Immunological Changes in Peripheral Blood of Ankylosing Spondylitis Patients during Anti-TNF-α Therapy and Their Correlations with Treatment Outcomes

Tumor necrosis factor-α (TNF-α) inhibitors are the main types of biological conventional synthetic disease-modifying antirheumatic drugs and have efficacy in treating ankylosing spondylitis (AS) which is not sensitive for nonsteroidal anti-inflammatory drug. However, the impact of TNF-α inhibitors on immune cells in patients with AS is still clearly undefined, and the impact of immune cells on treatment response is also largely elusive. This study is aimed at evaluating the longitudinal changes of circulating immune cells after anti-TNF-α therapy and their associations with treatment response in AS patients. Thirty-five AS patients receiving the treatment of anti-TNF-α therapy were included into this prospective observational study. The frequencies of immune cells including Th1, Th2, Th17, regulatory T cell (Treg), T follicular helper cell (Tfh), and regulatory B cell (Breg) in the peripheral blood were measured by flow cytometry at baseline and 4 time points after therapy. The difference in the circulating immune cells between responders and nonresponders was compared. This study suggested that anti-TNF-α therapy could significantly reduce circulating proinflammatory immune cells such as Th17 and Tfh, but significantly increased the percentages of circulating Treg and Breg. Moreover, circulating Breg may be a promising predictor of response to anti-TNF-α therapy in AS patients.

Download Full-text

Biomarkers for a histological chorioamnionitis diagnosis in pregnant women with or without group B streptococcus infection: a case-control study

BMC Pregnancy and Childbirth ◽

10.1186/s12884-021-03731-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jie Ren ◽

Zhe Qiang ◽

Yuan-yuan Li ◽

Jun-na Zhang

Keyword(s):

Cord Blood ◽

Pregnant Women ◽

Peripheral Blood ◽

Group B Streptococcus ◽

Diagnostic Value ◽

Adverse Outcomes ◽

Intercellular Adhesion Molecule ◽

Tnf Α ◽

Group B ◽

The Impact

Abstract Background Chorioamnionitis may cause serious perinatal and neonatal adverse outcomes, and group B streptococcus (GBS) is one of the most common bacteria isolated from human chorioamnionitis. The present study analyzed the impact of GBS infection and histological chorioamnionitis (HCA) on pregnancy outcomes and the diagnostic value of various biomarkers. Methods Pregnant women were grouped according to GBS infection and HCA detection. Perinatal and neonatal adverse outcomes were recorded with a follow-up period of 6 weeks. The white blood cell count (WBC), neutrophil ratio, and C-reactive protein (CRP) level from peripheral blood and soluble intercellular adhesion molecule-1 (sICAM-1), interleukin 8 (IL-8), and tumor necrosis factor α (TNF-α) levels from cord blood were assessed. Results A total of 371 pregnant women were included. Pregnant women with GBS infection or HCA had a higher risk of pathological jaundice and premature rupture of membranes and higher levels of sICAM-1, IL-8, and TNF-α in umbilical cord blood. Univariate and multivariate regression analysis revealed that sICMA-1, IL-8, TNF-α, WBC, and CRP were significantly related to an increased HCA risk. For all included pregnant women, TNF-α had the largest receiver operating characteristic (ROC) area (area: 0.841; 95% CI: 0.778–0.904) of the biomarkers analyzed. TNF-α still had the largest area under the ROC curve (area: 0.898; 95% CI: 0.814–0.982) for non-GBS-infected pregnant women, who also exhibited a higher neutrophil ratio (area: 0.815; 95% CI: 0.645–0.985) and WBC (area: 0.849; 95% CI: 0.72–0.978), but all biomarkers had lower value in the diagnosis of HCA in GBS-infected pregnant women. Conclusion GBS infection and HCA correlated with several perinatal and neonatal adverse outcomes. TNF-α in cord blood and WBCs in peripheral blood had diagnostic value for HCA in non-GBS-infected pregnant women but not GBS-infected pregnant women.

