Polyclonal free light chains: promising new biomarkers in inflammatory disease

References

• Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95.
   PubMed Web of Science ®Google Scholar
• Solomon A. Bence-Jones proteins and light chains of immunoglobulins (first of two parts). N Engl J Med. 1976;294(1):17–23.
   Web of Science ®Google Scholar
• Solomon A. Light chains of human immunoglobulins. Methods Enzymol. 1985;116:101–121.
   PubMed Web of Science ®Google Scholar
• Myatt EA, Westholm FA, Weiss DT, Solomon A, Schiffer M, Stevens FJ. Pathogenic potential of human monoclonal immunoglobulin light chains: relationship of in vitro aggregation to in vivo organ deposition. Proc Natl Acad Sci U S A. 1994;91(8):3034–3038.
   Web of Science ®Google Scholar
• Abraham RS, Charlesworth MC, Owen BA, et al. Trimolecular complexes of lambda light chain dimers in serum of a patient with multiple myeloma. Clin Chem. 2002;48(10):1805–1811.
   PubMed Web of Science ®Google Scholar
• Berggard I, Peterson PA. Polymeric forms of free normal kappa and lambda chains of human immunoglobulin. J Biol Chem. 1969;244(16):4299–4307.
   PubMed Web of Science ®Google Scholar
• Sølling K. Light chain polymerism in normal individuals in patients with severe proteinuria and in normals with inhibited tubular protein reabsorption by lysine. Scand J Clin Lab Invest. 1980;40(2):129–134.
   PubMed Web of Science ®Google Scholar
• Shapiro AL, Scharff MD, Maizel JV, Uhr JW. Synthesis of excess light chains of gamma globulin by rabbit lymph node cells. Nature. 1966;211(5046):243–245.
   Web of Science ®Google Scholar
• Nakano T, Matsui M, Inoue I, Awata T, Katayama S, Murakoshi T. Free immunoglobulin light chain: its biology and implications in diseases. Clin Chim Acta. 2011;412(11–12):843–849.
   PubMed Web of Science ®Google Scholar
• Askonas BA. Immunoglobulin formation in B lymphoid cells. J Clin Pathol Suppl (Assoc Clin Pathol). 1975;6:8–12.
   Google Scholar
• Milstein C, Brownlee GG, Harrison TM, Mathews MB. A possible precursor of immunoglobulin light chains. Nat New Biol. 1972;239(91):117–120.
   Google Scholar
• Schechter I. Partial amino acid sequence of the precursor of immunoglobulin light chain programmed by messenger RNA in vitro. Science. 1975;188(4184):160–162.
   Web of Science ®Google Scholar
• Wahren-Herlenius M, Dörner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet. 2013;382(9894):819–831.
   PubMed Web of Science ®Google Scholar
• Groot Kormelink T, Pardo A, Knipping K, et al. Immunoglobulin free light chains are increased in hypersensitivity pneumonitis and idiopathic pulmonary fibrosis. PLoS One. 2011;6(9):e25392.
   Web of Science ®Google Scholar
• Kraneveld AD, Kool M, van Houwelingen AH, et al. Elicitation of allergic asthma by immunoglobulin free light chains. Proc Natl Acad Sci U S A. 2005;102(5):1578–1583.
   Web of Science ®Google Scholar
• Elovaara I, Seppala I, Kinnunen E, Laaksovirta H. Increased occurrence of free immunoglobulin light chains in cerebrospinal fluid and serum in human immunodeficiency virus-1 infection. J Neuroimmunol. 1991;35(1–3):65–77.
   Web of Science ®Google Scholar
• Matsumori A, Shimada M, Jie X, Higuchi H, Groot KT, Redegeld FA. Effects of free immunoglobulin light chains on viral myocarditis. Circ Res. 2010;106(9):1533–1540.
   Web of Science ®Google Scholar
• Jones HB. Papers on chemical pathology, lecture III. Lancet. 1847;II:88–92.
   Google Scholar
• Bradwell AR, Carr-Smith HD, Mead GP, et al. Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine. Clin Chem. 2001;47(4):673–680.
   PubMed Web of Science ®Google Scholar
• Dispenzieri A, Kyle R, Merlini G, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009;23(2):215–224.
   PubMed Web of Science ®Google Scholar
• Solomon A, Waldmann TA, Fahey JL, McFarlane AS. Metabolism of Bence Jones proteins. J Clin Invest. 1964;43:103–117.
