Urine Free Light Chains in SLE: Clonal Markers of B-Cell Activity and Potential Link to In Vivo Secreted IG

Abstract

As a marker of in vivo B-cell activity, urine levels of free light chain (FLC) were measured twice weekly by radioimmunassay (RIA) and correlated with disease activity over periods of 5–10 months in seven patients with systemic lupus erythematousus (SLE). In addition, RIA-measured urine albumin was used to track glomerular injury, and α1-microglobulin (α1-M) levels, 28- to 32-kDa protein, provided control measurements on excretion of low-molecular-weight proteins. As controls, urine FLC levels were obtained from healthy normals and in subjects with acute pharyngitis, sickle-cell anemia, and acute sepsis or pneumonia. The control results showed that with acute sepsis/pneumonia had marked increases in urine FLC, while pharyngitis and sickle-cell controls had normal FLC levels. In SLE, active patients receiving intravenous cyclophsophamide and high-dose steroids exhibited highly increased urine FLC that fluctuated widely during therapy and fell to normal range levels with disease remission. During active SLE, urine albumin often was increased, while α1-M levels remained in normal range. In contrast to the increased FLC of active disease, inactive patients on low-dose maintenance therapy had predominantly normal FLC levels throughout the collection period. These results support our hypothesis that longitudinal levels of urine FLC can be used to track disease-related B-cell activity in SLE. Furthermore, we suggest that the urine FLC of active SLE would share LC idiotype with the clonal associated in vivo secreted Ig, and thus permit the identification of these antibodies that are targeted to the culprit immunogen(s) responsible for the pathogenesis of SLE.

This is a preview of subscription content, access via your institution.

REFERENCES

  1. 1.

    Lloyd W, Schur PH: Immune complexes, complement, and anti-DNA exacerbations of systemic lupus erythematosus (SLE). Medicine (Baltimore) 60:208-217, 1981

    Google Scholar 

  2. 2.

    Fauci A, Moutsopolulos HM: Polyclonally triggered B cells in the peripheral blood and bone marrow of normal individuals and in patients with systemic lupus erythematosus and primary Sjogren's syndrome. Arthr Rheum 24:577-584, 1981

    Google Scholar 

  3. 3.

    Budman DR, Merchant EB, Steinberg AD, Doft ME, Gershwin ME, Lozzio E, Reeves JP: Increased spontaneous activity of antibody-forming cells in the peripheral blood of patients with active SLE. Arthr Rheum 20:829-833, 1977

    Google Scholar 

  4. 4.

    Blaese RM, Grayson J, Steinberg AD: Increased immunoglobulinsecreting cells in the blood of patients with active SLE. Am J Med 69:345-350, 1980

    Google Scholar 

  5. 5.

    Steinberg AD, Klinman DM: Pathogenesis of systemic lupus erythematosus. Rheum Dis Clin N Am 14:25-41, 1988

    Google Scholar 

  6. 6.

    Ward MM, Dooley MA, Christenson VD, Pisetsky, D.S: The relationship between soluble interleukin 2 receptor levels and antidoubel stranded DNA antibody levels in patients with systemic lupus erythematosus. J Rheumatol 18:235-240, 1991

    Google Scholar 

  7. 7.

    Steinberg AD, Gourley MF, Klinman DM, Tsokos GC, Scott DE, Krieg AM: Systemic lupus erythematosus. Ann Intern Med 115: 548-559, 1991

    Google Scholar 

  8. 8.

    Hopper JE, Sequeira W, Martellotto JN, 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 9:338-350, 1989

    Google Scholar 

  9. 9.

    Donaldson MDC, Chambers RE, Woolridge MW, Whicher JT: Stability of alpha 1-microglobulin, beta-2-microglobulin and retinol binding protein in urine. Clin Chem Acta 179:73-78, 1989

    Google Scholar 

  10. 10.

    Yu H, Yanagisawa Y, Forbes MA, Cooper EH, Crockson RA, MacLennan ICM: Alpha-1-microglobulin: An indicator protein for renal tubular function. J Clin Pathol 36:253-259, 1989

    Google Scholar 

  11. 11.

    Hopper JE, Papagiannes E: Evidence by radioimmunoassay that mitogen activated human blood mononuclear cells secrete significant amounts of light chain Ig unassociated with heavy chain. Cell Immunol 101:122-131, 1986

    Google Scholar 

  12. 12.

