Immune regulation in tolerance (pregnancy) and inflammation (multiple sclerosis)

Del av cell från placenta, från forskning i reproduktions- och neuroimmunologi

During pregnancy the maternal immune system is strictly regulated to a state of transient tolerance in order to avoid rejection of the semi-foreign fetus. Failure to induce tolerance can lead to pregnancy complications such as recurrent miscarriage, preeclampsia and preterm labour.

Reproduktionsimmunologi, Jan Ernerudh med babyProfessor Jan Ernerudh (to the right) greets Nils Ibbe, a potential future
collaborator.Foto: Thor Balkhed
The general purpose of our research is (1) to reveal mechanisms of immune tolerance in pregnancy and how failure of tolerance mechanisms can lead to pregnancy complications, and (2) to use pregnancy as a model for successful immune tolerance to find out mechanisms of immune perturbations in MS and how these are corrected by the immune regulation that takes place in pregnancy.
The knowledge will be used both in the field of reproductive immunology to identify relevant biomarkers for prediction, monitoring and treatment of pregnancy complications, and in the field of neuroimmunology to identify biomarkers for personalized treatment and to find new targets and modes of treatment in MS.

Aberrant immune regulation of MS and improvement during pregnancy

Cell från placentaMS is a chronic inflammatory disease of the central nervous system (CNS). Immune cells enter the CNS and create inflammation, which leads to demyelination and neuronal damage.

T helper cells are immune cells specialized in regulating inflammation and several observations indicate that an aberrant function of T helper cells leads to CNS inflammation in MS1.
We use genome-wide methods and a systems medicine approach to reveal basic mechanisms that cause the aberrant function of T helper cells in MS2-4. This information is further used in a longitudinal study of immune regulation in pregnancy, which will help us to understand why patients with MS improve during pregnancy.
A multicentre prospective study, Pregnancy and MS (in Swedish “Graviditet och MS = GraMS), involves Linköping, Karolinska, Jönköping and Kalmar. In addition to T helper cells we will also investigate other immune cells and molecules and how these affect MS during pregnancy.
Labarbete, reproduktionsimmunologiPhoto credit: Thor BalkhedWe are also interested in the background to the immunological changes in pregnancy, including the role of pregnancy hormones and the role of thymus and its output of T helper cells. Finally, we hope to use the knowledge of molecular mechanisms to find better tools for prediction, monitoring and modes of treatment in MS.

Immune tolerance in pregnancy and complications of pregnancy 

Pregnancy is an immunological paradox since the fetus expresses genes of paternal origin and should therefore, according to immunological rules, be rejected by the maternal immune system. The maternal immune system therefore needs to be strictly regulated during pregnancy.
A dysfunctional maternal immune adaptation is a contributing factor in complications of pregnancy when a number of well-known causes (like genetic, anatomical, endocrinological) have been excluded. The fetal-maternal interface is where maternal leukocytes meet fetally derived trophoblast cells from the placenta. Macrophages and regulatory T (Treg) cells are enriched at the maternal-fetal interface and show distinct immune regulatory properties that promote tolerance5-10.
Frysförvaring av prover vid forskning i reproduktions- och neuroimmunologiPhoto credit: Thor BalkhedImportant initial signals to induce tolerance come from the placenta, thus the foreign organ itself secures that the maternal immune system switches to tolerance early in pregnancy11. We are now further investigating other cellular mechanisms that are responsible for initiation and maintenance of immune tolerance in pregnancy including projects on stromal cells, tissue cells with specialized functions during pregnancy.
We also aim at revealing which molecules are responsible and have special interests in cytokines, chemokines and complement proteins.
We will then test if aberrations in these molecular and cellular mechanisms are involved in complications of pregnancy like preeclampsia12,13, preterm birth and recurrent miscarriage. Finally, candidate molecules will be tested for their clinical usefulness in early blood samples from women that later during pregnancy develop complications. These samples are a part of a biobank “Graviditets-biobank, GraBB”, which is collected in collaboration with the department of obstetrics and gynaecology. 

Reproduktionsimmunologi, forskargruppenPhoto credit: Thor Balkhed

Selected references

  1. Raffetseder J, Lindau R, van der Veen S, Berg G, Larsson M, Ernerudh J.
    Mucosal-associated invariant T (MAIT) cells balance the requirements for immune tolerance and anti-microbial defense during pregnancy.
    Frontiers Immunol, accepted for publication.

  2. Papapavlou G, Hellberg S, Raffetseder J, Brynhildsen J, Gustafsson M, Jenmalm MC, Ernerudh J.
    Differential effects of estradiol and progesterone on human T cell activation in vitro.
    Eur J Immunol, accepted for publication.