   PubMed Web of Science ®Google Scholar
• Waldmann TA, Strober W, Mogielnicki RP. The renal handling of low molecular weight proteins. II. Disorders of serum protein catabolism in patients with tubular proteinuria, the nephrotic syndrome, or uremia. J Clin Invest. 1972;51(8):2162–2174.
   PubMed Web of Science ®Google Scholar
• Katzmann JA, Clark RJ, Abraham RS, et al. Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem. 2002;48(9):1437–1444.
   PubMed Web of Science ®Google Scholar
• Epstein WV, Tan M. Increase of L-chain proteins in the sera of patients with systemic lupus erythematosus and the synovial fluids of patients with peripheral rheumatoid arthritis. Arthritis Rheum. 1966;9(5):713–719.
   Google Scholar
• Cooper A, Bluestone R. Free immunoglobulin light chains in connective tissue diseases. Ann Rheum Dis. 1968;27(6):537–543.
   Web of Science ®Google Scholar
• Hirohata S, Miyamoto T. Increased intrathecal immunoglobulin synthesis of both kappa and lambda types in patients with systemic lupus erythematosus and central nervous system involvement. J Rheumatol. 1986;13(4):715–721.
   Web of Science ®Google Scholar
• Tsai CY, Wu TH, Sun KH, Lin WM, Yu CL. Increased excretion of soluble interleukin 2 receptors and free light chain immunoglobulins in the urine of patients with active lupus nephritis. Ann Rheum Dis. 1992;51(2):168–172.
   Web of Science ®Google Scholar
• Hopper JE, Golbus J, Meyer C, Ferrer GA. Urine free light chains in SLE: clonal markers of B-cell activity and potential link to in vivo secreted Ig. J Clin Immunol. 2000;20(2):123–137.
   Web of Science ®Google Scholar
• Aggarwal R, Sequeira W, Kokebie R, et al. Serum free light chains as biomarkers for systemic lupus erythematosus disease activity. Arthritis Care Res (Hoboken). 2011;63(6):891–898.
   PubMed Web of Science ®Google Scholar
• Sølling K, Sølling J, Rømer FK. Free light chains of immunoglobulins in serum from patients with rheumatoid arthritis, sarcoidosis, chronic infections and pulmonary cancer. Acta Med Scand. 1981;209(6):473–477.
   Google Scholar
• Gottenberg JE, Aucouturier F, Goetz J, et al. Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjögren’s syndrome. Ann Rheum Dis. 2007;66(1):23–27.
   PubMed Web of Science ®Google Scholar
• Gottenberg JE, Miceli-Richard C, Ducot B, Goupille P, Combe B, Mariette X. Markers of B-lymphocyte activation are elevated in patients with early rheumatoid arthritis and correlated with disease activity in the ESPOIR cohort. Arthritis Res Ther. 2009;11(4):R114.
   Web of Science ®Google Scholar
• Groot Kormelink T, Tekstra J, Thurlings RM, et al. Decrease in immunoglobulin free light chains in patients with rheumatoid arthritis upon rituximab (anti-CD20) treatment correlates with decrease in disease activity. Ann Rheum Dis. 2010;69(12):2137–2144.
   Web of Science ®Google Scholar
• Ye Y, Li SL, Xie M, Jiang P, Liu KG, Li YJ. Judging disease activity in rheumatoid arthritis by serum free kappa and lambda light chain levels. Kaohsiung J Med Sci. 2013;29(10):547–553.
   Web of Science ®Google Scholar
• Moutsopoulos HM, Steinberg AD, Fauci AS, Lane HC, Papadopoulos NM. High incidence of free monoclonal lambda light chains in the sera of patients with Sjögren’s syndrome. J Immunol. 1983;130(6):2663–2665.
   Web of Science ®Google Scholar
• Braber S, Thio M, Blokhuis BR, et al. An association between neutrophils and immunoglobulin free light chains in the pathogenesis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(8):817–824.
   Web of Science ®Google Scholar
• Powe DG, Groot KT, Sisson M, et al. Evidence for the involvement of free light chain immunoglobulins in allergic and nonallergic rhinitis. J Allergy Clin Immunol. 2010;125(1):139–145.
   PubMed Web of Science ®Google Scholar
• Groot Kormelink T, Calus L, De Ruyck N, et al. Local free light chain expression is increased in chronic rhinosinusitis with nasal polyps. Allergy. 2012;67(9):1165–1172.
   Web of Science ®Google Scholar
• Meng CD, Dong Z, Sha JC, Li L, Zhu DD. [Analysis of the level and significance of immunoglobulin free light chain in nasal secretion and in serum of patients with allergic rhinitis and non-allergic rhinitis]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2012;47(11):908–912. Chinese.
