MARIE WAHREN-HERLENIUS GROUP

About

Autoimmune disorders are a major cause of disease and disability, affecting around 5% of the population. We study the molecular and clinical pathology of the rheumatic autoimmune condition Sjögren’s syndrome, and the autoantibody mediated congenital heart block that may develop in the fetus of pregnant women with Sjögren’s syndrome.

Our projects aim at specifying key steps in generation of the autoimmune inflammation in both mother and child, and to identify immunologic components relevant to the tissue destruction. Our research is performed with a translational approach and involves both basic molecular studies, analysis in experimental models and clinical investigations. Generated data are important for developing preventive strategies, diagnostic assays and novel therapy.

 
180531_K13647-B3_63x_BRA_Merge2_CD38_FamA BESKÄRS ENL SUPPL FIGURE 3.jpg

Autoimmune Molecular Pathology

The autoimmune inflammation in Sjögren's syndrome targets the exocrine organs, in particular involving the salivary and lacrymal glands where large infiltrates of mononuclear cells are observed. Systemic manifestations include severe tiredness, muscle and joint pain. Patients with Sjögren's syndrome have a defective B cell differentiation, and serologically hypergammaglobulinemia with autoantibodies to the Ro/SSA autoantigen are characteristic features. The lymphocytic infiltrates that develop in the salivary glands of patients with Sjögren's syndrome consist of B cells, T cell and plasma cells. When extensive, the infiltrates may replace large portions of the glands and in some patients formation of germinal center-like structures can be observed. Such lymphoid neogenesis has also been observed in target organs in other autoimmune diseases, and proposed to contribute to the chronicity of the conditions. We focus on understanding the molecular basis for the lymphoid neogensis and how the germinal center-like structures promote formation of autoreactive clones, including formation of Ro/SSA autoantibody producing plasma cells.

 

Anti-citrullinated protein antibodies (ACPA)

Congenital atrio-ventricular heartblock (AVB) without cardiac malformations is a rare disease affecting ca 1/15.000-20.000 new-borns. Heartblock develops gradually but is often only diagnosed after the development into a complete block (AVBIII), where the affected fetus presents with a very slow heartbeat/low cardiac rhythm usually between gestational weeks 18-24. The majority of children born with complete heartblock need a pacemaker.

There is a well-established/known relation/connection/association between AVBIII and specific maternal autoantibodies, termed Ro/SSA and La/SSB antibodies. These autoantibodies, like antibodies in general, are transferred to the fetus via the placenta thereby affecting the fetal cardiac conduction system leading to block development. Often the mothers have a rheumatic disease/are diagnosed with (like) Sjögren´s Syndrome or SLE but may be asymptomatic as well.

Women carrying Ro/SSA and La/SSB autoantibodies have a risk of 2% to have a child with AVBIII and this risk is increased in women who already had a child with CHB.

Our research is focusing to understand the disease pathogenesis and by that identify risk factors for CHB to map women at high risk to have a child with CHB, with the aim to give these women better surveillance. Studies showed that early treatment can prevent the development into a complete AVB and reverse some of the milder forms of AVB, which strengthens the need for better and more specialized surveillance criteria for this life-threatening condition. 

Ro52-autoantibodies, a subgroup of the Ro/SSA autoantibodies, have been the most relevant risk factor/marker we identified mapping women with high risk to have a child with CHB. Women positive for Ro52 autoantibodies were offered to participate in a surveillance study with weekly echocardiography investigations during gestational weeks 18-24 when the block usually develops. The results of this study showed that mortality within the surveillance group was lower (4%) compared to the mortality for CHB in general/without special surveillance (15-20%). Better fetal outcome was due to prevention of complete block development by early detection of block (up to four weeks earlier than without surveillance) and early treatment possibilities. Additionally, pacemaker implantation for those patients with reversed AVB could be delayed from shortly after birth to several years of life. 

In a pilot study approach, home-monitoring of fetal heart rate by the mothers themselves is currently tested and the results are very promising. The possibility for this home surveillance for women at risk would ease the overloaded work burden of specialized health care.

In addition to the group of women known to be at risk to give birth to a child with CHB, the estimated number of women not knowing they are at risk is much higher as for those women their disease development remains undetected often due to very mild or no symptoms. Hence better and more specific disease markers for CHB development are needed to identify the group of women at high risk who should be offered better and specialized surveillance. 

