scholarly journals T- and B-lymphocytes subpopulations in the early and advanced rheumatoid arthritis

2021 ◽  
Vol 15 (2) ◽  
pp. 17-22
Author(s):  
A. V. Martynova ◽  
T. V. Popkova ◽  
A. P. Aleksankin ◽  
G. I. Gridneva ◽  
E. V. Gerasimova ◽  
...  

Objective: to evaluate changes in T- and B-lymphocyte subpopulations at different stages of rheumatoid arthritis (RA).Patients and methods. The study included 53 patients with a definite RA diagnosis according to the 2010 ACR/EULAR criteria (mean age 54.2 [47; 62] years). Group 1 included 27 patients (25 women and 2 men) without history of synthetic disease modifying anti-rheumatic drugs (sDMARDs) intake, group 2 included 26 patients (22 women and 4 men) receiving sDMARDs (methotrexate or leflunomide). The control group consisted of 29 healthy volunteers (23 women and 6 men), the median age was 58.5 [53; 62] years. In all participants flow cytofluorometry according to the standard technique with immunophenotyping of T- and B-lymphocytes was performed.Results and discussion. Compared to controls, patients in group 1 who had not previously received sDMARDs showed a transient increase in "switched" memory B-cells, transient B-cells, and plasmablasts, which was not observed in patients of group 2 (on sDMARDs therapy). Patients with advanced RA showed a statistically significant decrease in the absolute and relative number of memory B-cells, the absolute and relative number of "switched" B-lymphocytes, as well as the number of plasmablasts and transient cells. In RA patients, a statistically significant rela tionship was established between the number of swollen joints and the level of plasmablasts (r=0.51), memory cells (r=0.54), and "switched" B-cells (r=0.41), p< 0,05 in all cases. There were no statistically significant changes in other subpopulations of B-lymphocytes and the profile of T-lymphocytes.Conclusion. Changes in the B-lymphocyte profile are characteristic of different stages of RA. At an early stage, there is an increase in the number of transient B-lymphocytes, plasmablasts and plasmocytes, and in the advanced stage, a decrease in the level of certain populations of B-lymphocytes, such as memory B-cells and "switched" B-lymphocytes. It can be assumed that the ineffectiveness of sDMARDs is associated with a change in the population composition of B-lymphocytes, which requires further study.

2019 ◽  
Vol 56 (6) ◽  
pp. 731-738
Author(s):  
E. V. Gerasimova ◽  
T. V. Popkova ◽  
A. P. Aleksankin ◽  
A. V. Martynova ◽  
E. L. Nasonov

