ISSN 1301-109X | e-ISSN 2147-8325
TURKISH JOURNAL of IMMUNOLOGY - TJI: 9 (1)
Volume: 9  Issue: 1 - 2021
1.Cover

Page I

2.Advisory Board

Pages II - IV

3.Contents

Pages V - VI

4.Editorial

Page VII

REVIEW ARTICLE
5.Hyperinflammation Syndrome in COVID-19 Disease: Pathogenesis and Potential Immunomodulatory Agents
Moulid Hidayat, Diah Handayani, Fariz Nurwidya, Sita Laksmi Andarini
doi: 10.5222/TJI.2021.92486  Pages 1 - 11
The coronavirus disease 2019 (COVID-19) pandemic caused by infection of the SARS-CoV-2 virus has affected millions of people in the world. The pathogenesis and clinical manifestations of COVID-19 disease are tightly influenced by the host immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. In some condition, the immune response might be uncontrolled, giving rise to hyperinflammatory conditions marked by excessive release of proinflammatory cytokines (cytokine storms) in severe COVID-19 patients, which then can cause acute respiratory distress syndrome (ARDS), multiorgan failure, and death. Furthermore, treatment using immunomodulator agents including immunostimulatory and immunosuppressive agents can be an option in achieving successful treatment. In this review, we discuss the pathogenesis of the disease, including host immune responses to SARS-CoV-2 virus infection, and immune mechanisms which contribute to the disease severity and death as well as several potential immunomodulatory agents which can be used in the management of hyperinflammatory syndrome of severe COVID-19.

ORIGINAL RESEARCH
6.Flow Cytometric Analysis of T Cell Vβ Repertoire in Common Variable Immunodeficiency Patients with TACI Mutations
Sevil Oskay Halacli, Begum Ozbek, Elif Soyak Aytekin, Ismail Yaz, Cagman Tan, Deniz Cagdas Ayvaz, Ilhan Tezcan
doi: 10.5222/TJI.2021.43531  Pages 12 - 19
Objective: TCR (T Cell Receptor) which is expressed on T cells is responsible for recognizing antigens presented by HLA molecules of the APCs (Antigen Presenting Cells) and initiation of the immune response. It has been reported that TACI (Transmembrane activator and calcium modulating cyclophilin ligand interactor) mediates the interaction of B cells and dendritic cells which are both responsible for the processing of T cells.
Materials and Methods: In this study, 24 TCRVβ clones were analyzed by using multiparametric flow cytometry in seven patients with TACI mutation [two homozygous (c.310T> C) five heterozygous (c.310T> C, c.226G> C, c.260T> A)], four CVID (Common Variable Immunodeficiency) patients who had not TACI defect (non-TACI) and five healthy controls. In this study group, serum Ig levels and infection history, CD4+ and CD8+ cell percentages, and HLA profiles were investigated.
Results: Increased TCRVβ13.2 clone was observed in patients with TACI defects unlike control individuals and non-TACI-CVID patients (p=0.02). We found that there was a statistically significant decrease in TCRVβ8 clone (p=0.012) in TACI deficient CVID patients and non-TACI-CVID patients compared to control individuals. TCRVβ20 clones in non-TACI-CVID patients were decreased compared to TACI-CVID patients and control individuals (p=0.009). Decreased TCRVβ8 was also associated with TACI deficient CVID patients.
Conclusion: Further studies and large cohorts are needed to understand the relationship between TCRVβ8, TCRVβ13.2, and CVID with TACI mutations.

