Thymic stromal lymphopoietin (TSLP)-induced polyclonal B-cell activation and autoimmunity are mediated by CD4+ T cells and IL-4

Abstract

The cytokine thymic stromal lymphopoietin (TSLP) functions as a regulator of bone marrow B-cell development and a key initiator of allergic inflammation. In the current study, we show that mature B cells, derived from transgenic mice with systemically elevated levels of TSLP (K5-TSLP mice), exhibit markedly enhanced mitogenic responses in vitro and that this enhanced responsiveness leads to polyclonal B-cell activation and development of autoimmune hemolytic anemia in vivo. In contrast, B cells derived from K5-TSLP mice lacking CD4(+) T cells failed to show polyclonal activation. Furthermore, neither mature B-cell activation nor hemolytic anemia occurred in IL-4-deficient K5-TSLP mice. Consistent with these findings, activation of mature B cells occurred independently of B-cell intrinsic TSLP signals. Taken together, our results demonstrate that systemic alterations in TSLP, through induction of IL-4 from CD4(+) T cells and other cell types, functions as an important factor in peripheral B-cell homeostasis and promotion of humoral autoimmunity.

The Biology of Thymic Stromal Lymphopoietin (TSLP)

“…However, it is clear that aberrant TSLP signaling can have a significant impact on B cells, as has been demonstrated by the association of TSLPR mutations with a subtype of B cell leukemia(Chapiro et al, 2010; Roll & Reuther, 2010; Tasian & Loh, 2011). In addition, elevated systemic TSLP has been shown to lead to aberrant B cell development and function, with both direct effects on early B cell development and indirect effects leading to autoimmune hemolytic anemia(Astrakhan et al, 2007; Iseki et al, 2012). …”

“…TSLP over-expression in these mice was associated with the development of cryoglobulinemic glomerulonephritis due to increased production and kidney deposition of systemic polyclonal IgM and IgG via a monocyte/macrophage dependent mechanism (Taneda et al, 2001; Astrakhan et al, 2007). In addition, these mice developed red blood cell-specific auto-antibodies and autoimmune hemolytic anemia in a CD4 + T cell and IL-4-dependent manner (Iseki et al, 2012). Whether TSLP is involved in human mixed cryoglobulinemia or autoimmune hemolytic anemia is unknown.…”

Thymic Stromal Lymphopoietin (TSLP)

“…However, it is clear that aberrant TSLP signaling can have a signifi cant impact on B cells, as has been demonstrated by the association of TSLPR mutations with a subtype of B-cell leukemia (Chapiro et al 2010 ;Roll and Reuther 2010 ;Tasian and Loh 2011 ). In addition, elevated systemic TSLP has been shown to lead to aberrant B-cell development and function, with both direct effects on early B-cell development and indirect effects leading to autoimmune hemolytic anemia (Astrakhan et al 2007 ;Iseki et al 2012 ).…”

“…TSLP overexpression in these mice was associated with the development of cryoglobulinemic glomerulonephritis caused by increased production and kidney deposition of systemic polyclonal IgM and IgG via a monocyte/macrophage-dependent mechanism (Taneda et al 2001 ;Astrakhan et al 2007 ). In addition, these mice developed red blood cell-specifi c auto-antibodies and autoimmune hemolytic anemia in a CD4 + T-cell-and IL-4-dependent manner (Iseki et al 2012 ). Whether TSLP is involved in human mixed cryoglobulinemia or autoimmune hemolytic anemia is unknown.…”

Rituximab for Treatment of Focal Segmental Glomerulosclerosis in a Child: A Case Report

“…BCDT is specific for the removal of B cells by apoptosis; the most commonly use medicine currently is rituximab. Rituximab is an anti-CD20 humanrat mosaic monoclonal antibody that has been constructed by gene recombination technology [1,2]. It has been used in recent years in the treatment of B-cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, refractory nephrotic syndrome and other autoimmune diseases.…”