Identification of Bphs, an autoimmune disease locus, as histamine receptor H₁

Bphs controls Bordetella pertussis toxin (PTX)-induced vasoactive amine sensitization elicited by histamine (VAASH) and has an established role in autoimmunity. We report that congenic mapping links Bphs to the histamine H₁ receptor gene (Hrh1/H1R) and that H1R differs at three amino acid residues in VAASH-susceptible and -resistant mice. Hrh1^-/- mice are protected from VAASH, which can be restored by genetic complementation with a susceptible Bphs/Hrh1 allele, and experimental allergic encephalomyelitis and autoimmune orchitis due to immune deviation. Thus, natural alleles of Hrh1 control both the autoimmune T cell and vascular responses regulated by histamine after PTX sensitization.