Iranian Journal of Allergy, Asthma and Immunology 2017. 16(4):282-288.

Immunoglobulin Free Light Chains in the Pathogenesis of Lung Disorders
Esmaeil Mortaz, Ian M Adcock, Hamidreza Jamaati, Adnan Khosravi, Masoud Movassaghi, Johan Garssen, Mostafa Alavi Mogadam, Frank A Redegeld

Abstract


Inflammation is an important component of numerous cancers and chronic diseases and many inflammatory mediators have been shown to have potential prognostic roles. Tumor-infiltrating mast cells can promote tumor growth and angiogenesis, but the mechanism of mast cell activation is unclear. Early studies have shown that immunoglobulin free light chains (FLC) can trigger mast cell activation in an antigen-specific manner. Increased expression of FLC is observed within the stroma of many human cancers including those of breast, colon, lung, pancreas, kidney, and skin. These overexpressed FLCs are co-localized to areas of mast cell infiltration. Importantly, FLC expression is associated with basal-like cancers with an aggressive phenotype. Moreover, FLC is expressed in areas of inflammatory cell infiltration and its expression is significantly associated with poor clinical outcome. In addition, serum and bronchoalveolar fluid FLC concentrations are increased in patients with idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP) compared to control subjects. In this review, we provide an update on the role of FLC in the pathogenesis of several lung disorders and indicate how this may contribute to new therapeutic opportunities. 

 


Keywords


Asthma; Chronic obstructive lungs disease (COPD); Free light chain; Hypersensitivity pneumonitis (HP); Idiopathic pulmonary fibrosis (IPF); Lung cancer

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References


1) Dudeck A, Dudeck J, Scholten J, et al. Mast Cells Are Key Promoters of Contact Allergy that Mediate the Adjuvant Effects of Haptens. Immunity 2011; 34(6): 973-84.

2) Christopher Chiu and Peter J Openshaw. Antiviral B cell and T cell immunity in the lungs. Nat Immunol. 2015; 16(1):18-26.

3) Redegeld FA, Nijkamp FP. Immunoglobulin free light chains and mast cells: pivotal role in T-cell-mediated immune reactions? Trends Immunol 2003;24:181–185.

4) Katzmann JA, Clark RJ, Abraham RS, Bryant S, Lymp JF, Bradwell AR, Kyle RA. Serum reference intervals and diagnostic ranges for freekappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. ClinChem 2002;48:1437–1444.

5) Woloschak GE, Krco CJ.Regulation of kappa/lambda immunoglobulin light chain expression in normal murine lymphocytes. Mol Immunol 1987;24:751–757.

6) Thio M, Blokhuis BR, Nijkamp FP, Redegeld FA . Free immunoglobulin light chains: a novel target in the therapy of inflammatory diseases. Trends Pharmacol Sci 2008; 29: 170–174.

7) Matsumori A, Shimada M, Jie X, Higuchi H, Groot Kormelink T, et al. Effects of free immunoglobulin light chains on viral myocarditis. Circ Res 2010; 106:1533–1540.

8) Rijnierse A, Redegeld FA, Blokhuis BR, Van der Heijden MW, TeVelde AA, etal. 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.

9) Schouten B, van Esch BC, van Thuijl AO, Blokhuis BR, Groot Kormelink T, 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: 1308–1314.

10) Redegeld FA, van der Heijden MW, Kool M, Heijdra BM, Garssen J, Kraneveld AD, Van Loveren H, Roholl P, Saito T, Verbeek JS, Claassens J, Koster AS, Nijkamp FP Immunoglobulin-free light chains elicit immediate hypersensitivity-like responses Nat Med. 2002 ;8(7):694-701.

11) Larsen JT, Kumar SK, Dispenzieri A, et al. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia 2013; 27:941–6.

12) Jolly M, Francis S, Aggarwal R, et al. Serum free light chains, interferon-alpha, and interleukins in systemic lupus erythematosus. Lupus 2014; 23:881–8.

13) Groot Kormelink T, Tekstra J, Thurlings RM, Boumans MH, Vos K, Tak PP, Bijlsma JW, Lafeber FP, Redegeld FA, van Roon JA. 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):2137-44.

14) Gottenberg JE, Aucouturier F, Goetz J, et al. Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjogren's syndrome. Ann Rheum Dis 2007;66:23–7.

15) Gottenberg JE, Seror R, Miceli-Richard C, et al. Serum levels of beta2-microglobulin and free light chains of immunoglobulins are associated with systemic disease activity in primary Sjogren's syndrome. Data at enrollment in the prospective ASSESS cohort. PLoS One 2013;8:e59868.

