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Home , Infectious mononucleosis

J Clin Pathol 1984;37:1140-1143

Serum /32-microglobulin and C reactive protein concentrations in viral

EH COOPER, MA FORBES, MH HAMBLING From the Unitfor Research, University ofLeeds, Leeds LS2 9NL, and the Public Health Laboratory, Leeds LS15 7TR

SUMMARY Serum /82-microglobulin concentrations were assayed in a number of diseases. Infectious mononucleosis, , and A were associated with pronounced increases in serum ,82-microglobulin concentration. Smaller increases, with values generally <4 mg/l, were noted in other viral infections. Apart from in acute influenza A, the C reactive protein and /82-microglobulin responses were not associated. f82-microglobulin is a low molecular weight protein the balance of subsets and increase the (11-8 kilodaltons) that forms the light chain of the patient's susceptibility to viral infections. major histocompatibility (HLA, A, B, C). ,82-microglobulin in the serum is derived from HLA Material and methods turnover and shows little day to day variation in its concentration in healthy individuals. Serum 82- SERUM SAMPLES microglobulin values tend to increase with age One hundred and fifty eight serum sa\mples were owing to a gradual reduction of the efficiency of its studied, which were mainly from the serum bank of clearance from the by glomerular filtration.' the virology department of the Public Health There have been several reports of increased con- Laboratory in Leeds. The samples had been stored centrations of serum /32-microglobulin associated at -20°C after routine investigations to establish the with acute infectious mononucleosis.23 A more likely of the patient's . Additional detailed investigation of this phenomenon by Lame- samples from patients with cytomegalovirus infec- lin et a14 led to the suggestion that the serum /2- tions with normal serum creatinine concentrations microglobulin concentrations may provide a global and without any immunosuppressive disease were estimate of activation in vivo, reflecting the kindly provided by Dr Torsten Sandberg, Depart- activity of subsets of that do not neces- ment of Infectious Diseases, University of Gotten- sarily enter the peripheral blood. High concentra- berg. Except for infectious mononucleosis samples tions of serum /82-microglobulin have also been and some of the cytomegalovirus samples, pairs of found in cytomegalovirus infection in patients with sera from each patient were tested; these were the kidney transplants with normal serum creatinine presentation sample and a convalescent sample values.5 Similar increases in serum ,82-microglobulin taken 7-21 days later. Serum creatinine measure- have also been described in cytomegalovirus infec- ments on patients with other viral diseases were not tion after bone marrow grafts6 and cardiac trans- available; insufficient serum was available to allow plantation.' us to make the measurements. Two groups of We report a preliminary survey of the serum patients whose serum samples were sent for virolog- ,82-microglobulin concentrations found in several ical examination but who did not have virus infec- common forms of virus infection, including an out- tions were also examined. They included 10 patients break of influenza A. The serum f2-microglobulin with suspected infectious mononucleosis whose concentrations have been compared with the serum titres were not raised and 11 patients with C reactive protein response. The results emphasise Mycoplasma pneumoniae infection. the problems that may be encountered when trying to interpret the reason for a change in serum 12- PROTEIN ANALYSIS microglobulin concentration in diseases that disturb Serum f82-microglobulin concentrations were meas- ured in duplicate by a radioimmunoassay using the Accepted for publication 20 June 1984 Phadebas ,32-micro test 100 (Pharmacia Diagnostics 1140 Serum f32-microglobulin and C reactive protein concentrations in viral infections 1 141 10 0- a 9.0-

8.0- * A 870 - E - 7*0- S *0 * C 0% 3 0 E 60- eq c 0. .0o 5-0- t 2 0~ A 0 N' Id, I g 4.0- 0 :I y u C 320- i*: I Iwi. 1-% x 2.0- . N' t Normal 1 1 6 Normal S% range I range 0 0