The clinical efficacy and safety of interleukin-6 (IL-6) receptor blockade have been well studied, but the data on the impact of therapeutic inhibition of IL-6 on B cells are scarce and contradictory. Preliminary reports have shown that B cell function and a humoral immune response may be modulated by an IL-6 receptor inhibitor.Objective: to assess the effect of 12-month tocilizumab (TCZ) therapy on B-cell phenotype and gene expression in RA and to analyze the association between B-cell subsets and RA activity.Subjects and methods. Examinations were made in 24 active RA patients (20 women and 4 men) (median age, 55 [49; 64] years; disease duration, 72 [24; 108] months; DAS28 5.8 [5.3; 6.3]; the patients were seropositive for rheumatoid factor (RF) (100%) and for anti-cyclic citrullinated peptide antibodies (87.3%). The patients received TCZ 8 mg/kg every 4 weeks. After 12 months of therapy, 54% of patients were categorized as good responders, 46% as moderate responders according to the EULAR response criteria. A control group consisted of 29 volunteers (21 women and 8 men; median age, 58.5 [53.0; 62.0] years). Peripheral blood lymphocytes were immunophenotyped at the time of enrollment and after 12 months. The absolute and relative counts of CD19+B lymphocytes, memory B cells (CD19+CD27+), non-switched memory B cells (CD19+IgD+CD27+), switched memory B cells (CD19+IgDCD27+), naive (CD19+IgD+CD27-), double-negative (CD19+IgD-CD27-), transitional (CD19+IgD+CD10+CD38++CD27) B cells, plasma cells (CD19+СD38+), and plasmablasts (CD19+СD38+++IgD-CD27+CD20-) were estimated using multicolor flow cytometry. Results and discussion. The relative and absolute counts of memory B cells (CD19+CD27+) (1.3 [0.9; 1.7]%, 0015 [0.001; 0.003]•109/l), switched memory B cells (CD19+IgD-CD27+) (6.8 [3.6; 11.6]%, 0.01 [0.005; 0.02]•109/l), and the absolute number of transitional B cells (CD19+CD38++CD10+IgD+CD27-) (0.00009 [0; 0.00028]•109/l) were found to be lower in RA patients than in donors: 2.2 [1.1; 3.0]%, 0.003 [0.001; 0.007]•109/l; 12.8 [9.3; 17.0]%, 0.02 [0.01; 0.04]•109/l; 0.0001 [0; 0.0003]•109/l, respectively (p<0.05 for all cases). After 12 months of TCZ therapy initiation, there were decreases in the relative and absolute counts of plasmablasts (CD19+CD38+++CD27+IgD-CD20-) from 0.15 [0.1; 0.3] to 0.1 [0.01; 0.1]% and from 0.0003 [0.00007; 0.004]•109/l to 0.0001 [0; 0.0003]•109/l, respectively (p<0.05). At the same time, the relative and absolute counts of memory B cells (CD19+CD27+) and switched memory B cells (CD19+CD27+IgD-) remained lower in RA patients than in donors: 1.0 [0.7; 1.2] and 2.2 [1.1; 3.0]%; 0.001 [0.006; 0.003]•109/l and 0.003 [0.001; 0.007]•109/l; 3.1 [1.1; 4.2] and 12.8 [9.3; 17.0]%; 0.003 [0.002; 0.006]•109/l and 0.02 [0.01; 0.04]•109/l, respectively (p<0.05 for all cases). Following 12 months of TCZ therapy, the numbers of other B-cell subpopulations were not considerably altered. When included in the study, the patients with RA showed correlations between the absolute count of memory B cells (CD19+CD27+) and the level of C-reactive protein (r=0.50; p<0.05); between the absolute count of plasmablasts (CD19+CD38+++CD27+IgD-CD20-) and the level of RF (r=0.41 and r=0.52; p<0.05). There were no correlations of B cell subsets with clinical and laboratory findings after 12 months of TCZ initiation.Conclusion. Immunophenotyping of peripheral blood B lymphocyte subsets showed the lower relative and absolute counts of memory B cells (CD19+CD27+) and switched memory B cells (CD19+CD27+IgD-) in RA patients than in healthy donors. The found correlations between the counts of memory B cells and plasmablasts and the values of laboratory parameters in patients with high RA activity may suggest that B lymphocytes are involved in the pathogenesis of RA. There was a decline in plasmablast levels after 12 months of TCZ therapy.


Immunity ◽  
2018 ◽  
Vol 48 (1) ◽  
pp. 174-184.e9 ◽  
Author(s):  
Kevin R. McCarthy ◽  
Akiko Watanabe ◽  
Masayuki Kuraoka ◽  
Khoi T. Do ◽  
Charles E. McGee ◽  
...  

2014 ◽  
Vol 41 (4) ◽  
pp. 666-672 ◽  
Author(s):  
Mirko Scarsi ◽  
Lucia Paolini ◽  
Doris Ricotta ◽  
Antonio Pedrini ◽  
Silvia Piantoni ◽  
...  

