Epidemiology
This article is all about the introduction, epidemiology, etiology, histopathology, pathophysiology, history as well as physical nature, evaluation methods, treatment management, differential diagnosis, prognosis, as well as complications related to the disease pemphigus vulgaris (PV). This particular disease is an autoimmune disorder which can give rise to blisters on the outer surface of the body such as mucosal layer and cutaneous surface (Porro, Adriana Maria et al.). The disease PV is not considered as a contagious one but there are certain aspects which links the occurrence of PV in patients who has previous autoimmune diseases.
Although the etiology of this disease is not yet confirmed but it has been shown in multiple experiments that there is a genetic link to the disease onset. The HLA Class II alleles such as HLA DRB is known to be associated with Ashkenazi Jews and non-Jews patients. But there are other environmental factors which is also associated with the disease onset. PV is prevalent worldwide but there are certain ethnicities and geographic locations in which the disease prevalence is comparatively higher. In Ashkenazi Jewish people the disease occurrence is seem to be more around the age of 40 and 60. People residing in regions such as South East Europe, Middle East, India is at a higher chance of getting this disease (Kridin, Khalaf, and Enno Schmidt). The disease is equally prevalent in men and women with exceptions such as in Tunisia the occurrence in women is higher than the men.
The diseases caused by the circulating antibody attacking the keratinocytes adhesion thus resulting in acantholysis forming blisters. In recent studies autoantibodies against desmoglein have been shown to be responsible in damaging cell adhesion and in pathogenesis of this disease. The inhibition of desmoglein function affects the cell-cell adhesion and signaling pathways and further downstream processes. So, reduction in the number of circulating IgG can result in improvement in the disease. Another theory suggests that the circulating antibodies binds to each other preventing the cell adhesion mediated by desmoglein instead of directly binding to the desmoglein molecule. The genetic alleles such as DRB shown to be associated with the disease, in such patients there is a higher occurrence of circulating PV-Ig G. Other pre-exposure to particular medications such as penicillamine, captopril can facilitate the PV occurrence. These drugs interfere with the cell adhesion molecules and onset of disease. Other drugs such as nonsteroidal anti-inflammatory drugs, penicillin etc. also known to be causing PV and some foods such as garlic, pepper, red wine also is associated with the disease occurrence.
The confirmation of the disease pemphigus vulgaris is done by doing a biopsy of the blister which will confirm the acantholysis process. Doing immunofluorescence is a standard protocol in the diagnosis off the disease, ELISA testing is also available which will detect the circulating serum antibody against the desmoglein proteins (Russo, Irene et al.). The disease first occurred at the oral mucosa in around 80% of scenarios. The rapturing of the blisters is very painful in most of the patients with disease symptoms oral blisters is seen. The pain and suffering associated with the disease can impair the nutritional choices in the patients. Other mucosal surface such as nasal mucosa, larynx, vagina, conjunctiva etc. gets affected by PV, the cutaneous layers on face, armpit etc. also get affected. The confirmation of this disease could possibly be done using a biopsy report for direct immunofluorescence, physical observation shown to be positive in nasal, genital mucosal layers. TZANCK smear will also show the acantholysis process and ELISA can show the circulating antibodies. The severity of the disease condition must be assessed in patients and also the chance of getting osteoporosis should be evaluated.
Etiology
The first line of treatment is the systemic corticosteroids in the Pemphigus vulgaris disease and which is one of the principal modes of treatment in PV management (Kridin, Khalaf). It takes multiple weeks for the response to be seen in patients and the dose can be modified when the symptoms are somewhat improved. The second mode of treatment would be with azathioprine and mycophenolate mofetil MMF (Sukanjanapong, Siriorn et al.). The treatment with azathioprine would be stopped in case of no results within 3 months and also several side effects such as bone marrow suppression, pancytopenia etc. is seen with the use of azathioprine. The MMF is effective in reducing the symptoms with some minor side effects such as nausea diarrhea etc. The 3rd mode of treatment would be intravenous administration of immunoglobulin and compounds such as cyclophosphamide, dapsone etc. The treatment with monoclonal antibody such as Rituximab, has shown to be promising but it has a cost burden. Better understanding of the molecules and cytokines involved in this disease could produce better therapeutic options. There are certain complications such as osteoporosis, osteonecrosis associated with the principal treatment mode corticosteroids used in PV and it is been reported in almost 30 to 50% of patients having osteoporosis and 9 to 40% of patients having osteonecrosis.
