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.

Conclusion: 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.

Copyright © 2011 by the American College of Rheumatology.

Figures

Figure 1

A, Idiotype:antiidiotype (Id:anti-Id) ratio of antibodies against the major epitope of La/SSB after intravenous immunoglobulin (IVIG) administration, in mothers who gave birth to a child with neonatal lupus and mothers who gave birth to a healthy child. Horizontal dashed bars show the mean. The mean Id:anti-Id ratio was significantly higher in the mothers who gave birth to a child with neonatal lupus than in those who gave birth to a healthy child (P < 0.0001). CHB = congenital heart block. B, Id:anti-Id ratios in the IVIG preparations received by 13 of the 16 mothers. The Id:anti-Id ratio in the IVIG received by the mothers who gave birth to a child with neonatal lupus (stars) was ≥1, and the mean Id:anti-Id ratio in the IVIG received by these mothers was higher than that in the IVIG received by mothers who gave birth to a healthy child (P < 0.0001). Labels below the bars show the patient number and week of IVIG administration.

Figure 2

Direct effect of IVIG on the Id–anti-Id network and the level of pathogenic autoantibodies in 3 representative patients (patients 168 [A], 653 [B], and 467 [C]). Exogenous IVIG preparations (5.7 mg/ml) were added to serum that had been collected during pregnancy just prior to administration of IVIG treatments. Anti-Id activity (anti-cpep) was substantially increased, whereas Id activity (anti-pep) was not significantly affected. See Figure 1 for other definitions.