Monitoring Disease Activity in Multiple Sclerosis
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
Cerebrospinal fluid abnormalities are useful in the diagnosis of MS, but like evoked potentials are of limited value for monitoring disease activity. A high percentage of patients with MS will ultimately have elevated immunoglobulins and oligoclonal bands in the cerebrospinal fluid. While oligoclonal bands may be absent early in the disease, once present they remain. There is no correlation with severity, disease activity or duration.48 Immunoglobulin levels may increase over time, but there is no correlation of intrathecal IgG production and disease activity.6 Intravenous methylprednisolone decreased IgG synthesis in the CSF.49 CSF myelin basic protein levels fluctuate, including reports on increased levels during clinical activity.50 Myelin basic protein levels correlate with MRI disease activity.51 Myelin basic protein-like material in the CSF may predict response to glucocorticoids. However, myelin basic protein is not disease specific. Further, assays for myelin basic protein and oligoclonal bands are quite variable between laboratories limiting their use for disease monitoring. Accessing fluid is cumbersome and not without complications. Cytokines, chemokines and adhesion molecules are being investigated as potential markers to follow disease activity. At this time, there are no standardized, reliable markers available for large clinical trials, but many warrant further investigation.
Immunotherapeutic Approaches for Multiple Sclerosis*
George S. Eisenbarth in Immunotherapy of Diabetes and Selected Autoimmune Diseases, 2019
Copl is a synthetic peptide developed by scientists at the Weizmann Institute in the early 1970s, which was nonencephalitogenic and was effective in the treatment of EAE.23 It was originally designed as a myelin basic protein analog. Preliminary clinical trials did not show clear positive effects in MS,99 but a recent double-blind pilot trial in MS patients with early relapsing-remitting disease demonstrated a decrease in relapses, and an effect on disability in patients with Kurtzke disability scores of 0 to 2, i.e., those with virtually normal neurologic examinations.100,101 The drug did not affect disability in more severely affected patients. The mechanism of Copl action in MS is unknown, and there is no evidence at present that it works in humans by affecting myelin basic protein reactive cells,102 although Copl does have nonspecific immunologic effects on human lymphocytes.103 A larger trial to establish efficacy in early relapsing-remitting patients is planned, and a pilot trial in progressive MS is in progress. Copl is currently not available outside of ongoing clinical trials. One of the most important conceptual points to emerge from the Copl study is that it represents a nontoxic form of therapy that can be administered early in the course of the disease, and was conceptualized as an antigen-specific form of therapy. This is clearly the direction in which investigators would like to proceed as new forms of immunotherapy are developed.
Changes in Gene Expression During Aging of Mammals
Alvaro Macieira-Coelho in Molecular Basis of Aging, 2017
Alternative splicing of pre-mRNA is known to produce different mRNAs that are translated into different isoforms of a protein. Most pre-mRNAs transcribed from split genes are spliced in such a way that the original order of arrangement of the exons are maintained in the mature mRNAs. This is constitutive splicing. Some pre-mRNAs, however, are spliced in more than one way, thereby yielding a family of structurally related mRNAs that are translated into a family of protein isoforms. This is alternative splicing. Such splicing is seen in all organisms including humans, and occurs in several types of transcripts that encode varieties of proteins. This is a means of diversifying the output from a single gene without altering its genomic organization. In some cases, alternatively spliced mRNAs are produced concurrently in the same tissue, and several protein isoforms may perform the same or different functions. For example, four myelin basic protein isoforms derived from a single gene are all components of the myelin sheath. Some gene transcripts are spliced differently in different tissues. For example, the single mammalian calcitonin gene expresses calcitonin in the thyroid, but in the brain a different isoform is produced by a separate splicing pattern.
