A8.14 Effect of rituximab on B-cell phenotypes and on B-cell activating factor receptor expression in patients with thrombotic thrombocytopenic purpura

ObjectivesTo examine the expression of B-cell-activating factor receptor (BAFF-R) on naive CD27− and memory CD27+ B cells in normal individuals and patients with rheumatoid arthritis (RA) undergoing B-cell depletion therapy with rituximab.Patients and MethodsBAFF-R expression on B-cell subsets was determined in normal controls (NC; n=11), active patients with RA pre-rituximab (pre-RX; n=15), relapsing patients either concordant for B-cell repopulation (C-R, n=13) or discordant, with relapse more than 3 months after repopulation (D-R, n=11) and patients in remission over 3 months postrepopulation (discordant non-relapsing (D-NR), n=5). Serum BAFF was measured by ELISA and analysed using Mann–Whitney.ResultsThere was no significant difference between NC, pre-RX and D-NR patients in %BAFF-R-positive B cells or mean fluorescence intensity (MFI) in naive and memory B cells. Relapsing patients had significantly lower MFI and %BAFF-R-positive cells in both naive and memory compartments from NC and pre-RX (C-R and D-R; p<0.01). BAFF levels in pre-RX patients were within the normal range and did not correlate with BAFF-R expression in any patient group. D-NR patients had relatively lower proportions of pre and postswitch CD27+ B cells than pre-RX patients (D-NR vs pre-RX; p<0.05 for both) and also lower numbers of postswitch B cells than D-R patients (D-NR vs D-R, p<0.05).ConclusionBAFF-R expression was significantly reduced on both naive and memory B cells in patients at relapse, regardless of the relationship with B-cell repopulation or serum BAFF levels. Re-establishment of active disease was also associated with an increase in class-switch recombination. Factors responsible for lower levels of BAFF-R may relate to altered thresholds for autoreactive B-cell generation at relapse in patients with RA.

Download Full-text

Regulation of B cell activating factor (BAFF) receptor expression by NF-κB signaling in rheumatoid arthritis B cells

Experimental & Molecular Medicine ◽

10.3858/emm.2011.43.6.038 ◽

2011 ◽

Vol 43 (6) ◽

pp. 350 ◽

Cited By ~ 29

Author(s):

Yun-Ju Woo ◽

Bo-Young Yoon ◽

Joo-Yeon Jhun ◽

Hye-Jwa Oh ◽

Sewon Min ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

B Cells ◽

B Cell ◽

Receptor Expression ◽

B Cell Activating Factor

Download Full-text

Skewed peripheral B- and T-cell compartments in patients with ANCA-associated vasculitis

Rheumatology ◽

10.1093/rheumatology/keaa432 ◽

2020 ◽

Author(s):

Jonathan London ◽

Nicolas Dumoitier ◽

Sébastien Lofek ◽

Jérémie Dion ◽

Benjamin Chaigne ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Cell Polarization ◽

Receptor Expression ◽

T Cell Subsets ◽

Fluorescence Intensity Ratio ◽

Cell Compartments ◽

B Cell Activating Factor ◽

T Cell Polarization

Abstract Objectives To characterize lymphocytes dysregulation in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Methods Using flow cytometry, we analysed B- and T-cell subsets in peripheral blood from 37 untreated patients with active disease (29 GPA and 8 MPA) and 22 healthy controls (HCs). Results GPA patients had increased Th2 (1.8 vs 1.0%, P = 0.02), Th9 (1.1 vs 0.2%, P = 0.0007) and Th17 (1.4 vs 0.9%, P = 0.03) cells compared with HC. Patients with MPO-ANCAs had significantly more CD21– B cells than HC or PR3-ANCA patients (6.9 vs 3.3% and 4.4%, P = 0.01). CD69 expressing B cells were significantly higher in GPA and MPA (3.0 and 5.9 vs 1.4%, P = 0.02 and P = 0.03, respectively) compared with HC, whereas B-cell activating factor-receptor expression was decreased in GPA and MPA (median fluorescence intensity ratio 11.8 and 13.7 vs 45.1 in HC, P < 0.0001 and P = 0.003, respectively). Finally, IL-6-producing B cells were increased in GPA vs HC (25.8 vs 14.9%, P < 0.0001) and decreased in MPA vs HC (4.6 vs 14.9%, P = 0.005), whereas TNF-α-producing B cells were lower in both GPA and MPA patients compared with controls (15 and 8.4 vs 30%, P = 0.01 and P = 0.006, respectively). Conclusion Skewed T-cell polarization towards Th2, Th9 and Th17 responses characterizes GPA, whereas B-cell populations are dysregulated in both GPA and MPA with an activated phenotype and a decreased B-cell activating factor-receptor expression. Finally, inflammatory B cells producing IL-6 are dramatically increased in GPA, providing an additional mechanism by which rituximab could be effective.

Download Full-text

A beneficial effect of rituximab on autoimmune thrombotic thrombocytopenic purpura: Just a B-cell depletion?