_ h, 4 C-)4 1/3 n .. cr Fig. 2 Distribution of C reactive protein concentrations in the presentation serum samples. Number ofsamples with values <10 mgll are shown at the base ofeach column. EBV Fig. 1 Distribution of 182-microglobulin concentrations in = Epstein-Barr virus; CMV = cytomegalovirus; VZV = presentation serum samples sent for viral diagnosis. varicella zoster virus. *Patients with bone marrow transplants (for details see reference 6). EBV = Epstein-Barr virus; CMV = cytomegalovirus; VZV = varicella zoster virus. Serum C reative protein was measured by radial immunodiffusion using antisera and standards AB, Uppsala, Sweden). The mean and upper limit obtained from Behringwerke, Marburg/Lahn, Ger- of normal (+2 SD) of serum ,32-microglobulin in many. normal subjects under the age of 60 are 1-7 and 2-6 mg/l, respectively, and in subjects over the age of 60 Results are 2.0 and 3-1 mg/l, respectively. The ranges were calculated from blood donors and healthy subjects 2- MICROGLOBULIN examined in our laboratory during 1977-1984 and Fig. 1 shows the distribution of serum 2- agree with the kit manufacturer's recommendations. microglobulin concentations in the presentation

Serum 82-microglobulin concentrations in viral infections No ofpatients Serum /82-microglobulin concentrations Acute Convalescent Normal (age <60 yr) 1-7 + 0 45 Infectious mononucleosis (Epstein-Barr virus) 42 4-8 1-7 - Cytomegalovirus 11 6-5 + 2-0 6-1 + 2-2 (8 convalescent) Varicella zoster virus 17 2-5 + 1-0 2-2 + 1-6 Influenza A 33 4-2 ± 1-9 2-8 + 1-4 Influenza B 16 2-3 ± 0-6 1-5 + 0-4 Rubella 10 3-0 ± 0-7 2-0 ± 04 Herpes simplex 4 2-0 ± 0-8 1-8 ± 0 3 Measles 2 3-6 5-1 3-4 2-2 Respiratory syncytial virus 2 2-3 1-7 1-6 1-3 A 15 2-7 ± 0 5 Values given as mean + SD. 1142 Cooper, Forbes, Hambling serum samples from patients with virus infections. known whether the cytomegalovirus affects B lym- The means and standard deviations of the serum phocytes.'2 The serum,82-microglobulin response in 12-microglobulin concentations in virus infections herpes simplex and varicella zoster virus was not are given in the Table. ,82-microglobulin concentra- pronounced in this series; the highest concentration, tions in 10 patients aged 10-28 years with suspected 7.6 mg/I, was found in a woman with herpes zoster infectious mononucleosis but with no serological one week after presentation. High concentrations of evidence of this infection were not raised (mean + f32-microglobulin in cerebrospinal fluid have been SD = 1X5 + 0.3 mg/l). Epstein-Barr virus in infecti- reported in herpes simplex '4 15; the com- ous mononucleosis, cytomegalovirus, and influenza bination of lymphocyte activation and cell nec- A presented the strongest stimuli for increased rosis may be the origin of the increased value.'4 ,82-microglobulin release, and in cytomegalovirus is another strong stimulus for a and influenza A this tended to persist during the f32-microglobulin response. Destruction of polymor- convalescent period. In rubella there was a small phonuclear leucocytes in the respiratory tract with increase in the mean serum /32-microglobulin con- release of leucocyte pyrogen and various kinins is a centration. Infection with Mycoplasma pneumoniae feature of the pathology, but the mechanism of the produced a slight increase in the serum 132- f32-microglobulin response is unknown. The serum microglobulin concentration (mean + SD = 2-1 + ,f2-microglobulin concentrations, however, were 0-6 mg/l). considerably greater than those we have seen in 15 cases of bacterial (mean + SD = 3*1 + C REACTIVE PROTEIN 1.6 mg/l) (Juby, Brown, and Cooper; unpublished The C reactive protein response was variable. Gen- observations). Raised serum f82-microglobulin con- erally, there was no or only a small increase in centrations have also been found in and C reactive protein concentration in the viral infections non-A, non-B infections, but not in .'6 except in influenza and cytomegalovirus infection This indicates that the f32-microglobulin response (Fig. 2). In influenza A infection the 32- can occur in a variety of viral infections and is not microglobulin and C reactive protein responses were restricted to the herpes virus group. correlated (r = 0*74, p = 0-001; significantly The C reactive protein responses in this series Spearman' s rank test), but the concentrations of were generally similar to those noted in viral infec- these two plasma proteins were independent in the tions by Salonen and Vaheri.'7 The lack of high con- other virus infections and in the convalescent serum centrations among some of the groups, such as var- samples. icella zoster virus, may be due to the infections not Discussion being very severe or being complicated by secondary infection. In general, serum /82-microglobulin con- These studies have shown that a raised serum /2- centrations are not influenced by the acute phase microglobulin concentration can be induced by sev- reaction to injury or bacterial infection.'8 The eral forms of virus infection, but the mechanism of reasons for the strong correlation between C reac- the response is largely conjectural. In infectious tive protein and ,32-microglobulin concentrations in mononucleosis there is evidence that serum 12- influenza A infection are unclear; we did not find microglobulin concentrations are mainly a reflection this correlation in the 15 bacterial pneumonias, of T cell activation.4 The sequence of lymphocyte where the median C reactive protein concentration response to infection with Epstein-Barr virus in was 60 mg/l and the range 5-227 mg/l. While lym- infectious mononucleosis is unique, in that it affects phoid cells are the main source of increased serum a subset of B lymphocytes. The infection causes the f32-microglobulin in disease, there is evidence that B cells to proliferate, and this is followed by the high concentrations can be associated with condi- appearance of activated suppressor T cells that tions that cause a pronounced stimulation of the inhibit further activation. The T cells form the macrophage and reticuloendothelial system, as in majority of the transformed "atypical" lymphocytes ineffective erythropoiesis and hypersplenism'9 and that are seen in the peripheral blood.8" in myelomonocytic leukaemia.20 Furthermore, Cytomegalovirus produces a strong 132- leucocyte interferon will cause an increased expres- microglobulin response; the virus invades several sion of HLA antigens and ,82-microglobulin by lym- tissues and does not have a specific lymphotrophic phocytes in vitro.22 Whether this mechanism is effect.'2 In the infectious mononucleosis like syn- important in the f82-microglobulin response in vivo drome due to cytomegalovirus infection the ratio of to any of the we studied is still uncertain. helper to suppressor cytotoxic T cells is decreased,'3 These studies have shown that an increase in which could be a reason for the high /32- serum f82-microglobulin concentration may be microglobulin concentrations, although it is not induced by several types of viral infections. The Serum ,32-microglobulin and C reactive protein concentrations in viral infections 1143 non-specific response of serum 8,-microglobulin Epstein-Barr virus. J Natl Cancer Inst 1974;52:1081-6. and the variability of the response between patients 9 Tosato G, Magrath I, Koski I, Dooley N, Blaese M. Activation of suppressor T cells during Epstein-Barr virus induced infectious means that the test has no diagnostic value. The mononucleosides. N Engi J Med 1979;301: 1133-37. main practical importance is in the interpretation of '° Haynes BF, Schooley RT, Playing-Wright CR, Grouse JE, Dolin serum f,2-microglobulin concentrations in immuno- R, Fauci AS. Emergence of suppressed cells of immunoglobu- lin synthesis during acute Epstein-Barr virus induced infecti- suppressed patients-these include recipients of ous mononucleosis; J Immunol 1979; 123:2095-101. renal and bone marrow transplants, in whom infec- "Klein E, Emberg I, Masucci MG, Szigetti R, Wu YT, Masucci G, tions with cytomegalovirus are common,23 and in Svedmyr E. T cell response to B cells and Epstein Barr anti- children and younger adults with leukaemia or lym- gens in infectious mononucleosis. Cancer Res 1981;41:4210- phoma, who are susceptible to viral and unusual 5. 