    Hopper JE, O'Brien J, Papagiannes E: Restriction of blood and marrow CLL-B cells to free L chain Ig secretion: Implication for normal B cell function and control. Am J Hematol 29:125-133, 1988

    Google Scholar 

  13. 13.

    Maino, VC, Kurnick JT, Kubo RT, Gray HM: Mitogen activation of human chronic lymphocytic leukemia cells. I. Synthesis and secretion of immunoglobulin. J Immunol 118:742-748, 1977

    Google Scholar 

  14. 14.

    Fu SM, Winchester RJ, Kunkel HG: Occurrence of surface IgM, IgD, and free light chains on human lymphocytes. J Exp Med 139:451-456, 1977

    Google Scholar 

  15. 15.

    Gordon J, Smith JL: Free immunoglobulin light chain synthesis by neoplastic cells in leukemic reticuloendotheliosis. Clin Exp Immunol 31:244-250, 1978

    Google Scholar 

  16. 16.

    Hannam-Harris AC, Gordon J, Smith JL: Immunoglobulin synthesis by neoplatic B lymphocytes: Free light chain synthesis as a marker of B cell differentiation. J Immunol 125:2177-2181, 1980

    Google Scholar 

  17. 17.

    Stevenson FK, Hamblin TJ, Stevenson GT, Tutt AL: Extracellular idiotypic immunoglobulin arising from human leukemic B lymphocytes. J Exp Med 152:1484-1496, 1980

    Google Scholar 

  18. 18.

    Hannam-Harris AC, Smith JL: Free immunoglobulin light chain synthesis by human fetal liver and cord blood lymphocytes. Immunology 43:417-423, 1981

    Google Scholar 

  19. 19.

    Hannam-Harris AC, Smith JL: Induction of balanced Ig chain synthesis in free light chain producing lymphocytes by mitogen stimulation. J Immunol 26:1848-1851, 1981

    Google Scholar 

  20. 20.

    Johnstone AP, Jensenius JC, Millard RE, Hudson L: Mitogen stimulated immunoglobulin production by chronic lymphocytic leukaemic lymphocyytices. Clin Exp Immunol 47:697-705, 1982

    Google Scholar 

  21. 21.

    Buxbaum J: Aberrant immunoglobulin synthesis in light chain amyloidosis. Free light chain and light chain fragment production by human marrow cells in short term tissue culture. J Clin Invest 78:798-806, 1986

    Google Scholar 

  22. 22.

    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 51:2162-2174, 1972

    Google Scholar 

  23. 23.

    Painter RG, Sage HJ, Tanford C: Contributions of heavy and light chains of rabbit immunoglobulin G to antibody activity. I. Binding studies on isolated heavy and light chains. Biochemistry 11:1327-1337, 1972

    Google Scholar 

  24. 24.

    Nisonoff A, Hopper JE, Spring SB: The Antibody Molecule. Academic Press, New York, 1975.

    Google Scholar 

  25. 25.

    Froelich CJ, Wallman J, Skosey JL, Teodorescu M: Clinical value of an integrated ELISA system for the detection of six autoantibodies (SSDNA, dSDNA, Sm, RNP/Sm, SSA and SSB). J Rheumatol 17:192-200, 1990

    Google Scholar 

  26. 26.

    Morgensen CE: Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 310:356-360, 1984

    Google Scholar 

  27. 27.

    Morgensen CE, Christensen CK: Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med 311:89-93, 1984

    Google Scholar 

  28. 28.

    Cottiero RA, Madaio MP, Levey AS: Glomerular filtration rate and urinary albumin excretion rate in systemic lupus erythematosus. Nephron 69:140-146, 1995

    Google Scholar 

  29. 29.

    Bombardier C, Gladman DD, Caron D, Chang CH: Derivation of the SLEDAI. A disease activity index for lupus patients. Arthr Rhuem 35:630-640, 1992

    Google Scholar 

  30. 30.

    Arce-Salinas A, Cardiel MH, Guzman J, Alcocer-Varela J: Validity of retrospective disease activity assessment in systemic lupus erythematosus. J Rheum 23:846-849, 1996

    Google Scholar 

  31. 31.