7.Computational Mapping of Cytotoxic T Lymphocyte epitopes of Mycobacterium Tuberculosis and their Potential Role in Vaccine Design
Esakkimuthu Thangamariappan, Manikandan Mohan, Krishnan Sundar
doi: 10.5222/TJI.2021.54254  Pages 20 - 27
Amaç: Mycobacterium tuberculosis (M. tb) kaynaklı tüberküloz (TB), dünya çapında milyonlarca insanın ölümüne neden olan en amansız hastalıklardan biridir. TB’nin yaygın olduğu çoğu ülkede kullanılmakta olan tek aşı Bacillus Calmette-Guérin’dir (BCG). Aşılamaya rapmen bu hastalık, TB’ye karşı etkin bir aşının geliştirilmesini gerektiren şekilde gelişen ülkelerin çoğunda halen etkilidir. M. tb’nin intraselüler bir patojen olarak hareket etmesinden ötürü, hücre aracılıklı immün cevap, hastalığın kontrolünde önemli bir rol oynamaktadır. Bu nedenle M. tb antijenlerinin CD8+ T hücresi epitoplarının taranması, TB’ye karşı etkin bir aşının geliştirilmesine yardımcı olabilir. Mevcut çalışmada, M. tb için de gerekli olan virülan proteinlerdeki cytotoxic T lymphocyte (CTL) epitoplarının öngörülmesi ve haritalanması için ters aşı yaklaşımı kullanılmıştır.
Gereç ve Yöntem: M. Tb’nin virülan proteinlerinin tanımlanması için Temel Genler Veritabanı ve Virülans Faktörü Veritabanı kullanıldı ve antijenlikleri, VaxiJen sunucusu kullanılarak değerlendirildi. MHC sınıf I bağlayıcılığı, MHC işleme, immünojenisite, toksisite ve alerjiklik hakkında tahminde bulunmak üzere çeşitli immünoinformatik araçlar kullanıldı.
Bulgular: Tahmin analizleri için farklı araçlar kullanılarak M. tb antijenleri seçildi. Sonuçlar, insan HLA-A allellerine karşı öngörülen 20 yeni CTL epitopunun olduğunu gösterdi. Bu çalışmada aynı zamanda bir aşı bileşeni olarak da kullanılabilecek olan çoklu allel bağlayıcı epitop için de tarama yapıldı.
Sonuç: Bu çalışma, sınıf I HLA-A allellerine bağlanan ve şimdiye kadar bildirilmemiş birkaç CTL epitopunu ortaya koymuştur. Aşı adayları olarak potansiyellerini doğrulamak için daha fazla deneysel validasyon gereklidir.
Objective: Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) is one of the deadliest diseases causing millions of deaths worldwide. Bacillus Calmette-Guérin (BCG) is the only vaccine that has been used in many countries where TB is prevalent. Despite vaccination, this disease prevails in many of the developing countries, necessitating the development of an effective vaccine against TB. Since M. tb acts as an intracellular pathogen, cell-mediated immune response plays an important role in disease control. Therefore, screening of CD8+ T cell epitopes of M. tb antigens could aid in the development of an effective vaccine against TB. In the current study, a reverse vaccinology approach was utilized to predict and map cytotoxic T lymphocyte (CTL) epitopes in the virulent proteins that are also essential for M. tb.
Materials and Methods: Database of Essential Genes and Virulence Factor Database were used for identifying the virulent proteins of M. tb and their antigenicity was assessed using VaxiJen server. Various immunoinformatics tools were used to predict MHC class I binding, MHC processing, immunogenicity, toxicity and allergenicity.
Results: Twelve M. tb antigens were selected for the prediction analyses using various tools. The results indicated the presence of 20 novel CTL epitopes predicted against human HLA-A alleles. This study has also screened for multiple allele binding epitopes that could be used as a vaccine component.
Conclusion: This study has yielded a few hitherto unreported CTL epitopes binding to class I HLA-A alleles. Further experimental validation is necessary for confirming their potential as vaccine candidates.

