Mohsen Khademi

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Papers by Mohsen Khademi

γ-secretase directly sheds the survival receptor BCMA from plasma cells

Nature Communications, 2015

Survival of plasma cells is regulated by B-cell maturation antigen (BCMA), a membrane-bound recep... more Survival of plasma cells is regulated by B-cell maturation antigen (BCMA), a membrane-bound receptor activated by its agonist ligands BAFF and APRIL. Here we report that γ-secretase directly cleaves BCMA, without prior truncation by another protease. This direct shedding is facilitated by the short length of BCMA’s extracellular domain. In vitro, γ-secretase reduces BCMA-mediated NF-κB activation. In addition, γ-secretase releases soluble BCMA (sBCMA) that acts as a decoy neutralizing APRIL. In vivo, inhibition of γ-secretase enhances BCMA surface expression in plasma cells and increases their number in the bone marrow. Furthermore, in multiple sclerosis, sBCMA levels in spinal fluid are elevated and associated with intracerebral IgG production; in systemic lupus erythematosus, sBCMA levels in serum are elevated and correlate with disease activity. Together, shedding of BCMA by γ-secretase controls plasma cells in the bone marrow and yields a potential biomarker for B-cell involveme...

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Complement Component C3 and Butyrylcholinesterase Activity Are Associated with Neurodegeneration and Clinical Disability in Multiple Sclerosis

PloS one, 2015

Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating ... more Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with ≥9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity di...

Age-dependent effects on the treatment response of natalizumab in MS patients

Multiple sclerosis (Houndmills, Basingstoke, England), 2015

Natalizumab is approved for treatment of active forms of relapsing-remitting multiple sclerosis (... more Natalizumab is approved for treatment of active forms of relapsing-remitting multiple sclerosis (MS) based on a pivotal phase III study comprising patients aged 18-50 years. The effect of natalizumab has not been specifically studied in older patients. We analyzed age-dependent effects on treatment-related outcome measures in 1872 patients, 189 of whom were aged 50 or more, included in the Swedish post-marketing natalizumab surveillance program. In three MS centers registry data for patients aged >50 years were validated. At baseline older patients had longer disease duration, higher Expanded Disability Status Scale (EDSS) and lower Symbol Digit Modality Test (SDMT) scores than younger patients. The influence from natalizumab on outcome measures was significantly reduced and 18.7% of patients >50 years stopped treatment for lack of effect compared to 7.7% in the younger age group. At baseline, the cerebrospinal fluid levels of the chemokine CXCL13 and the leukocyte cell count ...

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Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study

Multiple sclerosis (Houndmills, Basingstoke, England), Jan 13, 2015

We explored which clinical and biochemical variables predict conversion from clinically isolated ... more We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year ...

No evidence of IL21 association with multiple sclerosis in a Swedish population

Tissue Antigens, 2011

Multiple sclerosis (MS) patients, with a second autoimmune disease after lymphocyte depletion, ha... more Multiple sclerosis (MS) patients, with a second autoimmune disease after lymphocyte depletion, had elevated serum IL‐21 before and after treatment which correlated to IL21 genotypes. In addition, the IL21 gene has been associated to several other autoimmune diseases. However, in a Spanish population there was no association to MS. Here, in a Swedish cohort (2090 MS cases and 1732 controls) 12 single nucleotide polymorphisms (SNPs) tagging IL21 were not associated to disease. There was no interaction with risk alleles of IL21R and HLA‐DRB1*15. Lack of genetic association was confirmed in a meta‐analysis with pooled data from the present study and the Spanish study. In conclusion, IL21 has not been shown to be a major risk gene for MS.

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Strain dependent differences in the inflammatory response to mechanical nerve injuries

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Nitric oxide formation in neuropsychiatric lupus erythematosus

Chronic inflammation in the central nervous system might be the cause of the complex symptomatology in the post-polio syndrome

Increased expression of IL-10, TNF, and IL-23 but no major Th1-Th2 shift in interferon-treated MS

Abnormally low surface CTLA4 expression on CD25hi CD4+ T cells correlates with Foxp3 mRNA expression and is normalised by treatment with interferon-beta

Pro-inflammatory and immunoregulatory cytokines in interferon-treated multiple sclerosis

Global expression profiling in multiple sclerosis: a disease of the central nervous system, but with relapses triggered in the periphery?