The recurrence rate for CHB, despite persisting maternal autoantibodies is 12-18% thus other factors do contribute to disease development. Potential factors are infection, cardiac surgery, genetics or to date unknown factors. Our current research focusses on investigating the impact of those factors to disease development to hopefully contribute to patient benefit in the future. 

 

Selected publications

Kyriakidis NC, Kockum I, Julkunen H, Hoxha A, Salomonsson S, Meneghel L, Ebbing C; 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 block. Ann Rheum Dis 2018 Sep;77(9):1381-1382.

Mentlein L, Thorlacius GE, Meneghel L, Aqrawi LA, Ramírez Sepúlveda JI, Grunewald J, Espinosa A, Wahren-Herlenius M. The rheumatic disease-associated FAM167A-BLK locus encodes DIORA-1, a novel disordered protein expressed highly in bronchial epithelium and alveolar macrophages. Clin Exp Immunol, 2018 Aug;193(2):167-177.

Lindén M, Ramírez Sepúlveda JI, James T, Thorlacius GE, Brauner S, Gómez-Cabrero D, Olsson T, Kockum I, Wahren-Herlenius M. Sex influences eQTL effects of SLE and Sjögren's syndrome-associated genetic polymorphisms. Biol Sex Differ 2017 Oct 25;8(1):34.

Brauner S, Folkersen L, Kvarnström M, Meisgen S, Petersen S, Franzén-Malmros M, Mofors J, Brokstad KA, Klareskog L, Jonsson R, Westerberg LS, 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 Oct;76(10):1755-1763.

Abrecht I, Wick C, Hallgren Å, Tjärnlund A, Nagaraju K, Andrade F, Thompson K, Coley W, Phadke A, Diaz-Gallo LM, Bottai M, Nennesmo I, Chemin K, Herrath J, Johansson K, Wikberg A, Ytterberg AJ, Zubarev RA, Danielsson O, Krystufkova O, Vencovsky J, Landegren N, Wahren-Herlenius M, Padyukov L, Kämpe O, Lundberg IE. Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies. J Clin Invest 2015, 125:4612-4624. 

Wahren-Herlenius M, Dörner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 2013, 382:819-831.   

Lessard CJ, et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome. Nat Genet 2013 Nov;45(11):1284-92.     

Sjöstrand M, Ambrosi A, Sullivan J, Malin S, Kuchroo VK, Espinosa A and Wahren-Herlenius M. Expression of the immune regulator TRIM21 is controlled by interferon regulatory factors. J Immunol 2013 Oct 1;191(7):375363.

  

Rusakiewicz S, et al. NCR3/NKp30 Contributes to Pathogenesis in Primary Sjogren's Syndrome. Sci Transl Med 2013 Jul 24;5(195):195ra96.

Strandberg L, Ambrosi A, Jagodic M, Dzikaite V, Janson P, Khademi M, Salomonsson S, Ottosson L, Klauninger R, Adén U, Sonesson SE, Sunnerhagen M, de Graaf KL, Kuchroo VK, Achour A, Winqvist O, Olsson T and Wahren-Herlenius M. Maternal MHC regulates generation of pathogenic antibodies and fetal MHC-encoded genes determine susceptibility in congenital heart block. J Immunol 2010 Sep 15;185(6):3574-82.

Espinosa A, Dardalhon V, Brauner S, Ambrosi A, Oukka M, Winqvist O, Eloranta ML, Sundelin B, Jefferies C, Rozell B, Kuchroo V, Wahren-Herlenius M.  Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by dysregulating the IL-23/Th17 pathway. J Exp Med 2009, 206:1661-1671.

Espinosa A, Zhou W, Ek M, Hedlund M, Brauner S, Popovic K, Horvath L, Wallerskog T, Oukka M, Nyberg F, Kuchroo VK, Wahren-Herlenius M. The Sjogren's syndrome-associated autoantigen Ro52 is an E3 ligase that regulates proliferation and cell death. J Immunol 2006, 176:6277-85.

Salomonsson S, Sonesson SE, Ottosson L, Muhallab S, Olsson T, Sunnerhagen M, Kuchroo VK, Thorén P, Herlenius E and Wahren-Herlenius M. Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis and mediate congenital heart block. J Exp Med 2005, 201:11-17.

Entesarian M, Matsson H, Klar J, Bergendal B, Olson L, Arakaki R, Hayashi Y, Ohuchi H, Falahat B, Bolstad AI, Jonsson R, Wahren-Herlenius M and Dahl N. Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands. Nature Genetics 2005, 37:125-128.