This article was published with the title “Long-term increase of Kcnn4 potassium channel surface expression on B cells in pemphigus patients after rituximab treatment “. Pemphigus vulgaris (PV) is an autoimmune disorder mediated by B cell which generates auto-antibodies against a cell adhesion molecules desmogleins. In an earlier study anti- CD20 antibody has found to be effective in long duration complete remission with continuous presence of transitional B cells in approximately 59% diseased patient. The disease came back severely after a period of 79 months. In this study the immunological background mechanism that were involved in this long-term remission effect is evaluated. Data of 52 previous patients were involved in three separate clinical trials such as patients treated with anti-CD20 antibody, individuals in complete remission, 3rd subset with partial remission within a period of after 61 months of average follow up.
Peripheral blood mononuclear cells were taken from 16 individual. B cells were then isolated using FACS. Next whole human genomic microarray was applied to analyze gene expression profile. These DNA microarrays were then scanned using DNA microarray scanner. Genespring GX software was explored in determining the mRNA expression by following student’s t- test by avoiding multiple testing. 9 out of 65 transcripts were chosen for data analysis. Real time polymerase chain reaction (RtPCR) was then performed. Potassium (K), calcium (Ca) stimulated channel subfamily (member 4) as well as 3 genes such as actin beta, beta-2 microglobulin, TATA box-binding protein – were found in a separate group of patients. They also had collagen 4A3, collagen 18A1, collagen 4A4, alpha-1, 6-Menosyl-blycopoprotein beta-1, 6-N-acetylglucosaminyltransferase, related to dendritic cell.
Flow cytometry was used to analyze KCNN4 channel on B cell, monoclonal antibodies targeted towards phenotypic markers IgD, IgM, IgG, CD19, CD27, CD24, CD138, CD38, and KCNN4. Analysis of the transcriptomic data has identified as 65 of the transcripts whose presence is unregulated in CR than what compared with IR patients. A gradient oriented sorting of these 6 patients was based upon the magnitude of these 65 transcripts showing a perfect segregation of the two groups CR as well as IR into two separate branches. Three out of 9 mRNA transcripts were confirmed to be differentially expressed as evident from the experiment. The expression of KCNN4, COL4A3 and also COL4A4 all were markedly diminished in the B cells in CR group compared with the IR group. Along with that in this experiment Assessment for the expression magnitude of the three transcripts in B cell from the control group and also with the untreated new groups were done. As evident from the experiment the expression of RNA was shown to be remarkably higher in NP patients when compared with the CR one’s interns of expression of KCNN4, COL4A3 and COL4A4. Where as in IR patients there was a moderate level of expression. During the differentiation process of B cell, the role of regulation of KCNN4 was known, thus, the expression levels of KCNN4 on the surface of B cells in the patients with Pemphigus vulgaris was assessed in this study. The expression of KCNN4 and also the frequency to which it appears on B cells was highly increased in CR patients in comparison to NP patients. Whereas an intermediate level of expression was found in IR patients. The potassium channel of KCNN4 expression was also increased in CR patients than when it is contrasted with NP patients on B cell population such as naive B cell, memory B cells without class switching, memory B cells with class switching. This expression of levels of RNA and proteins on the surface of the cell is commonly described as post transcriptional modification.
Histopathology
The above-mentioned experiment has shown that KCNN4 is highly expressed in the B cell surfaces in such patients who were suffering from Pemphigus vulgaris and achieved a state of complete remission (CR). The KCNN4 expression has shown to be upregulated in the B cell subset such as naive B cells and memory B cells without class switching but it was not found in class switched memory B cells. Along with l these findings epigenetic findings and associated modifications were also found in B cell genes which involves KCNN4, and also during naive B cell to memory B cell shift. One of the most interesting facts in this experiment is that the KCNN4 expression when down regulated imposed immunodeficiency syndrome in a variable manner in around 20 % of the scenarios with autoimmune disorders. Along with that the findings also have brought to the notice the fact that the immunological fundamentals in remission patients which is associated with B cell mediated mechanisms when treated with mabthera involves the expression of KCNN4 potassium channels on the B cell surface.
The third article selected is published by Hébert, Vivien, et al which was created to analyze the profile of the transcription level of 33 genes which have a potential in pemphigus vulgaris disease, on the one cell sorted auto-reactive population of B cells which are previously collected from pemphigus vulgaris individuals at different times in their disease cycle. 2 specific time cycle were chosen in this experiment one is during the acute disease progression stage and second is the time after two treatment procedures such as- one with the systemic corticosteroids used solely and second when this is combined with rituximab. The samples were then compared using a randomized control trial model.
