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  IN THIS Article
 ::  Abstract
 ::  Introduction
 ::  Material and methods
 ::  Results
 ::  Discussion
 ::  References
 ::  Article Tables

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Year : 1989  |  Volume : 35  |  Issue : 3  |  Page : 139-43

Cryoglobulin studies in systemic lupus erythematosus.

Correspondence Address:
F F Sikander

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Source of Support: None, Conflict of Interest: None

PMID: 0002634754

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 :: Abstract 

Twenty-two patients with systemic lupus erythematosus (SLE) were investigated to study the incidence and immunochemical nature of circulating immune complexes. In 68.18% of patients, the immune complexes were detected as cryoglobulins. A significantly high value of serum IgG and IgA (1980.64 +/- 1031.53 and 283.81 +/- 131.02 mg% respectively) were observed in these patients compared to those in normal (1097.04 +/- 298.10 and 200.93 +/- 89.96 mg% respectively). The patients also had significantly low levels of serum complement fraction C3 (61.35 +/- 22.64 mg%). Correlation of these parameters could help in understanding of the role of immunochemical factors in the pathogenesis of the disease.

Keywords: Adolescent, Adult, Aged, Cryoglobulins, analysis,immunology,Human, Immunoglobulin A, immunology,Immunoglobulin G, immunology,Immunoglobulin M, immunology,Lupus Erythematosus, Systemic, etiology,immunology,Middle Age,

How to cite this article:
Sikander F F, Salgaonkar D S, Joshi V R. Cryoglobulin studies in systemic lupus erythematosus. J Postgrad Med 1989;35:139

How to cite this URL:
Sikander F F, Salgaonkar D S, Joshi V R. Cryoglobulin studies in systemic lupus erythematosus. J Postgrad Med [serial online] 1989 [cited 2023 Feb 3];35:139. Available from:

 :: Introduction Top

Circulating immune complexes have been implicated in the pathology of various diseases including multiple myeloma, macroglobulinaemia, malignant lymphomas, as also diseases of autoimmune origin.[20]

A large number of methods designed to detect immune complexes in biological fluids, based on their physical, chemical and biological properties have been reported.[8] A commonly used method for assessing circulating immune complexes is their behaviour as "cryoglobulins"-proteins that precipitate reversibly in cold.[12],[13],[23]

A study of these cryoglobulins was undertaken in patients of SLE in order to determine their significance in the pathogenesis of the disease.

 :: Material and methods Top

Twenty-two patients (age range 15-65 years) with a confirmed diagnosis of SLE attending the rheumatology clinic of B.Y.L. Nair Charitable Hospital were studied. Twenty-seven healthy volunteers (age range 18-60 years) were included as controls.

Detection of cryoprecipitates: A modification of the method used by Zvaifler[23] was used. A brief summary of the technique utilised is shown in Fig. 1. Sera negative for cryoprecipitates were diluted in a 1 : 1 proportion with distilled water for the detection of hypotonic cold precipitates.

Analysis of cryoprecipitates: The cold precipitates were tested for protein content by the method of Lowry.[10] Ouchterlony's double diffusion technique in agar[14] was utilised for determining the type of immunoglobulin present (IgG, IgA and/or IgM). The latex-agglutination test of Singer and Plotz[17] was carried out for detecting the presence of IgM-rheumatoid factor (RF) in the precipitates.

Serum parameters: The serum immunoglobulins (IgG, IgA, IBM) and the third component of complement, C3 were estimated using the single radial immunodiffusion technique of Mancini.[11] A semiquantitative assay for serum IgM-RF was carried out using the latex agglutination test.[17]

 :: Results Top

The results of the studies on cryoprecipitates are shown in [Table - 1]and [Table - 2]. An incidence of 68.18% of cold precipitation was found in SLE patients; of these 27.27% cases showed precipitation only after the sera were rendered hypotonic. No cryoprecipitation could be detected in any of the normal sera, either before or after dilution.

The protein content of cryoprecipitates in SLE patients was found to be 0.074 0.053 mg/ml. The immunoglobulin content of these precipitates is depicted in[Table - 2]. Based on the classification of Brouet et al,[1] the cryoprecipitates were divided into "simple" (those containing only one class of immunoglobulins) and "mixed" cryoglobulins (those composed of more than one class of immunoglobulins). A distribution of simple and mixed cryoglobulins in the ratio of 47 : 53 was seen in these SLE cryoprecipitates. Of the mixed cryoglobulins IgG and IgM immunoglobulins were detected in 26.66% and IgG and IgA in 20% of the precipitates; only one precipitate (6.66%) showed all the three: IgG, IgA and IgM immunoglobulins.