   Google Scholar
• Kayserova J, Capkova S, Skalicka A, et al. Serum immunoglobulin free light chains in severe forms of atopic dermatitis. Scand J Immunol. 2010;71(4):312–316.
   Web of Science ®Google Scholar
• Schouten B, van Esch BC, van Thuijl AO, et al. Contribution of IgE and immunoglobulin free light chain in the allergic reaction to cow’s milk proteins. J Allergy Clin Immunol. 2010;125(6):1308–1314.
   Web of Science ®Google Scholar
• Rijnierse A, Redegeld FA, Blokhuis BR, 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(1):653–659.
   Web of Science ®Google Scholar
• Rudick RA, Peter DR, Bidlack JM, Knutson DW. Multiple sclerosis: free light chains in cerebrospinal fluid. Neurology. 1985;35(10):1443–1449.
   Web of Science ®Google Scholar
• DeCarli C, Menegus MA, Rudick RA. Free light chains in multiple sclerosis and infections of the CNS. Neurology. 1987;37(8):1334–1338.
   Web of Science ®Google Scholar
• Fagnart OC, Sindic CJ, Laterre C. Free kappa and lambda light chain levels in the cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases. J Neuroimmunol. 1988;19(1–2):119–132.
   Web of Science ®Google Scholar
• Krakauer M, Schaldemose Nielsen H, Jensen J, Sellebjerg F. Intrathecal synthesis of free immunoglobulin light chains in multiple sclerosis. Acta Neurol Scand. 1998;98(3):161–165.
   Web of Science ®Google Scholar
• Presslauer S, Milosavljevic D, Brucke T, Bayer P, Hübl W. Elevated levels of kappa free light chains in CSF support the diagnosis of multiple sclerosis. J Neurol. 2008;255(10):1508–1514.
   PubMed Web of Science ®Google Scholar
• Dobson R, Miller RF, Palmer HE, et al. Increased urinary free immunoglobulin light chain excretion in patients with multiple sclerosis. J Neuroimmunol. 2010;220(1–2):99–103.
   Web of Science ®Google Scholar
• Senel M, Tumani H, Lauda F, et al. Cerebrospinal fluid immunoglobulin kappa light chain in clinically isolated syndrome and multiple sclerosis. PLoS One. 2014;9(4):e88680.
   PubMed Web of Science ®Google Scholar
• Stockley RA. Biomarkers in COPD: time for a deep breath. Thorax. 2007;62(8):657–660.
   PubMed Web of Science ®Google Scholar
• Fauci AS, Moutsopoulos HM. Polyclonally triggered B cells in the peripheral blood and bone marrow of normal individuals and in patients with systemic lupus erythematosus and primary Sjögren’s syndrome. Arthritis Rheum. 1981;24(4):577–583.
   Google Scholar
• Hanaoka M, Gono T, Kawaguchi Y, et al. Urinary free light chain is a potential biomarker for ISN/RPS class III/IV lupus nephritis. Rheumatology (Oxford). 2013;52(12):2149–2157.
   Web of Science ®Google Scholar
• Mastroianni-Kirsztajn G, Nishida SK, Pereira AB. Are urinary levels of free light chains of immunoglobulins useful markers for differentiating between systemic lupus erythematosus and infection? Nephron Clin Pract. 2008;110(4):c258–c263.
   Google Scholar
• Hopper JE, Sequeira W, Martellotto J, Papagiannes E, Perna L, Skosey JL. Clinical relapse in systemic lupus erythematosus: correlation with antecedent elevation of urinary free light-chain immunoglobulin. J Clin Immunol. 1989;9(4):338–350.
   Web of Science ®Google Scholar
• Chiche L, Cournac JM, Mancini J, et al. Normalization of serum-free light chains in patients with systemic lupus erythematosus upon rituximab treatment and correlation with biological disease activity. Clin Rheumatol. 2011;30(5):685–689.
   Web of Science ®Google Scholar
• Martinez-Gamboa L, Brezinschek HP, Burmester GR, Dörner T. Immunopathologic role of B lymphocytes in rheumatoid arthritis: rationale of B cell-directed therapy. Autoimmun Rev. 2006;5(7):437–442.
   PubMed Web of Science ®Google Scholar
• Tzioufas AG. B-cell lymphoproliferation in primary Sjögren’s syndrome. Clin Exp Rheumatol. 1996;14 Suppl 14:S65–S70.
   Google Scholar
• Gottenberg JE, Seror R, Miceli-Richard C, et al. Serum levels of β2-microglobulin and free light chains of immunoglobulins are associated with systemic disease activity in primary Sjögren’s syndrome. Data at enrollment in the prospective ASSESS cohort. PLoS One. 2013;8(5):e59868.
