Rheum Maternal Antibodies

Basic & Clinical Research

Title: Maternal Autoantibodies — Pathogenesis of Neonatal Lupus

Investigator: Jill P. Buyon, M.D.

Funding: NIH - NIAMS (5 R01 AR42455)

Dates: 02/01/94 - 01/31/04

Summary: One of the central questions in autoimmunity is whether autoantibodies are directly responsible for tissue injury. Complete congenital heart block, detected at or before birth in a structurally normal heart, is strongly associated with autoantibodies reactive with 48kD SSB/La, 52kD SSA/Ro and 60kD SSA/Ro proteins. This serious and permanent manifestation of neonatal lupus is of special importance, since it serves as a model for passively acquired disease expressed in a fetus. The aims of the first five years of this study were (1) to determine the antigenic targets in fetal cardiac myocytes, (2) to determine whether there is diminished surface expression of complement regulatory proteins on fetal cardiac cells, and 3) to localize the antigenic determinants of the 52Ro peptide. The aims to be accomplished over the coming five years are: (1) to identify proteins of the human fetal heart that interact with 48kD SSB/La, 52kD SSA/Ro, 52¥, or 60kD SSA/Ro, or are novel autoantigens recognized by anti-sera from mothers of children with CHB; (2) to determine whether the candidate autoantigens related to autoimmune-CHB are present at the surface of apoptotic human fetal cardiocytes; and (3) to establish an antibodyspecific murine model to correlate arrhythmogenic effects of maternal autoantibodies with the in vivo genesis of CHB.

PUBLICATIONS:

Peer Reviewed Journals:

1. Buyon JP, Slade SG, Reveille JD, Hamel JC, Chan EKL. Autoantibody responses to the "native" 52kD SS-A/Ro protein in neonatal lupus syndromes, systemic lupus erythematosus and Sjögren's syndrome. J Immunology 1994; 152:3675-84.

2. Buyon JP, Waltuck J, Crawford B, Slade S, Copel J, Chan EKL. Relationship between maternal and neonatal levels of antibodies to 48kD SSB/La, 52kD SSA/Ro, and 60kD SSA/Ro in pregnancies complicated by congenital heart block. J Rheumatology 1994; 21:1943-50.

3. Buyon JP, Waltuck J, Kleinman C, Copel J. In utero identification and therapy of congenital heart block (CHB). Lupus 1995; 4:116-21.

4. Friedman DM, Borg M, Rutkovsky L, Buyon JP. Benign fetal bradycardias diagnosed by echocardiography. Am J Perinatology 1995; 12:87-90.

5. Silverman ED, Buyon J, Laxer RM, Hamilton R, Bini P, Chu JL, Elkon KB. Autoantibody response to the Ro/La particle may predict outcome in neonatal lupus erythematosus. Clin Exp Immunol 1995; 100:499-505.

6. Copel J, Buyon J, Kleinman C. Successful in utero therapy of fetal heart block. Am J Obstet Gynecol 1995; 173:1384-1390.

7. Gorelick A, Oglesby T, Rashbaum W, Atkinson J, Buyon JP. Ontogeny of membrane cofactor protein: phenotypic divergence in the fetal heart. Lupus 1995; 4:293296.

8. Niimi Y, Ioannides D, Buyon J, Bystryn JC. Heterogeneity in the expression of Ro and La antigens in human skin. Arthritis Rheum 1995; 38:1271-1276.

9. Chan EKL, DiDonato F, Hamel JC, Tseng CE, Buyon JP. 52-kD SS-A/Ro: Genomic structure and identification of an alternatively spliced transcript encoding a novel leucine zipper-minus autoantigen expressed in fetal and adult heart. J Exp Med 1995; 182:983992.

10. Tseng C, Caldwell K, Feit S, Chan EKL, Buyon JP. Subclass distribution of maternal and neonatal anti-SSA/Ro and -SSB/La antibodies in congenital heart block. J Rheum 1996; 23:925-932.

11. Tseng C, Di Donato F, Buyon JP. Stability of immunoblot profile of anti-SSA/Ro-SSB/La antibodies over time in mothers whose children have neonatal lupus. Lupus 1996; 5:212-215.