Objective.Abatacept (ABA) is a chimeric molecule, able to block the CD28-mediated costimulatory pathway. To evaluate the hypothesis that, through this mechanism of action, ABA may down-modulate the immune responses of B lymphocytes in rheumatoid arthritis (RA), we investigated the serum levels of immunoglobulins (Ig), free light chains (FLC), anticitrullinated protein antibodies (ACPA), and rheumatoid factor (RF), as well as the number of B lymphocytes differentiated into post-switch memory cells in patients treated with ABA.Methods.The serum levels of Ig, FLC, different ACPA, RF isotypes, and the B cell phenotype were longitudinally evaluated in 30 patients with RA treated with ABA.Results.At baseline, the proportion of total and post-switch memory B cells was lower in RA than in healthy individuals. After 6 months of ABA treatment we observed significant reductions of serum levels of IgG, IgA, and IgM, as well as FLC, with a normalization in many patients who had initially abnormal values. A significant reduction of the titers of IgG- and IgA-ACPA, as well as of IgM-, IgA-, and IgG-RF was also observed. A decrease of autoantibodies below the upper limits of normal values was found in 2 of 26 patients (8%) initially seropositive for IgG-ACPA, 1 of 14 (7%) for IgA-ACPA, 5 of 22 (23%) for IgM-RF, 7 of 22 (30%) for IgA-RF, and 5 of 16 (31%) for IgG-RF. After treatment, the proportion of circulating post-switch memory B cells was also further significantly decreased.Conclusion.ABA treatment in patients with RA can reduce signs of polyclonal B cell activation, inducing a trend toward normalization of serum levels of different classes of Ig and of FLC, decreasing titers of ACPA and RF, and percentages of post-switch memory B cells.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2311-2311
Author(s):  
Inken Hilgendorf ◽  
Brigitte Mueller-Hilke ◽  
Guenther Kundt ◽  
Ernst Holler ◽  
Petra Hoffmann ◽  
...  

Abstract Abstract 2311 Background: Chronic graft-versus host disease (cGVHD) features certain similarities with autoimmune diseases. The pathogenesis of cGVHD after allogeneic hematopoietic stem cell transplantation (alloHSCT), however, is poorly understood. Methods: Peripheral blood samples from 52 pts with active (median day 976, range 177–2773) (group 1), 28 pts with resolved (median day 1207, range 147–2849) (group 2) and 18 pts without cGVHD (median day 1015, range 124–2655) (group 3) were analysed for T and B cell subsets by FACS. 47 pts were transplanted from matched related donors, 40 pts from matched and 11 from mismatched unrelated donors. In addition, blood samples from 20 patients with and 10 patients without history of cGVHD were tested for: antinuclear antibody (ANA), anti-neutrophil cytoplasmatic antibody (ANCA), antimitochondrial antibody (AMA), anti-smooth-muscle antibody (ASMA) and double stranded DNA (dsDNA). Chronic GVHD was evaluated using criteria and guidelines of the National Institute of Health (mild n=16, moderate=18, severe n=18). Results: The absolute CD19+ B cell counts (median in 109/l) in pts with active chronic GVHD (0.03; range 0–2.59) were subnormal and lower than in pts of group 2 (0.140; range 0.001–0.856; p 0.019) and group 3 (0.175; range 0.20–0.553; p 0.002). Significant differences in absolute numbers of the CD27− B cell compartment, including immature (CD19+ CD27− CD38++CD20+IgM+) and transitional B cells (CD19+ CD27− CD38++CD10+CD20+IgM+), (median in 109/l: group1: 0.015; range 0–0.499 vs. group 2: 0.090; range 0–0.667 or vs. group 3: 0.158; range 0.02–0.52; both p<0.001) as well as class switched memory B cells (median in 106/l: 0.045; range 0–96.00 vs. 3.40; range 0–69.35; p 0.032 or vs. 7.40; range 0–56.83; p 0.003) were observed between the groups. Of interest, the CD 27+IgD+IgM+ B cell subpopulation (median in 106/l) is lacking in pts with active cGVHD (0; range 0–1.35) in contrast to patients with resolved (0.43, range 0–17.47; p<0.001) or pts who never experienced cGVHD (1.69; range 0–10.00; p<0.001). The counts of CD8+ T cells (median in 109/l) were significantly lower in pts of group 1 (0.257, range 0.01–1.76) compared to pts of group 2 (0.373; range 0 –1.96; p 0.010) or group 3 (0.545; range 0.06–1.61; p 0.027). No significant differences in CD4+ T cell counts (median in 109/l: 0.274 vs. 0.355 vs. 0.293) including naïve and memory CD4+ T cells as well as regulatory CD25+CD4+ FoxP3+ T cell counts (median in 106/l: 8.11 vs. 6.55 vs. 9.72) were observed between the three groups. In patients with cGVHD ANA was positive in 35% (7/20), ASMA in 20% (4/20) and AMA in 5% (1/20). ANA was positive in 36% (4/11) and ASMA in 27% (3/11) of patients without cGVHD. AMA and dsDNA were negative in all patients without cGVHD and ANCA was negative in all tested patients. 10% (3/31) of patients showed more than one autoantibody. Conclusion: Our data confirm a close association of diminished B cell counts with cGVHD while no difference of the tested autoantibodies was observed between pts with and without cGVHD. The lack of CD 27+IgD+IgM+ B cells in pts with cGVHD indicates functional asplenia in these pts, because IgM+ memory B cells are dependent upon a functional spleen for their generation and/or survival. Analysis of B cell subsets can provide a diagnostic tool for monitoring cGVHD activity but requires prospective evaluation. Disclosures: No relevant conflicts of interest to declare.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Gombozhapova ◽  
Y Rogovskaya ◽  
M Rebenkova ◽  
J Kzhyshkowska ◽  
V Ryabov

