Comment on Astermark et al, page 3167
Astermark and colleagues present data that represent a new avenue of investigation to understand the pathogenesis of inhibitor development in patients with hemophilia.
Since the advent of pathogen-safe clotting factor replacement therapy, the development of neutralizing alloantibodies (inhibitors) to the genetically deficient clotting factor (VIII of IX) has become the most significant therapeutic complication in hemophilia.FIG1
It is scarcely surprising that a person who is deficient in a circulating protein and who has an intact immune system would make an alloantibody against that protein after multiple immunologic challenges (in this case, by direct intravascular inoculation). What is less clear is why all hemophilic individuals deficient in the protein (factor VIII or IX) do not.1 The intricacies of an individual host handling of infused proteins that were absent during the original recognition repertoire of “self” are clearly complex. Influences may include (but not be limited to) host immunologic genotype, quantitative and frequency effects of protein exposure, concurrent immune stimuli, and the primary mutation creating the protein deficiency. Certainly, in the case of hemophilia, it is apparent that the genetic mutation in the factor VIII gene is highly influential in determining individual risk for inhibitor development,2 with large deletions conferring the greatest likelihood.3 Discordancy in inhibitor development among hemophilic siblings (even monozygotic twins) indicates that genotype alone is not decidedly predictive. Other host risk factors such as HLA appear to influence predilection slightly. Epidemiologic data suggest that concurrent immune activation during antigen presentation (eg, factor VIII infusion in the context of bacteremia) may exacerbate risk, perhaps by augmenting proinflammatory cytokine expression in proximity to antigen presentation (see the figure).
In this issue, Astermark and colleagues offer the first genomic data to indicate that a specific polymorphism for variability in cytokine expression (IL10; specifically a 134-bp variant of a CA microsatellite in the promoter region) appears to influence propensity for inhibitor development. The authors analyzed genotype and phenotype data from a carefully constructed multicenter cohort of brothers with hemophilia A. This Malmö International Brother Study (MIBS) cohort consists of 78 unrelated pedigrees from which 164 individuals were available for study. Each brother pair or set (3 or more siblings) was characterized for its family-specific FVIII gene mutation, and comparisons were stratified for the common mutations (eg, the intron 22 inversion that accounts for 40% of all severe hemophilia A). The candidate genes chosen for their potential for influencing inhibitor development were cytokines that were known from other disease cohorts to be associated with autoantibody production: specifically known polymorphisms for the agonists IL-α, IL-β, the receptor IL-1Ra, and cytokines regulatory for antibody production (IL-4 and IL-10). Only the IL-10 polymorphism conferred a statistically significant enhancement of inhibitor risk among these cytokines in this cohort.
The evolution toward a clearer understanding of why morbid neutralizing anti–factor VIII antibodies develop requires a scrupulous examination of all identifiable influences on the host immune system. It has been demonstrated that individuals with hemophilia and those with normal factor VIII genes produce both nonneutralizing factor VIII antibodies and anti-idiotypic anti-FVIII antibodies.4 Therefore, deciphering the individualized and unique genetic (and likely, environmental as well) risk factors for antibodies that preclude protein replacement therapy will require concerted, multifactorial investigations. The outcome of these efforts, of which the study by Astermark et al represents a significant milestone, will ultimately determine whether we can predict individual risk for inhibitor development in hemophilia and create strategies to pre-empt this significant morbidity. ▪