12. Wang D, Chan EKL. 17-¥-estradiol increases expression of the 52 and 60-kD SS-A/Ro autoantigens in human keratinocytes and breast cancer cell line MCF-7. J Invest Dermatol 1996; 107-610-614.

13. Boutjdir M, Chen L, Zhang Z, Tseng C, DiDonato F, Rashbaum W, Morris A, El-Sherif N, Buyon JP. Arrhythmogenicity of IgG and anti-52kD SSA/Ro affinity purified antibodies from mothers of children with congenital heart block. Circulation Research 1997; 80:354-362.

14. Tseng C, Chan E, Miranda E, Gross M, DiDonato F, and Buyon JP. The 52kD protein is a target of intermolecular spreading of the immune response to components of the SSA/Ro-SSB/La complex. Arth Rheum 1997; 40:936-944.

15. Buyon JP, Tseng C-E, DiDonato F, Rashbaum W, Morris A, Chan EKL. Cardiac expression of 52¥, an alternative transcript of the congenital heart block-associated 52-kD SS-A/Ro autoantigen, is maximal during fetal development. Arthritis Rheum 1997; 40:655-660.

16. Boutjdir M, Chen L, Zhang ZH, Tseng CE, El-Sherif N, Buyon JP. Serum and IgG from the mother of a child with congenital heart block induce conduction abnormalities and inhibit L-type calcium channels in a rat heart model. Ped. Research 1998; 44:11-19.

17. Miranda-Carus ME, Tseng CE, Rashbaum W, Ochs RL, Casiano CA, DiDonato F, Chan EKL, Buyon JP. Accessibility of SSA/Ro and SSB/La antigens to maternal autoantibodies in apoptotic human fetal cardiac myocytes. J. Immunol. 1998; 161:5061-6059.

18. MirandaCarús ME, Boutjdir M, Tseng CE, DiDonato F, Chan EKL, Buyon JP. Induction of antibodies reactive with SSA/RoSSB/La and development of congenital heart block in a murine model. J. Immunol. 1998; 161:5886-5892.

19. Tseng CE, Miranda E, DiDonato F, Boutjdir M, Rashbaum W, Chan EKL, Buyon JP. mRNA and protein expression of SSA/Ro and SSB/La in human fetal cardiac myocytes cultured using a novel application of the Langendorff procedure. Ped. Research (in press, 1999).

Invited Reviews

1. Buyon JP. Neonatal lupus syndromes. Current Opinion in Rheumatology 1994; 6:523-9.

2. Chan EKL, Buyon JP. The SS-A/Ro antigen. In Manual of Biological Markers of Disease, Section B. Autoantigens and Clinical Significance of Autoantibodies. Eds. RN Maini, WJ Van den Roit. Kluwer Academic Publishers, Netherlands, 1994; B4.1:1-18.

3. Buyon JP, Nelson JL, Lockshin MD. The effects of pregnancy on autoimmune diseases. Clin Immunol Immunopath 1996; 78: 99-104.

4. Buyon, JP. Neonatal lupus: Bedside to bench and back. Scand J Rheumatol 1996; 25:271-276,

5. Buyon JP. Neonatal lupus. Current Opinion in Rheumatology 1996; 8:485-490.

6. Tseng C, Buyon JP. Neonatal lupus syndromes. Rheum Dis Clin North America 1997; 23:31-54.

7. Buyon JP. Neonatal lupus. In Rheumatology, 2nd Ed. Klippel JH, Dieppe PA, eds. Mosby International, London. 1998; 7.8.18-20.

8. Buyon JP. The effects of pregnancy on autoimmune diseases. J Leukocyte Biol 1998; 63:281287.

9. Buyon JP. Neonatal lupus syndromes. In Systemic Lupus Erythematosus, 3rd Ed. Lahita R, ed. Academic Press. 1998; pp. 337-359.

10. Buyon JP, Brucato A. Neonatal lupus. Seminars in Clinical Immunology 1998; 15:5-19.

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