Cellular changes and change in cellular physiology are synonymous with any disease. In multiple sclerosis, there are changes in the physiology of nerve cells and immune cells related to cellular immunity specifically but the overall inflammation causes harm to other cells including red blood cells and others are secondary changes caused due to primary responses generated by alterations in the major cells associated with causative factors of multiple sclerosis. On broader changes, there are changes in th-17 cells which will cause alterations in MAIT cells (Mucosa-associated T cells) and mucosa-associated T cells cause a change in astrocytes and dendritic cells. There is the formation of lesions. Changes include a change in the number of cells, function, appearance and others. Certain cells get increased and there are certain which gets decreased such as CD 20+ cells which get decreased during MS whereas tumour cells get substantially increased. There is an increase inTh1 and Th7 cells as well. MS affects cells of the spinal cord as well. It is obvious that cells of the nervous system are responsible for message and stimulus generation as well as transport, demyelination caused by MS leads to alteration in the function. These all changes bring out alteration in self antigenicity.
- Multiple sclerosis is a multifactorial disease that includes genetic factors, biochemical factors, changes in cellular physiology etc. The disease can be caused in a variety of ways.
- There are changes in cells of the immune system such as T cells, B cells, dendritic cells etc that causes the development of disease.
- There is misregulation of certain protein factors and mutation at the transcriptional level that causes the development of the disease.
CHANGES IN CELLULAR PHYSIOLOGY
Changes in T Cells – T cells get hyper-activated and enters the central nervous system. When MS is caused by the virus the mechanism of molecular mimickers come into the picture which induces an autoimmune response. There is a wide variety of T cell targets on which cellular signalling takes place. The activation of T cells is aided by antigen-presenting cells which get activated once antigens get expressed on their surface. They are responsible for the production of mediator molecules which act as a message for the adjacent cells. Apart from the helper and cytotoxic cells, there are regulatory T cells that are involved in the pathogenesis.
Changes in B cells- Proceeding with the study on disease, brought out new modifications which are recently been reported. Oligoclonal bands are being produced by immunoglobulins generated by B cells. There is diversity in the number of immunoglobulins generated in the case of MS. It is found that there is a substantial decrease in the number of IgG but the cellular samples taken from patients had a huge number of IgM antibodies. IgM generated by B cells attacks on the lipid component of antigens (such as a component of the cell wall) causing to generate an inflammation response. B cells also found to generate ectopic follicles which later found to generate lesions. T cell and B cell act in collaboration where B cell cytokine generation activate T cells, changes in T cell activate B cells. B cells generate more amounts of tumour necrosis factor and lymphotoxin. However, B cells sometimes lead to a reduction in autoimmunity level by acting on T cells. In simple words, the Generation of antibodies by B cells in the CNS lead to generating an autoimmune response against the neural cells.
Changes in axon and dendritic cells- Damage is generally in the form of cutting (transection) instead of cellular inactivation. The damage to the axon is most during the initial first year of disease initiation.
Macrophages are found to be near the axonic cells. There is associated neuronal loss including injury in the grey matter. The most affected part includes parvalbumin interneurons. There is a significant reduction in macular volume in multiple sclerosis.
Changes in Antigen-presenting cells – It is the antigen-presenting cells that activate T cells by presenting antigens. The earliest inflammation caused by APC is due to lesions caused by the blood-brain barrier. T cells enter the CNS with the aid of APC. Dendritic cells are APC which are involved in initial activation. Interestingly, APC is involved in tissue repair mechanism as well for example by the generation of suppressor myeloid cells. However TREM 2 proteins most of the times make this effort futile. In pathogenic conditions, these cells are present in perivascular space. MHC 2 type along with co-stimulatory molecules is presented by MHC.
Other cells such as astrocytes, endothelial cells, neutrophils and natural killer cells also undergo certain kind of modifications.
Misregulation in Multiple sclerosis
Certain factors such as TYK2 and STAT 4 have altered transcription during the case of multiple sclerosis where TYK 2 is up-regulated and STAT 4 is down-regulated. Most of the data suggest that genes which are only involved with one fold risk factor associated with IFN signalling are not much conserved; so even if they get dysregulated so might not continue in the later stage of the disease. This has come with the possible situations where interferone may modify itself according to the disease type after the development of the disease. There are certain instances when IFN beta treatment which is given to the blood cells of patients has caused dysregulation of associated transcription factors. Some genes may get dysregulated (related to IFN) and then get related to the therapy. Gene expression profiles associated with interferon and mapping of changes which are caused in the genes is the strategy for studying dysregulation which has brought out that there is a clear cut connection with the transcriptional changes of interferon and inflammation in the cells of the central nervous system. Transcriptome analysis has also brought out that some common IRG targets are misregulated such as the pyrin domain-containing NLRP and nod like receptors. Certain factors and proteins which are important for the survival of T cells are found to be misregulated in the patients such as cytosolic proteins which are required for CD4+ T cells survival. Two genes are involved in encephalomyelitis are also dysregulated in MS. IRF is responsible for EAE expression in PBMC cells in only the SP-MS stage and not all the stages suggesting that interferon dysregulation is not constant during all the stages of the disease.
The relapsing-remitting form of multiple sclerosis has much more to do with transcriptional alterations.
Already 100 IRG has been found and proved to be involved in this. The enzyme which is involved in
the conversion of interleukin (Caspase 1) found to be involved in inflammation and gets upregulated. The gene associated with caspase 1 is overexpressed. S100 A9 takes immune cells to the site of tissue damage. Transcription factors such as MAF which is responsible for T cell differentiation gets overexpressed in RR-MS. ARBP 1 and CHP1 codes for inhibition of factors responsible for T cell activation. This gets upregulated in the diseased patients. It is found that the beta treatment after the condition of MS solves the problem for ARBP 1 and CHP 1 misregulation. This proves that several IRG markers are misregulated in multiple sclerosis.
Kotelnikova, E. et al. (2019) ‘MAPK pathway and B cells overactivation in multiple sclerosis revealed by phosphoproteomics and genomic analysis, Proceedings of the National Academy of Sciences of the United States of America, 116(19), pp. 9671–9676. doi: 10.1073/pnas.1818347116.
Rodrigues, H. (2016) ‘Seismic performance evaluation of non-engineered RC irregular structures Giammarco Neri Humberto Varum Loris Vincenzi’, 1(3), pp. 289–310. doi: 10.1016/j.ncl.2010.12.009.The.