Abundant kif21b is associated with accelerated progression in neurodegenerative diseases

Kinesin family member 21b (kif21b) is one of the few multiple sclerosis (MS) risk genes with a presumed central nervous system function. Kif21b belongs to the kinesin family, proteins involved in intracellular transport of proteins and organelles. We hypothesised that kif21b is involved in the neurodegenerative component of MS and Alzheimer¿s (AD) disease. Post-mortem kinesin expression was assessed in 50 MS, 58 age and gender matched non-demented controls (NDC) and 50 AD. Kif21b expression was five-fold increased in AD compared to MS and NDC aged below 62 years (p¿=¿8*10¿5), three-fold between 62¿72 years (p¿=¿0.005) and not different above 72 years. No significant differences were observed between MS and NDC. In AD, kif21b expression was two-fold increased in Braak stage 6 (scoring for density of neurofibrillary tangles) compared with stage 5 (p¿=¿0.003). In MS patients, kif21b correlated with the extent of grey matter demyelination (Spearman¿s rho¿=¿0.31, p¿=¿0.03). Abundant kif21b, defined as expression above the median, was associated with a two-fold accelerated development of the Kurtzke Expanded Disability Status Scale (EDSS) 6.0 (median time in low kif21b group 16 years vs. high kif21b 7.5 years, log-rank test p¿=¿0.04) in MS. Given the genetic association of kif21b with MS, the results were stratified according to rs12122721[A] single nucleotide polymorphism (SNP). No association was found between kif21b expression or the time to EDSS 6 in kif21b risk SNP carriers compared to non-risk carriers. Kif21b was expressed in astrocytes in addition to neurons. Upon astrocyte activation, kif21b increased nine-fold. Abundant kif21b expression is associated with severe MS and AD pathology and with accelerated neurodegeneration independent of the kif21b risk SNP

Differential Runx3, Eomes, and T-bet expression subdivides MS-associated CD4⁺ T cells with brain-homing capacity

Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the CNS. CD4 + T cells are assumed to be the first to cross the blood–central nervous system (CNS) barrier and trigger local inflammation. Here, we explored how pathogenicity-associated effector programs define CD4 + T cell subsets with brain-homing ability in MS. Runx3- and Eomes-, but not T-bet-expressing CD4 + memory cells were diminished in the blood of MS patients. This decline reversed following natalizumab treatment and was supported by a Runx3 +Eomes +T-bet − enrichment in cerebrospinal fluid samples of treatment-naïve MS patients. This transcription factor profile was associated with high granzyme K (GZMK) and CCR5 levels and was most prominent in Th17.1 cells (CCR6 +CXCR3 +CCR4 −/dim). Previously published CD28 − CD4 T cells were characterized by a Runx3 +Eomes −T-bet + phenotype that coincided with intermediate CCR5 and a higher granzyme B (GZMB) and perforin expression, indicating the presence of two separate subsets. Under steady-state conditions, granzyme K high Th17.1 cells spontaneously passed the blood–brain barrier in vitro. This was only found for other subsets including CD28 − cells when using inflamed barriers. Altogether, CD4 + T cells contain small fractions with separate pathogenic features, of which Th17.1 seems to breach the blood–brain barrier as a possible early event in MS.</p

Differential Runx3, Eomes, and T-bet expression subdivides MS-associated CD4⁺ T cells with brain-homing capacity

Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the CNS. CD4 + T cells are assumed to be the first to cross the blood–central nervous system (CNS) barrier and trigger local inflammation. Here, we explored how pathogenicity-associated effector programs define CD4 + T cell subsets with brain-homing ability in MS. Runx3- and Eomes-, but not T-bet-expressing CD4 + memory cells were diminished in the blood of MS patients. This decline reversed following natalizumab treatment and was supported by a Runx3 +Eomes +T-bet − enrichment in cerebrospinal fluid samples of treatment-naïve MS patients. This transcription factor profile was associated with high granzyme K (GZMK) and CCR5 levels and was most prominent in Th17.1 cells (CCR6 +CXCR3 +CCR4 −/dim). Previously published CD28 − CD4 T cells were characterized by a Runx3 +Eomes −T-bet + phenotype that coincided with intermediate CCR5 and a higher granzyme B (GZMB) and perforin expression, indicating the presence of two separate subsets. Under steady-state conditions, granzyme K high Th17.1 cells spontaneously passed the blood–brain barrier in vitro. This was only found for other subsets including CD28 − cells when using inflamed barriers. Altogether, CD4 + T cells contain small fractions with separate pathogenic features, of which Th17.1 seems to breach the blood–brain barrier as a possible early event in MS.</p