    Hopper JE, Haren JM, Kmiecik TE: Evidence for shared idiotype expressed by the IgM, IgG, and IgA serum proteins of a patient with a complex multiple paraprotein disorder. J Immmunol 122: 2000-2007, 1979.

    Google Scholar 

  32. 32.

    Bayer EA, Wilchek M: The use of the avidin–biotin complex. Meth Biochem Anal 26:1-45, 1980

    Google Scholar 

  33. 33.

    Vestergaard P, Leverett R: Constancy of urinary creatinine excretion. J Lab Clin Med 51:211-218, 1958

    Google Scholar 

  34. 34.

    Sessoms SK, Mehta K, Kovansky J: Quantitation of proteinuria in systemic lupus erythematosus by use of a random spot urine collection. Arthr Rheum 26:918-920, 1983.

    Google Scholar 

  35. 35.

    Watts GF, Morris RW, Khan K, Polak A: Urinary albumin excretion in healthy adult subjects: Reference values and some factors affecting their interpretation. Clin Chim Acta 172:191-198, 1988

    Google Scholar 

  36. 36.

    Waldmann TA, Strober W: Metabolism of immunoglobulins. Prog Allergy 13:1-110, 1969

    Google Scholar 

  37. 37.

    Solomon A, Waldmann TA, Fahey JL, McFarlane AS: Metabolism of Bence Jones proteins. J Clin Invest 43:103-117, 1964

    Google Scholar 

  38. 38.

    Coonrod JD, Drennan DP: Pneumococcal pneumonia: Capsular polysaccharide antigenemia and antibody responses. Ann Intern Med 84:254-260, 1976

    Google Scholar 

  39. 39.

    Wheat J, Kohler RB, White A: Solid phase immunoassay for immunoglobulin G staphylococcus aureus antibody in serious staphylococcal infection. Ann Intern Med 89:467-472, 1978

    Google Scholar 

  40. 40.

    Epstein WV, Tan M: Increase of L-chain proteins in sera of patients with systemic lupus erythematosus and the synovial fluids of patients with peripheral rhuematoid arthritis. Arthr Rheum 9:713-719, 1966

    Google Scholar 

  41. 41.

    Epstein WV: Immunoglobic events preceding a clinical exacerbation of systemic lupus erythematosus. Am J Med 54:631-636, 1973

    Google Scholar 

  42. 42.

    Sriggs B, Epstein WV: Clinical and laboratory correlates of L chain protenuria in systemic lupus erythematosus. J Rheumatol 1:287-292, 1974

    Google Scholar 

  43. 43.

    Tan M, Epstein WV: A direct immunologic assay of human sera for Bence Jones proteins (L-chains). J Clin Lab Med 66:344-356, 1965

    Google Scholar 

  44. 44.

    Andres GA, McClusky RT: Tubular and interstitial renal disease due to immunologic mechanisms. Kidny Int 7:271-289, 1975

    Google Scholar 

  45. 45.

    Brentjens JR, Sepulveda M, Baliah T, Bentzel C, Erlanger BF, Elwood C, Montes M, Hsu KC, Andres GA: Interstitial immune complex nephtritis in patients with systemic lupus erythematosus.

  46. 46.

    Schwartz MM, Fenell JS, Lewis ET: Pathologic changes in the renal tubule in systemic lupus erythematosus. Hum Pathol 6:534-547, 1982

    Google Scholar 

  47. 47.

    Bollengier FA, Lowenthal Henrotin W: Bound and free light chains in subacute sclerosing panencephalitis and multiple sclerosis serum and cerebrospinal fluid. J Clin Chem Clin Biochem 13:305-310, 1975

    Google Scholar 

  48. 48.

    Solling K, Solling J, Romer FK: Free light chains of immunoglobulins in serum from patients with rheumatoid arthritis, sarcoidosis, chronic infections, and pulmonary cancer. Acta Med Scand 209:473-477, 1981

    Google Scholar 

  49. 49.

    Solling K: A review. Free light chains of immunoglobulins. J Scand Clin Lab Invest Suppl 157:1-83, 1981

    Google Scholar 

  50. 50.

    Rocchelli B, Poloni M, Mazzarello P, Delodonci H: Identification of the k and l light chains within the CSF immunoglobulin region in multiple sclerosis and subacute sclerosing panencephalitis by immunofixation after isoelectric focusing. J Neurol 226:169-179, 1981

    Google Scholar 

  51. 51.