Download Full-text

Anti-inflammatory reflex action of splanchnic sympathetic nerves is distributed across abdominal organs

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00298.2018 ◽

2019 ◽

Vol 316 (3) ◽

pp. R235-R242 ◽

Cited By ~ 15

Author(s):

Davide Martelli ◽

David G. S. Farmer ◽

Michael J. McKinley ◽

Song T. Yao ◽

Robin M. McAllen

Keyword(s):

Sympathetic Nerves ◽

Target Organ ◽

Inflammatory Pathway ◽

Splanchnic Nerves ◽

Abdominal Organs ◽

Tnf Α ◽

Anti Inflammatory ◽

The Difference ◽

Factor Α ◽

Inflammatory Action

The splanchnic anti-inflammatory pathway has been proposed as the efferent arm of the inflammatory reflex. Although much evidence points to the spleen as the principal target organ where sympathetic nerves inhibit immune function, a systematic study to locate the target organ(s) of the splanchnic anti-inflammatory pathway has not yet been made. In anesthetized rats made endotoxemic with lipopolysaccharide (LPS, 60 µg/kg iv), plasma levels of tumor necrosis factor-α (TNF-α) were measured in animals with cut (SplancX) or sham-cut (Sham) splanchnic nerves. We confirm here that disengagement of the splanchnic anti-inflammatory pathway in SplancX rats (17.01 ± 0.95 ng/ml, mean ± SE) strongly enhances LPS-induced plasma TNF-α levels compared with Sham rats (3.76 ± 0.95 ng/ml). In paired experiments, the responses of SplancX and Sham animals were compared after the single or combined removal of organs innervated by the splanchnic nerves. Removal of target organ(s) where the splanchnic nerves inhibit systemic inflammation should abolish any difference in LPS-induced plasma TNF-α levels between Sham and SplancX rats. Any secondary effects of extirpating organs should apply to both groups. Surprisingly, removal of the spleen and/or the adrenal glands did not prevent the reflex splanchnic anti-inflammatory action nor did the following removals: spleen + adrenals + intestine; spleen + intestine + stomach and pancreas; or spleen + intestine + stomach and pancreas + liver. Only when spleen, adrenals, intestine, stomach, pancreas, and liver were all removed did the difference between SplancX and Sham animals disappear. We conclude that the reflex anti-inflammatory action of the splanchnic nerves is distributed widely across abdominal organs.

Download Full-text

Effects of long-term closed environment on human saliva microbiota and salivary cytokines

10.1101/2020.10.12.336750 ◽

2020 ◽

Author(s):

Yinzhen Zhu ◽

Zikai Hao ◽

Yuming Fu ◽

Jianlou Yang ◽

Chen Dong ◽

...

Keyword(s):

Human Saliva ◽

Mucosal Barrier ◽

Future Research ◽

Controlled Environment ◽

List Type ◽

Tnf Α ◽

Normal Environment ◽

The Difference ◽

Sharing Space ◽

The Impact

AbstractCompared with the normal environment, the microbiota in controlled closed cabins such as space capsules, Lunar/Mars bases have changed. To ensure the health of crewmembers, it’s necessary to understand the effects of these changes on human symbiotic microorganisms and immunity. In this study, the experimental platform “Lunar Palace 1” with a similar closed and controlled environment was used to research the effects of changed microbial exposure on human saliva microbiota and salivary cytokines. This paper studied on four crewmembers who participated in the third phase of the “Lunar Palace 365” experiment, analyzing the dynamic changes of saliva microbiota and salivary cytokines, and further studying the correlation between salivary cytokines and highly abundant genera. According to our data, the crewmembers’ saliva microbiota and salivary cytokines fluctuated smoothly throughout the whole experiment. Although a part of microbes increased or decreased some times, they recovered quickly after leaving the controlled environment. The level of IL-6, IL-10 and TNF-α in crewmembers’ saliva decreased from normal environment to the controlled environment, showing reduced levels of oral inflammatory response in crewmembers. In addition, although there were significant individual differences in crewmembers’ saliva microbiota, sharing living space reduced the difference. Furthermore, the level of TNF-α showed a consistent positive correlation with the abundance of Actinomyces and Rothia in the controlled environment, indicating healthy individuals’ oral mucosal barrier may be sensitive to changes in saliva microbiota. According to the result, semi-sterile environments in controlled closed cabins didn’t cause persistent changes in human saliva microbiota and oral immunity. Besides, it provides a new idea for future research on the impact of the controlled environment on crewmembers health, and provides guidance for studying the effect of semi-sterile environments on human immunity based on saliva microbiota.Key pointsSaliva microbes kept stable for individual but got convergent when sharing space;The level of salivary cytokines reduced after entering the controlled environment;There were complex correlations between salivary cytokines and saliva microbes;The crewmembers adapt well to the controlled environment.

