labeled TEC. Primed TEC responded to anti-PR3 with a dose- and time-dependent activation of phosphoinositide hydrolysis, resulting in a remarkable accumulation of inositolphosphates. Control IgG was entirely ineffective, whereas PR3-ANCA reproduced the phosphoinositide response. The signaling response was accompanied by a pronounced release of superoxidanion into the cell supernatant. Moreover, large amounts of PGE(2) and, to a lesser extent, of thromboxane B(2), the stable metabolite of TxA(2), were secreted from anti-PR3-stimulated TEC. In parallel, a rise in intracellular cAMP levels was observed, which was blocked by the cyclooxygenase inhibitor indomethacin. We conclude that anti-PR3 Abs directly target renal TECs, thereby provoking pronounced activation of the phosphoinositide-related signal transduction pathway. Associated metabolic events such as the release of reactive oxygen species and lipid mediators may directly contribute to the development of renal lesions and loss of kidney function in WG.     

Alpha-actinin-binding antibodies in relation to systemic lupus erythematosus and lupus nephritis

This study investigated the overall clinical impact of anti-α-actinin antibodies in patients with pre-selected autoimmune diseases and in a random group of anti-nuclear antibody (ANA)-positive individuals. The relation of anti-α-actinin antibodies with lupus nephritis and anti-double-stranded DNA (anti-dsDNA) antibodies represented a particular focus for the study. Using a cross-sectional design, the presence of antibodies to α-actinin was studied in selected groups, classified according to the relevant American College of Rheumatology classification criteria for systemic lupus erythematosus (SLE) (n = 99), rheumatoid arthritis (RA) (n = 68), Wegener's granulomatosis (WG) (n = 85), and fibromyalgia (FM) (n = 29), and in a random group of ANA-positive individuals (n = 142). Renal disease was defined as (increased) proteinuria with haematuria or presence of cellular casts. Sera from SLE, RA, and Sj?gren's syndrome (SS) patients had significantly higher levels of anti-α-actinin antibodies than the other patient groups. Using the geometric mean (± 2 standard deviations) in FM patients as the upper cutoff, 20% of SLE patients, 12% of RA patients, 4% of SS patients, and none of the WG patients were positive for anti-α-actinin antibodies. Within the SLE cohort, anti-α-actinin antibody levels were higher in patients with renal flares (p = 0.02) and correlated independently with anti-dsDNA antibody levels by enzyme-linked immunosorbent assay (p < 0.007) but not with other disease features. In the random ANA group, 14 individuals had anti-α-actinin antibodies. Of these, 36% had SLE, while 64% suffered from other, mostly autoimmune, disorders. Antibodies binding to α-actinin were detected in 20% of SLE patients but were not specific for SLE. They correlate with anti-dsDNA antibody levels, implying in vitro cross-reactivity of anti-dsDNA antibodies, which may explain the observed association with renal disease in SLE.     

Serum soluble IL-2 receptor as a marker of lymphocyte activation in some autoimmune diseases. Effect of immunosuppressive therapy

Our experience regarding serum soluble interleukin-2 receptor (sIL-2R) measurement as a marker of lymphocyte activation consists of patients with autoimmune disease: 37 with systemic lupus erythematosus (SLE), 23 with autoimmune hepatitis (AIH), 74 with inflammatory bowel disease and six with Wegener's granulomatosis (WG). The influence of immunosuppressive therapy has also been assessed. Serum sIL-2R in SLE is significantly higher than in healthy controls and good correlation is found between sIL-2R and disease activity. Severity of kidney inflammation in lupus nephritis can be reflected by the increased excretion of sIL-2R. It was found that sIL-2R level significantly falls when the disease becomes clinically inactive after immunosuppressive therapy, but in many cases (up to 50%) it does not reach normal levels. The last finding suggests that lymphocyte activation may still be present even though the disease is considered inactive under clinical criteria and support the need of prolonged immunosuppression after the first signs of remission. In AIH the serum levels of sIL-2R are elevated in all patients with active disease; all cases with "highly active" disease have significantly higher concentrations than patients with "mild activity". A good correlation has been demonstrated between elevated serum sIL-2R values and anti-asialoglycoprotein receptor (ASGPR) titer (the specific marker of AIH). The follow-up study showed a significant decrease of both sIL-2R levels and anti-ASGPR titer after 3-9 month immunosuppressive therapy. The findings support that sIL-2R and anti-ASGPR titer could serve as reliable humoral markers for disease-specific activity. Compared with inactive ulcerative colitis (UC) and Crohn's disease (CD), significantly higher levels of sIL-2R were present in the serum of patients with active disease, and in inactive disease than in healthy age-matched controls. Methotrexate (MTX) therapy of patients with refractory UC resulted in sIL-2R decrease at the end of therapeutic period (20 i.m. injections of once a week 25 mg), good responders showing > 50% decrease even at 5-7 weeks of treatment. Serum sIL-2R is elevated in all six patients with WG. Contrary to anti-neutrophil cytoplasmic antibodies (ANCA), sIL-2R remains elevated above cut-off for normal range, despite clinical improvement following immunosuppressive treatment. The last observation suggests that serum sIL-2R is not a good measure of the disease activity and argue for the need of longer immunosuppressive therapy just after the first days of clinical remission.     

Heterogeneity of CD4 and CD8+ memory T cells in localized and generalized Wegener's granulomatosis

Memory T cells display phenotypic heterogeneity. Surface antigens previously regarded as exclusive markers of naive T cells, such as L-selectin (CD62L), can also be detected on some memory T cells. Moreover, a fraction of CD45RO+ (positive for the short human isoform of CD45) memory T cells reverts to the CD45RA+ (positive for the long human isoform of CD45) phenotype. We analyzed patients with biopsy-proven localized Wegener's granulomatosis (WG) (n = 5), generalized WG (n = 16) and age- and sex-matched healthy controls (n = 13) to further characterize memory T cells in WG. The cell-surface expression of CD45RO, CD45RA, CD62L, CCR3, CCR5 and CXCR3 was determined on blood-derived T cells by four-color flow cytometric analysis. The fractions of CCR5+ and CCR3+ cells within the CD4+CD45RO+ and CD8+CD45RO+ memory T cell populations were significantly expanded in localized and generalized WG. The mean percentage of Th1-type CCR5 expression was higher in localized WG. Upregulated CCR5 and CCR3 expression could also be detected on a fraction of CD45RA+ T cells. CD62L expression was seen on approximately half of the memory T cell populations expressing chemokine receptors. This study demonstrates for the first time that expression of the inducible inflammatory chemokine receptors CCR5 and CCR3 on CD45RO+ memory T cells, as well as on CD45RA+ T cells ('revertants'), contributes to phenotypic heterogeneity in an autoimmune disease, namely WG. Upregulated CCR5 and CCR3 expression suggests that the cells belong to the effector memory T cell population. CCR5 and CCR3 expression on CD4+ and CD8+ memory T cells indicates a potential to respond to chemotactic gradients and might be important in T cell migration contributing to granuloma formation and vasculitis in WG.