The complement component C3 could not be detected in any of the precipitates.

Forty per cent of the cryoprecipitates were observed to show a positive latex agglutination test[Table - 1]. A much greater protein content (0. 115 0.06 mg/ ml) was observed in RF-positive precipitates as compared to RF-negative precipitates (0.0471 0.024 mg/ml). A significantly lower percentage (33.33%) of mixed cryoglobulins was noted in the RF-negative precipitates (Z > 1.96).

The serum immunochemical parameters of SLE patients are depicted in[Table - 2]. Significantly higher mean values of serum IgG and IgA were observed as compared to those in normal subjects. Also, a highly significant decrease in the serum C3 values was observed; (p < 0.01).

A highly significant close association between seropositivity and presence of circulating immune complexes in SLE sera was revealed by the Chi-square test (p < 0.01) [Table - 2].

 :: Discussion Top

The role of circulating immune complexes in the pathogenesis of rheumatoid diseases is being widely investigated; indeed, SLE has now been regarded as an autoimmune disease by an increasingly large number of workers. The study of the seropathology and the presence and nature of the circulating immune complexes in SLE was, therefore, undertaken in the present study.

As in the present study, a high incidence of cryoprecipitates has been reported by many workers.[2],[4],[5] No cold precipitates could be detected in any of the 27 normal control sera in the present study. This finding is consistent. with the earlier reports.[4],[9] A few workers have found limited quantities of cryoglobulins in the normal sera e.g. Cream[3] found less than 80 g/ml, Weisman and Zvaifler[22] less than 30 g/ml of serum, and Erhardt et al,[5] less than 10 g/ml.

It has been suggested by Grey and Kohler[6] that cryoglobulins may be more appropriately termed as "Cryoimmunoglobulins" since the vast majority contain either monoclonal immunoglobulins or mixtures of immunoglobulins. Predominance of IgG class of immunoglobulins with lesser amounts of IgM and IgA have been reported in rheumatoid sera by Erhardt et al[5] as was also seen in the present study.

The observation that cryoprecipitates representing circulating immune complexes are composed of immunoglobulins, as also the detection of antiglobulin IgM RFs in several precipitates points towards the immunochemical nature of SLE. The IgM RFs probably play an important role in both, the formation and the pathogenic influences of immune complexes in this disease. This contention is supported by the highly significant association obtained between seropositivity and cryopositivity in the present study.

The highly significant decrease in serum complement values obtained in the present study is supported by the results of several other workers in the field;[16],[18],[19] reduced levels have been found to be indicative of renal involvement in many cases.[15] Depressions of serum complement may be probably due to localisation on glomerular lesions[7] or a consequence of binding to the widespread vascular lesions,[21] after being fixed by circulating antigen antibody complexes. The present study may thus help in the understanding of immunochemical parameters of SLE which are involved in systemic immuno-inflammation.