Download Full-text

Distinct changes of in BTLA, ICOS, PD-1, and TIGIT expression on peripheral blood and decidual CD8+ T cells in women with unexplained recurrent spontaneous abortion†

Biology of Reproduction ◽

10.1093/biolre/ioaa127 ◽

2020 ◽

Vol 103 (5) ◽

pp. 1012-1017

Author(s):

Qianqian Liang ◽

Lingxia Tong ◽

Liping Xiang ◽

Sujuan Shen ◽

Chenhuan Pan ◽

...

Keyword(s):

T Cells ◽

Spontaneous Abortion ◽

Cd8 T Cells ◽

Immune Cells ◽

Peripheral Blood ◽

Immune Escape ◽

Recurrent Spontaneous Abortion ◽

Decidual Tissue ◽

Unexplained Recurrent Spontaneous Abortion ◽

The Difference

Abstract The two-way communication between the mother and the fetus is accomplished by immune cells. CD8+ T cells of normal pregnant (NP) women express progesterone receptor (PR). Binding of PR to progesterone (P) and the production of progesterone-induced blocking factor (PIBF) can aid immune escape, which is an important factor in the maternal immune response. We detected the proportion of CD8+ T cells and the expression of the surface costimulatory molecules BTLA, TIGIT, ICOS, and PD-1 in peripheral blood and decidual tissues of women with unexplained recurrent spontaneous abortion (URSA) and in NP women. All patients were at 8 -10 weeks of gestation. The results showed that there was no change in the proportions of CD8+ T cells in peripheral blood and decidual tissues of URSA patients compared to those of NP women. In peripheral blood, compared with the NP group, the URSA group showed decreased expression of BTLA + CD8+ T cells and the difference was statistically significant, but there was no difference between the groups in terms of TIGIT + CD8+, PD-1 + CD8+, and ICOS + CD8+ T cells. There was no change in the levels of TIGIT + CD8+, PD-1 + CD8+, ICOS + CD8+, and BTLA + CD8+ T cells in decidual tissue. These data confirm that the number of CD8+ T cells in peripheral blood and decidual tissue is not the main factor leading to the pathogenesis of URSA, and other immune cells may play an important role in URSA, but this hypothesis needs further exploration and research.

Download Full-text

Usporedba učinkovitosti i trogodišnjeg preživljenja TNF-α inhibitora u liječenju ankilozantnog spondilitisa

Medicina Fluminensis ◽

10.21860/medflum2020_232817 ◽

2020 ◽

Vol 56 (1) ◽

pp. 51-58

Author(s):

Filip Mirić ◽

Srđan Novak

Keyword(s):

