REVIEW ARTICLE
Pathogenesis of systemic sclerosis: Altered B cell function is the key linking systemic autoimmunity and tissue fibrosis

https://doi.org/10.1016/j.jdermsci.2005.03.013Get rights and content

Summary

Systemic sclerosis (SSc) is characterized by autoimmunity and tissue fibrosis. There is a close association between specific autoantibodies and clinical features in patients with SSc. A number of studies have demonstrated that various cytokines, such as transforming growth factor-β, modulate the synthesis of extracellular matrix by fibroblasts. However, it is not clear as to how autoimmunity and tissue fibrosis interact with each other. Recent studies have revealed that B cells play a critical role in various systemic autoimmune disorders. CD19 is a central regulator of B cell signaling threshold, and B cells from SSc patients exhibit an increased expression of CD19 that induces SSc-specific autoantibody production in transgenic mice. Furthermore, SSc patients have intrinsic B cell abnormalities characterized by decreased but activated memory B cells, which is possibly due to CD19 overexpression. Similarly, B cells from a tight-skin mouse, a model of SSc, show augmented CD19 signaling and chronic B cell activation. Remarkably, CD19 loss results in inhibition of chronic B cell hyper-reactivity and elimination of autoantibody production, which is associated with improvement in skin fibrosis and a parallel decrease in IL-6 production by B cells. Therefore, augmented cytokine production by B cells is a potential candidate for the induction of skin sclerosis. Alternatively, B cells may influence tissue fibrosis by regulating T cell activation and cytokine production through their antigen-presenting and co-stimulatory abilities. Thus, altered B cell function may result in tissue fibrosis, as well as autoimmunity, in SSc.

Introduction

Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis of the skin and internal organs, with an autoimmune background. SSc is a heterogeneous disorder ranging from a mild (limited cutaneous SSc) to a severe form (diffuse cutaneous SSc). The detection of specific circulating autoantibodies is one of the most common features and usually precedes the disease onset. The presence of anti-topoisomerase I Ab or anti-RNA polymerases Ab associates with diffuse cutaneous SSc. By contrast, anticentromere Ab or anti-Th/To Ab is generally detected in limited cutaneous SSc. However, this Abs is not considered to contribute directly to tissue fibrosis.

The maintenance of extracellular matrix (ECM) structure and function occurs via a remodeling process, involving regulated phases of degradation and synthesis of ECM components, such as collagen and fibronectin, by fibroblasts. Over-deposition of ECM results in tissue fibrosis in SSc. There are a number of studies concerning the pathogenetic mechanisms of tissue fibrosis and immune activation in SSc [1], [2], [3]. Various cytokines produced by immune-activated cells modulate the synthesis of ECM by fibroblasts. However, it is not clear as to how systemic autoimmunity and tissue fibrosis interrelate with each other.

Recently, autoreactive B cells have been considered to play a key role in the development of systemic autoimmune diseases [4], [5]. In fact, B cell depletion therapy by chimeric anti-human CD20 Ab is reported to be effective in various autoimmune diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis. Although the effect of B cell depletion has not been investigated in SSc, B cell activation has been observed in SSc patients or tight skin heterozygous (TSK/+) mice, a genetic model for SSc [6], [7], [8], [9]. Therefore, chronic B cell activation may cause a breakdown of peripheral tolerance with subsequent autoantibody production in SSc.

In this review, we will highlight how altered B cell function may link autoimmunity with tissue fibrosis in SSc. Chronic B cell activation is likely to be critical for the development of autoimmunity. Furthermore, polarized cytokine expression derived from altered B cell function may induce the tissue fibrosis that characterizes SSc.

Section snippets

Intrinsic B cell abnormalities in SSc

Recent studies have revealed that B cells play critical roles in a variety of systemic autoimmune diseases [4], [5], [9]. The B cell signaling thresholds are regulated by response regulators that augment or diminish B cell signals during responses to self and foreign antigens. Abnormal regulation of the response regulator function and expression may result in autoimmunity. Among these response regulators, CD19, which is a critical cell-surface signal transduction molecule of B cells, is the

Th1/Th2 balance in SSc

CD4+ helper T cells (Th cells) consist of two subgroups, Th1 and Th2, characterized by distinct cytokine secretion patterns. While Th1 cells secrete interferon (IFN)-γ, interleukin (IL)-2, and tumor necrosis factor (TNF)-α, thus promoting cell mediated immunity, Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13, thereby facilitating humoral immunity. These Th2 cytokines enhance the immunoglobulin production by B cells. Furthermore, IL-4, IL-6, and IL-13 stimulate the synthesis of collagen by

A link between B cell activation and cytokine imbalance

Activated B cells are known to produce IL-6 and IL-10, both of which induce Th2-dominant immune responses [50], [51]. Since IL-6 has a potential effect on tissue fibrosis [14], [52], [53], increased IL-6 production by activated B cells may directly promote the tissue fibrosis in SSc patients. In an animal model, TSK/+ B cells stimulated with anti-IgM Ab plus anti-CD40 mAb produce high amounts of IL-6 compared with wild type B cells [7].

Activated B cells express high levels of class II MHC and

A model linking autoimmunity and tissue fibrosis

A possible model concerning the relationship between systemic autoimmunity and tissue fibrosis in SSc and TSK/+ mice is shown in Fig. 2. Polymorphism or mutation of B cell response regulators such as CD19 may increase B cell signaling, resulting in autoantibody production through breakdown of B cell peripheral tolerance, as shown in mice overexpressing CD19 [10]. B cells from human SSc and TSK/+ mice are chronically activated in vivo, possibly due to enhanced B cell signaling, which may result

Minoru Hasegawa received the MD degree from Kanazawa University Graduate School of Medical Science, and the PhD degree from the same University, in 1991 and 1998, respectively. He has been at Kanazawa University Graduate School of Medical Science, Kanazawa, Japan since 1991, and is currently an assistant professor in the Department of Dermatology. Between 1998 and 2001, he worked as a research associate at the Department of Immunology (Chairman: Thomas F. Tedder, PhD), Duke University Medical

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    Minoru Hasegawa received the MD degree from Kanazawa University Graduate School of Medical Science, and the PhD degree from the same University, in 1991 and 1998, respectively. He has been at Kanazawa University Graduate School of Medical Science, Kanazawa, Japan since 1991, and is currently an assistant professor in the Department of Dermatology. Between 1998 and 2001, he worked as a research associate at the Department of Immunology (Chairman: Thomas F. Tedder, PhD), Duke University Medical Center, Durham, NC, USA. His interests include systemic sclerosis, autoimmunity, B cell immunity, and skin ulcer (anti-phospholipid syndrome).

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