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Multiple sclerosis (MS) and stroke share a number of mechanisms of neuronal damage. In both cases the balance between neurodestruction and neuroprotection appears modulated by the function of the adaptive immune system. MS is a chronic inflammatory disease of the central nervous system (CNS), leading to permanent disability. It seems certain that an autoimmune response directed against the CNS is central to the pathogenesis of the disease. While these CNS-specific T cells are activated in MS patients, they are inactive and naive in healthy. Therefore it is believed that an activation of autoreactive T cells by cross-reactivity with pathogens occurs outside of the CNS. In consequence T cells express adhesion molecules and proteinases which enable them to cross the blood-brain barrier. In stroke, however, the blood-brain barrier is disturbed in its integrity caused by the decreased blood flow. Cells can freely migrate from the periphery into the brain. CNS autoreactive cells from the periphery can be activated within the CNS and thus contribute to further tissue damage. While the local autoimmune response remains temporary in stroked brains, it is chronically destroyed in MS. The differences between the underlying mechanisms are not understood. This thesis investigated T cell responses in Multiple Sclerosis in response to the therapeutics Mitoxantrone and IFN-b. The induction of a TH1 to TH2 cytokine response appears to be a shared mechanism of action between both therapeutic agents. Primarily the post stroke immune response was investigated. Patients developed a stroke induced immune suppression characterized by monocytic dysfunction and lymphocytopenia explaining the high frequency of post stroke infections. Moreover early post stroke predictors of subsequent infections, like the CD4+ T cell count, were identified. The T cell response of stroke patients appeared primed to proinflammation and unsuppressed after mitogen stimulation. A detailed understanding of post stroke immune alterations may offer new avenues of intervention to improve the clinical fate of stroke victims. In addition, such knowledge could also further our understanding of Multiple Sclerosis, because, while increasing the infection risk, the dampening of the immune system could have an important protective function, if it limits autoimmune brain damage triggered by the massive release of brain antigens during stroke. If these two pathways could be modulated separately it would create the opportunity to develop distinct therapeutic approaches that inhibit autoimmunity and strengthen antibacterial defenses. To further delineate these mechanisms it is crucial to investigate the role of the innate immune system as compared to the adaptive immune system in stroke induced immune suppression.
The Effect of the Patients Nutritional Status on Immune Alterations Induced by Ischemic Stroke
(2018)
Ischemic stroke is one of the leading causes of death and disability throughout the world.
One important aspect of stroke pathophysiology are immunological changes after stroke, especially a combination of post stroke immunodepression, leading to
infectious complications after stroke and an activation of the immune system, leading to cerebral injury. Adipose tissue has several immunological functions and obesity
leads to immunological complications and is accompanied by a chronic immune activation.
To study the effects of body weight and obesity on the immune system and measure weight and fat tissue changes after ischemic stroke we conducted the LIPS Trial and enrolled 50 stroke patients and 16 control subjects between July 2015 and July 2016. On the day of admission and on the days 1, 2, 3, 4, 5, 7, 30, 90 and 180 after admission stroke patients were weighed with an in-bed scale, body composition was measured with BIA, the triceps-skin fold thickness was measured, the NIHSS scale was obtained and blood was drawn. FACS-analysis was performed and triglycerides,cholesterol, CRP and PCT were measured at the central laboratory facility of the Universitätsmedizin Greifswald. Luminex-multiplex analysis for multiple cyto- and chemokines was performed at the Multiplex Facility at the University Leiden. A cerebral MRI and an abdominal MRI were performed shortly after admission and on days 5-7 for most patients and the infarct volume, abdominal fat and hepatic fat percentage were measured. On days 30, 90 and 180 after stroke Bartel Index and mRS were obtained.
After stroke our patients showed the typical immunological changes described previously as stroke induced immune alterations, namely a post stroke immunodepression as well as signs of an activated immune system and an acute
phase response. Our patients lost weight, but only 1.7 ± 0.5 kg. Skinfold thickness did not change during the course of our trial and abdominal fat measurement did not change in stroke patients. Immunological parameters (leukocytes, neutrophils,CRP, PCT, IL-6) did not differ between BMI subgroups (normal weight: BMI < 25,overweight: BMI ≥ 25, < 30, obese: BMI ≥ 30) and in this trial we could not detect a
difference in patients with normal weight, overweight or obesity in the post stroke periode. In an additional analysis we could show that rapid clinical improvement
did result in a rapid improvement of post stroke immune alterations, especially for leukocytes, neutrophils, IL-6 and CRP.
The proteasome is a major part of the ubiquitin-proteasome-system playing an important role in cell homeostasis due to its protein quality control function. Moreover, the proteasome is involved in cell cycle regulation and in the regulation of transcription factors. Upon induction of interferons, or treatment with lipopolysaccharides, an isoform of the standard-proteasome is composed, named immunoproteasome (i-proteasome). The i-proteasome is constitutively expressed in immune cells and deficiency of proteolytic subunits of this multiprotein complex has been associated with a poor outcome during infectious diseases. I-proteasome-deficiency has been shown to result in reduced MHC class I presentation. Using mice which are deficient for all three proteolytic active subunits LMP2, MECL-1 and LMP7, we could demonstrate that i-proteasome-deficiency lead to an altered recruitment of immune cells to the CNS when challenged with the intracellular parasite Toxoplasma gondii, resulting in increased frequencies of neutrophils and other cells of myeloid origin. The shift to reduced frequencies of CD45highCD11blow lymphocytes can be further explained by a decreased migratory capacity of i-proteasome-deficient CD8+ T cells. In contrast to previous studies using other pathogens, effector function of CD8+ as well as CD4+ T cells, measured by frequencies of IFNγ, TNF, IL-2 and granzyme B producing cells, were not impaired in these mice, whereas induction of CD4+ Tregs was strongly reduced. In addition, we found that parasite control was comparable to control mice and that i-proteasome deletion caused an overall pro-inflammatory cytokine milieu within the brain. Our results indicate that i-proteasome-deficiency lead to prolonged tissue inflammation during T. gondii infection which could be an explanation for the more severe course of disease observed in these mice.
The Src homology domain containing phosphatase 2 (SHP2) is a tyrosine phosphatase modulating several signaling pathways and therefore has an influence in cell cycle, differentiation, proliferation and cell activation. However, SHP2 is assumed to play a negative role during T-cell activation as the phosphatase has been shown to inhibit T-cell receptor-induced signaling cascades. Although, various gain-of-function mutations in the SH2 or PTP domain of this phosphatase, such as D61Y, have been associated with myeloproliferative diseases such as juvenile myelomonocytic leukemia (JMML), effects of such mutations on T cells have not been addressed in scientific literature so far. Therefore, in the second part of this thesis we could demonstrate that D61Y mutation in the SH2 domain of SHP2 did not cause JMML pathology when only introduced into T cells. Especially in aged mice, T cells of SHP2 mutant mice showed an increased expression of cell adhesion molecule CD44. In accordance with these findings, we observed increased influenza A virus-specific T cells in the bone marrow of SHP2 D61Y mutant mice, indicating a role of the phosphatase in memory formation or maintenance of CD8+ Tem. Although SHP2D61Y mice revealed a comparable viral clearance, IFNγ production of virus experienced CD4+ and CD8+ T cells was diminished compared to control mice, underlining a negative involvement of the phosphatase in the JAK/STAT1 signaling axis as suggested before by studies using mice with SHP2-/- T cells.