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.

Conventional and intravenous immunoglobulin therapy in paediatric antiphospholipid antibodies-related chorea

“…29 These data suggest that IVIG treatment is beneficial and useful in paediatric aPL-related chorea, and it should be considered as a treatment option in children who do not respond to conventional treatment. Moreover, IVIG could be important not only for the clinical effect but also to prevent prothrombotic disease in APS.…”

Pregnancy implications for systemic lupus erythematosus and the antiphospholipid syndrome

“…However, two multicenter prospective studies failed to find any benefit from the infusion of low dose IVIG as prophylactic therapy for the recurrence of CHB in high risks mothers [51,52]. A reason for this failure could be a high idiotype: antiidiotype antibody ratio in both the IVIG preparation and the maternal serum [53]. Plasmaphaeresis, as an alternative method for lowering or eliminating maternal autoantibodies, was proposed but did not result in a lower incidence of cardiac NL [54].…”

Mechanisms of Immunological Tolerance Disruption

“…Некоторые авторы связывают нарушение супрессорной функции Treg-кле-ток с IL-2, который необходим для дифферен- . В ряде работ на мышиных мо-делях было продемонстрировано, что дефицит IL-2, IL-2Ra или IL-2Rβ приводит к формирова-a или IL-2Rβ приводит к формирова-или IL-2Rβ приводит к формирова-нию аутоиммунной патологии [Bettini, Vignali, 2009;Russell et al, 2012;Garg et al, 2012] [Malek, Castro, 2010]. Так, в ис-Treg-клеток [Malek, Castro, 2010].…”