Association of leukocyte CR1 gene transcription with the disease severity and renal involvement in systemic lupus erythematosus

Abstract

The reduced level of complement receptor 1 (CR1) on erythrocytes is speculated as a key mechanism contributing to immune complex (IC) overload and exaggerated complement (C) activation in systemic lupus erythematosus (SLE). Comparatively, fewer studies documented lower levels of CR1 on leukocytes and glomerular podocytes in this disease. The decline in E-CR1 is largely believed as an acquired phenomenon caused due to the proteolytic cleavage of CR1 from erythrocyte membrane. The mechanism underlying reduced CR1 expression on nucleated cells is under constant investigation. Recently, reduced leukocytes CR1 gene transcription had been demonstrated in SLE and was suggested as the main cause of decline in leukocyte CR1 (L-CR1). The relationship of L-CR1 gene transcription with severity and pathophysiology of disease needs to be elucidated. We determined the levels of L-CR1 in 30 active SLE patients and compared with normal healthy controls (n = 30). Patients were categorized into two groups i.e., with nephritis (n = 14) or without nephritis (n = 16). The expression of L-CR1 at transcriptional level was correlated with the levels of serum CIC, C3 and anti dsDNA antibodies. The levels of L-CR1 transcription were significantly reduced in all SLE patients as compared to controls (P, 0.001). This decline in L-CR1 however, was more marked in patients with nephritis than those without nephritis. In addition, the serum levels of CIC, anti dsDNA antibodies were higher and the levels of serum C3 were lower than the normal range in the patients. The difference was much more marked in SLE patients with nephritis than those without nephritis. The levels of L-CR1 transcription correlated negatively with the levels of CIC and anti dsDNA antibodies and positively with serum C3 levels. Thus, between SLE patients with and without nephritis, we found significant difference in the levels of L-CR1 transcription (P, 0.01), CIC (P, 0.05), anti dsDNA antibodies (P, 0.01) and C3 (P, 0.01). Our findings suggest that L-CR1 is drastically reduced in patients with severe form of SLE, i.e., lupus nephritis. Determination of L-CR1 expression at transcriptional level in addition to disease hallmarks like C3, CIC and anti-dsDNA antibodies may facilitate the assessment of severity of SLE and discrimination between patients with or without renal involvement.

Keywords

leukocyte CR1 lupus nephritis RT-PCR systemic lupus erythematosus

Get full access to this article

View all access options for this article.

References

Belmont HM. Lupus Clinical Overview 2003 at http://www.cerebel.com/lupus/overview (accessed 5 November 2004).

Hawke CG , Painter DM , Kirwan PD , Van Driel RR , Baxter AG. Mycobacteria, an environmental enhancer of lupus nephritis in a mouse model of systemic lupus erythematosus . Immunology, 2003; 108: 70-78 .

Dr Koop. Lupus nephritis. Web site: http://www.dr.koop.com (accessed 5 November 2004).

Churg J , Bernstein J , Glassock RJ. Renal disease: classification and atlas of glomerular diseases. New York: Igaku-Shoin Medical Publishers, Inc. , 1995.

Petri M. Treatment of systemic lupus erythematosus: an update. American family physician, published by American Academy of Family Physician . June 1998, 1-11. Web site: www.aafp.org/ofp/980600ap/petri.html (accessed 5 November 2004).

Arora M , Arora R , Tiwari SC , Das N Srivastava LM. Expression of complement regulatory proteins in diffuse proliferative glomerulonephritis . Lupus 2000; 9: 127-131 .

Katyal M , Sivasankar B , Das N. Complement receptor 1 in autoimmune disorders . Current Science 2001; 81: 907-914 .

Arora V , Verma J , Dutta R , Marwaha V , Kumar A , Das N. Reduced transcription of CR1 (CD35) gene in systemic lupus erythematosus . Mol Immunol 2004; 41: 449-456 .

Kazatchkine MD , Fearon DT , Appay MD , Mandet C , Bariety J. Immunohistochemical study of human glomerular C3b receptor in normal kidneyandin75casesofrenaldiseases:lossofC3breceptorantigeninfocal hyalinosis and in proliferative nephritis of SLE . J Clin Invest 1982; 69: 900-900 .

10.

Pascual M , Duchosal MA , Steiger G , Giostra E , Pechere A , Schifferli JA. Circulating soluble CR1 (CD35). Serum levels in diseases and evidence for its release by human leukocytes . J Immunol 1993; 151: 1702-1711 .

11.

Sivashankar B , Dinda AK , Tiwari SC , Srivastava LM , Das N. Modulation of urinary CR1 in systemic lupus erythematosus . Lupus 2004; 13: 1-6 .

12.

Wilson JG , Ratnoff WD , Schur PH , Fearon DT. Decreased expression of the C3b/C4b receptor (CR1) and the C3d receptor (CR2) on B-lymphocytes and of CR1 on neutrophils of patients with systemic lupus erythematosus . Arthritis Rheum 1986; 29: 739-747 .

