The Research Group of Immunology and Rheumatology

Marie Wahren-Herlenius Group

The majority of autoimmune diseases are more common in women than in men, but the molecular basis for this sex-bias remains poorly understood. In our projects we focus on the autoimmune exocrinopathy Sjögren's syndrome which has among the highest observed female-to-male ratios, to dissect the genetic and hormonal contribution to sex-dependent immune regulation at single cell resolution and how these differences may lead to autoimmune disease.

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Marie Wahren-Herlenius did part of her PhD training and a postdoctoral period at the Broegelmann Research Laboratory during the 90s, and has continued collaboration with the environment ever since. She was appointed professor II in a bistilling, University of Bergen in 2020. She is also a professor at Karolinska Institutet, Stockholm, Sweden.

Projects in the group

Autoimmune diseases affect around 5% of the population, entailing high morbidity and increased mortality rates. There is a critical need for better diagnostic tools, preventive measures and specific therapies for this family of disorders, but we still lack understanding of the pathogenic mechanisms that lead to these diseases. Women are at much higher risk of developing autoimmune disease, with the most extreme numbers in systemic disorders such as SLE and Sjögren’s syndrome for which more than nine out of ten patients are women (see figure 1). There is a clear genetic contribution to these diseases and genome-wide studies have identified polymorphisms clustered in the TLR/interferon, lymphocyte signaling and antigen presentation pathways as associated with Sjögren’s syndrome. Interestingly, many of the associated genetic variants lead to differential gene regulation, so called expression quantitative loci (eQTL) effects. However, the influence of sex, or why these immune-pathways and related genes would become dysregulated specifically in women is not clear.

Notably, there is no difference in the frequency of these polymorphisms between women and men in the general population. In our projects, we build on the observation that genetic polymorphisms associated with Sjögren's syndrome that we identify thus dramatically increase the likelihood for the disease to develop in women carrying these genetic traits compared to men. Consequently, the context “female sex” may lead to a different functional impact of the genetic polymorphisms associated with systemic autoimmunity than the context “male sex”. This novel idea bridges the sex-bias in Sjögren’s syndrome with the specificity of genetic associations. Our projects aim to identify such sex-influenced eQTLs, and dissect the genetic and hormonal contribution to sex-dependent immune regulation at single cell resolution and how these differences may lead to autoimmune disease. Novel technology now allows transcriptional analysis at the single cell level rather than bulk samples of tissues, for detecting fundamental sex differences in the immune system and to identify the molecular drivers underlying them (see figure 2). We use unique human cohorts of patients with Sjögren's syndrome, and the project is funded by the European organization FOREUM and the Norweigan Research Council.

More information about our research can be found here https://ki.se/en/meds/research-group-marie-wahren-herlenius

Sex ratio and methods
Marie Wahren-Herlenius

Selected publications

Sjöstrand M, Ambrosi A, Sullivan J, Malin S, Kuchroo V, Espinosa A, Wahren-Herlenius M. Expression of the immune regulator TRIM21 is controlled by interferon regulatory factors. J Immunol 2013, 191:3753-3763.              

Rusakiewicz S, Nocturne G, Lazure T, Semeraro M, Flament C, Caillat-Zucman S, Sène D, Delahaye N, Vivier E, Chaba K, Poirier-Colame V, Nordmark G, Eloranta ML, Eriksson P, Theander E, Forsblad-d'Elia H, Omdal R, Wahren-Herlenius M, Jonsson R, Rönnblom L, Nititham J, Taylor KE, Lessard CJ, Sivils KL, Gottenberg JE, Criswell LA, Miceli-Richard C, Zitvogel L and Mariette X. NCR3/NKp30 Contributes to Pathogenesis in Sjogren's Syndrome. Sci Transl Med 2013, 5:195ra96.

Lessard CJ, He Li, ´Adrianto I, Ice J, Rasmussen A, Grundahl K, Kelly J, Dozmorov M, Miceli-Richard C, Bowman S, Lester S, Eriksson P, Eloranta M, Brun J, Gøransson L, Harboe E, Guthridge J, Kaufman K, Kvarnström M, Cunninghame Graham G, Grandits M, Nazmul-Hossain A, Patel K, Adler A, Maier-Moore J, Farris A, Brennan M, Lessard J, Chodosh J, Gopalakrishnan R, Hefner K, Houston G, Huang A, Hughes P, Lewis D, Radfar L, Rohrer M, Stone D, Wren J, Vyse T, Gaffney P, James J, Omdal R, Wahren-Herlenius M, Illei G, Witte T, Jonsson R, Rischmueller M, Rönnblom L, Nordmark G, Ng W for UK primary Sjögren's syndrome registry, Mariette X, Anaya J, Rhodus N, Segal B, Scofield H, Montgomery C, Harley J and Moser Sivils K. Identification of multiple genetic variants associated with Sjögren’s syndrome involved in both the innate and adaptive immune responses. Nature Genetics 2013, 45:1284-1292.

Ambrosi A and Wahren-Herlenius M. Update on the immunobiology of Sjögren’s syndromeCurr Opin Rheumatol 2015, 27:468-75.