Abstract Introduction The functional characteristics of tissue macrophages associated with the progression of cardiac fibrosis in clinic are still unknown. Purpose The purpose was to study cardiac macrophage phenotypes contributing to the development of chronic inflammation and fibrosis in patients with myocardial infarction (MI). Methods The study included 41 patients with fatal MI type 1. Group 1 (n=24) comprised patients who died within 72 hours of MI (the inflammatory phase) and group 2 (n=17) comprised patients who died 4–28 days after MI (the regenerative phase). Macrophage infiltration (number of cells) in the heart was assessed by double immunofluorescence in the non-infarct area. Each area was evaluated in 20 random fields. We used CD163, CD206, stabilin-1, α-smooth muscle actin (α-SMA), interleukin-10 (IL-10) as markers of M2-like macrophages. Results The number of CD163+/CD206− (p=0.087) and CD163+/206+ (p=0.072) macrophages was higher during the regenerative phase of MI. The number of CD163-/CD206+, stabilin-1+/α-SMA-, stabilin-1+/α-SMA+, stabilin-1+/IL-10−, stabilin-1+/IL-10+, stabilin-1-/IL-10+ did not significantly change throughout the entire period of MI. The comparison of various M2 macrophage subpopulations into groups revealed following. In group 1 the number of CD163+/CD206− and CD163+/CD206+ cells prevailed over CD163−/CD206+ (p=0.033 and p=0.003, respectively), stabilin1+/α-SMA− cells over stabilin-1+/α-SMA+ (p<0.001), and stabilin-1+/IL-10+ cells over stabilin-1+/IL-10− (p=0.018). In group 2 the quantity of stabilin-1+/α-SMA− macrophages prevailed over stabilin-1+/α-SMA+ (p=0.005) and stabilin-1+/IL-10+ over stabilin-1−/IL-10+ (p=0.028). In group 1 the number of CD163+/CD206+ cells correlated with the absolute and the relative number of peripheral blood monocytes prior to the onset of death (R=0.97), while the quantity of stablin-1+/α-SMA+ cells correlated with the absolute number of peripheral blood monocytes at admission (R=-0.53). In group 2 the quantity of CD206+/CD163− cells correlated with the absolute and the relative number of monocytes in the peripheral blood at admission (R=0.73 and R=0.59, respectively), the quantity of CD163+/CD206− macrophages with the incidence of recurrent MI (R= 0.54), and the number of stabilin-1+/α-SMA+ macrophages with the age of patients (R=-0.58). Conclusions We have suggested that the key cardiac macrophage phenotypes contributing to the development of chronic inflammation and cardiac fibrosis in the regenerative phase of MI were stabilin-1+/α-SMA− and stabilin-1+/IL-10+. We revealed subpopulation of stabilin-1+/α-SMA+ macrophages, that indicated the possibility of cellular transdifferentiation and macrophage plasticity. Thus, our results supports that understanding the role of macrophages in initiation, progression, and resolution of cardiac fibrosis is one of the most promising goal in the design of anti-fibrotic treatment strategies for patients with MI.


