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Women and Inflammation

Research group
Active research
Project owner
Sahlgrenska Academy, Institute of Medicine, Krefting Research Centre

Financier
Swedish Research Council, Novo Nordisk Foundation, ALF VG-region, Swedish Society of Rheumatism, Professor Nanna Swartz foundation, IngaBritt & Arne Lundberg foundation

Short description

Sex hormones have major effects on the immune system, which greatly influences the risk of developing certain diseases. For example there is a clear female bias in the development of both autoimmune diseases and asthma. The research group studies how the female sex hormone estrogen affect immune responses during inflammatory diseases caused by autoimmunity, allergy or infections. The projects focus, among others, on determining whether the protective effects of estrogen on rheumatoid arthritis, osteoarthritis and osteoporosis are mediated via lymphocytes or stromal cells in lymph nodes and bone marrow. Another focus area is to define immunological mechanisms involved in the stimulating effects of estrogen on immune responses during infection- and allergy-induced airway inflammation.

Our research

The projects range from basic research (in vitro and in vivo), to clinical studies in collaboration with medical doctors at the Sahlgrenska University hospital.

Main research projects

Effects of estrogen on the immune system in arthritis and osteoporosis

Rheumatoid arthritis (RA) is a chronic inflammatory disease resulting in joint inflammation. The peak incidence of RA in women coincides with the time of menopause and RA is highly associated with development of osteoporosis. Treatment with 17b-estradiol (estrogen) is beneficial both by reducing inflammation and protecting against bone loss in RA, but it is not recommended as therapy due to severe side effects. Th17 cells are involved in the pathogenesis of both arthritis and osteoporosis. The effects of estrogen on Th17 cells are largely unknown, but recent studies from the research group strongly support involvement of Th17 cells in the RA-reducing effects of estrogen. The aims of this project are to; (1) identify the mechanisms underlying the positive effects of estrogen in RA to provide opportunities for development of new therapies, and to; (2) explore a possible new technique to predict early development of osteoporosis in postmenopausal RA patients using data from a clinical study.

Group members working in this project:

Intracellular interactions between estrogen- and adenosine-signaling in osteoarthritis

Osteoarthritis (OA) is a chronic disabling disease where the joint cartilage is destroyed, leading to pain and loss of joint function. During recent years, the importance of inflammation in OA pathogenesis has gained attention, but the specific mechanisms involved in the disease initiation and progression needs to be clarified. Women have a increased risk of developing OA compared to men, and the risk increases at the time of menopause when the levels of estrogen decreases. Epidemiological studies also suggest that estrogen may play an important role in OA disease development. Adenosine is an endogenously produced molecule that can exert both pro- and anti-inflammatory effects in the joints, regulated by signaling through different adenosine receptors. It has been shown that mice lacking adenosine receptor A2A spontaneously develop OA, with milder disease symptoms in female compared to male mice. Interestingly, estrogen can modulate the cellular expression of adenosine receptors.
The aims of this project are to
1) determine how estrogen- and adenosine-signaling interact in immune cells during OA development and

2) define how these pathways can be targeted for development of new OA therapies.

Group member working in this project:

Effects of estrogen on immune responses during airway inflammation

Sex hormones affect the development and function of the immune system, which is illustrated by a stronger immune response in females towards e.g. influenza virus infections and by the increased risk for females to develop asthma. The specific mechanisms underlying the sex differences in immune responses during airway inflammation is not clear. However, it is well known that estrogen can display stimulatory or inhibitory effects on different parts of the immune system depending on the settings. For example, estrogen stimulates the secretion of antibodies from B cells but decreases the production of different pro-inflammatory cytokines. The aims of this project are to; (1) define the specific mechanisms involved in the effects of estrogen on allergen- and virus-induced airway inflammation, and to; (2) determine the importance of stromal cells in primary and secondary lymphoid organs for the estrogen-mediated regulation of immune responses.

Group members working in this project:

  • Aidan Barrett, MSc – PhD student 
  • Piotr Humeniuk, PhD – postdoctoral fellow

Key publications

1. Scheffler JM, Grahnemo L, Engdahl C, Drevinge C, Gustafsson KL, Corciulo C, Lawenius L, Iwakura Y, Sjögren K, Lagerqvist MK, Carlsten H, Ohlsson C, Islander U 
Interleukin-17A: a Janus-faced regulator of osteoporosis
Sci Rep. 2020 Mar 30;10(1):5692. 

Results from this study show that IL-17A is an important mediator of cortical but not trabecular bone loss after ovariectomy. Also, IL-17A induces a two-sided effect on bone remodelling in the absence of estrogen, by increasing osteoclastogenesis and decreasing adipogenesis.

2. Andersson A, Törnqvist A, Moverare-Skrtic S, Bernardi A, Farman HH, Krust A, Chambon P, Engdahl C, Lagerquist M, Windahl SH, Carlsten H, Ohlsson C, Islander U
Roles of activating functions 1 and 2 of estrogen receptor a in estrogen receptor-mediated regulation of lymphopoiesis
J Endocrinol. 2018 Feb;236(2):99-109

This is the first study to establish in detail that the presence of activating functions 1-2 of estrogen receptor alpha (ERαAF-1 and ERαAF-2) are required for the effects that estradiol and selective estrogen receptor modulators (lasofoxifene and raloxifene) confer on the development of B- and T-lymphocytes in bone marrow and thymus. 

3. Andersson A, Bernardi A, Nurkkala Karlsson M, Stubelius A, Ohlsson C, Carlsten H, Islander U
Suppression of experimental arthritis and associated bone loss by a tissue-selective estrogen complex
Endocrinology. 2016 Jan 8:en20151820. 

This paper shows that a tissue-selective estrogen complex, comprising estradiol and the selective estrogen receptor modulator Bazedoxifene, suppresses experimental arthritis and prevents associated bone loss in a manner that is equally efficient to that of estradiol alone, albeit with minimal uteroproliferative effects.

4. Andersson A, Stubelius A, Nurkkala Karlsson M, Engdahl C, Erlandsson MC, Grahnemo L, Lagerquist MK, Islander U
Estrogen regulates T helper 17 phenotype and localization in experimental autoimmune arthritis
Arthritis Res Ther. 2015 Feb 13;17:32. 

This is the first study to characterize the effects of estradiol on Th17 cells in experimental autoimmune arthritis. We report that while estradiol treatment results in an increase in the numbers of Th17 cells in lymph nodes during the early phase of arthritis development, it also leads to a decrease in the numbers of Th17 cells in joints during established arthritis. Our data suggest that this may be caused by interference with the CCR6-CCL20 migration pathway, which is important for Th17-cell migration.