   PubMed Web of Science ®Google Scholar
• Saussine A, Tazi A, Feuillet S, et al. Active chronic sarcoidosis is characterized by increased transitional blood B cells, increased IL-10-producing regulatory B cells and high BAFF levels. PLoS One. 2012;7(8):e43588.
   PubMed Web of Science ®Google Scholar
• Owens GP, Bennett JL, Gilden DH, Burgoon MP. The B cell response in multiple sclerosis. Neurol Res. 2006;28(3):236–244.
   PubMed Web of Science ®Google Scholar
• Mehta PD, Cook SD, Troiano RA, Coyle PK. Increased free light chains in the urine from patients with multiple sclerosis. Neurology. 1991;41(4):540–544.
   Web of Science ®Google Scholar
• Rinker JR 2nd, Trinkaus K, Cross AH. Elevated CSF free kappa light chains correlate with disability prognosis in multiple sclerosis. Neurology. 2006;67(7):1288–1290.
   Google Scholar
• Rudick RA, Medendorp SV, Namey M, Boyle S, Fischer J. Multiple sclerosis progression in a natural history study: predictive value of cerebrospinal fluid free kappa light chains. Mult Scler. 1995;1(3):150–155.
   Google Scholar
• Villar LM, Espiño M, Costa-Frossard L, Muriel A, Jiménez J, Alvarez-Cermeño JC. High levels of cerebrospinal fluid free kappa chains predict conversion to multiple sclerosis. Clin Chim Acta. 2012;413(23–24):1813–1816.
   PubMed Web of Science ®Google Scholar
• Landgren O, Goedert JJ, Rabkin CS, et al. Circulating serum free light chains as predictive markers of AIDS-related lymphoma. J Clin Oncol. 2010;28(5):773–779.
   Web of Science ®Google Scholar
• Moir S, Buckner CM, Ho J, et al. B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy. Blood. 2010;116(25):5571–5579.
   PubMed Web of Science ®Google Scholar
• Smedby KE, Hjalgrim H, Askling J, et al. Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype. J Natl Cancer Inst. 2006;98(1):51–60.
   PubMedGoogle Scholar
• Brito-Zeron P, Retamozo S, Gandia M, et al. Monoclonal gammopathy related to Sjögren syndrome: a key marker of disease prognosis and outcomes. J Autoimmun. 2012;39(1–2):43–48.
   PubMed Web of Science ®Google Scholar
• Walters MT, Stevenson FK, Herbert A, Cawley MI, Smith JL. Urinary monoclonal free light chains in primary Sjögren’s syndrome: an aid to the diagnosis of malignant lymphoma. Ann Rheum Dis. 1986;45(3):210–219.
   PubMed Web of Science ®Google Scholar
• Maurer MJ, Cerhan JR, Katzmann JA, et al. Monoclonal and polyclonal serum free light chains and clinical outcome in chronic lymphocytic leukemia. Blood. 2011;118(10):2821–2826.
   Web of Science ®Google Scholar
• Morabito F, De Filippi R, Laurenti L, et al. The cumulative amount of serum-free light chain is a strong prognosticator in chronic lymphocytic leukemia. Blood. 2011;118(24):6353–6361.
   PubMed Web of Science ®Google Scholar
• Thompson CA, Maurer MJ, Cerhan JR, et al. Elevated serum free light chains are associated with inferior event free and overall survival in Hodgkin lymphoma. Am J Hematol. 2011;86(12):998–1000.
   Web of Science ®Google Scholar
• Maurer MJ, Micallef IN, Cerhan JR, et al. Elevated serum free light chains are associated with event-free and overall survival in two independent cohorts of patients with diffuse large B-cell lymphoma. J Clin Oncol. 2011;29(12):1620–1626.
   PubMed Web of Science ®Google Scholar
• Bibas M, Lorenzini P, Cozzi-Lepri A, et al. Polyclonal serum-free light chains elevation in HIV-infected patients. AIDS. 2012;26(16):2107–2110.
   Web of Science ®Google Scholar
• Shiels MS, Landgren O, Costello R, Zingone A, Goedert JJ, Engels EA. Free light chains and the risk of AIDS-defining opportunistic infections in HIV-infected individuals. Clin Infect Dis. 2012;55(10):e103–e108.
   Web of Science ®Google Scholar
• Gallo P, Piccinno MG, De Rossi A, et al. Free light chains of immunoglobulins in the cerebrospinal fluid of human immunodeficiency virus type 1-infected patients. J Neuroimmunol. 1990;26(3):229–238.
