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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.

Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis. High vascular resistance in PAH arises from an imbalance between vasodilatory mediators (prostacyclin, NO) and vasoconstrictive mediators (endothelin, thromboxane A-2). Inhaled iloprost and the dual endothelin receptor antagonist bosentan have recently been shown to be effective in controlled clinical trials. Our case report demonstrates that patients with bosentan-refractory PAH can be successfully treated with iloprost inhalation.

To determine the prevalence, target antigens and clinical associations of antineutrophil cytoplasmic antibodies (ANCA) in chronic hepatitis C without extrahepatic manifestations and in chronic hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) in two European centers.50 sera from patients with chronic hepatitis C and 116 sera from HCV-associated MC were tested for cytoplasmic or perinuclear pattern (C-ANCA/P-ANCA) by indirect immunofluorescence test (IFT). ANCA target antigens were determined by enzyme-linked immunosorbent assay (ELISA).Clinical characteristics of the patients were not different between the two centers. Cryoglobulinemic vasculitis (CV) was biopsy-proven in about 90% of the MC patients. Two patients with HCV-associated MC and 1 patient with chronic hepatitis C had a P-ANCA. A C-ANCA was detected in 1 patient with HCV-associated MC. Eight patients with a HCV-associated MC and 5 patients with chronic hepatitis C had an ANCA either directed against bactericidal/permeability increasing protein (BPI) or cathepsin G (CG). BPI- or CG-ANCA positivity was not associated with a more severe disease course. The C-ANCA titer followed disease activity in one C-ANCA positive HCV-associated MC patient. The subspecificity of the C-ANCA was not determinable in that patient.Two new target antigens of ANCA have been identified in HCV-associated MC and chronic hepatitis C in this study. BPI-ANCA and GC-ANCA were present in about 10% of patients with HCV-associated MC or chronic hepatitis C. ELISA proved to be more sensitive in the detection of ANCA than IFT. The present study on chronic HCV infection adds to various reports on the induction of CG- and BPI-ANCA in chronic infections.

Wegener's granulomatosis (WG) is characterized by granulomatous inflammation and systemic vasculitis with a predilection for the lungs and kidneys. In most patients WG begins with a localized organ involvement of the upper respiratory tract that progresses to systemic disease (generalized WG) (1). Because of the life-threatening nature of systemic vasculitis, much effort has concentrated on elucidating the pathogenesis of the vasculitis. However, based upon a renewed interest in (innate) immune defenses against microbes, a better understanding of the chronic granulomatous inflammation may contribute to a more precise insight into the early genesis of WG. Thus, this review focuses on summarizing and discussing data for a potential pattern of disease, i.e. from localized to generalized WG with a special emphasis on granulomatous lesions of the upper respiratory tract and their alterations during the disease course.

Vasculitides are a heterogeneous group of inflammatory disorders of the blood vessels. The etiology and pathogenesis of vasculitides is incompletely understood, and the nomenclature and classification of vasculitides remains a challenge. A number of vasculitides were not included in the Chapel Hill Consensus (CHC) Conference definitions, thus, have remained 'unclassified', but may be included in a revised version of the nomenclature, e.g. Goodpasture's syndrome. In other cases the term 'unclassified' implies 'unclassifiable', i.e. a vasculitis cannot be assigned to any of the known entities. Vasculitis-induced acral necrosis including giant cell arteritis of small arteries as well as isolated forms of intestinal vasculitis including granulomatous giant cell polyphlebitis may belong to this category of rare 'unclassified' vasculitides. In some entities the relationship between vasculitis and other manifestations remains unclear, e.g. in Behçet's disease and IgG4-related systemic disease. In this review the clinical and pathological aspects of 'unclassified' vasculitides are briefly discussed.

Introduction In granulomatosis with polyangiitis (GPA), a complex autoimmune small-vessel vasculitis frequently associated with chronic necrotizing inflammation of the nasal mucosa, elevated nasal Staphylococcus (S.) aureus carrier rates are a risk factor for relapse. As cytokines are primarily involved in the regulation of defense against potentially pathogenic microorganisms, the aim of this study was to compare healthy individuals and GPA patients with respect to their baseline cytokine expression of nasal epithelial cells (NEC), which form the first barrier against such triggers. The ability of S. aureus to influence the nasal microenvironment's cytokine secretion was assessed by exemplary stimulation experiments. Methods Baseline expression of 19 cytokines of primary NEC of GPA patients and normal controls (NC) was quantified by a multiplex cytokine assay. Stimulation experiments were performed with supernatants of S. aureus and expression of interleukin-8 was determined by ELISA. Results In GPA, an altered pattern of baseline cytokine expression with significantly up-regulated G-CSF and reduced interleukin (IL)-8 concentrations was observed. Both NEC of GPA patients and NC responded to stimulation with S. aureus, but GPA patients displayed a significantly lower IL-8 secretion and a diminished dynamic range of response towards the stimulus. Conclusions The data presented underline the hypothesis of a disturbed epithelial nasal barrier function in GPA. The dysregulated baseline expression of G-CSF and IL-8 and the reduced response to microbial stimulation may facilitate changes in the composition of the nasal flora and favour an imbalanced inflammatory response, which might be relevant for the disease course.