Polyclonal Immunoglobulin Free Light Chain and Chronic Inflammation

To the Editor:

With great interest, we read the article by Dispenzieri et al¹ in the June 2012 issue of Mayo Clinic Proceedings in which they reported their investigation of the association of polyclonal immunoglobulin free light chains (FLCs) and the mortality rate in a large population of normal persons. The authors concluded that nonclonal elevation of FLCs is a significant predictor of worse overall survival in persons without plasma cell disorders. The increased risk of death was independent of renal function, sex, and age but not restricted to any particular cause of death. As also discussed in the editorial that introduced this paper,² normal immunoglobulin production is accompanied by an excess of FLC synthesis. Free light chains are secreted by plasma cells and can be found in body fluids such as blood, synovial and cerebrospinal fluid, urine, and saliva. Although FLCs have been considered spillover products of antibody synthesis, FLCs can also have diverse biological activities, including antiangiogenic, prothrombinase, proteolytic, and complement-activating activities.³

In addition, we have described that FLCs can trigger inflammation via activation of mast cells.⁴ Passive sensitization of mice with antigen-specific FLCs followed by antigen challenge induces an immediate hypersensitivity-type response.⁴ Mast cells may not be the sole cellular target for FLCs, because neutrophils and neural cells have also been found to respond to FLCs.^5,6 In previous work, we showed that FLCs may play a crucial role in the pathogenesis of disease in preclinical models for asthma, inflammatory bowel disease, and food allergy.^7-10 In extension to these studies, we found increased local or systemic FLC concentrations in patients with food allergy¹⁰ inflammatory bowel disease,⁸ rheumatoid arthritis,¹¹ viral myocarditis,¹² and upper and lower airway diseases such as rhinitis,¹³ asthma,⁷ idiopathic pulmonary fibrosis and hypersensitivity pneumonia,¹⁴ and chronic obstructive pulmonary disease (Figure).⁵ Therapeutic intervention with rituximab in patients with rheumatoid arthritis showed that decreases in FLCs correlate with a decrease in disease activity.¹¹ Our studies suggest that FLCs may be responsible for an antigen-specific initiation and perpetuation of chronic inflammation.

FIGURE.

Immune disorders associated with increased immunoglobulin free light chains (FLC) and effector functions of immunoglobulin FLC leading inflammatory diseases via mast cell and neutrophil activation. COPD = chronic obstructive pulmonary disease; IBD = inflammatory bowel disease; IPF = idiopathic pulmonary fibrosis; RA = rheumatoid arthritis.

These findings may be of particular importance in relation to the study described by Dispenzieri et al.¹ Increased FLCs could stimulate the progression of chronic inflammatory responses via the activation of specific immune cells. It would therefore be of interest in future studies to investigate whether polyclonal FLC concentrations may also be associated with specific markers of cellular activation. These data, including those from Mayo Clinic Proceedings,¹ suggest that measurement of FLCs may not only be important to investigate aberrant FLCs leading to plasma cell disorders but may also give insight into ongoing inflammatory immune reactions.