Altered monocyte phenotype with decreased vascular endothelial growth factor-A in progressive multiple sclerosis

Multivariate analysis of inflammatory and neuronal injury markers in cerebrospinal fluid of multiple sclerosis: higher levels are associated with younger age

Multivariate analysis of inflammatory and neuronal injury markers in cerebrospinal fluid of multi... more

Genetic Risk Variants in Multiple Sclerosis and Gene Expression in Stimulated Peripheral Blood Mononuclear Cells

Follicular T-helper cell activation in progressive multiple sclerosis

Posttranslational modifications of myelin antigens and their role in MS pathology

Secondary progressive multiple sclerosis is associated with an altered monocyte phenotype

Correction: Systemic Inflammation in Progressive Multiple Sclerosis Involves Follicular T-Helper, Th17-and Activated B-Cells and Correlates with Progression

by Mohsen Khademi and J. Christensen

Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation in... more Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation including Th17-cells and meningeal inflammation with ectopic lymphoid follicles, B-cells and plasma cells, the latter indicating a possible role of the newly identified subset of follicular T-helper (T FH) cells. Although previous studies reported increased systemic inflammation in progressive MS it remains unclear whether systemic inflammation contributes to disease progression and intrathecal inflammation. This study aimed to investigate systemic inflammation in progressive MS and its relationship with disease progression, using flow cytometry and gene expression analysis of CD4 + and CD8 + T-cells, B-cells, monocytes and dendritic cells. Furthermore, gene expression of cerebrospinal fluid cells was studied. Flow cytometry studies revealed increased frequencies of ICOS + T FH-cells in peripheral blood from relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients. All MS subtypes had decreased frequencies of Th1 T FH-cells, while primary progressive (PPMS) MS patients had increased frequency of Th17 T FH-cells. The Th17-subset, interleukin-23-receptor + CD4 + T-cells, was significantly increased in PPMS and SPMS. In the analysis of B-cells, we found a significant increase of plasmablasts and DC-SIGN + and CD83 + B-cells in SPMS. ICOS + T FH-cells and DC-SIGN + B-cells correlated with disease progression in SPMS patients. Gene expression analysis of peripheral blood cell subsets substantiated the flow cytometry findings by demonstrating increased expression of IL21, IL21R and ICOS in CD4 + T-cells in progressive MS. Cerebrospinal fluid cells from RRMS and progressive MS (pooled SPMS and PPMS patients) had increased expression of T FH-cell and plasmablast markers. In conclusion, this study is the first to demonstrate the potential involvement of activated T FH-cells in MS. The increased frequencies of Th17-cells, activated T FHand B-cells parallel findings from pathology studies which, along with the correlation between activated T FH-and B-cells and disease progression, suggest a pathogenic role of systemic inflammation in progressive MS. These observations may have implications for the treatment of progressive MS.

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Soluble BCMA is shed from B cells by gamma-secretase, functions as APRIL-specific decoy and reflects intrathecal Ig-production in multiple sclerosis

We have identified an oral inhibitor of HA production, 4-methylumbelliferone (4-MU), that prevent... more We have identified an oral inhibitor of HA production, 4-methylumbelliferone (4-MU), that prevents development of EAE. We found that treatment with 4-MU significantly decreases the incidence (13/21 vs. 28/30 in untreated animals), delays the onset (24.9 ± 1.5 days post immunization vs. 13.3 ± 0.6 days) and reduces the severity (average score of 1.5 ± 0.1 vs. 2.8 ± 0.2, peak score of 1.9 ± 0.1 vs. 3.6 ± 0.2) of EAE. In addition, 4-MU treatment substantially reduces clinical deficits in already established EAE (average score of 1.9 ± 0.2 vs. 2.8 ± 0.1, peak score of 2.6 ± 0.2 vs. 3.7 ± 0.2). Using multi-parameter flow cytometry, we further analyzed the immunological mechanism of this therapeutic effect. We found that 4-MU treatment skews the immune response towards an antiinflammatory profile, characterized by an increase in the number of FoxP3 + regulatory T-cells. Together, our data provides the therapeutic profile and immunological mechanism of 4-MU treatment in EAE. Considering that 4-MU is already an approved drug currently used in people throughout Europe and Asia, we therefore propose that 4-MU has great promise for the treatment of MS.

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γ-secretase directly sheds the survival receptor BCMA from plasma cells

Nature Communications, 2015

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Complement Component C3 and Butyrylcholinesterase Activity Are Associated with Neurodegeneration and Clinical Disability in Multiple Sclerosis

PloS one, 2015