Free light chains

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Schematic representation of the immunoglobulin structure:
  • Heavy chains
  • Light chains
    • A:  Fab fragment , B:  Fc fragment , C:  joint ( hinge ) , 1:  antigen-binding variable region, 2: constant region

    The unbound light chains are referred to as free light chains (FLC, from English Free Light Chain ) . Together with the heavy chains, light chains form intact immunoglobulins ( antibodies ).

    Immunoglobulins are made by plasma cells (part of the immune system ) that develop from hematopoietic stem cells in the bone marrow . They consist of two identical heavy chains and two identical light chains, with five different isotypes (classes) of heavy chains (G, A, M, D and E). There are two isotypes of the light chains, which are referred to as kappa (κ) and lambda (λ) (see also: Structure of antibodies ). Light chains are formed in excess in every person and released into the blood by the cells as free light chains. The natural function of the free light chains is largely unexplained and is part of current research.

    Occurrence

    Production of intact immunoglobulins and FLC by plasma cells.

    Small amounts of free light chains, in addition to the light chains bound in the immunoglobulins, are present in the blood of every human being (normal values: κ = 3.30-19.40 mg / l, λ = 5.71-26.30 mg / l). The free light chain κ is present as a monomer (a single molecule, approx. 25  kilodaltons , kDa), while the free light chain λ predominantly forms a dimer (consists of two linked molecules, approx. 50 kDa). The production ratio of the free light chain κ to λ is 2: 1. The body's metabolism reverses this relationship (see next section).

    metabolism

    The free light chains are filtered by the kidney due to their small size . The human's two kidneys each consist of about a million nephrons , with the nephron being the filtration unit of the kidney. Since the free light chain κ, in contrast to the dimeric free light chain λ, is present as a monomer, it is filtered by the kidneys about three times faster and thus removed from the blood more quickly. Therefore, there are more free light chains λ in the blood than κ and thus the ratio of the concentrations in the blood does not correspond to the κ: λ production ratio of 2: 1, but reverses to about 1: 2 (the κ / λ ratio is on average at 0.63; the normal range in serum is between 0.26 and 1.65).

    Nephron, Filtration of the Free Light Chains.

    Because of this filtration, the free light chains remain in the blood for a very short time. Their half-life is 2-6 hours, the free light chain κ has a half-life of 2 to 3 and the free light chain λ of 4 to 6 hours. For comparison: The intact immunoglobulin IgG, which is not filtered by the kidneys because it is too large for the pores with a mass of 150,000 Daltons, has a half-life of up to 20 days.

    After the free light chains have been filtered through the glomeruli, they enter the proximal tubule of the kidney, where they are reabsorbed and metabolized via the proximal tubular cells . The organism thus ensures that no major amounts of proteins ( proteins go) lost in the urine.

    In healthy people, around 500 mg of free light chains are produced per day, which are completely filtered and reabsorbed by the kidneys. An intact kidney can reabsorb 10 to 30 g of protein per day. Therefore, in healthy people, only negligible amounts, or none at all, of free light chains get into the urine. As a result, the concentration of free light chains in the blood must first increase very sharply (as can be the case with monoclonal gammopathies ) before the reabsorption capacity of the kidneys is exceeded and the free light chains are also excreted in the urine (overflow proteinuria , proteinuria ).

    Clinical significance

    In the case of monoclonal gammopathies, there are pathologically altered plasma cells that multiply in an uncontrolled manner. These plasma cells are monoclonal and are therefore identical, as they are all derived from the same cell. Among the monoclonal gammopathy include the multiple myeloma , the myeloma, Waldenstrom that AL amyloidosis , the light chain storage disease (Light Chain Deposition Disease), the monoclonal gammopathy of undetermined significance (MGUS), the monoclonal gammopathy renal significance (MGRS) and other similar diseases. Most monoclonal gammopathies produce large quantities of monoclonal proteins. These can be monoclonal immunoglobulins and / or monoclonal free light chains that are released into the blood. The monoclonal free light chains are formed, for example, in light chain myeloma as the only tumor product, but also occur in the majority of all myeloma forms (85-95%) at least as an additional tumor product. Only intact immunoglobulins without free light chains can be detected as tumor products in only 5-10% of cases.

    The free light chains can be used as tumor markers in the diseases mentioned. Their determination in the serum is of importance in the diagnosis, the assessment of the risk of disease progression, the control of the success of therapy and a relapse or relapse of the disease. The κ / λ ratio (κ / λ ratio) provides information about the clonality of the disease present.

    Furthermore, the free light chains are a suitable parameter for monitoring the course and therapy of all monoclonal gammopathies with the involvement of free light chains, as their short half-life of a few hours enables a timely assessment of the disease process. Changes in tumor mass and activity are therefore very quickly reflected in the concentration of free light chains.

    The change in the concentration of free light chains also has a prognostic significance with regard to the course of the disease in multiple myeloma and AL amyloidosis. In addition, the κ / λ ratio is a criterion for the risk assessment of monoclonal gammopathies of unclear significance. If abnormal values ​​are observed here, this can be an indication of an imminent or (compared to patients with normal values) earlier progression of the disease.