  3. Badam TV, Hellberg S, Mehta RB, Lechner-Scott J, Lea RA, Tost J, Mariette X, Svensson-Arvelund J, Nestor CE, Benson M, Berg G, Jenmalm MC, Gustafsson M*, Ernerudh J*. *Contributed equally
    CD4+ T-cell DNA methylation changes during pregnancy significantly correlate with disease-associated methylation changes in autoimmune diseases.
    Epigenetics, accepted for publication.

  4. Hellberg S, Raffetseder J, Rundquist O, Magnusson R, Papapavlou G, Jenmalm MC, Ernerudh J*, Gustafsson M*. *Contributed equally
    Progesterone dampens immune responses in in vitro activated CD4+ T cells and affects genes associated with autoimmune diseases that improve during pregnancy.
    Front Immunol. 2021;12:672168.

  5. Lindau R, Vondra S, Spreckels J, Solders M, Svensson-Arvelund J, Berg G, Pollheimer J, Kaipe H, Jenmalm MC, Ernerudh J.
    Decidual stromal cells support tolerance at the human fetal-maternal interface by inducing regulatory M2 macrophages and regulatory T-cells.
    J Reprod Immunol 2021;146:103330.

  6. Gawel DR, Serra-Musach J, Lilja S,….Ernerudh J, et al.
    A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases.
    Genome Med. 2019;11:47

  7. Hellberg S, Mehta RB, Forsberg A, Berg G, Brynhildsen J, Winqvist O, Jenmalm MC, Ernerudh J.
    Maintained thymic output of conventional and regulatory T cells during human pregnancy.
    J Allergy Clin Immunol. 2019;143:771

  8. Lindau R, Mehta RB, Lash GE, Papapavlou G, Boij R, Berg G, Jenmalm MC, Ernerudh J, Svensson-Arvelund J.
    Interleukin-34 is present at the fetal-maternal interface and induces immunoregulatory macrophages of a decidual phenotype in vitro.
    Hum Reprod, 2018:33.

  9. Bruno V, Svensson-Arvelund J, Rubér M, Berg G, Piccione E, Jenmalm MC, Ernerudh J.
    Effects of low molecular weight heparin on the polarization and cytokine profile of macrophages and T helper cells in vitro.
    Sci Rep, 2018:8.

  10. Håkansson I, Tisell A, Cassel P, Blennow K, Zetterberg H, Lundberg P, Dahle C, Vrethem M, Ernerudh J.
    Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis.
    J Neuroinflammation, 2018:18

  11. Håkansson I, Tisell A, Cassel P, Blennow K, Zetterberg H, Lundberg P, Dahle C, Vrethem M, Ernerudh J.
    Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing remitting multiple sclerosis.
    Eur j Neurol, 2017:24.

  12. Hellberg, S., D. Eklund, D. Gawel, M. Kopsén, H. Zhang, C.E. Nestor, I. Kockum, T. Olsson, M. Vrethem, I. Håkansson, M. Benson, M.C. Jenmalm, M. Gustafsson, J. Ernerudh.
    Dynamic response genes in CD4+ T cells reveals a protein network that accurately classifies disease activity in multiple sclerosis.
    Cell Reports, 2016:16.

  13. Svensson-Arvelund, J., R.B. Mehta, R. Lindau, E. Mirrasekhian, H. Rodriguez-Martinez, G. Berg, G.E. Lash, M.C. Jenmalm, and J. Ernerudh.
    The human fetal placenta promotes tolerance against the semiallogeneic fetus by inducing regulatory T cells and homeostatic M2 macrophages.
    J Immunol, 2015:194.

  14. Gustafsson M., D. R. Gawel, L. Alfredsson, S. Baranzini, J. Bjorkander, R. Blomgran, S. Hellberg, D. Eklund, J. Ernerudh, I. Kockum, A. Konstantinell, R. Lahesmaa, A. Lentini, H. R. Liljenstrom, L. Mattson, A. Matussek, J. Mellergard, M. Mendez, T. Olsson, M. A. Pujana, O. Rasool, J. Serra-Musach, M. Stenmarker, S. Tripathi, M. Viitala, H. Wang, H. Zhang, C. E. Nestor, M. Benson.
    A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases.
    Science translational medicine 2015:7.

  15. Gustafsson M, Edström M, Gawel D, Nestor CE, Wang H, Zhang H, Barrenäs F, Tojo J, Kockum I, Olsson T, Serra-Musach J, Bonifaci N, Pujana MA, Ernerudh J, Benson M.
    Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment.
    Genome Med. 2014:6.