There were some key points associated with this experiment procedure-
Firstly, in this experiment the ex vivo analysis of auto reactive by lymphocytes were done because these autoantibodies are associated with the pemphigus vulgaris disease and act against the DST molecule.
Secondly, the B cells in this phase are in the pre stage of plasma sales which secrete antibodies; thus, these cannot be normally studied in ex vivo model.
Thirdly the one cell sorting assay is effective because only a small quantity of circulating B cells of autoreactive property is enough to induce the Pemphigus vulgaris disease.
It is the first study involving the analysis of single cell transcriptome of autoreactive B cells for patients who are suffering from autoimmune disorder. The transcriptomic profile of autoreactive as well as non-autoreactive B cells were observed to be different during the active disease phase, this was evidenced in the study. It was also found that IL-1 beta, IL-12p35, IL-23p19 and IRF5, these four genes were expressed in abundant, out of 31 total genes in the autoreactive B cell population.
One of the most important observations in this study was that the B cells which were DSG positive were found to be detectable after treatment with rituximab. It was found that the incomplete remission was overlapping with the DSG positive B cells from the active Pemphigus patients, the distinction was evident only in the fact that the IL-1beta as well as the CD27 was found to be downregulated in patients receiving rituximab treatment that in control group. The diminished expression of the marker CD27 appears to be blocking the B cell development, this results in long term sustainability of naive B cells and the reoccurrence of memory B cells. The auto-antibodies was observed to be generated from a certain sub population of autoreactive plasma blast which gets the refund from class switched memory B cells (CD20 + IgG + CD27 +). The long-term remission after the rituximab treatment was due to the fact that reduction in number of DSG positive B lymphocytes as a result of changes in the expression of CD27. Another suggestion was that the DSG3 + CD27+ B cells were able to contrast into plasma cells but not the DSG3 + CD27- B cells upon stimulation with IL2 and R848. The above model was exclusive to rituximab because it was not seen in patients who were treated with CS alone, in spite of they are present complete or partial remission phase. There was absence of any modifications in the level of IgG post rituximab treatment. In DSG + B cells the IL1 beta expression were higher in PV patients than normal with no modifications in DSG – B cells suggesting to a correlation of IL1 Beta to the pathogenesis of TB. More expression of IL1 Alpha and IL1 Beta was observed in the untreated TB patients than the control group along with that in vivo and in vitro expression of these two cytokines was lowered in patients with remission after administering IVIG. DSG+CD27+IgG+memory B cells exclusively arise in TB patients, not in controls, because of the patient’s unique gene expression profile. Thus, the significance of IL-12P35 in rituximab-treated patients’ healing mechanisms appears unconvincing since DSG+ and DSG-negative B cells expressed similar levels of IL-12P35. The study observed that the self-reactive as well as non-self-reactive B cell population express different subset of genes and also DSG + autoreactive B cells were still found in rituximab treated patients in complete remission after B cell reappeared after a phase of initial treatment with rituximab. The other gene expression was similar except for the CD27 which was reduced in rituximab treated patients.
References
Hébert, Vivien, et al. “Modifications of the transcriptomic profile of autoreactive B cells from pemphigus patients after treatment with rituximab or a standard corticosteroid regimen.” Frontiers in immunology (2019): 1794.
Ingold, Curtis J., and Moien AB Khan. “Pemphigus Vulgaris.” (2020).
Kridin, Khalaf, and Enno Schmidt. “Epidemiology of pemphigus.” JID innovations 1.1 (2021): 100004.
Kridin, Khalaf. “Emerging treatment options for the management of pemphigus vulgaris.” Therapeutics and clinical risk management vol. 14 757-778. 27 Apr. 2018, doi:10.2147/TCRM.S142471
NCT01299857, NCT00213512. “Long-term increase of Kcnn4 potassium channel surface expression on B cells in pemphigus patients after rituximab treatment.” Journal of Investigative Dermatology 138 (2018): 2666e2668.
Porro, Adriana Maria et al. “Pemphigus vulgaris.” Anais brasileiros de dermatologia vol. 94,3 264-278. 29 Jul. (2019),
Russo, Irene et al. “Evaluation of anti-desmoglein-1 and anti-desmoglein-3 autoantibody titers in pemphigus patients at the time of the initial diagnosis and after clinical remission.” Medicine vol. 96,46 (2017): e8801.
Sukanjanapong, Siriorn et al. “A Comparison of Azathioprine and Mycophenolate Mofetil as Adjuvant Drugs in Patients with Pemphigus: A Retrospective Cohort Study.” Dermatology and therapy vol. 10,1 (2020): 179-189.
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