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Beta-2 Microglobulin—An Immunogenetic Marker of Inflammatory and Malignant Origin DONALD T

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Beta-2 Microglobulin—An Immunogenetic Marker of Inflammatory and Malignant Origin DONALD T ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 12, No. 6 Copyright © 1982, Institute for Clinical Science, Inc. Beta-2 Microglobulin—An Immunogenetic Marker of Inflammatory and Malignant Origin DONALD T. FORMAN, Ph .D. Departments of Pathology, Biochemistry, and Nutrition University of North Carolina School of Medicine, Chapel Hill, NC 27514 ABSTRACT Major contributions have been made in the last few years to the knowl­ edge of the structure, fate and cellular origin of beta-2 microglobulin (B2M); but the question of its function still remains unclear. The concept of B2M being simply a marker of renal physiology seems less satisfactory when reference is made to its relationship to the immunogenetic system. Although assay of B2 M cannot be considered as a specific diagnostic tool, it still may be regarded as a useful parameter in monitoring inflammatory, malignant, and auto-immune disease activity. Introduction Structure and Function Beta-2 microglobulin (B2M) was iso­ Beta-2 microglobulin is a protein of low lated in 1964 by Berggard7 from the relative molecular weight (Mr 11800) that urine of patients with Wilson’s disease or is present in small amounts of normal chronic cadmium poisoning. Its charac­ urine, serum, and other biological fluids. terization in 1968 determined that it con­ It is structurally related to immunoglobu­ sisted of a single polypeptide chain of lin G25 and to the cell-surface histocom­ about 100 amino acids.4 Research regard­ patibility antigens. It is synthetized by all ing this particular microprotein has nucleated cells and is present on their sur­ evolved along two lines. The first, mostly face. Its biological role remains unclear. clinical, established its importance as a At least 30 different microproteins origi­ marker of renal function.24 The more nating from plasma have been identified recent, more fundamental, led to the dis­ since 1964 in the urine of healthy individ­ covery of its close association with immu­ uals.13 With its 11800 molecular weight noglobulins and cell surface histocom­ and a 16 A size, B2M is one of the small patibility antigens.22 Although the two sized proteins ideally designed to pass areas overlap, various aspects of beta-2 freely through the glomerular sieve. Some microglobulin and its relationship to the physicochemical properties of B2M are immunogenetic system will be reviewed. listed in table I. 0091-7370/82/1100-0447 $00.90 © Institute for Clinical Science, Inc. 448 FORMAN TABLE I of almost all nucleated circulating cells, Physiochemical Properties of Beta-2 Microglobulin mesenchymal and epithelial cells as well.14 Although there is a significant amino acid Electrophoretic mobility at Like beta-globulin homology between B2 M and the constant pH 8.6 Isoelectric pH 5.4 - 5.7 domains of IgG, B2 M does not react with Molecular weight 11600 - 11800 Sedimentation coefficient (S20w ) 1-65 antisera to the heavy or light chains of the Carbohydrate content 0 immunoglobulins. In table II are de­ N 2 content 16.3 percent Molecular stokes radius scribed various immunologic properties 16Á of B2M. The small size of B2M has made it a suitable candidate for determining the se­ Clinical Chemistry of B2M quence of the amino acid residues that Beta-2 microglobulin circulates in the make up the peptide (figure 1). From stud­ blood at detectable levels and is also pres­ ies of the amino acid sequences of B2M, it ent in urine, saliva, colostrum, and am- appears that the arrangement of the 100 niotic fluid. In healthy subjects, the con­ amino acids of this moiety bears a very centration of B2M in serum fluctuates striking homology with the constant do­ within a narrow range of values, from 900 mains of the heavy and light chains of to 2800 ¡mg per L.13 The urine range is 6.0 the immunoglobulins, especially with the to 300 ¡ig per L. These values appear to be CH3 domain.28 However, the circulating independent of the immunoassay used. B2M does not stem from a splitting of Determination of B2 M in human urine or immunoglobulins. In fact it has been serum was initially by single radial im­ shown to be present on the surface of munodiffusion,6 but this method is not lymphocytes23 and later on the surface sensitive enough for detecting B2M in F ig u re 1. Structural char­ acteristics of Beta2-micro- globulin. (Taken from Poulik, M. D. and Bloom, A. D. J. Immunol. 