Submitted March 25, 2004
Accepted September 13, 2004
Mapping of Genes that Control the Antibody Response to Human Factor IX in Mice
Jay N Lozier*, Nahid Tayebi, and Pei Zhang
FDA Center for Biologics Evaluation and Research, Bethesda, MD, USA
* Corresponding author; email: lozier{at}cber.fda.gov.
We tested the hypothesis that the antibody response to human factor IX in mice is controlled by genetic factors, especially histocompatibility antigens. Seven inbred mouse strains were immunized against human factor IX by adenoviral gene transfer or serial injections of human factor IX protein. A/J mice had the highest antibody response and two C57 mouse strains had the lowest response. We used the adenovirus vector to immunize 26 recombinant inbred mouse strains (AXB and BXA) derived from A/J and C57BL/6J mice and observed highly significant linkage (LOD scores ~4.8) for the polymorphic D17Mit62 marker that is 1 centimorgan (~300,000 base pairs) from the mouse MHC locus (H-2). Experiments in mice with chimeric major histocompatibility complex genes indicated that class IaK and/or class II H-2 genes were critical, but other gene(s) contributed to the antibody response. Polymorphic markers from chromosomes 1 and 10 that are near important immunoregulatory genes such as IL-10 and the interferon-
gene show suggestive linkage (LOD scores of ~2.3-2.6) to the factor IX antibody response. This study confirms the hypothesis that H-2 (and other) genes control factor IX antibody development in mice and suggests their potential importance for factor IX antibody development in humans with hemophilia B.
