CD21low B cells in systemic sclerosis: A possible marker of vascular complications
Introduction
Systemic sclerosis (SSc) is an autoimmune disease with multifactorial etiopathogenesis [1]. It is characterized by an aberrant activation of the immune system, widespread functional and structural vascular damage and progressive fibrosis of skin and internal organs [2]. Endothelial dysfunction, microvascular and macrovascular damage are the hallmarks of SSc. Many clinical manifestations of SSc, such as digital ulcers (DUs), scleroderma renal crisis, pulmonary arterial hypertension (PAH) showed a vascular pathogenesis [3]. An imbalance of pro-angiogenic factors and angiogenesis inhibitors has been implicated in the progression of peripheral microvascular damage, defective vascular repair and fibrosis [4].
B cells play a critical role in systemic autoimmunity and disease expression through various functions, not only by autoantibody production but also by producing inflammatory and profibrotic cytokines (i.e. IL-6, PDGF, TGFbeta) [5].
Efficacy of B cell depletion with rituximab in SSc patients further support the involvement of B cells in disease development and/or progression [6]. SSc patients show an impairment of B cell homeostasis and the main characteristics are an increased frequency of naïve B cells compared to memory B cells that show features of chronic activation and are apoptosis-prone [[7], [8], [9], [10], [11]]. The reduction of memory B cells in SSc patients has been suggested as the result of their increased activation-induced apoptosis [7]. Recently Forestier et al. found in SSc patients an increased percentage of a particular B cell subpopulation characterized by the reduced expression of the complement receptor 2, CD21, and therefore called CD21low B cells [8]. These CD21low B cells have been described in different diseases with profound B cell alteration that include infections as human immunodeficiency virus (HIV) [12] and hepatitis C virus associated mixed cryoglobulinemia (HCV-MC) [13] and immunological disorders as common variable immunodeficiency (CVID) [14], rheumatoid arthritis (RA) [15], Sjogren syndrome (SS) [16] and systemic lupus erythematosus (SLE) [17,18]. This particular B cell population is predominantly composed by memory B cells including double negative (DN) switched (CD27− IgD−) memory B cells [19,20] and express high level of activation markers, inhibitory receptors and a peculiar pattern of homing receptors. Functionally these lymphocytes have the features of anergic and exhausted cells [21,22] and have been found enriched in peripheral inflammatory tissue with a role in joint destruction in patients with RA [14,15]. In health, CD21low B cells have been described in the human tonsil and in the thymus with a possible role as antigen presenting cells and in peripheral blood they account for less than 5% of the total B cell pool [19,23]. In SSc, CD21low B cells seem not to correlate with a particular clinical phenotype and no differences in their frequency were found between patients with diffuse (dcSSc) or limited (lcSSc) cutaneous SSc [8] and, although increased in frequency, a possible role in the pathophysiology of the disease remain still obscure.
Aims of this study were to analyse SSc patients with expanded CD21low B cells, to evaluate the influence of CD21low B cells in B cell homeostasis and apoptosis and to correlate this B cell subset with clinical manifestations of disease. Since impaired angiogenesis and deficit of apoptosis of B cell, endothelial cells and myofibroblasts are reported in SSc, we also investigated a possible interplay between CD21low B cells and the pro-angiogenic factor VEGF implicated in the progression of peripheral microvascular damage in SSc patients.
Section snippets
Subjects
Seventy-four SSc patients (F = 64, mean age 54.5 ± 10.9 years), fulfilling the American College of Rheumatology/European League Against Rheumatism Collaborative Initiative criteria for SSc, were enrolled in this study [24] (Table 1). Thirty-four (45.9%) have a dcSSc and forty (54.1%) lcSSc according to Le Roy et al. [25].
Patients with hematological malignancies, chronic kidney disease, scleroderma renal crisis, renal artery stenosis, pulmonary and cardiovascular diseases not related to SSc were
Activated CD21low B cells accumulate in some systemic sclerosis patients characterized by distinct B cell subsets distribution
The percentage of total B cells in SSc patients compared to HD was similar (8.84 ± 4.44 vs 8.42 ± 2.54), whereas altered B cell subsets distribution with increased naïve and decreased switched and IgM+ memory B cells characterized SSc patients. We found an increased percentage of B cells with reduced expression of the complement receptor 2 (CD21low B cells) in SSc patients compared to HD (6.8 ± 4.36 vs 4.6 ± 2.18, p < .01) (supplementary Fig. 1).
We divided enrolled SSc-patients as follows:
Discussion
The role of B cells in the pathogenesis of SSc is becoming more and more evident from recent and constantly emerging data from the literature [5,[7], [8], [9], [10], [11]]. Peripheral B cell subset distribution with a predominance of naïve B cells seem to be a hallmark in SSc patients and increased apoptosis of memory B cells might be responsible for their reduced frequency [7]. In our cohort of patients we confirmed previous observations and found an increased percentage of CD21low B-cells.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for profit sector.
Declaration of Competing Interest
None.
Acknowledgements
None.
References (40)
- et al.
Scleroderma: an insight into causes, pathogenesis and treatment strategies
Pathophysiology
(2019) - et al.
The role of endothelial cells in the vasculopathy of systemic sclerosis: a systematic review
Autoimmun. Rev.
(2017) - et al.
Angiogenic and angiostatic factors in renal scleroderma-associated vasculopathy
Microvasc. Res.
(2017) Pathogenic roles of B lymphocytes in systemic sclerosis
Immunol. Lett.
(2018)- et al.
Altered B lymphocyte homeostasis and functions in systemic sclerosis
Autoimmun. Rev.
(2018) - et al.
Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis
Mol. Immunol.
(2004) - et al.
A new CD21low B cell population in the peripheral blood of patients with SLE
Clin. Immunol.
(2004) - et al.
Clonal B cells in patients with hepatitis C virus-associated mixed cryoglobulinemia contain an expanded anergic CD21low B-cell subset
Blood
(2011) - et al.
The EUROclass trial: defining subgroups in common variable immunodeficiency
Blood
(2008) - et al.
Intrarenal hemodynamic parameters correlate with glomerular filtration rate and digital microvascular damage in patients with systemic sclerosis
Semin. Arthritis. Rheum.
(2012)
Guidelines for the Echocardiographic Assessment of the Right Heart in Adults: a report from the American Society of Echocardiography Endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography
J. Am. Soc. Echocardiogr.
Clonal expansion and functional exhaustion of monoclonal marginal zone B cells in mixed cryoglobulinemia: the yin and yang of HCV-driven lymphoproliferation and autoimmunity
Autoimmun. Rev.
Fresh insights into disease etiology and the role of microbial pathogens
Curr. Rheumatol. Rep.
Impaired angiogenesis in systemic sclerosis: the emerging role of the antiangiogenic VEGF(165)b splice variant
Trends Cardiovasc. Med.
Scleroderma
N. Engl. J. Med.
Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study
Ann. Rheum. Dis.
Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naïve B cells and diminished but activated memory B cells
Arthritis Rheum.
Systemic sclerosis patients present alterations in the expression of molecules involved in B-cell regulation
Front. Immunol.
Reduced non-switched memory B cell subsets cause imbalance in B cell repertoire in systemic sclerosis
Clin. Exp. Rheumatol.
Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals
J. Exp. Med.
Cited by (0)
- 1
These authors contributed equally to this work.