12 Kirchner H. Immunobiology of infection with human infections. In immunosuppressive states, whether cytomegalovirus. Adv Cancer Res 1983;40:31-105. induced by drugs or part of the disease process, the 3 Rinaldo CR, Ho M, Hamoudi WH, Gui X-E, Debiasio RL. lymphocyte subsets are altered, which may enhance Lymphocyte subsets and natural killer cell response during the response. In two patients sharp cytomegalovirus mononucleosis. Infect Immun 1983;40:472- ,82-microglobulin 7. increases in serum ,32-microglobulin concentrations 4 Hallgren R, Terent A, Venge P. Lactoferrin, lysozyme and f8 2 were noted, which coincided with cytomegalovirus microglobulin levels in cerebrospinal fluid: Differential indices infections shortly after bone marrow grafts at a time of CNS inflammation. Inflammation 1982;6:291-304. when the circulating lymphocyte count was low. In '5 Ibsen KK. j32-microglobulin in cerebrospinal fluid from children with different diseases. Acta Paediatr Scand 1980;69:633-5. this context it is interesting that in the acquired 6 Beorchia J, Trepo C, Vincent C, Revillard J-P, Brette R. Interet immune deficiency syndrome a raised serum 12- prognostique et pathogenique de l'elevation de la ,2- microglobulin concentration appears to be a feature microglobulin dans le hepatites aigues et chroniques. Gas- in patients who have generalised troenterol Clin Biol 1982;6:679-87. "Salonen E-M, Vaheri A. C-reactive protein in acute viral infec- as well as when the disease is complicated by tions. J Med Virol 1981;8: 161-7. Pneumocystis carinii infection or Kaposi' s sar- 6 Shuster J, Gold P, Poulik MD. ,32-microglobulin levels in cancer- coma.2425 The possible role of cytomegalovirus in ous and other disease states. Clin Chim Acta 1976;67:307-13. the aetiology of Kaposi's sarcoma in homosexual '9 Cooper EH, Forbes MA, Bowen M, Gabutti V, Piga A. Plasma f32-microglobulin and fibronectin levels in beta thalassaemia. men suggests a connection between cytomegalovirus Acta Haematol 1984;302:257-62. infection and raised serum ,32-microglobulin con- 20 Norfolk DR, Child JA, Roberts BE, Forbes MA, Cooper EH. centrations."' Serum ,82-microglobulin in disorders of myeloid proliferation. Acta Haematol 1983;69:361-36. 21 Fellous K, Kamoun M, Gresser I, Bono R. Enhanced expression References of HLA antigens and f82-microglobulin in interferon-treated human lymphoid cells. Eur J Immunol 1979;9:446-9. Berggard I, Bjork L, Cigen R, Lofdberg L. 8,2-microglobulin. 22 Hokland M, Heron I, Bert K. Increased expression of ,2- Scand J Lab Invest 1980;40 (suppl 154):13-25. microglobulin and histocompatibility antigens on human lym- 2 Ibsen KK, Krabbe S, Hesse J. 132-microglobulin serum levels in phoid cells induced by interferon. J Interferon Res infectious mononucleosis in childhood. Acta Pathol Microbiol 1981; 1:483-94. Scand 1981;89:205-8. 23 Pass RF, Long WK, Whitley RJ, et al. Productive infection with Cooper EH, Kerruish SM, Gunven P. Serum ,/2-microglobulin in cytomegalovirus and in renal transplant African Burkitt tumour: and con- recipients: role of source of kidney. J Infect Dis trols. Biomedicine 1981;35: 104-7. 1978; 137:556-63. 4 Lamelin J-P, Vincent C, Fontaine-Legrand C, Revillard J-P. 24 Bhalla RB, Safai B, Mertelsmann R, Schwartz MK. Abnormally Elevation of serum 132-microglobulin levels during infectious high concentrations of /32-microglobulin in acquired mononucleosis. Clin Immunol Immunopathol 1982; 24:55-62. syndrome (AIDS) patients. Clin Chem 'Schweizer RT, Moore R, Bartus SA, Bou L, Hayden J. 8/- 1983;29:1560. microglobulin monitoring after renal transplantation. Trans- 25 Francioli P, Clement F, Glauser MP. f32-microglobulin: a sensi- plant Proc 1981; 13:1620-3. tive non-specific marker of acquired immune deficiency syn- 6 Norfolk DR, Barnard DL, Child JA. Plasma 182-microglobulin drome. Eur J Clin Microbiol 1984;3:68-9. levels in bone marrow transplant patients with cytomegalovirus infection. Lancet 1984;i:685-6. 'Goldman MH, Landwehr R, Lippman R, et al. 8,2-microglobulin in rejection and cytomegalovirus infection in a cardiac trans- plant recipient. Transplant Proc 1982; 14:437-9. Requests for reprints to: Professor EH Cooper, Unit for 8 Pattengale PK, Smith RW, Gerber P. B-cell characteristics of Cancer Research, The School of Medicine, University of human peripheral and cord blood lymphocytes transformed by Leeds, Leeds LS2 9NL, England.