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PhD student MS Pathology

Type
Research
Location
Amsterdam
Description
For a project aiming at unravelling early pathology of MS we have a vacancy for a PhD student MS Pathology.
FTE
1.0 fte
Period
4 years


Description

The Neuroimmunology Research (IMM) group, led by Prof Inge Huitinga, studies the molecular and cellular factors underlying the pathology and heterogeneity of multiple sclerosis (MS). Special emphasis is put on the role of microglia and T cells in MS-lesion development using post mortem MS brain tissue provided by the Netherlands Brain Bank (NBB). For a project aiming at unravelling early pathology of MS we have a vacancy for a PhD student MS Pathology

Background

We recently analyzed neuropathological changes in multiple sclerosis (MS) in relation to clinical features and sex in an autopsy cohort of the Netherlands Brain Bank (NBB) of 182 brain donors with MS (2,6). We found an unexpected high percentage (57%) of lesions with innate inflammatory activity, showing ongoing demyelination in this cohort with a mean disease duration of 29 (2-64) years. 78% of the brain donors still had inflammatory active MS lesions. The proportion of these active MS lesions strongly correlated with disease severity, demonstrating the burden of these active lesions for disease progression. This finding was unexpected, since on MRI no gadolinium enhanced lesions are visible late in MS and anti-inflammatory treatment is not effective in the secondary chronic phase of the disease. Males have more of these inflammatory active MS lesions and more MS lesions in the cortical grey matter as compared to females.
Also T and B cells infiltrate the CNS in late stages in MS. MS brain donors show an increased number of T cells in normal-appearing white matter, and the number of T cells is further increased in inflammatory active MS lesions. 15% of the MS patients even show larger perivascular lymphocyte cuffs, correlating with more lesion activity and a progressive disease course. The T cells are mainly CD8-positive and have a tissue resident memory effector cell (Trm) phenotype. And while they stay perivascular in healthy controls, they infiltrate the parenchyma in inflammatory active MS lesions, suggesting involvement in MS-lesions formation and/or expansion (3). Thus, both innate and adaptive immune responses are ongoing in the late stages of
disease. This insight may open new possibilities for the development of immunomodulatory therapies for the late stages of MS, for which there is currently no treatment available.
Our group also studies the initiation phase of MS. We found that microglia are already altered in normal-appearing white and grey matter, indicative for early myelin uptake, which was confirmed by whole tissue analyses. Also in tissue adjacent to active expanding lesions early signs of myelin uptake are present (1,4, 5). What is driving these early changes is currently not known. We postulate that small clusters of microglia and associated T cells that we find in MS patients are the initiation points of lesion development
A final focus of our research is the repair seen in some MS patients. Of the 182 brain donors in our MS cohort, the majority had a progressive disease course, and only 14 had a relapsing–remitting disease course. These relapsing–remitting patients had a significantly higher proportion of remyelinating lesions and less mixed active/inactive lesions. We hypothesize that the relapsing–remitting patients have a higher potential to remyelinate and therefore have less mixed active/inactive lesions.
The clinically, pathologically, and genetically well-characterized post-mortem brain autopsy cohort of MS donors of the NBB provides a worldwide unique opportunity to analyze disease heterogeneity in MS and identify cellular and molecular mechanisms of disease to eventually improve diagnosis and treatment of MS.

Aim of the project

To explore the heterogeneity of neuro-axonal loss and damagein the MS autopsy cohort in relation to clinico-pathological characteristics, to study (early) axonal and myelin changes in different stages of MS lesion development, and to identify factors that promote remyelination of MS lesions.

Work plan

  1. Analyze the MS-autopsy cohort for neuroaxonal loss and damage in relation to MS-lesion load and activity as well as clinical disease severity
  2. Study microglia nodules in normal-appearing white matter using RNA sequencing and immunohistochemistry
  3. Compare lesions from relapsing–remitting and progressive MS brain donors for (mechanisms underlying) remyelinating activity

Techniques

  • Quantitative immunohistochemistry
  • mRNA and hnRNA sequencing, qPCR
  • Laser-dissection microscopy

References

  1. Hendrickx DAE, van Scheppingen J, van der Poel M, Bossers K, Schuurman KG, van Eden CG, Hol EM, Hamann J, Huitinga I. Gene Expression Profiling of Multiple Sclerosis Pathology Identifies Early Patterns of Demyelination Surrounding Chronic Active Lesions. Front Immunol. 8 (2017)1810.
  2. Luchetti S, Fransen NL, van Eden CG, Ramaglia V, Mason M and Huitinga I. Progressive Multiple Sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis. Acta Neuropathol. 135 (2018) 511-528.
  3. Smolders J Heutinck KM, Fransen NL, Remmerswaal EB, Hombrink P, Ten Berge IJM, van Lier RAW, Huitinga I, Hamann J. Tissue-resident memory T cells populate the human brain. Nat Commun. 9(2018)4593.
  4. van der Poel M, Ulas T, Mizee MR, Hsiao C, Miedema SSM, Adelia A, Schuurman KA, Helder B, Tas SW, Schultze JL, Hamann J and Huitinga I. Transcriptional profiling of human microglia reveals grey–white matter heterogeneity and multiple sclerosis-associated changes. Nat. Comm. 10(2019)1139.
  5. Melief J, Orre M, Bossers K, van Eden CG, Schuurman KG, Mason MRJ, Verhaagen J, Hamann J, Huitinga I. Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis. Acta Neuropathol Commun. 7(2019)60.
  6. Fransen NL, Crusius JBA, Smolders J, Mizee MR, van Eden CG, Luchetti S, Remmerswaal EBM, Hamann J, Mason MRJ, Huitinga I. Post-mortem multiple sclerosis lesion pathology is influenced by single nucleotide polymorphisms. Brain Pathol. 2019 Jun 22. doi: 10.1111/bpa.12760. [Epub ahead of print]

Profile

We are looking for a candidate with a neurobiological or medical background and a keen interest in neurological diseases. Experience with the analysis of human brain tissue and molecular techniques is appreciated.

Information

For further information about the project please contact Inge Huitinga: i.huitinga@nin.knaw.nl, tel. +31205665521.