 :: References Top

1.Brouet, J. C., Clarvel, J. P., Danon, F., Klein, M. and Seligmann, M.: Biological and clinical significance of cryoglobulins. (A Report of 86 cases). Amer. J. Med.. 57: 775-778, 1933.  Back to cited text no. 1    
2.Chorazak, T.: Cryoglobulins in the chronic lupus erythematosus. In, Medical Literature Abstracts. From: Acta Dermat. Venerol. 38: 322-328, 1958. J. Amer. Med. Assoc., 169: 1805-1806, 1959.   Back to cited text no. 2    
3.Cream, J. J.: Cryoglobulins in vasculitis. Clin. Exp. Immunol., 10: 117-126, 1972.  Back to cited text no. 3    
4.Druet, P., Letonturier, P., Contet, A. and Mandet, C.: Cryoglobulinaemia in human renal diseases. A study of seventy-six cases. Clin. Exp. Immunol., 15: 483-496 1973.  Back to cited text no. 4    
5.Erhardt, C. C., Mumford, P. and Maini, R. N.: Differences in immunochemical characteristics of cryoglobulins in rheumatoid arthritis and systemic lupus erythematosus and their complement binding properties. Ann. Rheum. Dis., 43: 451-456, 1984.  Back to cited text no. 5    
6.Grey, H. M. and Kohler, P. F.: Cryoimmunoglobulins, Semin. Haematol., 10: 87-112, 1973.  Back to cited text no. 6    
7.Lachmann, P. J., Muller-Eberhard, H. J., Kunkel, H. G. and Paronetto, A.: The localization of in vivo bound complement in tissue sections. J. Exp. Med., 115: 63-82, 1962.  Back to cited text no. 7    
8.Lambert, P. H., Dixon, F. J., Zubler, R. H., Agnello, V., Cambiaso, C. Casali, P., Clarke, J., Cowdery, J. S., McDufie, F. C., Hay, F. C., MacLennan, I. C. M., Masson, P., Muller Eberhard, H. J., Penttinen, K., Smith, M., Tappeiner, G., Theofilopoulos, A. N. and Verroust, P.: A WHO collaborative study for the evaluation of eighteen methods for detecting immune complexes in serum. J. Clin. Lab. Immunol., 1: 1-15, 1978.  Back to cited text no. 8    
9.Lerner, A. B., Barnum, C. P. and Watson, C. J.: Studies of cryoglobulins. II-The spontaneous precipitation of protein from serum at 5C in various disease states. Amer. J. Med. Sci., 214: 416-421, 1947.  Back to cited text no. 9    
10.Lowry, O. H., Rosebrough, N., J., Farr, A. L. and Randall, R. J.: Protein measurement with the Folin phenol reagent. J. Biol. Chem., 193: 265-275, 1951.  Back to cited text no. 10    
11.Mancini, G., Carbonara, A. O. and Heremons, J. F.: Immunochemical quantitation of antigens by single radial immunodiffusion. Int. J. Immunochem., 2: 235-254, 1965.  Back to cited text no. 11    
12.McLeod, B. C. and Sassetti, R. J.: Hypocryoglobulins: Enhanced cryoprecipitation from hypotonic serum in patients with vasculitis. Arch. Int. Med., 144: 1381-1385, 1984.  Back to cited text no. 12    
13.Meltzer, M. and Franklin, E. C.: Cryoglobulinemia-A study of twenty-nine patients. I-IgG and IgM cryoglobulins and factors affecting cryoprecipitability. Amer. J. Med., 40: 828-836, 1966.  Back to cited text no. 13    
14.Ouchterlony, O.: Antigen-antibody reactions in gels; types of reactions in coordinated systems of diffusion. Acta Path. et Microbiol. Scand., 32: 231-240, 1953.  Back to cited text no. 14    
15.Schur, P. H.: Complement in lupus. Clin. Rheumatol., 1: 519, 1975.  Back to cited text no. 15    
16.Schur, P. H. and Sandson, J.: Immunologic factors and clinical activity in systemic lupus erythematosus New Engl. .1. Med., 278: 533-538, 1968.  Back to cited text no. 16    
17.Singer, J. M. and Plotz, C. M.: The latex fixation test. I-Application to the serologic diagnosis of rheumatoid arthritis. Amer. J. Med., 21: 888-892, 1956.  Back to cited text no. 17    
18.Sturfelt, G., Johnson, U. and Sjoholm, A. G.: Sequential studies of complement activation in systemic lupus erythematosus. Scand. J. Rheumatol., 14: 184-196, 1985.  Back to cited text no. 18    
19.Townes, A. S., Stewart, C. R. (Jr.) and Osler, A. G.: Immunologic studies of systemic lupus erythematosus. II-Variations of nucleoprotein reactive gamma globulin and hemolytic serum complement levels with disease activity. Bull. Johns. Hopkins Hosp., 112: 202-219, 1963.  Back to cited text no. 19    
20.Volpe, R., Bruce-Robertson, A., Fletcher A. A. and Charles, W. B.: Essential cyoglobulinaemia. Review of the literature and report of a case treated with ACTH and cortisone. Amer. J. Med., 20: 533-537, 1956.  Back to cited text no. 20    
21.Ward, P. A. and Cochrane, C. G.: Bound complement and immunological injury of blood vessels. J. Exp. Med., 121: 215-233, 1965.  Back to cited text no. 21    
22.Weisman, M. and Zvaifler, N.: Cryoimmunoglobulinemia in rheumatoid arthritis. Significance in serum of patients with rheumatoid vasculitis. J. Clin. Invest, 56: 725-739, 1975.  Back to cited text no. 22    
23.Wintrobe, M. M. and Buell, H. V.: Hyperproteinemia associated with multiple myeloma, with report of case in which extraordinary hyperproteinemia was associated with thrombosis of renal veins and symptoms suggesting Raynaud's disease. Bull. Johns Hopkins Hosp., 52: 156-165, 1933.  Back to cited text no. 23    


[Table - 1], [Table - 2]

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Online since 12th February '04
2004 - Journal of Postgraduate Medicine
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