PD-1 Regulates Neural Damage in Oligodendroglia-Induced Inflammation

Abstract

We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes associated with immune homeostasis and autoimmunity. PLPtg/PD-1-deficient double mutants and the corresponding bone marrow chimeras were generated and analysed using immunohistochemistry, light- and electron microscopy, with particular emphasis on immune-cell number and neural damage. In addition, the immune cells in both the CNS and the peripheral immune system were investigated by IFN-gamma elispot assays and spectratype analysis. We found that mice with combined pathology exhibited significantly increased numbers of CD4+ and CD8+ T-lymphocytes in the CNS. Lack of PD-1 substantially aggravated the pathological phenotype of the PLPtg mutants compared to genuine PLPtg mutants, whereas the PD-1 deletion alone did not cause alterations in the CNS. CNS T-lymphocytes in PLPtg/PD-1-/- double mutants exhibited massive clonal expansions. Furthermore, PD-1 deficiency was associated with a significantly higher propensity of CNS but not peripheral CD8+ T-cells to secrete proinflammatory cytokines. PD-1 could be identified as a crucial player of tissue homeostasis and immune-mediated damage in a model of oligodendropathy-induced inflammation. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. Our finding may have implications for understanding the mechanisms leading to the high clinical variability of polygenic or even monogenic disorders of the nervous system.

Accelerated Course of Experimental Autoimmune Encephalomyelitis in PD-1-Deficient Central Nervous System Myelin Mutants

“…12 When investigating healthy 12-month-old PD-1 Ϫ/Ϫ and PLPtg/PD-1 Ϫ/Ϫ mice, we always detected higher numbers of peaks, 6 -9 indicating oligoclonal expansions, but no significant differences between these two groups. 24 To our knowledge, this is the first study describing clonal expansions in BL/6 mice during EAE. Interestingly, there was no difference in the number of oligoclonal expansions between PLPtg and wild-type mice, which both displayed approximately eight to nine oligoclonal expansions, whereas in the absence of PD-1, independent from an additional myelin mutation, the number was approximately twice as high (17 and 15, respectively).…”

“…Second, the absence of the coinhibitory molecule PD-1 induced a stronger inflammatory stimulus, and the combination of both culprits resulted in the accelerated, stable, homogenous exacerbation of disease. Importantly, the combination of the two factors without EAE induction already led to an aggravation of myelin and axon damage 24 but at a much later time point. It is tempting to speculate that, in the young double mutants, a not yet visible predisposition for severe inflammatory disease progression already exists and becomes triggered by EAE induction.…”

“…PD-1 deficient mice develop spontaneous strain-dependent autoimmune diseases such as lupus-like disease in C57/ BL/6 mice 19 or autoantibody-mediated cardiomyopathy in BALB/c mice. 20 Similarly, blockade and deletion of PD-1 has been shown to result in exacerbation of diseases such as EAE, 21,22 inherited peripheral nerve, 23 and CNS demyelination, 24 diabetes, 25,26 or allograft rejection. 27 Our group could demonstrate that a PD-1 polymorphism was associated with a progressive disease course of MS, 28 indicating that PD-1 acts as a disease-modifying factor in human autoimmunity.…”

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

“…PD-1 and its ligands were found to be strongly expressed on immune infiltrates in the CNS during the peak phase of EAE (9)(10)(11). In EAE studies, PD-1-deficient mice or the use of blocking antibodies that inhibit PD-1 engagement by ligands resulted in earlier disease onset, increased inflammatory infiltrates, and increased severity of clinical symptoms compared with normal disease progression (10)(11)(12)(13)(14)(15)(16). It has been demonstrated that ligand engagement of PD-1 inhibits T-cell activation, expansion, and cytokine production (17)(18)(19).…”

Effect of postlactation iron deficiency on the composition of fatty acids of whole brain myelin

“…8,9 By histological luxol fast staining, a severely reduced myelin was observed in rat pups born from irondeficient dams, 10 and mice made iron deficient from gestation up to the postnatal age of 75 days showed significant alterations in myelin fatty acid composition compared to control and iron-replete groups. 11 In Sprague-Dawley rats, alterations of myelin molecular and metabolic activity markers as well as in fatty acid composition were determined in hind brain myelin from pre-and postweaning pups, 12 alterations which behaviourally were mirrored by an experimental animal model.…”