Ig-Free Light Chains Play a Crucial Role in Murine Mast Cell-Dependent Colitis and Are Associated with Human Inflammatory Bowel Diseases

Abstract

Traditionally, mast cells were regarded as key cells orchestrating type I hypersensitivity responses. However, it is now recognized that mast cells are widely involved in nonallergic (non-IgE) chronic diseases. Also, in inflammatory bowel disease (IBD), a disease not associated with increased IgE concentrations, clear signs of activation of mast cells have been found. In this study, we investigated if Ig-free L chain-induced hypersensitivity-like responses through activation of mast cells could contribute to the pathophysiology of IBD. As a mast cell-dependent model for IBD, mice were skin-sensitized with dinitrofluorobenzene followed by intrarectal application of the hapten. In this murine IBD model, F991 prevented mast cell activation and also abrogated the development of diarrhea, cellular infiltration, and colonic lymphoid follicle hyperplasia. Furthermore, passive immunization with Ag-specific Ig-free L chains (IgLCs) and subsequent rectal hapten challenge elicited local mast cell activation and increased vascular permeability in the colon of mice. Clinical support is provided by the observation that serum concentrations of IgLCs of patients suffering from Crohn’s disease are greatly increased. Moreover, increased presence of IgLCs was evident in tissue specimens from colon and ileum tissue of patients with IBD. Our data suggest that IgLCs may play a role in the pathogenesis of IBD, which provides novel therapeutic means to prevent or ameliorate the adverse gastrointestinal manifestations of IBD.

Immunoglobulin free light chains are biomarkers of poor prognosis in basal-like breast cancer and are potential targets in tumor-associated inflammation

“…In our previous studies, FLC-mediated mast cell activation has been associated with the induction of several inflammatory disorders [19, 49, 50]. Present data suggest that FLC could contribute to tumor growth.…”

Association of Serum Ig Free Light Chains with Mortality and ESRD among Patients with Nondialysis-Dependent CKD

“…cells and other circulating cells in a range of autoimmune and inflammatory diseases (33,34). However, the nature of the interactions between polyclonal LCs and specific receptors is uncertain; this area is under investigation.…”

The cumulative amount of serum-free light chain is a strong prognosticator in chronic lymphocytic leukemia

“…For instance, despite being usually regarded as a mere spillover product of Ig synthesis/assembly, FLCs could activate mast cells, which enrich the CLL microenvironment. 35 Activated mast cells may in turn support tumor cell growth and foster immune stimulation through different pathways, including CD40-and IL-6-mediated signaling. 36 In conclusion, our findings support that the cumulative amount of circulating FLC, irrespective of their clonality, is a strong and independent prognostic predictor in CLL.…”