Brauner S, Folkersen L, Kvarnström M, Meisgen S, Petersen S, Franzén-Malmros M, Mofors J, Brokstad KA, Klareskog L, Jonsson R, Westerberg L, Trollmo C, Malmström V, Ambrosi A, Kuchroo VK, Nordmark G, Wahren-Herlenius M. H1N1 vaccination in Sjögren's syndrome triggers polyclonal B cell activation and promotes autoantibody production. Ann Rheum Dis 2017, 76:1755-1763.

Brauner S, Jiang X, Thorlacius GE, Lundberg AM, Östberg T, Yan ZQ, Kuchroo VK, Hansson GK, Wahren-Herlenius M. Augmented Th17 differentiation in Trim21 deficiency promotes a stable phenotype of atherosclerotic plaques with high collagen contentCardiovasc Res 2018, 114:158-167.

Aqrawi LA, Mentlein L, Meneghel L, Björk A, Thorlacius GE, Ivanchenko M, Ramírez Sepúlveda JI, Skarstein K, Kvarnström M, Brauner S, Espinosa A, Wahren-Herlenius M. Clinical associations and expression pattern of the autoimmunity susceptibility factor DIORA-1 in patients with primary Sjögren's syndromeAnn Rheum Dis 2018, 77:1840-1842.

Kyriakidis N, Kockum I, Julkunen H, Hoxha A, Salomonsson S, Meneghel L, Ebbing C, The Swedish Congenital Heart Block Study Group, Dilthey A, Eronen M, De Carolis S, Kiserud T, Ruffatti A, Kere J, Meisgen S, Wahren-Herlenius M. European families reveal MHC class I and II associations with autoimmune-mediated congenital heart blockAnn Rheum Dis 2018, 77:1381-1382. 

Mofors J, Arkema EV, Björk A, Westermark L, Kvarnström M, Forsblad-d’Elia H, Magnusson Bucher S, Eriksson P, Mandl T, Nordmark G, Wahren-Herlenius M. Infections increase the risk of developing Sjögren’s syndromeJ Intern Med 2019, 285:670-680.

Mofors J, Eliasson H, Ambrosi A, Salomonsson S, Skog Andreasson A, Fored M, Ekbom A, Bergman G, Soncesson SE, Wahren-Herlenius M. Comorbidity and long-term outcome in patients with congenital heart block and their siblings exposed to Ro/SSA autoantibodies in uteroAnn Rheum Dis 2019, 78:696-703.

Björk A, Thorlacius GE, Mofors J, Richardsdotter Andersson E, Ivanchenko M, Tingström J, James T, Brokstad KA, Cox RJ, Jonsson R, Kvarnström M, Wahren-Herlenius M. Viral antigens elicit augmented immune responses in primary Sjögren's syndrome. Rheumatology (Oxford) 2020, 59:1651-1661.

Mofors J, Björk A, Smedby KE, Kvarnström, M, Forsblad-d’Elia H, Magnusson Bucher S, Eriksson P, Mandl T, Baecklund E, Nordmark G, Wahren-Herlenius M. Increased risk of multiple myeloma in primary Sjögren’s syndrome is limited to individuals with Ro/SSA and La/SSB autoantibodiesAnn Rheum Dis 2020, 79:307-308.

Sonesson SE and Wahren-Herlenius M. Surveillance of congenital heart block in highly specialised careLancet Rheumatology, 2020, 2:e203-204.

Sonesson SE and Wahren-Herlenius M. Mortality in congenital heart block. Lancet Rheumatology 2020, 2(10):e588-599.       

Björk A, Mofors J, Wahren-Herlenius M. Environmental factors in the pathogenesis of primary Sjögren’s syndromeJ Intern Med 2020, 287:475-492.

Wahren-Herlenius M, Rönnblom L. Learning from similarities between vaccine responses and SLE. Nat Rev Rheumatol 2020, 16:355-356.

Gao Y, Liu R, He C, Basile J, Vesterlund M, Wahren-Herlenius M, Espinoza A, Hokka-Zakrisson C, Zadjali F, Yoshimura A, Karlsson M, Carow B, Rottenberg ME. SOCS3 Expression by Thymic Stromal Cells Is Required for Normal T Cell DevelopmentFront Immunol 2021, 12:642173.

Thorlacius GE, Hultin-Rosenberg L, Sandling JK, Bianchi M, Imgenberg-Kreuz J, Pucholt P, Theander E, Kvarnström M, Forsblad-d'Elia H, Bucher SM, Norheim KB, Johnsen SJA, Hammenfors D, Skarstein K, Jonsson MV, Baecklund E, Aqrawi LA, Jensen JL, Palm Ø, Morris AP; DISSECT consortium; the ImmunoArray consortium, Meadows JRS, Rantapää-Dahlqvist S, Mandl T, Eriksson P, Lind L, Omdal R, Jonsson R, Lindblad-Toh K, Rönnblom L, Wahren-Herlenius M, Nordmark G. Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome. Rheumatology (Oxford) 2021, 60:837-848.

Ivanchenko M, Thorlacius GE, Hedlund M, Ottosson V, Meneghel L, Björkander S, Ossoinak A, Tingström J, Bremme K, Sverremark-Ekström E, Gemzell-Danielsson K, Sonesson SE, Chemin K, Wahren-Herlenius M. Natural killer cells and type II interferon in Ro/SSA and La/SSB autoantibody-exposed newborns at risk of congenital heart block.
Ann Rheum Dis 2021, 80:194-202.