8.Effect of Hypnotherapy on Immune Response and Standard Therapy in Psychogenic Asthma Patients
Yusup Subagio Sutanto, Handono Kalim, Kusworini Handono, Aris Sudiyanto
doi: 10.5222/TJI.2021.22931  Pages 28 - 35
Amaç: Astım, kompleks inflamatuvar bir hastalıktır. Astım tedavisi genellikle farmakoterapidir ancak uzun vadede yan etkileri arttırabilir. Hipnoz, astımın klinik olarak tedavi edilmesi için kullanılmaktadır. Bu çalışmanın amacı, immün cevap, stres mediatörleri ve astım kontrol seviyesine ilişkin olarak psikojen astım hastalarında tedavi standardını arttıracak olan hipnoterapinin etkililiğini araştırmaktır.
Gereç ve Yöntem: Bu araştırma, Surakarta, Endonezya’da bulunan Dr. Moewardi Hastanesinin polikliniğinde yürütülen çapraz tasarımlı bir çift kör, deneysel, randomize kontrollü bir deney grubu çalışmasıdır. Astım kontrolü seviyelerindeki varyasyonları değerlendirmek için Friedman testi ve ardından marjinal homojenlik testi kullanıldı. Çalışmada rastgele yöntem ile A ve B gruplarına ayrılmış 30 hasta yer aldı. Her iki grup da, farklı bir sırayla standart astım tedavisi ve hiponoterapi aldı.
Bulgular: Hipnoterapi, aşağıda belirtilen şekilde her grup içinde SCO 90 skorlarında anlamlı bir azalma sağladı: Grup A (A1 vs A2; p=0.004) ve Grup B (B2 vs B3; p=0.001). Astım kontrol seviyeleri, her iki grupta da anlamlı olarak iyileşme gösterdi (A1 karşı A2; p=0.001 ve B2 karşı B3; p=0,004). Hipnoterapi, yine her iki grupta, norepinefrin seviyelerini anlamlı olarak iyileştirdi (A1 karşı A2; p=0.001 ve B2 karşı B3; p=0.073). Hipnoterapi, IL-13 (p=0.132) ve IL-17 (p=0.149) seviyelerini istatistiksel olarak anlamlı olmayan düzeylerde azalttı.
Sonuç: Bu çalışma, psikojen astım hastalarına uygulanan hipnoterapinin standart tedaviye verdikleri yanıtı iyileştirebildiği sonucuna varmıştır. Bu gelişmiş standart tedavi yanıtı da kontrolsüz astımın tedavisini, önlenmesini ve tedavisini etkileyecektir.
Objective: Asthma is a complex inflammatory disease. The therapy for asthma is usually pharmacotherapy but it can increase the side effects in the long run. Hypnosis has been used to clinically treat asthma. This study aimed to investigate the efficacy of hypnotherapy which will increase the standard of therapy in psychogenic asthma patients on immune response, stress mediators, and asthma control level.
Materials and Methods: This research is a double-blind experimental randomized control trial group study with a crossover design conducted in the outpatient clinic of Dr. Moewardi Hospital, Surakarta, Indonesia. The Friedman test followed by the marginal homogeneity statistic test was used to assess variations in the levels of asthma control. The study subjects were 30 respondents who were divided randomly into groups A and B. Both groups had standard asthma therapy and hypnotherapy with a different sequence.
Results: Hypnotherapy made a significant decrease in SCL 90 score within each group as follows: Group A (A1 vs A2; p=0.004) and Group B (B2 vs B3; p=0.001). Levels of asthma control improved significantly in both groups (A1 vs A2; p=0.001 and B2 vs B3; p=0.004). Hypnotherapy significantly improved the norepinephrine levels in both groups as well (A1 vs A2; p=0.001 and B2 vs B3; p=0.073). Hypnotherapy insignificantly reduced IL-13 (p=0.132) and IL-17 (p=0.149) levels.
Conclusion: This study concluded that hypnotherapy applied to psychogenic asthma patients can improve their standard therapy response. This improved standard therapy response will affect the treatment, prevention, and management of uncontrolled asthma.

9.Effect of Adipose-Derived Mesenchymal Stem Cell on the Expressions of Bax/Bcl-2, Ki67, VEGF, TNF-α, and Endometrial Implants in Metformin-Administered Endometriosis Mice (A Mouse Model in Endometriosis Study)
Inu Mulyantoro, Noor Pramono Noerpramana, Yuda Heru Febrianto, Widjiati Widjiati, Purwati Purwati, Suhartono Suhartono, Tono Djuwantono, Indra Wijaya
doi: 10.5222/TJI.2021.29292  Pages 36 - 49
Objective: Endometriosis is a gynecological syndrome that affects many women around the world. The effective management for this illness has not been determined. The aim of this study was to explore the effect of mesenchymal stem cells (MSCs) and metformin on Bax/Bcl-2, Ki67, VEGF, TNF-α, and endometrial implants in endometriosis mice.
Materials and Methods: Thirty mice with endometriosis were equally divided into 5 experimental groups (S1: 0.1 ml MSCs + 4 mg metformin; S2: 0.1 ml MSCs; S3: 4 mg metformin; S4: 0.1 ml NaCl 9%; and S5: 4 mg metformin + subsequent 0.1 ml MSCs) for 14 days. On the 15th day, peritoneal tissues of mice and endometrial implants were removed to examine the expressions of Bax/Bcl-2, Ki67, VEGF, and TNF-α using immunohistochemical staining, and Allred index and endometrial implants using image tracing method with a computer. The obtained data were analyzed using the Kruskal-Wallis and ANOVA tests, followed by the Least Significant Difference (LSD) and Mann-Whitney Post-hoc tests.
Results: There were significant differences in the expressions of Bax/Bcl-2 (p=0.002), Ki67 (p=0.004), TNF-α (p=0.017), and endometrial implants (p=0.001) in all groups, except for VEGF (p=0.079). The values of S2 didn’t differ much compared to the control group (S4) in the Bax/Bcl-2 (p=0.487), TNF-α (p=0.191), and endometrial implants (p=0.2). S1 was found to have the highest Bax/Bcl-2 (1.67±0.845) and lowest TNF-α (4.67±2.15) and endometrial implant (0.86±2.11).
Conclusion: MSCs alone had not any beneficial effect on the treatment of endometriosis, whereas metformin by itself exhibited favorable results. The combination of MSCs and metformin at the same time shows superior outcomes.