   Web of Science ®Google Scholar
• Grimaldi LM, Castagna A, Maimone D, et al. Kappa light chain predominance in serum and cerebrospinal fluid from human immunodeficiency virus type 1 (HIV-1)-infected patients. J Neuroimmunol. 1991;32(3):259–268.
   Web of Science ®Google Scholar
• Contini C, Fainardi E, Cultrera R, et al. Evidence of cerebrospinal fluid free kappa light chains in AIDS patients with Toxoplasma gondii encephalitis. J Neuroimmunol. 2000;108(1–2):221–226.
   PubMed Web of Science ®Google Scholar
• Dispenzieri A, Katzmann JA, Kyle RA, et al. Use of nonclonal serum immunoglobulin free light chains to predict overall survival in the general population. Mayo Clin Proc. 2012;87(6):517–523.
   PubMed Web of Science ®Google Scholar
• Anandram S, Assi LK, Lovatt T, et al. Elevated, combined serum free light chain levels and increased mortality: a 5-year follow-up, UK study. J Clin Pathol. 2012;65(11):1036–1042.
   PubMed Web of Science ®Google Scholar
• Bellary S, Faint JM, Assi LK, et al. Elevated serum free light chains predict cardiovascular events in type 2 diabetes. Diabetes Care. 2014;37(7):2028–2030.
   Web of Science ®Google Scholar
• Haynes R, Hutchison CA, Emberson J, et al. Serum free light chains and the risk of ESRD and death in CKD. Clin J Am Soc Nephrol. 2011;6(12):2829–2837.
   Web of Science ®Google Scholar
• Hutchison CA, Burmeister A, Harding SJ, et al. Serum polyclonal immunoglobulin free light chain levels predict mortality in people with chronic kidney disease. Mayo Clin Proc. 2014;89(5):615–622.
   Web of Science ®Google Scholar
• Cohen G, Rudnicki M, Deicher R, Hörl WH. Immunoglobulin light chains modulate polymorphonuclear leucocyte apoptosis. Eur J Clin Invest. 2003;33(8):669–676.
   Web of Science ®Google Scholar
• Cohen G, Haag-Weber M, Mai B, Deicher R, Hörl WH. Effect of immunoglobulin light chains from hemodialysis and continuous ambulatory peritoneal dialysis patients on polymorphonuclear leukocyte functions. J Am Soc Nephrol. 1995;6(6):1592–1599.
   Web of Science ®Google Scholar
• Redegeld FA, van der Heijden MW, Kool M, et al. Immunoglobulin-free light chains elicit immediate hypersensitivity-like responses. Nat Med. 2002;8(7):694–701.
   PubMed Web of Science ®Google Scholar
• Huang ZQ, Sanders PW. Localization of a single binding site for immunoglobulin light chains on human Tamm-Horsfall glycoprotein. J Clin Invest. 1997;99(4):732–736.
   PubMed Web of Science ®Google Scholar
• Hutchinson AT, Jones DR, Raison RL. The ability to interact with cell membranes suggests possible biological roles for free light chain. Immunol Lett. 2012;142(1–2):75–77.
   Web of Science ®Google Scholar
• Sun M, Li L, Gao QS, Paul S. Antigen recognition by an antibody light chain. J Biol Chem. 1994;269(1):734–738.
   Web of Science ®Google Scholar
• Thio M, Groot Kormelink T, Fischer MJ, Blokhuis BR, Nijkamp FP, Redegeld FA. Antigen binding characteristics of immunoglobulin free light chains: crosslinking by antigen is essential to induce allergic inflammation. PLoS One. 2012;7(7):e40986.
   Web of Science ®Google Scholar
• van Houwelingen AH, Kaczynska K, Kraneveld AD, Kool M, Nijkamp FP, Redegeld FA. Topical application of F991, an immunoglobulin free light chain antagonist, prevents development of contact sensitivity in mice. Clin Exp Allergy. 2007;37(2):270–275.
   Web of Science ®Google Scholar
• Presslauer S, Milosavljevic D, Huebl W, Parigger S, Schneider-Koch G, Bruecke T. Kappa free light chains: diagnostic and prognostic relevance in MS and CIS. PLoS One. 2014;9(2):e89945.
   Web of Science ®Google Scholar
• Burmeister A, Assi LK, Ferro CJ, et al. The relationship between high-sensitivity CRP and polyclonal free light chains as markers of inflammation in chronic disease. Int J Lab Hematol. 2014;36(4):415–424.
   PubMed Web of Science ®Google Scholar