16) Aurélia Lanteri , Vincent Sobanski , Carole Langlois , Guillaume Lefèvre , Carine Hauspie , Sébastien Sanges , Marc Lambert , Sandrine Morell-Dubois , Pierre-Yves Hatron , Eric Hachulla , David Launay , Sylvain Dubucquoi, Serum  free light chains of immunoglobulins as biomarkers for systemic sclerosis characteristics, activity and severity. Autoimmunity Reviews2014; 13 ,974–980.

17) Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532–555,

18) Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for diagnosis, management, and prevention of chronic obstructive pulmonary disease [Internet; updated 2009]. NHLBI/ WHO workshop report. Available from: www.goldcopd.org.

19) Barnes PJ.Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin Chest Med. 2014 ;35(1):71-86.

20) Mortaz E, Folkerts G, Redegeld F. Mast cells and COPD. Pulm Pharmacol Ther. 2011 Aug;24(4):367-72.

21) Mortaz E, Folkerts G, Nijkamp FP, Henricks PA. ATP and the pathogenesis of COPD. Eur J Pharmacol. 2010;  25;638(1-3):1-4.

22) Mortaz E, Folkerts G, Engels F, Nijkamp FP, Redegeld FA. Cigarette smoke suppresses in vitro allergic activation of mouse mast cells. Clin Exp Allergy. 2009 ;39(5):679-87.

23) Mortaz E, Adcock IM, Ito K, Kraneveld AD, Nijkamp FP, Folkerts G. Cigarette smoke induces CXCL8 production by human neutrophils via activation of TLR9 receptor. Eur Respir J. 2010;36(5):1143-54.

24) Barnes PJ. Mechanisms in COPD: differences from asthma. Chest 2000; 117:10S–14S.

25) Pesci A, BalbiB,Majori M, Cacciani G, Bertacco S, Alciato P, Donner CF. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J  1998;12:380–386.

26) Cohen G, Rudnicki M, Deicher R, Horl WH. Immunoglobulin light chains modulate polymorphonuclear leucocyte apoptosis. Eur J Clin Invest 2003;33:669–676.

27) Saskia Braber , Marco Thio , Bart R. Blokhuis, Paul A. J. Henricks, Pim J. Koelink, Tom Groot Kormelink, Gillina F. G. Bezemer, Huib A. M. Kerstjens, Dirkje S. Postma, Johan Garssen, Aletta D. Kraneveld1, Frank A. Redegeld, and Gert Folkerts. 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.

28) Zhang M, Tao HC, Li YQ, Pei HS, Zhu SY, Chen B, Zhou RJ, Zhang MW. Expression and significance of immunoglobulin free light chains in serum and lung tissues from patients with chronic obstructive pulmonary disease. ZhonghuaJie He He Hu Xi ZaZhi. 2013 ;36(12):945-9.

29) Pearce, N., Pekkanen, J. & Beasly, R. How much asthma is really attributable to atopy? Thorax 1999; 54, 268–272.

30) Douwes, J., Gibson, P., Pekkanen, J. & Pearce, N.  Non-eosinophilic asthma: importance and possible mechanisms Thorax 2002; 57, 643–648.

31) Aletta D. Kraneveld, Mirjam Kool, Anneke H. van Houwelingen, Paul Roholl, Alan Solomon, Dirkje S. Postma, Frans P. Nijkamp, and Frank A. Redegeld. Elicitation of allergic asthma by immunoglobulin free light chains. PNAS  2005,102, 1578–1583.

32) Frank A Redegeld, Cornelis H Wortel.  IgE and immunoglobulin free light chains in allergic disease: New therapeutic opportunities. Current Opinion in Investigational Drugs 2008; 9(11):1185-91.

33) Statement on sarcoidosis,” American Journal of Respiratory and Critical Care Medicine, 1999; 160, 2, 736–755.

34) Rossi G, Cavazza A, Colby TV. Pathology of Sarcoidosis. Clin Rev Allergy Immunol. 2015;12.

35) N. Hamzeh, “Sarcoidosis,” Medical Clinics of North America, 2011;. 95,. 1223–1234.

36) V. Vardhanabhuti, N. Venkatanarasimha, G. Bhatnagar et al., “Extra-pulmonary manifestations of sarcoidosis,” Clinical Radiology, 2012; 67, 3, 263–276.

37) Mortaz E, Masjedi MR, Tabarsi P, Pourabdollah M, Adcock IM. Immunopathology of sarcoidosis.  Iran J Allergy Asthma Immunol. 2014 ;13(5):300-6

38) Romer, F.K. and Solling, K. Repeated measurements of serum immunoglobulin-free light chains in early sarcoidosis. Eur. J. Respir. Dis.1984; 65, 292–295.

39) Sølling KSølling JRømer 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):473-7.

