| 1. |
- Langefeld, Carl D., et al.
(author)
-
Transancestral mapping and genetic load in systemic lupus erythematosus
- 2017
-
In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
-
Journal article (peer-reviewed)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
|
|
| 2. |
- van der Geld, Ymke M., et al.
(author)
-
Rats and mice immunised with chimeric human/mouse proteinase 3 produce autoantibodies to mouse Pr3 and rat granulocytes
- 2007
-
In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 66:12, s. 1679-1682
-
Journal article (peer-reviewed)abstract
- Aim: In this study, we employed chimeric human/ mouse Proteinase 3 ( PR3) proteins as tools to induce an autoantibody response to PR3 in rats and mice. Method: Rats and mice were immunised with recombinant human PR3 ( HPR3), recombinant murine PR3 ( mPR3), single chimeric human/ mouse PR3 ( HHm, HmH, mHH, mmH, mHm, Hmm) or pools of chimeric proteins. Antibodies to mPR3 and HPR3 were measured by ELISA. Antibodies to rat PR3 were determined by indirect immunofluorescence ( IIF) on rat white blood cells. Urinalysis was performed by dipstick analysis. Kidney and lung tissue was obtained for pathological examination. Results: In mice, immunisation with the chimeric human/ mouse PR3 Hmm led to an autoantibody response to mPR3. Rats immunised with the chimeric human/ mouse PR3 Hmm, HmH and mmH, or a pool of the chimeric human/ mouse PR3 proteins, produced antibodies selectively binding to rat granulocytes as detected by IIF. No gross pathological abnormalities could be detected in kidney or lungs of mice or rats immunised with chimeric human/ mouse PR3. Conclusion: Immunisation with chimeric human/ mouse proteins induces autoantibodies to PR3 in rats and mice. Chimeric proteins can be instrumental in developing experimental models for autoimmune diseases.
|
|
| 3. |
- Basu, Neil, et al.
(author)
-
EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis
- 2010
-
In: Annals of the Rheumatic Diseases. - London, UK : BMJ. - 1468-2060 .- 0003-4967. ; 69:10, s. 1744-1750
-
Journal article (peer-reviewed)abstract
- Objectives The systemic vasculitides are multiorgan diseases where early diagnosis and treatment can significantly improve outcomes. Robust nomenclature reduces diagnostic delay. However, key aspects of current nomenclature are widely perceived to be out of date, these include disease definitions, classification and diagnostic criteria. Therefore, the aim of the present work was to identify deficiencies and provide contemporary points to consider for the development of future definitions and criteria in systemic vasculitis. Methods The expert panel identified areas of concern within existing definitions/criteria. Consequently, a systematic literature review was undertaken looking to address these deficiencies and produce 'points to consider' in accordance with standardised European League Against Rheumatism (EULAR) operating procedures. In the absence of evidence, expert consensus was used. Results There was unanimous consensus for re-evaluating existing definitions and developing new criteria. A total of 17 points to consider were proposed, covering 6 main areas: biopsy, laboratory testing, diagnostic radiology, nosology, definitions and research agenda. Suggestions to improve and expand current definitions were described including the incorporation of anti-neutrophil cytoplasm antibody and aetiological factors, where known. The importance of biopsy in diagnosis and exclusion of mimics was highlighted, while equally emphasising its problems. Thus, the role of alternative diagnostic tools such as MRI, ultrasound and surrogate markers were also discussed. Finally, structures to develop future criteria were considered. Conclusions Limitations in current classification criteria and definitions for vasculitis have been identified and suggestions provided for improvement. Additionally it is proposed that, in combination with the updated evidence, these should form the basis of future attempts to develop and validate revised criteria and definitions of vasculitis.
|
|
| 4. |
|
|