Curcumin promotes functional recovery and inhibits neuronal apoptosis after spinal cord injury through the modulation of autophagy
Published in The Journal of Spinal Cord Medicine, 2021
Weichao Li, Shaoping Yao, Hongrong Li, Zengdong Meng, Xianrun Sun
Our histopathological examination revealed that Iba-1 signal intensity in the DMSO group was approximately 3-fold higher than in the sham control group (P < 0.05) and more than 1-fold lower in the curcumin treatment group compared to the DMSO group (P < 0.05). Likewise, the percentage of GFAP-positive cells was significantly increased in the DMSO group and significantly decreased in the curcumin treatment group (both P < 0.05) (Fig. 2A). To determine the effect of curcumin on the inflammatory response, ELISAs were performed to determine inflammatory cytokine concentrations. TNF-α, IL-6, and IL-1β were significantly higher in the DMSO group (P < 0.01) compared to the sham group, and their levels were remarkably reduced (P < 0.01) with curcumin treatment compared to DMSO alone (Fig. 2B). In addition, myelination of nerves was determined by examining the expression level of myelin basic protein (MBP) by immunohistochemical staining analysis. MBP was lower (P < 0.01) in the DMSO group than the sham controls, but significantly higher (P < 0.05) in the curcumin treatment group compared to the DMSO group (Fig. 2C). The effect of curcumin on spinal cord edema was assessed with the wet/dry ratio method. The results showed that the spinal cord water content was higher in the DMSO group compared to the sham controls (P < 0.05) but was significantly lower in the curcumin treatment group compared to the DMSO group (P < 0.05) (Fig. 2D).
Tofacitinib enhances remyelination and improves myelin integrity in cuprizone-induced mice
Published in Immunopharmacology and Immunotoxicology, 2021
Caner Günaydın, M. Emin Önger, Bahattin Avcı, Ayhan Bozkurt, Murat Terzi, S. Sırrı Bilge
The MS pathophysiology hallmarks are loss of myelin sheath, oligodendrocytes, microglia, and astrocyte activation, which fails remyelination [20]. These mechanisms deter axonal conductivity and cause resulting disability seen in MS patients. However, different animal models were proposed to mimic MS physiopathology and clinical symptoms, and cuprizone offers the advantage of studying the central process and remyelination during disease pathogenesis [6]. Extensively myelinated areas in the brain are heavily affected and caused significant loss in the MBP. Based on the knowledge that chronic inflammation and severe tissue damage at the chronic stage of MS, therapeutic candidates, and mechanisms should be investigated for central and peripheral actions. However, contradictory reports demonstrated JAK/STAT inhibitor therapy's effects in different models of MS [14,21].
Enhanced cerebellar myelination with concomitant iron elevation and ultrastructural irregularities following prenatal exposure to ambient particulate matter in the mouse
Published in Inhalation Toxicology, 2018
Carolyn Klocke, Valeriia Sherina, Uschi M. Graham, Jakob Gunderson, Joshua L. Allen, Marissa Sobolewski, Jason L. Blum, Judith T. Zelikoff, Deborah A. Cory-Slechta
Immunohistochemical detection of myelin basic protein (MBP) was performed as described previously (Klocke et al., 2017). Briefly, whole brains (N = 6–11/sex/exposure group; total N = 33) were extracted at PNDs 11–15 following rapid decapitation and fixed in 4% paraformaldehyde (PFA) for 24 h and post-fixed in 30% sucrose. Post-fixed brains were sectioned sagittally at 40 μm in a 6-series on a freezing-sliding microtome into cryoprotectant and stored at −20 °C until staining. Free-floating sections were washed to remove cryoprotectant and quench endogenous peroxidases, then blocked in 10% normal goat serum (NGS) followed by overnight incubation in a solution containing primary antibody against MBP (1:1000; Millipore, Billerica, MA) and 1% NGS. A single well of tissue incubated overnight in 1% NGS without primary antibody served as a negative control. Tissue was incubated with biotinylated secondary antibody and Vectastain ABC solution (Vector Labs, Burlingame, CA) the following day. Chromogenic antibody detection was then performed using metal-enhanced 3,3′-diaminobenzidinetetrahydrochloride (DAB; Sigma Aldrich, St. Louis, MO). Tissue sections were mounted onto Superfrost Plus slides (VWR, Radnor, PA) and coverslipped with Cytoseal 60 (Thermo Fisher Scientific, Waltham, MA).
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