1998 ◽  
Vol 72 (1) ◽  
pp. 330-338 ◽  
Author(s):  
Lijuan Yuan ◽  
S.-Y. Kang ◽  
Lucy A. Ward ◽  
Thanh L. To ◽  
Linda J. Saif

ABSTRACT Newborn gnotobiotic pigs were inoculated twice perorally (p.o.) (group 1) or intramuscularly (i.m.) (group 2) or three times i.m. (group 3) with inactivated Wa strain human rotavirus and challenged with virulent Wa human rotavirus 20 to 24 days later. To assess correlates of protection, antibody-secreting cells (ASC) were enumerated in intestinal and systemic lymphoid tissues from pigs in each group at selected postinoculation days (PID) or postchallenge days. Few virus-specific ASC were detected in any tissues of group 1 pigs prior to challenge. By comparison, groups 2 and 3 had significantly greater numbers of virus-specific immunoglobulin M (IgM) ASC in intestinal and splenic tissues at PID 8 and significantly greater numbers of virus-specific IgG ASC and IgG memory B cells in spleen and blood at challenge. However, as for group 1, few virus-specific IgA ASC or IgA memory B cells were detected in any tissues of group 2 and 3 pigs. Neither p.o. nor i.m. inoculation conferred significant protection against virulent Wa rotavirus challenge (0 to 6% protection rate), and all groups showed significant anamnestic virus-specific IgG and IgA ASC responses. Hence, high numbers of IgG ASC or memory IgG ASC in the systemic lymphoid tissues at the time of challenge did not correlate with protection. Further, our findings suggest that inactivated Wa human rotavirus administered either p.o. or parenterally is significantly less effective in inducing intestinal IgA ASC responses and conferring protective immunity than live Wa human rotavirus inoculated orally, as reported earlier (L. Yuan, L. A. Ward, B. I. Rosen, T. L. To, and L. J. Saif, J. Virol. 70:3075–3083, 1996). Thus, more efficient mucosal delivery systems and rotavirus vaccination strategies are needed to induce intestinal IgA ASC responses, identified previously as a correlate of protective immunity to rotavirus.


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1008.2-1008
Author(s):  
L. Fang ◽  
Z. Lin ◽  
Z. Liao ◽  
O. Jin ◽  
Y. Pan ◽  
...  

