Identification of Bphs , an Autoimmune Disease Locus, as Histamine Receptor H ₁

Abstract

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.

Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis

“…The best approach to confirm and narrow these localizations will be the production of congenic and polycongenic inbred strains, as it has been successful in other infectious, viral and immunological disease models. [40][41][42] An alternative approach, which may allow the identification of the causative gene(s) in each interval, is the characterization of relevant candidate genes. Multiple Figure 5 Genome-wide scan of 123 (A/J Â B10.A-H2 a )F2 individuals with extreme phenotypes.…”

Aod1Controlling Day 3 Thymectomy-Induced Autoimmune Ovarian Dysgenesis in Mice Encompasses Two Linked Quantitative Trait Loci with Opposing Allelic Effects on Disease Susceptibility

“…With respect to other autoimmune disease QTL within the Aod1a region, eae11 (experimental allergic encephalomyelitis-11) (45) and Pgia10 (proteoglycan-induced arthritis-10) (46) at ϳ41.0 and ϳ57.0 cM, respectively, are worth noting in light of the recent validation of the shared autoimmune disease susceptibility gene hypothesis (35,36). Given the importance of cytokines and cytokine receptors in immunoregulation, two candidate genes of interest that reside within the Aod1a interval are Infar (IFN-␣ and -␤ receptors) at 64.0 cM and IL10rb (IL-10 receptor ␤) at 61 cM (http://www.informatics.jax.org/).…”

“…The hypothesis that QTL could affect more than one autoimmune disease was first proposed by this laboratory (35). This shared QTL hypothesis was recently validated by identifying histamine H 1 receptor as the autoimmune disease susceptibility locus, Bphs, which controls susceptibility to both experimental allergic encephalomyelitis and autoimmune orchitis (36).…”

Modulation of in vivo immunoglobulin production by endogenous histamine and H1R and H2R agonists and antagonists

“…Histamine regulates dendritic cells, T-lymphocytes, B-lymphocytes and related antibody isotype responses. Recently, accumulating evidence has highlighted the importance of histamine receptors in immunomodulation [3,6,8,13]. Histamine can modulate the immune response when it is released from mast cells and basophils during inflammatory reactions [3].…”

“…This has been observed in many pathological processes regulating several essential events in allergy and autoimmune diseases in experimental animals, especially in knock-out mice (either H1-or H2-deficient) [8,11,12]. However, studies evaluating the role of intact histamine receptors blocked by their respective agonists or antagonists and the resulting immunomodulatory profile over time are lacking in the existing literature.…”