    Analytical determination

    The determination of the free light chains by immunoassays using serum samples has been the method of choice for almost 20 years, which has largely replaced urine, a sample material that was previously used more frequently. An important analytical advantage of immunoassays over electrophoretic methods (e.g. serum protein electrophoresis and immunofixation electrophoresis) and the determination of the total light chains is the significantly higher sensitivity and high specificity of the test. The diagnosis, therapy and progress control of many monoclonal gammopathies can therefore be significantly improved by determining the free light chains in the serum. This method has now also found its way into the national and international guidelines for the diagnosis and follow-up of monoclonal gammopathies. The hematological guidelines refer to the so-called Freelite test for determining free light chains . Measurement results that are determined on the basis of tests from different manufacturers are not comparable. The different composition as well as the z. Sometimes analytical differences in the tests are expressed in differences in the direct comparison of the measurement results, especially of pathological samples.

    literature

    Web links

    Individual evidence

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    2. ↑ FA Redegeld et al .: Polyclonal immunoglobulin free light chain and chronic inflammation . In: Mayo Clin Proc . 87, No. 10, October 6, 2012, pp. 1032-3. doi : 10.1016 / j.mayocp.2012.07.012 . PMID 23036675 .
    3. ↑ U. Basile et al .: Plasmatic free light chains as inflammatory marker in insulin resistance: comparison of metabolic syndrome with adult growth hormone deficiency . In: Biofactors . 44, No. 5, 2018, pp. 480-484. doi : 10.1002 / biof.1444 . PMID 30175865 .
    4. ↑ a b J. A. Katzmann 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 . In: Clinical Chemistry . 48, No. 9, May 2, 2002, pp. 1437-1444. PMID 12194920 .
    5. ↑ a b c A. R. Bradwell et al .: Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine . In: Clinical Chemistry . 47, No. 4, March 29, 2001, pp. 673-680. PMID 11274017 .
    6. ↑ A. Solomon et al .: Light chains of human immunoglobulins. . In: Methods Enzymol . 116, 2018, pp. 101-121. doi : 10.1016 / S0076-6879 (85) 16008-8 . PMID 3937021 .
    7. ^ TA Waldmann et al .: The renal handling of low molecular weight proteins: II. Disorders of serum protein catabolism in patients with tubular proteinuria, the nephrotic syndrome, or uremia . In: J Clin Invest . 51, No. 8, August 1, 1972, pp. 2162-74. doi : 10.1172 / JCI107023 . PMID 5054468 . PMC 292373 (free full text).
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    16. ↑ M. Drayson et al .: Effects of paraprotein heavy and light chain types and free light chain load on survival in myeloma: an analysis of patients receiving conventional-dose chemotherapy in Medical Research Council UK multiple myeloma trials . In: Blood . 108, No. 6, 2006, pp. 2013-9. doi : 10.1182 / blood-2006-03-008953 . PMID 16728700 .
    17. ↑ A. Dispenzieri et al .: Effects Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study . In: Lancet . 375, No. 9729, May 15, 2010, pp. 1721-8. doi : 10.1016 / S0140-6736 (10) 60482-5 . PMID 20472173 . PMC 2904571 (free full text).
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    19. ↑ a b S. V. Rajkumar et al .: Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance . In: Blood . 106, No. 3, August 2005, pp. 812-7. doi : 10.1182 / blood-2005-03-1038 . PMID 15855274 . PMC 1895159 (free full text).
    20. ↑ a b A. Dispenzieri et al .: Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma . In: Blood . 111, No. 2, October 17, 2007, pp. 785-789. doi : 10.1182 / blood-2007-08-108357 . PMID 17942755 . PMC 2200851 (free full text).
    21. ↑ a b A. Durie et al .: International uniform response criteria for multiple myeloma . In: Leukemia . 20, No. 9, July 21, 2006, pp. 1467-73. doi : 10.1038 / sj.leu.2404284 . PMID 16855634 .
    22. ^ RA Kyle et al .: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management . In: Leukemia . 24, No. 6, April 22, 2010, pp. 1121-7. doi : 10.1038 / leu.2010.60 . PMID 20410922 .
    23. ↑ AR Bradwell et al .: Serum free light chain immunoassays for monitoring patients with light chain producing and nonsecretory multiple myeloma . In: ASH Meeting Philadelphia . 2002.
    24. ↑ A. Dispenzieri et al .: International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders . In: Leukemia . 23, No. 2, February 2009, pp. 215-224. doi : 10.1038 / leu.2008.307 . PMID 19020545 .
    25. ↑ Onkopedia - with guidance about the DGHO Accessed December 4 2018th
    26. ↑ MA Bätsch et al .: Current aspects in the diagnosis and therapy of plasma cell myeloma . In: Deutsches Ärzteblatt . 142, No. 11, June 1, 2017, pp. 800–804. doi : 10.1055 / s-0043-100295 . PMID 28564730 .