Ankylosing Spondylitis ◽

Analogue Scale ◽

Activity Index ◽

Disease Activity Index ◽

C Reactive Protein ◽

Functional Index ◽

Reactive Protein ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

Cilj: Svrha rada bila je utvrditi i usporediti učinkovitost te preživljenje TNF-α (engl. tumor necrosis factor-α) inhibitora (adalimumab, golimumab, infliksimab) tijekom trogodišnjeg praćenja u liječenju ankilozantnog spondilitisa. Materijali i metode: Ovim retrospektivnim istraživanjem obuhvaćena je skupina od 29 ispitanika koji su primili prvi biološki lijek na Odjelu reumatologije i kliničke imunologije Kliničkog bolničkog centra Rijeka. Započeli su s biološkim lijekom u razdoblju od siječnja 2009. do lipnja 2015. godine i bili praćeni tri godine nakon početka terapije. Parametri kojima se pratila aktivnost bolesti bili su BASDAI (engl. Bath Ankylosing Spondylitis Disease Activity Index), BASFI (engl. Bath Ankylosing Spondylitis Functional Index), CRP (engl. C reactive protein) i VAS (engl. Visual Analogue Scale), a mjereni su prije početka terapije te nakon 3 i 36 mjeseci od njenog uvođenja. Rezultati: Od ukupno 29 ispitanika, 11 ih je bilo na adalimumabu, 10 na golimumabu, a 8 na infliksimabu. Analizirajući parametre uključene u ovo istraživanje (BASDAI, BASFI, CRP, VAS), ni u jednom promatranom periodu nije zabilježena statistički značajna razlika između ispitanika s obzirom na primijenjeni TNF-α inhibitor (svi p > 0,05). Ukupno trogodišnje preživljenje TNF-α inhibitora iznosilo je 75,8 %. Kod ispitanika liječenih adalimumabom trogodišnje preživljenje iznosilo je 72,8 %, za golimumab 80 % te infliksimab 75 % (svi p > 0,05). Zaključci: Uspoređujući ispitanike liječene adalimumabom, golimumabom i infliksimabom u prvoj liniji biološke terapije, naše istraživanje na malom broju ispitanika pokazalo je kako nema značajne razlike u njihovoj učinkovitosti i preživljenju.

Download Full-text

Dosage Adjustment of Anti-Tumor Necrosis Factor-α Inhibitor in Ankylosing Spondylitis Is Effective in Maintaining Remission in Clinical Practice

The Journal of Rheumatology ◽

10.3899/jrheum.111337 ◽

2012 ◽

Vol 39 (7) ◽

pp. 1418-1423 ◽

Cited By ~ 25

Author(s):

JULIEN PACCOU ◽

MARIE-ASTRID BACLÉ-BOUTRY ◽

ELISABETH SOLAU-GERVAIS ◽

PEGGY BELE-PHILIPPE ◽

RENÉ-MARC FLIPO

Keyword(s):

Ankylosing Spondylitis ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Dosage Adjustment ◽

Treatment Frequency ◽

Response Predictors ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

Objective.While remission is possible in patients with ankylosing spondylitis (AS), it is often unclear what attitude should be adopted once remission has occurred. We investigated whether dosage adjustment is an effective means of maintaining remission.Methods.This was a retrospective study drawn from clinical situations. Remission was defined using clinical measures [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≤ 20/100 and no peripheral joint disease] and biological measures [C-reactive protein (CRP) levels ≤ normal value]. The tumor necrosis factor-α (TNF-α) inhibitors used were infliximab, adalimumab, and etanercept. Response predictors of remission were evaluated by logistic regression (age, CRP, HLA-B27 positivity, sex, duration of disease, and anti-TNF-α naivety). CRP and BASDAI were evaluated before and after dosage adjustment at about 6, 12, 24, and 36 months.Results.One hundred eighty-nine patients with AS were included in the study, with a mean followup of 43.5 (± 17.9) months after the introduction of the first anti-TNF-α inhibitor. Mean age was 45.6 (± 12.5) years. Remission had occurred in 65 patients (35%). Significant response predictors of remission were male sex (p = 0.003) and anti-TNF-α naivety (p < 0.001). Dosage adjustment was observed 49 times, and progressively reducing treatment frequency was effective to maintain remission in a large number of patients for 36 months. The cumulative probability of continuing anti-TNF-α after dosage adjustment was 79.0% at 12 months, 70.5% at 24 months, and 58.8% at 36 months.Conclusion.Remission had occurred in 35% of the patients with AS under anti-TNF-α inhibitor therapy. Dosage adjustment and progressively reducing treatment frequency was effective in maintaining remission.