    Mattson DH, Ross RP, Hopper JE, Arnasom BGW: Light chain composition of CSF oligoclonal IgG in MS and SSPE. J Neuroimmunology 3:63-76, 1982

    Google Scholar 

  52. 52.

    Rudick RA, Peter DR, Bidlack JM, Knutson DW: Multiple sclerosis: Free light chains in cerebrospinal fluid. Neurology 35:1443-1449, 1985

    Google Scholar 

  53. 53.

    Vakaet A, Thompson EJ: Free light chains in the cerebrospinal fluid: An indicator of recent immunological stimulation. J Neurol Neurosurg Psychiatry 48:995-998, 1985

    Google Scholar 

  54. 54.

    DeCarli C, Menegus MA, Rudick RA: Free light chains in multiple sclerosis and infections of the CNS. Neurology 37:1334-1338, 1987

    Google Scholar 

  55. 55.

    Lolli F, Siracusa G, Amato MP, Fratiglioni L, Dal Pozzo G, Galli G, Amaducci L: Intrathecal synthesis of free immunoglobulin light chains and IgM in initial multiple sclerosis. Acta Neurol Scand 83:239-243, 1991

    Google Scholar 

  56. 56.

    Mehta PD, Cook SD, Troiano RA, Coyle PK: Increased free light chains in the urine from patients with multiple sclerosis. Neurology 41:540-544, 1991

    Google Scholar 

  57. 57.

    Tsai CU, Wu TU, 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 nephtritis. Ann Rheum Dis 51:168-172, 1992

    Google Scholar 

  58. 58.

    Dul JL, Aviel S, Melnick J, Argon Y: Ig light chains are secreted predominantly as monomers. J Immunol 157:2969-2975, 1996

    Google Scholar 

  59. 59.

    Heiter PA, Korsmeyer SJ, Waldmann TA, Leder P: Human immunoglobulin kappa light chain genes are deleted or rearranged in lambda-producing B cells. Nature 290:368-372, 1981

    Google Scholar 

  60. 60.

    Waldmann TA, Korsmeyer SJ, Bakhshi A, Kirsch IR: Molecular genetic analysis of human lymphoid neoplasms. Immunoglobulin genes and the C-myc onocogene. Ann Intern Med 102:497-510, 1985

    Google Scholar 

  61. 61.

    Grilli MJ, Chiu JJ-S, Lenardo MJ: NF-кB and Rel: Participants in a multiform transcriptional regulatory system. Int Rev Cytol 143:1-62, 1993

    Google Scholar 

  62. 62.

    Hagman J, Rudin CM, Haasch D, Chaplin D, Storb U: A novel enhancer in the immunoglobulin lambda locus is duplicated and functionally independent of NF kappa B. Genes Dev 4:978-992, 1990

    Google Scholar 

  63. 63.

    Klein S, Gerster T, Picard D, Radburch A, Schaffner W: Evidence for transient requirement of the IgH enhancer. Nucleic Acid Res 13:8901-8912, 1985

    Google Scholar 

  64. 64.

    Atchison ML, Perry RP: The role of the кenhancer and its binding factor NF-кB in the developmental regulation of к gene transcription. Cell 48:121-128, 1987

    Google Scholar 

  65. 65.

    Kreig AM, Gourley MF, Perl A: Endogenous retroviruses: Potential etiologic agents in autoimmunity. FASEB J 6:2537-2554, 1992

    Google Scholar 

  66. 66.

    Talal N, Flescher E, Dang H: Evidence for possible retroviral involvement in autoimmune diseases. Ann Allergy 69:221-224, 1992

    Google Scholar 

  67. 67.

    Blomberg J, Nived O, Pipkorn R, Bengtsson A, Erlinge D, Sturfelt G: Increased antiretroviral antibody reactivity in sera from a defined population of patients with systemic lupus erythematosus. Arthr Rheum 37:57-66, 1994.

    Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hopper, J.E., Golbus, J., Meyer, C. et al. Urine Free Light Chains in SLE: Clonal Markers of B-Cell Activity and Potential Link to In Vivo Secreted IG. J Clin Immunol 20, 123–137 (2000). https://doi.org/10.1023/A:1006686514743

Download citation

  • Systemic lupus erythematosus
  • urine free light chain
  • disease activity
  • B-cell activity