Immunoglobulin free light chains: A possible link between autoimmune disease and mast cell activation

An antibody (also called an immunoglobulin) is shaped like a Y.  The base of the Y is called the Fc region.  The arms of the Y are made of pieces called light chains and heavy chains.  Light chains (described as K or λ) have variable sequences that allow the complete antibody to stick to specific things, like bacteria or allergens.  Light chains are part of how your body fights infections and responds to allergens.  Importantly, free light chains do not work as antibodies.  They are not able to stick to the target the way the total antibody can.

Antibodies are made by white blood cells called plasma cells, which are B cells that circulate and release antibodies as needed.  When producing antibodies, B cells normally make more light chains than heavy chains.  Only about 60% of the light chains made are needed to produce antibodies.  The rest of the light chains are released into plasma and are present there for 2-6 hours, until they are cleared by kidneys.  Light chains that are released into plasma are called immunoglobulin free light chains, shortened as Ig-fLCs.

Another way Ig-fLCs are formed is when they antibody is bound and degraded by a cell.  Antibodies bind things like allergens.  Once they bind allergens (or something else), the antibodies can then bind to receptors on the outside of cells to tell the cells what they found.  Once the antibody is bound to the receptor, it can be partially broken down.  However, light chains are not damaged in this process, and they may be released back into serum.

Ig-fLCs are the subject of ongoing research in various disease models.  Ig-fLC elevation has been linked to a number of inflammatory conditions, including autoimmune diseases.  Systemic lupus erythematosus (SLE) patients demonstrate a significant elevation of Ig-fLCs in urine 4-8 weeks prior to a symptomatic flare.  SLE is an antibody driven disease and the extra Ig-fLCs may be produced as a byproduct of making more autoantibodies in advance of a flare.  In this capacity, it would demonstrate hyperactivity of the B cells that make the autoantibodies.

Ig-fLCs were also found to be elevated in 1/3 patients with rheumatoid arthritis and 1/5 patients with systemic sclerosis.  A number of cancers also induce elevation of Ig-fLCs.

Ig-fLCs are involved in a number of allergic processes.  In allergic asthma animal models, Ig-fLCs have been found to induce bronchoconstriction and acute mast cell degranulation.  Using an experimental light chain antagonist can prevent this reaction.  Κ light chains are elevated in serum of asthmatics, regardless of whether or not the asthma is atopic is nature. λ light chains are not elevated in this population.

Ig-fLCs are also involved in other allergic mouse models, including contact dermatitis, food allergy and inflammatory bowel disease.  In these models, the Ig-fLCs can sensitize mast cells to allergens so that exposure to the allergen causes mast cell activation and degranulation.

Ig-fLCs have also been implicated in mast cell dependent colitis and inflammatory bowel diseases such as ulcerative colitis and Crohn’s.  It is believed that antigen specific Ig-fLC sensitizes mast cells to cause activation and degranulation.  This is especially important because it describes a mechanism that occurs in the absence of IgE.  Serum κ and λ light chains are elevated in Crohn’s models and using an experimental blocker prevents these bowel symptoms.  Research has indicated that the IgE, IgG and paired Ig-like receptor A receptors are not involved in binding Ig-fLCs in these models.

Many mast cell patients have a primary inflammatory condition, such as IBD or autoimmune disease.  Mast cell activation via Ig-fLCs is, to me, the most plausible explanation for this relationship.  Currently, mast cell activation by Ig-fLCs has not been demonstrated in humans, though present in many animal models.  However, Ig-fLC correlation to autoimmune diseases such as lupus has been shown in humans.


Kraneveld A, et al. Elicitation of allergic asthma by immunoglobulin free light chains. PNA 2005: 102(5); 1578-1583.

Thio M, et al. Antigen binding characteristics of immunoglobulin free light chains: crosslinking by antigen is essential to induce allergic inflammation. PLoS One 7(7): e40986.

Rijnierse A, et al. Ig-free light chains play a crucial role in murine mast cell-dependent colitis and are associated with human inflammatory bowel diseases. J Immunol 2010; 185:653-659.

Gottenberg JE, et al. Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjogren’s syndrome. Ann Rheum Dis 2007; 66:23-27.

Aggarwal R, et al. Serum free light chains as biomarkers for systemic lupus erythematosus disease activity. Arthritis Care and Research 2011: 63(6): 891-898.

7 Responses

  1. Kelly November 18, 2015 / 6:45 pm

    Interesting theory. Is there a simple serum test that can be done locally for IG-fLCs?

    Undoubtedly there is a connection between autoimmunity and mast cell activation. Left asking myself why the difference in Attack in localized regions in autoimunne disease such as RA vs. systemic reactions in systemic Mastocytosis.

    I continue to love following your posts and so happy to be connected with you!

    • Lisa Klimas November 18, 2015 / 8:57 pm

      Yes, kappa and lambda light chains can be tested in serum pretty easily. The test is widely known and available. Thanks for the kind words! 🙂

  2. Emily H November 20, 2015 / 11:19 pm

    Nice post. How does that relate to NF-kB? My parent has kappa light chain amyloidosis and MGUS/MM. My tryptase is negative (though never run during an attack) so I have not had a bone marrow biopsy though I have anaphylaxis/degranulation often. I’m on ketotifen but the dose isn’t high enough to keep things under control. During my attack today my left elbow swelled up (as it likes to do oddly enough) and the right one started bleeding at the antecubital (I had bloodwork there five days ago). I have Serping 1 mutations of some sort but the complement components aren’t low enough to put me in the hereditary angioedema category I guess. Weird stuff this is…

    • Lisa Klimas January 5, 2016 / 9:45 am

      It is linked to NF-kB. This requires a detailed response. I will get back to this by the end of the week.

  3. Carol Wong December 29, 2015 / 2:49 pm

    I just found your blog by a happy accident! I have MGUS and my Kappa Light Chains have been increasing rapidly then I was put on Methotrexate for inflammatory arthritis and the K/L ratio fell to 1/2. Also I notice that I have a skin disease called Nodular Prurigo and plus about five other autoimmune diseases. I don’t understand what you have enough but I was struck by the title of your post! It seems like all this fits together somehow. Any suggestions would greatly welcomed!

    • Lisa Klimas January 5, 2016 / 9:39 am

      It makes sense that the K/L ratio would fall because methotrexate inhibits autoimmune disease. There are fewer antibodies being made so there are fewer free light chains.

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