Download Full-text

Inflammatory Cytokine Neutralizing Antibody Treatment Could Recover Increased Follicular Helper and Follicular Regulatory T Cells in Murine Models of Arthritis

10.21203/rs.3.rs-880040/v1 ◽

2021 ◽

Author(s):

Xingyue Zeng ◽

Meng Li ◽

Mohan Zheng ◽

Tianci Liu ◽

Rui Kang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Peripheral Blood ◽

Neutralizing Antibody ◽

Mouse Spleen ◽

Inflammatory Factor ◽

Antibody Treatment ◽

Follicular Helper ◽

Anti Inflammatory ◽

And Function ◽

The Impact

Abstract Objective. We aimed to illustrate the changes of follicular helper (TFH) and follicular regulatory (TFR) cells in rheumatoid arthritis using the collagen-induced arthritis (CIA) model and clarity the impact of anti-inflammatory treatment on TFH and TFR cells.Methods. We established 10-week-old CIA model and used flow cytometry to analyze the changes of TFH and TFR cells in peripheral blood and spleen at different time points (5w, 7w, 10w,13w). The expression of TIGIT, CD226, ICOS and PD-1 characterizing the functions of TFH and TFR were also analyzed. The function of spleen TFH and TFR cells from CIA was further analyzed. The effects of anti-inflammatory antibody treatments on the subpopulation and function changes of TFH and TFR were also analyzed in CIA mice.Results. The levels of TFH and TFR were significantly increased in spleen and peripheral blood of CIA mice. After treatment, TFH and TFR cells decreased significantly. TIGIT+ and TIGIT+CD226-TFH cells in CIA mouse spleen were elevated and PD-1 and ICOS expression on TFH and TFR cells in the spleen were also significantly increased. The ability of TFH to secrete IL-21 and help B cells, and TFR to secrete IL-10 and inhibit TFH were both enhanced in CIA mouse spleen. After antibody treatment, cell subsets and functions were significantly recovered.Conclusion. In the pathogenesis of rheumatoid arthritis, TFH and TFR cells in the germinal center increases and their functions are enhanced. After the treatment by inflammatory factor antibodies, TFH and TFR subsets and their functions can be significantly recovered.

Download Full-text

LPS-induced depolymerization of cytoskeleton and its role in TNF-α production by rat pneumocytes

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.3.l606 ◽

1999 ◽

Vol 277 (3) ◽

pp. L606-L615 ◽

Cited By ~ 10

Author(s):

Noritaka Isowa ◽

Alexandre M. Xavier ◽

Ewa Dziak ◽

Michal Opas ◽

Donna I. McRitchie ◽

...

Keyword(s):

Epithelial Cells ◽

Immune Cells ◽

Protein Production ◽

Mrna Level ◽

Alveolar Epithelial Cells ◽

Immunofluorescent Staining ◽

Alveolar Epithelial ◽

Tnf Α ◽

Factor Α

Lipopolysaccharide (LPS) polymerizes microfilaments and microtubules in macrophages and monocytes. Disrupting microfilaments or microtubules with cytochalasin D (CytoD) or colchicine can suppress LPS-induced tumor necrosis factor-α (TNF-α) gene expression and protein production from these cells. We have recently demonstrated that primary cultured rat alveolar epithelial cells can produce TNF-α on LPS stimulation. In the present study, we found that the LPS-induced increase in TNF-α mRNA level and protein production in alveolar epithelial cells was not inhibited by CytoD or colchicine (1 nM to 10 μM). In fact, LPS-induced TNF-α production was further enhanced by CytoD (1–10 μM) and inhibited by jasplakinolide, a polymerizing agent for microfilaments. Immunofluorescent staining and confocal microscopy showed that LPS (10 μg/ml) depolymerized microfilaments and microtubules within 15 min, which was prolonged until 24 h for microfilaments. These results suggest that the effects of LPS on the cytoskeleton and the role of the cytoskeleton in mediating TNF-α production in alveolar epithelial cells are opposite to those in immune cells. This disparity may reflect the different roles between nonimmune and immune cells in host defense.

