title: Association of the idiotype:antiidiotype antibody ratio with the efficacy of intravenous immunoglobulin treatment for the prevention of recurrent autoimmune-associated congenital heart block.
abstract: OBJECTIVE
  Congenital heart block (CHB), a manifestation of neonatal lupus, is associated with maternal anti-Ro/SSA and anti-La/SSB autoantibodies and recurs in ∼18% of subsequent pregnancies. This study was undertaken to investigate the effect of the idiotype:antiidiotype (Id:anti-Id) antibody ratio in the ability of intravenous immunoglobulin (IVIG) administered during subsequent pregnancies to prevent CHB.
  
  
  METHODS
  We studied 16 anti-Ro/SSA and anti-La/SSB-positive pregnant women from the Preventive IVIG Therapy for Congenital Heart Block study who had previously given birth to a child with neonatal lupus. In 3 of the mothers, the study pregnancy resulted in the birth of a child with neonatal lupus (2 with CHB and 1 with rash). Sequential serum samples were obtained from all mothers immediately before the administration of IVIG during pregnancy and were evaluated for antibodies against the major B cell epitope 349-364aa of La/SSB (idiotype) and its antiidiotypic antibodies.
  
  
  RESULTS
  Following IVIG treatment, serum titers of anti-La(349-364) (Id antibodies) decreased in 80% of the mothers, and in 60% an increase in anti-Id antibodies against anti-La(349-364) was observed. The Id:anti-Id ratio was significantly higher in mothers whose offspring developed neonatal lupus compared to mothers who gave birth to a healthy child (P<0.0001). Removal of anti-Id antibodies substantially increased the reactivity against La(349-364) in sera from 5 of 7 mothers tested. All IVIG preparations were examined for Id and anti-Id antibody activity. IVIG from batches administered to mothers who gave birth to a healthy child had an Id:anti-Id activity ratio of <1, in contrast to that given to mothers who gave birth to a child with neonatal lupus. Addition of the IVIG preparations to the maternal sera further enhanced antiidiotypic activity (by up to 4.7-fold) in 11 of 13 patients studied.
  
  
  CONCLUSIONS
  This is the first study in humans to demonstrate that IVIG influences the Id-anti-Id network of a specific pathogenic autoantibody. Specifically, we showed that IVIG enhanced the anti-Id antibody response in pregnant women with anti-La/SSB antibodies. A high Id:anti-Id ratio in both the IVIG preparation and the maternal serum may explain the absence of an effect of IVIG in preventing recurrent neonatal lupus in some cases.
authors: Department of Pathophysiology, Medical School, University of Athens, Athens, Greece.
authors: John G
authors: JG
authors: Routsias
authors: Nikolaos C
authors: NC
authors: Kyriakidis
authors: Deborah M
authors: DM
authors: Friedman
authors: Carolina
authors: C
authors: Llanos
authors: Robert
authors: R
authors: Clancy
authors: Haralampos M
authors: HM
authors: Moutsopoulos
authors: Jill
authors: J
authors: Buyon
authors: Athanasios G
authors: AG
authors: Tzioufas
references: J Intern Med. 2009 Jun;265(6):653-62
references: 19493059
references: J Immunol. 2000 Nov 1;165(9):5345-51
references: 11046070
references: Diabetes. 1996 Jul;45(7):926-33
references: 8666144
references: J Pediatr. 2003 Jun;142(6):678-83
references: 12838197
references: Immunol Lett. 1992 Sep;34(1):1-5
references: 1282496
references: Curr Opin Immunol. 1995 Dec;7(6):812-8
references: 8679125
references: Eur J Immunol. 1992 Jul;22(7):1701-6
references: 1623919
references: Arthritis Rheum. 2001 Feb;44(2):487-8
references: 11229483
references: Arthritis Rheum. 2006 Jul;54(7):2228-34
references: 16802359
references: Semin Arthritis Rheum. 2003 Dec;33(3):140-54
references: 14671725
references: Scand J Immunol. 2005 Apr;61(4):357-63
references: 15853919
references: Arthritis Rheum. 2010 Apr;62(4):1138-46
references: 20391423
references: J Autoimmun. 1995 Jun;8(3):405-13
references: 7576001
references: Nature. 1990 Sep 13;347(6289):151-6
references: 1697648
references: Arthritis Rheum. 2004 Jan;50(1):173-82
references: 14730614
references: J Autoimmun. 2001 Mar;16(2):163-72
references: 11247642
references: N Engl J Med. 1999 Jan 21;340(3):227-8
references: 9895405
references: Mol Med. 2002 Jun;8(6):293-305
references: 12428060
references: Obstet Gynecol. 2007 Aug;110(2 Pt 1):249-55
references: 17666597
references: J Immunol. 1996 Oct 15;157(8):3317-22
references: 8871627
references: Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5471-6
references: 18367670
references: J Autoimmun. 2003 Aug;21(1):17-26
references: 12892732
references: Clin Exp Immunol. 2008 Oct;154(1):30-7
references: 18727629
references: Am J Obstet Gynecol. 2000 Jan;182(1 Pt 1):122-7
references: 10649166
references: Arthritis Rheum. 2001 Aug;44(8):1832-5
references: 11508435
references: Arthritis Rheum. 2010 Apr;62(4):1147-52
references: 20131278
references: Arthritis Rheum. 2009 Oct;60(10):3091-7
references: 19790064
references: Eur J Haematol. 2005 Feb;74(2):101-10
references: 15654899
references: J Am Coll Cardiol. 1998 Jun;31(7):1658-66
references: 9626848