Background:Targeted synthetic DMARDs (ts-DMARDs) are becoming more available and affordable in developing countries, where the prevalence of hepatitis B virus (HBV) infection is still an important public health issue. The safety of ts-DMARDs therapy in terms of the reactivation of hepatitis B virus (HBV) infection need more concern. Rare data from a prospective study focus on the use of ts-DMARDs in patients with concurrent rheumatoid arthritis (RA) and HBV infection were available by now.Objectives:To evaluate the influence of tofacitinib on reactivation of HBV infection in HBsAg carriers with RA.Methods:In this 52 weeks observation, HBsAg carriers with active RA (DAS28>5.1) despite failed combined treatment with MTX and other non-biological DMARDs were enrolled. Patients must have normal liver function prior to study. All patients received therapy with tofacitinib (5mg twice daily) and concomitant MTX (10-12.5mg/w). Entecavir was prescribed preventively for patients who had a baseline HBV load >2000 copy/ml (group 1), and Lamivudin for patients with HBV load ≤ 2000 copy/ml (group 2). Liver enzymes (AST/ALT) and HBV viral load were monitored every 4 weeks. Increased viral load and abnormal liver function were managed according to expert opinion.Results:Thirteen patients (10 female) were recruited. Nine patients had a baseline viral load >2000 copy/ml (group 1, with preventive Entecavir), and the other 4 patients had a viral load ≤ 2000 copy/ml (group 2, with preventive Lamivudin). Two patients from group 1 discontinued tofacitinib at week 12 due to ineffectiveness, and both continued taking Entecavir for another 3 months after the discontinuation of tofacitinib.No reactivation of hepatitis B was observed in patients from group 1. One patients (female, 54 years old) from group 2 underwent a mild increase of both ALT and AST (67 and 56 IU/L, respectively) at week 16. An elevated viral load (4.9e6 copies/ml, baseline 1.4e3) and a HBV YMDD mutant was also found. The tofacitinib treatment continued. After prescription of Adefovir (combined with the pre-existing Lamivudin), both liver enzyme and viral load decreased to normal range in 8 weeks and remained normal throughout the study.Conclusion:An aggressive Tofacitinib + MTX therapy may be a safe option for HBsAg carriers with cs-DMARDs refractory RA. More active and effective prophylaxis strategy may be recommended to reduce the risk of HBV reactivation during the treatment.References:[1]Chen YM, Huang WN, Wu YD, et al. Reactivation of hepatitis B virus infection in patients with rheumatoid arthritis receiving tofacitinib: a real-world study. Ann Rheum Dis 2018; 77:780-2.Disclosure of Interests: :None declared


2015 ◽  
Vol 17 (1) ◽  
Author(s):  
Zafar Mahmood ◽  
Khalid Muhammad ◽  
Marc Schmalzing ◽  
Petra Roll ◽  
Thomas Dörner ◽  
...  

Author(s):  
Myron R. Szewczuk

ABSTRACTThe effect of age on the ability of B lymphocytes and thymus cells from donors of various ages to be capable of producing an anti-idiotype-blocked, hapten-augmentable PFC was studied by adoptive cell transfer techniques. Lethally irradiated mice were reconstituted with syngeneic B lymphocytes and thymus cells from donors of various ages. Recipients were immunized with trinitrophenylated bovine gamma globulin (TNP-BGG) one or seven days after cell transfer. Splenic IgG anti-TNP plaque-forming cell (PFC) responses were assayed in the absence and presence of hapten for anti-idiotype (Id)-blocked, hapten-augmentable PFC, 14 days after immunization. It was found that the B lymphocyte population from 2 month old donors together with thymus cells from donors of various ages (2 to 19 months) were incapable of reconstituting mice to produce anti-Id-blocked, hapten-augmentable PFC. Similar results were obtained when mice were reconstituted with thymus cells from 2-month-old donors together with B cells from donors of various ages (2 to 14 months). In contrast, mice reconstituted with B cells plus thymus cells from the same 8-month or older donors produced a significantly high percentage of anti-Id-block, hapten augmentable PFC. Mice reconstituted with B cells from 8 months or older donors plus thymus cells from donors of various ages (8 to 19) months also produced a significantly high percentage of hapten-augmentable PFC. Experiments with B cells and thymus cells from 2-or 8-month old donors parked in lethally irradiated 2-or 8-months old recipients for 7 days revealed that neither lymphocytes from old donors or old recipients were capable of inducing the appearance of anti-Id-blocked, hapten-augmentable PFC in the lymphocyte population from 2-month-old donors. Thus, the results of this study indicate syner-gistic co-operation between B lymphocytes and thymus cells from old donors for the production of auto-anti-idiotypic antibody regulation with age. This production of auto-anti-Id antibody with age seems not to be an induced maturation event but perhaps an intrinsic property unique to lymphocytes from old donors.


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