Download Full-text

Cellular localisation of the kinin B1R in the pancreas of streptozotocin-treated rat and the anti-diabetic effect of the antagonist SSR240612

Biological Chemistry ◽

10.1515/hsz-2015-0230 ◽

2016 ◽

Vol 397 (4) ◽

pp. 323-336 ◽

Cited By ~ 8

Author(s):

Nejla Tidjane ◽

Louis Gaboury ◽

Réjean Couture

Keyword(s):

Immune Cells ◽

Diabetic Rats ◽

Diabetic Rat ◽

Β Cells ◽

Langerhans Islets ◽

B1 Receptor ◽

Cellular Localisation ◽

Tnf Α ◽

Kinin B1 Receptor ◽

The Impact

Abstract The mechanism by which kinin B1 receptor (B1R) contributes to type 1 diabetes is addressed by determining the impact of its inhibition on diabetes and on its pancreatic expression and cellular localisation on immunocompetent cells and primary sensory C-fibres. Rats were made diabetic with streptozotocin (STZ). On day 4, they were treated daily for 7 days with a B1R antagonist (SSR240612, 10 mg/kg) or its vehicle. The surviving β-cells were measured by immunostaining. The expression of B1R, iNOS, TNF-α, macrophages, TCD4+, CGRP and TRPV1 was measured by Western blotting, qRT-PCR and immunofluorescence. Macrophages and TCD4+ lymphocytes were absent in control, but distributed abundantly in the pancreas of STZ-diabetic rats. B1R was upregulated on these immune cells infiltrating the diabetic rat pancreas while it was not expressed on primary sensory C-fibres even if the expression of TRPV1 and CGRP was enhanced. SSR240612 prevented the infiltration of macrophages and TCD4+ lymphocytes and the upregulation of B1R, iNOS, TNF-α and TRPV1. SSR240612 corrected hyperglycaemia and hypoinsulinaemia by improving the Langerhans islets survival or regeneration. It is concluded that kinin B1R antagonism exerts anti-diabetic action by preventing the infiltration of immune cells in the pancreas and by preserving the integrity of Langerhans islets β-cells.

Download Full-text

PP387 Budget Impact Analysis Of Adalimumab In The Treatment Of Ankylosing Spondylitis In China

International Journal of Technology Assessment in Health Care ◽

10.1017/s0266462320001695 ◽

2020 ◽

Vol 36 (S1) ◽

pp. 32-33

Author(s):

Chengaxin Duan ◽

Binyan Sui ◽

Kun Zhao ◽

Dandan Ai ◽

Qian Xu

Keyword(s):

Ankylosing Spondylitis ◽

Impact Analysis ◽

Budget Impact ◽

Treatment Options ◽

Medical Insurance ◽

Common Disease ◽

Current Price ◽

Factor Α ◽

The Impact ◽

Insurance Expenditure

IntroductionAnkylosing spondylitis (AS) is a common disease that causes pain and affects productivity. Tumor necrosis factor-α (TNF-α) like adalimumab can bring better clinical efficacy and improve quality of life. Adalimumab is likely to be covered by health insurance. It is necessary to assess the impact of adalimumab for patients with AS on the medical insurance budget in China. Our research aims to give support evidence for policy-making.MethodsFrom the perspective of medical insurance payers, a budget impact model was established to evaluate the impact of adalimumab for the treatment of adults with severe active AS that has responded inadequately to conventional therapy. The time horizon was 5 years (2020–2024). The cost of measurement included drug and treatment costs for adverse events. Scenario analysis was conducted to evaluate the results under different drug price reimbursement ratios and treatment ratios.ResultsBased on the current price of adalimumab (CNY 3,160 [USD 446]/unit), under the reimbursement ratio of 70 percent, adalimumab will increase medical insurance expenditure by CNY 162 [USD 22] million, CNY 152 [USD 21] million, CNY 114 [USD 16] million, CNY 100 [USD 14] million and CNY 88.11 [USD 12] million in the next 1–5 years, respectively. The increased medical insurance expenditure accounts for 0.091, 0.085, 0.064, 0.056, and 0.049 percent of the annual medical insurance expenditure in the next 1–5 years, respectively, which is assumed to be equivalent to the expenditure in 2018 of CNY 1782.2 [USD 251] billion.ConclusionsThe budget impact of adalimumab for AS on medical insurance expenditure is limited, and including adalimumab in the medical insurance catalogue can reduce the burden on individuals, enrich treatment options, and satisfy clinical needs better.

Download Full-text