40) Esmaeil Mortaz, Hale Abdoli Sereshki, Atefeh Abedini, Arda Kiani, Mehdi Mirsaeidi, Dina Soroush, Johan Garssen, Aliakbar Velayati, Frank A Redegeld, Ian M Adcock Alternation of serum TNF-alpha, IL-8 and free light chain with HLA-DR B alleles expression in pulmonary and extra-pulmonary sarcoidosis. Inflammation Journal,  March 2015.

41) Groot Kormelink G1, Powe DG, Kuijpers SA, Abudukelimu A, Fens MH, Pieters EH, Kassing van der Ven WW, Habashy HO, Ellis IO, Blokhuis BR, Thio M, Hennink WE, Storm G, Redegeld FA, Schiffelers RM. Immunoglobulin free light chains are biomarkers of poor prognosis in basal-like breast cancer and are potential targets in tumor-associated inflammation. Oncotarget. 2014; 30;5(10):3159-67.

42) Selman M Idiopathic interstitial pneumonias. In: Mason R, Broaddus V, eds. Murray & Nadal’s Textbook of Respiratory Medicine. Philadelphia: Elsevier Inc.2010; 1356–1397.

43) American Thoracic Society, European Respiratory Society (2002) American thoracic Society/European respiratory society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. this joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, june 2001 and by the ERS executive committee, . Am J Respir Crit Care Med 2001; 165(2): 277–304.

44) Selman M, King TE, Pardo A Idiopathic pulmonary fibrosis: Prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134(2): 136–51.

45) Gross TJ, Hunninghake GW , Idiopathic pulmonary fibrosis. N Engl J Med 2001; 345(7): 517–525.

46) Bjoraker JA, Ryu JH, Edwin MK, Myers JL, Tazelaar HD, et al.  Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;157(1): 199–203.

47)  King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.

N Engl J Med. 2014; 29;370(22):2083-92

48)  Idiopathic Pulmonary Fibrosis Clinical Research Network, Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr, Raghu G. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis.N Engl J Med. 2014; 29;370(22):2093-101.

49) Fernandez IE, Eickelberg O. New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis. Lancet. 2012; 18;380(9842):680-8.

50) Selman M ,  Hypersensitivity pneumonitis: A multifaceted deceiving disorder. Clin Chest Med 2004; 25(3): 531–47.

51) Fink JN, Ortega HG, Reynolds HY, Cormier YF, Fan LL, et al. (2005) Needs and opportunities for research in hypersensitivity pneumonitis. Am J Respir Crit Care Med 2005; 171(7): 792–798.

52) Akashi T, Takemura T, Ando N, Eishi Y, Kitagawa M, et al.  Histopathologic analysis of sixteen autopsy cases of chronic hypersensitivity pneumonitis and comparison with idiopathic pulmonary fibrosis/usual interstitial pneumonia. Am J Clin Pathol 2009;131(3): 405–415.

53)  Churg A, Muller NL, Flint J, Wright JL . Chronic hypersensitivity pneumonitis. Am J Surg Pathol 2006; 30(2): 201–208.

54) Barrera L, Mendoza F, Zuniga J, Estrada A, Zamora AC, et al. Functional diversity of T-cell subpopulations in subacute and chronic hypersensitivity pneumonitis. Am J Respir Crit Care Med 2008; 177(1): 44–55.

55) Drent M, Wagenaar S, van Velzen-Blad H, Mulder PG, Hoogsteden HC, et al. Relationship between plasma cell levels and profile of bronchoalveolar lavage fluid in patients with subacute extrinsic allergic alveolitis. Thorax 1993; 48(8): 835–9.

56) McSharry C. B lymphocytes in allergic alveolitis. Clin Exp Allergy 2003; 33(2): 159–162.

57) Tom Groot Kormelink1, Annie Pardo2, Karen Knipping1,3, Ivette Buendı´a-Rolda´n4, Carolina Garcı´a-de- Alba4, Bart R. Blokhuis1, Moises Selman4, Frank A. Redegeld Immunoglobulin Free Light Chains Are Increased in Hypersensitivity Pneumonitis and Idiopathic Pulmonary Fibrosis. PLoS ONE, 2011 , 6 , 9 ;e25392.

58) Rinker II JR, Trinkaus K, Cross AH. Elevated CSF free kappa light chains correlate with disability prognosis in multiple sclerosis. Neurology 2006; 67:1288–90.

59) Presslauer S, Milosavljevic D, Brucke T, Bayer P, Hubl W. Elevated levels of kappa free light chains in CSF support the diagnosis of multiple sclerosis. J Neurol  2008 ;255(10):1508-14.

60) Redegeld FA, Thio M, Groot Kormelink T. Polyclonal immunoglobulin free light chain and chronic inflammation. Mayo Clin Proc. 2012 Oct;87(10):1032.

 


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