T cells in ANCA-associated vasculitis: what can we learn from lesional versus circulating T cells?

Anti-neutrophil cytoplasmic antibody (ANCA) - associated vasculitis (AAV) is a life-threatening autoimmune disease characterized by an antibody-mediated glomerulonephritis and necrotizing vasculitis. Apart from antibodies, T cells are also involved in disease pathogenesis. This review stresses the hallmarks of T cell-mediated pathology in AAV and highlights the characteristics of lesional and circulating T cells in the immune response in AAV. Circulating effector T-cell populations are expanded and are in a persistent state of activation. Circulating regulatory T-cell subsets are less well characterized but seem to be impaired in function. Lesional effector T cells are present in granulomas, vasculitic lesions, and nephritis. Lesional T cells usually show pro-inflammatory properties and promote granuloma formation. Apart from T cells, dendritic cells are abundantly present at the sites of inflammation and locally orchestrate the immune response. Targeting the above-mentioned T cell-mediated disease mechanisms will potentially provide powerful therapeutic tools for AAV

Evaluation of antibodies against human HSP60 in patients with MPO-ANCA associated glomerulonephritis: a cohort study

BACKGROUND: Human Heat Shock Protein 60 (hHSP60) has been implicated in autoimmunity through molecular mimicry, based on the high degree of homology with HSP65 of micro-organisms leading to autoimmune recognition of the human protein. Additionally, sequence homology between hHSP60 and myeloperoxidase (MPO) has been described. MPO is a major autoantigen in vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA). We hypothesized that infections may trigger the ANCA response against MPO through hHSP60. METHODS: In 86 consecutive patients with ANCA-associated vasculitis (AAV), anti-hHSP60 and anti-mycobacterial HSP65 were measured by ELISA. Patients were compared with 69 healthy controls (HC). Continuous data between groups were compared using Wilcoxon signed rank test and Kruskal-Wallis test with Dunn's post-test when appropriate. Correlations between data were derived using Spearman correlation. Odds ratios and 95% confidence intervals were obtained using Fisher's exact test. RESULTS: At diagnosis, median anti-mHSP65 level was higher in AAV (median [range]: 42.5 [0–500]), and subsequently in MPO-ANCA (44 [7–500]), compared to HC (22 [0–430]). Anti-hHSP60 levels in AAV were not higher compared to HC (18 [0–319] and 18.5 [0–98], respectively). However, in MPO-ANCA anti-hHSP60 levels were increased (32.5 [0–319]) compared to PR3-ANCA (13 [0–79]) and HC. We could not detect cross-reactivity between hHSP60 and MPO-ANCA. There was a correlation between anti-mHSP65 and anti-hHSP60 levels (r = 0.32, P = 0.003) but not between anti-hHSP60 and MPO-ANCA (r = -0.064, P = 0.69). CONCLUSION: Antibodies against mHSP65 are higher in AAV compared to HC, and anti-hHSP60 antibodies are higher in patients with MPO-ANCA than in patients with PR3-ANCA and HC. Although this finding may be indicative for cross-reactivity between MPO-ANCA and hHSP60, additional assays did not support this hypothesis

Harmonization of antineutrophil cytoplasmic antibodies (ANCA) testing by reporting test result-specific likelihood ratios: position paper

Acknowledgments: We thank Ingrid Zegers and Evanthia Monogioudi (European Commission, Joint Research Centre, Geel, Belgium) for providing the reference materials and for helpful discussions

Realisation of the guidelines for faculty-internal exams at the Department of General Medicine at the University of Munich

Graded exams are prerequisites for the admission to the medical state examination. Accordingly the exams must be of good quality in order to allow benchmarking with the faculty and between different universities. Criteria for good quality need to be considered - namely objectivity, validity and reliability. The guidelines for the processing of exams published by the GMA are supposed to help maintaining those criteria. In 2008 the Department of General Medicine at the University of Munich fulfils only 14 of 18 items. A review process, appropriate training of the staff and the introduction of the IMSm software were the main changes that helped to improve the ‘GMA-score’ to 30 fulfilled items. We see the introduction of the IMSm system as our biggest challenge ahead. IMSm helps to streamline the necessary workflow and improves their quality (e.g. by the detection of cueing, item analysis). Overall, we evaluate the steps to improve the exam process as very positive. We plan to engage co-workers outside the department to assist in the various review processes in the future. Furthermore we think it might be of value to get into contact with other departments and faculties to benefit from each other’s question pools

Position paper: Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis.

Anti-neutrophil cytoplasmic antibodies (ANCAs) are valuable laboratory markers used for the diagnosis of well-defined types of small-vessel vasculitis, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). According to the 1999 international consensus on ANCA testing, indirect immunofluorescence (IIF) should be used to screen for ANCAs, and samples containing ANCAs should then be tested by immunoassays for proteinase 3 (PR3)-ANCAs and myeloperoxidase (MPO)-ANCAs. The distinction between PR3-ANCAs and MPO-ANCAs has important clinical and pathogenic implications. As dependable immunoassays for PR3-ANCAs and MPO-ANCAs have become broadly available, there is increasing international agreement that high-quality immunoassays are the preferred screening method for the diagnosis of ANCA-associated vasculitis. The present Consensus Statement proposes that high-quality immunoassays can be used as the primary screening method for patients suspected of having the ANCA-associated vaculitides GPA and MPA without the categorical need for IIF, and presents and discusses evidence to support this recommendation

Renin inhibition: a tool to assess the role of the renin-angiotensin aldosterone system in renal hemodynamics and sodium handling in human hypertension

Section I of this thesis- Pharmacology- focuses on the systemic and renal effects of the specific renin inhibitor remikiren (Ro 42-5892) in hypertensive patients with different degrees of renal function impairment. It tests the hypothesis that remikiren is an effective antihypertensive agent with a favorable renal profile. This was the first study on the renal effects of an orally administered renin inhibitor in this target population. In section II- Pathophysiology- the renin inhibitor is used as a specific pharmacologic tool to study the role of the RAAS in the pathophysiology of renal sodium handling in primary hypertension. Since it is not feasible to measure local intrarenal RAAS-activity, the response to remikiren was used as a surrogate indicator for the state of activation of the RAAS. In these studies we tested the hypothesis that dysregulation of the (intrarenal) RAAS, leading to inappropriately elevated levels of the effector hormone angiotensin II, plays al role in the impaired renal sodium handling and abnormal renal hemodynaics, either or not in mutual interaction, in primary hypertension. ... Zie: Summary.