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2013.11.022 ◽

2014 ◽

Vol 133 (2) ◽

pp. 600 ◽

Cited By ~ 5

Author(s):

Jae Il Shin ◽

Michael Eisenhut

Keyword(s):

Beneficial Effect ◽

B Cell ◽

Thrombotic Thrombocytopenic Purpura ◽

Cell Depletion ◽

B Cell Depletion ◽

Thrombocytopenic Purpura

Download Full-text

Decreased B cell activating factor receptor expression on peripheral lymphocytes associated with increased disease activity in primary Sjogren's syndrome and systemic lupus erythematosus

Annals of the Rheumatic Diseases ◽

10.1136/ard.2006.065656 ◽

2007 ◽

Vol 66 (6) ◽

pp. 790-797 ◽

Cited By ~ 54

Author(s):

J. Sellam ◽

C. Miceli-Richard ◽

J.-E. Gottenberg ◽

M. Ittah ◽

F. Lavie ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

B Cell ◽

Lupus Erythematosus ◽

Primary Sjögren’S Syndrome ◽

Receptor Expression ◽

Systemic Lupus ◽

Primary Sjogren’S Syndrome ◽

Peripheral Lymphocytes ◽

B Cell Activating Factor

Download Full-text

Antibody Against Macrophage Receptor with Collagenous Structure (Anti-MARCO IgG) in Thrombotic Thrombocytopenic Purpura Patients.

Blood ◽

10.1182/blood.v120.21.2201.2201 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2201-2201

Author(s):

Phandee Watanaboonyongcharoen ◽

Jessica L. Allen ◽

Yuri D. Fedoriw ◽

Herbert C. Whinna ◽

Rommel P. Lu ◽

...

Keyword(s):

Western Blot ◽

B Cell ◽

Thrombotic Thrombocytopenic Purpura ◽

Area Under The Curve ◽

Healthy Controls ◽

Adamts13 Activity ◽

Thrombocytopenic Purpura ◽

High Background ◽

Number Of Patients ◽

Collagenous Structure

Abstract Abstract 2201 Idiopathic thrombotic thrombocytopenic purpura (TTP) is typically associated with severe ADAMTS13 deficiency due to the production of autoantibodies against ADAMTS13. Recent studies have demonstrated that B cell activating factor (BAFF), a TNF family member known to promote activation and survival of autoreactive B cells, is increased in TTP patients (Thomas et al. 2011 155:620 Br J Haematol; Watanaboonyongcharoen et al. 2011, AABB Abstract # 1118421). We hypothesized that high BAFF levels in TTP results in loss of B cell tolerance and the production of autoantibodies. Since defective clearance of apoptotic cells by macrophages has been found in autoimmune diseases, antibodies against MARCO (Macrophage Receptor with Collagenous structure) represented good candidate for study as a potentially pathophysiologically relevant autoantibody. Such anti-MARCO antibodies may lead to defective apoptotic cell clearance and the development of TTP. We measured anti-MARCO antibodies by ELISA and Western blot in 34 idiopathic TTP patients between 1999 and 2012: 25 female and 9 male with a median age of 40 years (range 25–72). All patients were diagnosed on the clinical basis of microangiopathic hemolytic anemia and thrombocytopenia without any other cause. ADAMTS13 activity and the presence of anti-ADAMTS13 inhibitor tests were performed in all patients. Fifty percent of patients had ADAMTS13 activity less than 10%, while 56% had ADAMTS13 inhibitor. All 34 patients underwent therapeutic plasma exchange (TPE) daily until the platelet count was at least 150 × 109/l for two consecutive days. High dose steroids were initiated immediately after first TPE. While direct binding ELISA did not yield specific results due to high background, specific MARCO bands were detected by Western blotting of recombinant MARCO protein with patient plasma IgG. Ninety-seven percent of patients with TTP (33/34) were positive for anti-MARCO IgG antibody compared to forty percent (10/25) of healthy controls, p < 0.001 (Table 1). As a surrogate for antibody titer, intensity of each Western blot band was quantified by densitometry using NIH ImageJ software. Patients with TTP had significantly increased anti-MARCO IgG as defined by the densitometric area under the curve (1.3 × 103; range 0–8.2 × 103) compared to healthy controls (0, range 0–4.5 × 103), p < 0.001. A cut-off point for high titer anti-MARCO IgG was calculated by using mean + 2SD of the area under the curve (AUC) of anti-MARCO IgG Western blot band density measured in healthy controls. Patients with an increased amount of anti-MARCO IgG (AUC > 2.9× 103) tended to have a higher relapse rate compared to those with normal anti-MARCO IgG (4 of 6 patients [67%] vs. 10 of 28 patients [36%], respectively, p = 0.20), although statistical significance was not reached due to the limited number of patients. Thus, for the first time, we identify anti-MARCO IgG in idiopathic TTP, suggesting a role for macrophage inhibition in the pathophysiology of TTP. Studies of anti-MARCO antibodies in larger numbers of patients may lead to development of a novel prognostic marker for TTP patients. Table 1. Presence of anti-MARCO IgG on Western blot Anti-MARCO IgG Population group TTP n (%) Healthy n (%) Yes, (n = 43) 33 (97) 10 (40) No, (n = 16) 1 (3) 15 (60) p < 0.001. Disclosures: No relevant conflicts of interest to declare.

Download Full-text