Canine to human immunological diseases

Our studies in canine systemic lupus erythematosus (SLE) pointed to multiple genes and pathways some of which overlapped with human immunological diseases. To follow up on these results, we generated an array to sequence  ~600 human genes in cases and controls for each disease. This array was then used to study SLE, Sjögrens disease, myositis, vasculitis and ankylosing spondylitis.

DISSECT: SLE, Sjögren’s syndrome, Myositis

To understand the genetics underlying three immunological diseases a large collaborative network, DISSECT, was formed. This focused on SLE,  an autoimmune disease characterized by the production of autoantibodies and inflammation in multiple organs such a kidneys. Sjögrens’ disease generates dry eyes and a dry mouth. The condition is often accompanied by other immune system disorders, such as rheumatoid arthritis and SLE. For myositis, the muscles are the most affected tissue. We have recently performed an association analysis for the 600 target genes in all three diseases and the results contain both well known and some novel genes.

ANCA-associated vasculitides

The ANCA-associated vasculitides are severe autoimmune diseases with potentially fatal outcome. Yet, the treatment options are limited and there are significant gaps in our understanding of the disease pathogenesis. In order to increase our basic knowledge of the disease mechanisms, we have performed resequencing of a large cohort of patients and will follow up with transcriptome analysis. Additionally, to improve diagnostics of patients in the clinical setting, we are currently analyzing potential biomarkers for disease severity and activity. The study is led by Johanna Dahlkvist, MD, PhD.

Scientific publications:

Dahlqvist J, Ekman D, Sennblad B, Kozyrev SV, Nordin J, Karlsson Å, Meadows JRS, Hellbacher E, Rantapää-Dahlqvist S, Berglin E, Stegmayr B, Baslund B, Palm Ø, Haukeland H, Gunnarsson I, Bruchfeld A, Segelmark M, Ohlsson S, Mohammad AJ, Svärd A, Pullerits R, Herlitz H, Söderbergh A, Rosengren Pielberg G, Hultin Rosenberg L, Bianchi M, Murén E, Omdal R, Jonsson R, Eloranta ML, Rönnblom L, Söderkvist P, Knight A, Eriksson P, Lindblad-Toh K. 2021. Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA. Rheumatology. 2022 Aug 3;61(8):3461-3470. doi: 10.1093/rheumatology/keab912.

Lundtoft C, Pucholt P, Martin M, Bianchi M, Lundström E, Eloranta ML, Sandling JK, Sjöwall C, Jönsen A, Gunnarsson I, Rantapää-Dahlqvist S, Bengtsson AA, Leonard D, Baecklund E, Jonsson R, Hammenfors D, Forsblad-d’Elia H, Eriksson P, Mandl T, Magnusson Bucher S, Norheim KB, Auglaend Johnsen SJ, Omdal R, Kvarnström M, Wahren-Herlenius M, Notarnicola A, Andersson H, Molberg Ø, Diederichsen LP, Almlöf J, Syvänen AC, Kozyrev SV, Lindblad-Toh K; DISSECT Consortium; ImmunoArray Development Consortium, Nilsson B, Blom AM, Lundberg IE, Nordmark G, Diaz-Gallo LM, Svenungsson E, Rönnblom L. 2022. Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases. Arthritis Rheumatol. 2022 Aug;74(8):1440-1450. doi: 10.1002/art.42122. Epub 2022 Jun 27.

Lundtoft C, Sjöwall C, Rantapää-Dahlqvist S, Bengtsson AA, Jönsen A, Pucholt P, Wu YL, Lundström E, Eloranta ML, Gunnarsson I, Baecklund E, Jonsson R, Hammenfors D, Forsblad-d’Elia H, Eriksson P, Mandl T, Bucher S, Norheim KB, Johnsen SJA, Omdal R, Kvarnström M, Wahren-Herlenius M, Truedsson L, Nilsson B, Kozyrev SV, Bianchi M, Lindblad-Toh K; DISSECT consortium; ImmunoArray consortium, Yu CY, Nordmark G, Sandling JK, Svenungsson E, Leonard D, Rönnblom L. 2022. Combined genetic deficiencies of the classical complement pathway are strongly associated with both systemic lupus erythematosus and primary Sjögren’s syndrome. Arthritis Rheumatol. 2022 Jun 21. doi: 10.1002/art.42270. Online ahead of print.

Bianchi M, Kozyrev SV, Notarnicola A, Hultin Rosenberg L, Karlsson Å, Pucholt P, Rothwell S, Alexsson A, Sandling JK, Andersson H, Cooper RG, Padyukov L, Tjärnlund A, Dastmalchi M; ImmunoArray Development Consortium, The DISSECT consortium, Meadows JRS, Pyndt Diederichsen L, Molberg Ø, Chinoy H, Lamb J, Rönnblom L, Lindblad-Toh K, Lundberg IE. 2021. Contribution of rare genetic variation to disease susceptibility in a large Scandinavian myositis cohort. Arthritis Rheumatol. Jul 19. doi: 10.1002/art.41929.

Farias, F.H.G., Dahlqvist, J., Kozyrev, S.V., Leonard, D., Wilbe, M., Abramov, S.N., Alexsson, A., Pielberg, G.R., Hansson-Hamlin, H., Andersson, G., Tandre, K., Bengtsson, A.A., Sjowall, C., Svenungsson, E., Gunnarsson, I., Rantapaa-Dahlqvist, S., Syvänen, A.-C., Sandling, J.K., Eloranta, M.-L., Rönnblom, L., Lindblad-Toh, K., 2019. A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts. Eur J Hum Genet 27, 432–441. doi:10.1038/s41431-018-0297-x