A. R. Exley

Disease assessment and management of the vasculitides.

The improvement in survival with chemotherapy has resulted in a change of the natural history of the systemic vasculitic syndromes. The vasculitides are now viewed as chronic disease rather than fatal conditions. Their course is frequently characterized by relapse as well as the scars of irreversible organ damage from disease and drug toxicity. Assessment tools are available which can serve as outcome measures in clinical trials as well as a guide to better management of individual patients. Improvements in therapy in future are dependent on a better understanding of the pathogenesis of these conditions and the ability to assess disease accurately.

A case of primary immunodeficiency due to a defect of the major histocompatibility gene complex class I processing and presentation pathway

INTRODUCTION We report a case of primary immunodeficiency due to a defect of the TAP transporter, an heterodimeric complex which controls the expression of HLA class I molecule by delivering peptides from the cytosol into the lumen of the endoplasmic reticulum. Since childhood, the 36 year old female suffered from recurrent sinusitis/bronchitis. She later developed bronchiectasis and destructive nasal epitheloid granulomata in conjunction with a generalized vasculitic syndrome that did not improve upon immunosuppression and antibiotics. METHODS The class I monomorphic W6/32 was used for cell surface staining and immunoprecipitation of MHC class I molecules. Peptide transport assay was carried out in semi-permeabilized cells with iodinated peptides. Antigen presentation experiments were performed using chromium 51 labelled patient B cell line and EBV specific CTL. TAP1 and TAP2 specific antibodies were used for Western blotting and immunoprecipitation of the TAP complex. RESULTS AND CONCLUSIONS A severe reduction of MHC class I molecules at the cell surface of the B-cell lines was observed, whereas MHC class II expression was not altered. Isoelectric focusing of metabolically labelled MHC class I molecules revealed that class I heavy chains remain unsialylated, consistent with a block of TAP dependent peptide translocation. These conclusions were confirmed by further experiments showing that peptide translocation was completely abolished. We also demonstrated that presentation of viral antigens through endogenous class I molecules was severely impaired. Immunoprecipitation and Western blotting of TAP1/2 complex showed that TAP2 was not detectable. Further, experiments are in progress to identify the site of the mutation.

Localized bowel vasculitis: Postoperative cyclophosphamide or not?

We describe 2 patients with necrotizing vasculitis localized to the bowel, who were treated by excision of the involved tissue. Postoperatively, there was no evidence of active vasculitis, and both patients remain in remission on followup, without the use of immunosuppressive treatment. Evidence that an abnormal local microenvironment is necessary to sustain chronic inflammation may explain why surgical excision can be an important tool in the treatment of vasculitis.

Clinical disease activity in systemic vasculitis

Long-term follow-up data indicate that the systemic vasculitides are chronic relapsing diseases with high morbidity. It is therefore of paramount importance to distinguish activity, which requires cytotoxic or immunosuppressive therapy, from damage requiring rehabilitation. Damage due to underlying disease or treatment highlights the need for more effective, less toxic treatment regimens. An integrated package for clinically based assessment of disease activity in systemic vasculitis, the Vasculitis Integrated Assessment Log, has been accepted for further evaluation and implementation by the European Community Study Group for use in therapeutic trials. The added value of serologic tests and inflammatory markers in clinical assessment is becoming more clear, and unsuspected disease activity has been revealed by biopsy and imaging of standard sites or affected areas. Integration of these data should enable characterization of high- and low-risk patient subgroups to determine specific therapies.