10.Acute Effect of Repeated Sprint and Aerobic Endurance Training on Foxp3+ Regulatory T Cells and Cytokine Levels
Orkun Akkoç, Deniz Genç, Hakan Özel, Recep Fatih Kayhan, Muazzez Gökalp, Özlem Kırandı, Ilker Yücesir, Tunç Akkoç
doi: 10.5222/TJI.2021.95530  Pages 50 - 58
Amaç: Çalışmanın amacı, tekrarlayan sprint ve aerobik dayanıklılık antremanının Foxp3+ T regülatör hücreleri ve sitokinler üzerindeki akut etkisini araştırmaktır.
Gereç ve Yöntem: Çalışmaya 16 sprinter ve 16 uzun mesafe koşucusu katıldı. Sprinter ve mesafe antrenmanı yapmak üzere her denek kendi branş grubuna ayrıldı. Çalışma kapsamında deneklerin boy, vücut ağırlığı, spor yaşı, Foxp3+ T regülatör hücre ve sitokin değerleri kaydedildi. Antrenman öncesi ve sonrası alınan venöz kan örneklerinde bağışıklık alt parametreleri karşılaştırıldı. Wilcoxon testi eğitim öncesi ve sonrası değerleri karşılaştırmak için kullanıldı ve anlamlılık p<0.05 olarak kabul edildi.
Bulgular: Sprinter ve mesafe sporcularının antrenman öncesi ve sonrasında Foxp3+ T regülatör hücrelerinde düzeylerinde artış, istatistiksel seviyelerinde değişiklik gözlenmemiş, (sprinterlerde p=0.47, mesafecilerde p=0.52). Sprinter seviyelerinde artış (p=0.00), seviyesinde değişiklik gözlenmemesine karşılık (p=0.02), IL-17 (p=0.000) ve TNF-α artmış, IFN-γ değişmemiş, IL-6’da azalma saptandı (p<0.05). Mesafecilerde IL-4, IL-10, IL-17 artmış, IL-6 ve IFN-γ değişmemiş, TNF-α ve IL-2 seviyelerinde azalma saptanmıştır (p<0.05).
Sonuç: Sonuç olarak immün sistem egzersiz şiddeti ve egzersiz türünden etkilenmektedir. Yüksek şiddette yapılan sprint tarzı anaerobik egzersizlerin immün sistemi daha çok baskıladığı söylenebilir.
Objective: The aim of our study was to investigate the acute effect of repeated sprints and aerobic endurance training on Foxp3+ T regulatory cells and cytokines.
Materials and Methods: The study population consisted of 16 sprinters and 16 long distance runners. Each subject was divided into his/her own branch as sprinting and distance training. Within the scope of the study, the height, body weight, sporting age, Foxp3+ T regulatory cells and cytokine values of subjects were recorded. Immunity subparameters were compared in venous blood samples taken before and after training. The Wilcoxon test was used to compare the values before and after training with level of statistical significance accepted as p<0.05.
Results: A statistically significant change was not observed for Foxp3+ T regulatory cells before and after training in sprinter (p=0.47) and distance runners (p=0.52). Sprinters had increased IL-2 (p=0.00), IL-4 (p=0.00), IL-10 (p=0.02), IL-17 (p=0.000) and TNF-α (p=0.000), decreased IL-6 (p=0.000) and unchanged IFN-γ levels (p=0.81). Distance runners had increased IL-4 (p=0.000), IL-10 (p=0.000), IL-17 levels (p<0.00), decreased TNF-α (p=0.00), IL-2 (p=0.05) and unchanged IFN-γ (p=0.15) and IL-6 (p=0.15).
Conclusion: Immune system is affected by the intensity and type of exercise. It can be said that anaerobic exercises like sprinting with high intensity supress the immune system more severely.

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