13.

Arora M , Jain D , Dinda AK et al. Reduced CR1 expression on erythrocytes of idiopathic focal-segmental glomerulosclerosis patients . Nephron 1998; 79: 365-366 .

14.

Ross GD , Yount WJ , Walport MJ et al. Disease associated loss of erythrocyte complement receptors (CR1, c3b receptors) in patients with systemic lupus erythematosus and other disease involving autoantibodies and/or complement activation . J Immunol 1985; 135: 2005-2014 .

15.

Iida K , Nussenzweig V. Complement receptor is an inhibitor of complement cascade . J Exp Med 1982; 153: 1138-1138 .

16.

Moll S , Mio S , Sadallah S , Gudat F , Mihatsch MJ , Schifferli JA. No complement receptor 1 stump on podocytes in human glomerulopathies . Kidney Internatl 2001; 59: 160-168 .

17.

Barbosa JE , Harrisson RA , Barker PJ. An anti-peptide Ab that recognizes a neo antigen in CR1 stump remaining on erythrocytes after proteolysis . Clin Exp Immunol 1992; 87: 144-149 .

18.

Wilson JG , Wong WM , Murphy EE , Schur PH , Fearon DT. Deficiency of the C3b/C4b receptor (CR1) of erythrocytes in systemic lupus erythematosus: analysis of the stability of the defect and of a restriction fragment length polymorphism of the CR1 gene . J Immunol 1987; 138: 2706-2708 .

19.

Mitchell JA , Sim E. Size polymorphism of the erythrocyte complement receptor type 1 (CR1) in systemic lupus erythematosus induced by hydralazine . Complement and Inflammation 1989; 6: 88-93 .

20.

Tan EM , Cohen AS , Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus . Arthritis Rheum 1982; 25: 1271-1277 .

21.

Sai Baba KSS , Moudgil KD , Jain RC , Srivastava LM. Complement activation in pulmonary tuberculosis . Tubercle 1990; 71: 103-107 .

22.

Wilson JG , Wong WW , Schur PH et al. Mode of inheritance of decreased C3b receptors on erythrocytes of patients with systemic lupus erythematosus . N Eng J Med 1982; 307: 981-986 .

23.

Walport MJ , Ross GD , Mackworth-Young C et al. Family studies of erythrocyte complement receptor type 1 levels: reduced levels in patients with SLE are acquired, not inherited . Clin Exp Immunol 1985; 59: 547-554 .

24.

Iida K , Mornaghi R , Nussenweiz V. Complement receptor 1 deficiency in erythrocytes from patient with systemic lupus erythromatosus . J Exp Med 1981; 155: 1427-1438 .

25.

Walport MJ , Lachmann PJ. Erythrocytes complement receptor 1, immune complexes and the rhematic diseases . Arthritis Rheum 1988; 31: 153-158 .

26.

Baral N , Lamsal M , Srivastava LM. Significance of complement profile and complement receptor 1 expression in RBC and kidney tissue in immune complex mediated disease . J Nepal Medical Association 2002; 41: 481-484 .

27.

Chen CY , Tseng HM , Chen LC et al. Use of new flourescence immunoassay to detect anti-dsDNA antibodies is more correlated with disease activity and complement than the ELISA method in SLE patients . Lupus 2003; 12: 266-273 .

28.

Alba P , Bento L , Cuadrado MJ et al. Anti-dsDNA, anti-Sm antibodies and the lupus anticoagulant: significant factors associated with lupus nephritis . Ann Rheum Dis 2003; 62: 556-560 .

29.

Reichlin M , Wolfson-Reichlein M. Correlation of anti dsDNA and anti-ribosomal P autoantibodies with lupus nephritis . Clin Immunol 2003; 108: 69-72 .

30.

Oelzner P , Deliyska B , Funfustuck R , Hein G , Herrmann D , Stein G. Anti-C1q antibodies and antiendothelial cell antibodies in systemic lupus erythematosus-relationship with disease activity and renal involvement . Clin Rheumatol 2003; 22: 271-278 .

31.

Levinsky RJ , Cameron JS , Soothill JF. Serum immune complexes and disease activity in lupus nephritis . The Lancet 1977; 564-567 .

32.

Maquart HV , Svendsen A , Ramusen JM , Leslie RGQ. Complement receptor expression and activation of the complement cascade on B lymphocytes from patients with systemic lupus erythematosus (SLE) . Clin Exp Immunol 1995; 101: 60-65 .

33.

Forger F , Mathhias T , Oppermann M , Becker H , Helmke K. Clinical significance of anti-dsDNA antibodies as a prognostic marker for lupus nephritis . Lupus 2004; 13: 36-44 .

34.

Navratil JS , Manzi SM , Ruffling MJ et al. A novel complement based for SLE diagnosis and assessment of disease activity . Int Immunopharmacol 2002; 2: 1323-1323 (abstract 310).