110: 1430-1433, 1973.) Amino-acid residues: 100 BETA-2 MICROGLOBULIN— AN IMMUNOGENETIC MARKER 449 reference population urine without a pre­ TABLE II liminary concentration step. Radioim­ Immunologic Properties of Beta-2 Microblogulin (B2M) munoassay (RIA) methods were then de­ Amino acid homology and structural similarity to CH3 veloped which can accurately measure region of igG B2M in normal urine or serum without Antigenically distinct from IgG B 2 M does not bind with Staph A protein sample preconcentration. B 2 M is non-covalently linked to major histo­ The two available radioimmunoassay compatibility antigens (HLA) on the surface of (RIA) methods for B2M are the solid phase nucleated cells RIA technique of Evrin12 and the double­ antibody method of Shuster et al.32 Solid phase RIA has also been commercial­ detection of tubular damage from exces­ ized.* The disadvantages of the radioiso­ sive exposure to cadmium. Recent reports tope methods (short shelf-life, cost, health have also implicated increased B2M in hazards, time of assay [six to eight hours]) cerebrospinal fluid of patients with leuke­ have been previously discussed.15 A mia or lymphoma and early relapse in the lymphocytotoxicity inhibition technique central nervous system.19 Increased B2M for determining B2M has recently been has been reported in Crohn’s disease,11 proposed,10 but the method is less accu­ Sjogren’s syndrome,20 and rheumatoid rate and sensitive than RIA and gives arthritis.18 a semi-quantitative estimate. Bernard5 has recently published a highly sensitive method for the determination of B2 M in Beta-2 Microglobulin and Its human urine or serum based on the direct Relationship to the agglutination by B2M of latex particles on Immunogenetic System which an antibody against B2M is ab­ Welsh et al36 demonstrated that lym­ sorbed. The agglutination is quantitated phocytes in culture produce B2 M and this by counting the remaining unagglutin­ production could be stimulated by mito- ated particles or by turbidimetry. genic substances. Peterson25 showed that Interindividual variations in B2M, still B2M is part of the major histocompati­ unexplained, exist, but in a given refer­ bility cell-bound human leukocyte anti­ ence individual the level is stable. Serum gen (HLA) complex responsible to a great levels of B2 M are independent of body extent for immuno-rejection of trans­ mass or sex but are slightly increased in planted organs and tissues in non-geneti- elderly persons.34 The narrow reference cally related hosts. Although conflicting range of values are higher in malignant data, mainly owing to the methodology of disorders,34 particularly in multiple mye­ cell-bound HLA solubilization, have ap­ loma and monocytic leukemia. Elevated peared,26 the proposed structure of HLA values of serum B2M are considered a antigens has been postulated.10 Human very sensitive indicator of the impairment leukocyte antigen is composed of two of glomerular filtration rate.3,37 Healthy glycopeptide chains, so-called heavy subjects excrete very small quantities of chains, carrying the antigenic specificity B2M in urine (6 to 300 /«.g per L)13 but its and linked together through a S-S-bond excretion increases considerably in tubu­ embedded in the cell surface membrane. lar dysfunction, as observed in chronic Each of the heavy chains is linked, seem­ cadmium poisoning, Fanconi’s syndrome, ingly through a non-covalent bond, to a so- Balkan nephropathy, and Wilson’s dis­ called light chain which is precisely B2 M. ease.21,27 In occupational medicine, B2M The heavy chain has allotype variants in urine is the most sensitive test for early whereas the light chain has not; in other * Phadebas, B2 Micro Test, Pharmacia Diagnostic words, different HLAs bear the same A.B., Uppsala, Sweden. B2M. It appears that HLA is always bound 450 FORMAN to B2 M and the same situation exists in the in females than in males of each patient equivalent histocompatibility system of group. After statistical correction for these the mouse. A common ancestor gene cod­ age and sex effects, mean values for B2M ing for the 100 amino acid sequence of remained significantly higher in each of immunoglobulins and surface antigens the cancer groups than in their benign has been suggested.2 controls. Patients with more advanced breast cancer had higher levels of serum B2M than those subjects with early dis­ B2M in Solid Malignancies ease. This was true for patients with stom­ Several studies indicate that in patients ach cancer compared to those with colo­ with a wide variety of malignant tumors, rectal carcinoma. A possible interpretation serum B2M levels may be abnormally of these findings is that B2M concentra­ elevated as compared to those of age- tions increased with increasing tumor bulk matched controls.34 In primary bronchial and, therefore, this determination may be cancer, 44 percent of cancer patients had of value in the treatment and management elevated serum levels when compared to of cancer patients. their controls which had an elevated B2 M Studies relating differences in the cell in 11 percent of cases.31 Serum B2M levels surface of malignant cells with normal were measured by RIA in patients with cells suggest that solid and superficial various malignant neoplasms, ascites, and basal cell carcinomas lack immuno-reac- also with definite or suspected hepatoma tive B2M on the cell surface.
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