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Drainage of central nervous system (CNS) antigens to the brain-draining cervical lymph nodes (CLN) is likely crucial in the initiation and control of autoimmune responses during multiple sclerosis (MS). We demonstrate neuronal antigens within CLN of MS patients. In monkeys and mice with experimental autoimmune encephalomyelitis (EAE) and in mouse models with non-inflammatory CNS damage, the type and extent of CNS damage was associated with the frequencies of CNS antigens within the cervical lymph nodes. In addition, CNS antigens drained to the spinal-cord-draining lumbar lymph nodes. In human MS CLN, neuronal antigens were present in pro-inflammatory antigen-presenting cells (APC), whereas the majority of myelin-containing cells were anti-inflammatory. This may reflect a different origin of the cells or different drainage mechanisms. Indeed, neuronal antigen-containing cells in human CLN did not express the lymph node homing receptor CCR7, whereas myelin antigen-containing cells in situ and in vitro did. Nevertheless, CLN from EAE-affected CCR7-deficient mice contained equal amounts of myelin and neuronal antigens as wild-type mice. We conclude that the type and frequencies of CNS antigens within the CLN are determined by the type and extent of CNS damage. Furthermore, the presence of myelin and neuronal antigens in functionally distinct APC populations within MS CLN suggests that differential immune responses can be evoked

Improving Glucocorticoid Sensitivity of Brain-Homing CD4+ T Helper Cells by Steroid Hormone Crosstalk

In early multiple sclerosis (MS), an IFN-γhighGM-CSFhighIL-17low CD4+ T-cell subset termed T helper 17.1 (Th17.1) reveals enhanced capacity to infiltrate the central nervous system. Th17.1 cells express high levels of multidrug resistance protein 1 (MDR1), which contributes to their poor glucocorticoid responsiveness. In this study, we explored whether glucocorticoid sensitivity of Th17.1 cells can generically be improved through synergy between steroid hormones, including calcitriol (1,25(OH)2D3), estradiol (E2) and progesterone (P4). We showed that human blood Th17.1 cells were less sensitive to 1,25(OH)2D3 than Th17 cells, as reflected by lower vitamin D receptor (VDR) levels and reduced modulation of MDR1, IFN-γ and GM-CSF expression after 1,25(OH)2D3 exposure. Upon T-cell activation, VDR levels were increased, but still lower in Th17.1 versus Th17 cells, which was accompanied by a 1,25(OH)2D3-mediated decline in MDR1 surface expression as well as secretion of IFN-γ and GM-CSF. In activated Th17.1 cells, 1,25(OH)2D3 amplified the suppressive effects of methylprednisolone (MP) on proliferation, MDR1 surface levels, secretion of IFN-γ and granzyme B, as well as expression of brain-homing markers CCR6 and VLA-4. The addition of P4 to 1,25(OH)2D3 further enhanced MP-mediated reduction in proliferation, CD25, CCR6 and CXCR3. Overall, this study indicates that glucocorticoid sensitivity of Th17.1 cells can be enhanced by treatment with 1,25(OH)2D3 and further improved with P4. Our observations implicate steroid hormone crosstalk as a therapeutic avenue in Th17.1-associated inflammatory diseases including MS

Pregnancy-induced effects on memory B-cell development in multiple sclerosis

Abstract In MS, pathogenic memory B cells infiltrate the brain and develop into antibody-secreting cells. Chemokine receptors not only define their brain-infiltrating capacity, but also assist in their maturation in germinal centers. How this corresponds to pregnancy, as a naturally occurring modifier of MS, is underexplored. Here, we aimed to study the impact of pregnancy on both ex vivo and in vitro B-cell differentiation in MS. The composition and outgrowth of peripheral B cells were compared between 19 MS pregnant patients and 12 healthy controls during the third trimester of pregnancy (low relapse risk) and postpartum (high relapse risk). Transitional, and not naive mature, B-cell frequencies were found to drop in the third trimester, which was most prominent in patients who experienced a pre-pregnancy relapse. Early after delivery, these frequencies raised again, while memory B -cell frequencies modestly declined. CXCR4 was downregulated and CXCR5, CXCR3 and CCR6 were upregulated on postpartum memory B cells, implying enhanced recruitment into germinal center light zones for interaction with T follicular helper (TFH) cells. Postpartum memory B cells of MS patients expressed higher levels of CCR6 and preferentially developed into plasma cells under TFH-like in vitro conditions. These findings imply that memory B- cell differentiation contributes to postpartum relapse risk in MS