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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.

An important approach to understanding complex diseases is to reduce them into well-characterized subphenotypes that are under monogenic control. One such example is Bordetella pertussis toxin-induced histamine sensitization in mice, a subphenotype of experimental allergic encephalomyelitis and experimental allergic orchitis. This subphenotype is controlled by a single locus, Bphs, previously mapped to a 33 cM region on mouse Chromosome (Chr) 6. We achieved considerable reduction of this candidate region and constructed a YAC contig across the refined interval. Our results demonstrate that Bphs is located between D6Mit151 and a newly developed marker, EC108RR, a region containing a small cluster of genes belonging to the TNF receptor superfamily. Sequence and quantitative analysis of the candidate gene, tumor necrosis factor receptor 1 (Tnfr1, p55), indicates that it is unlikely to be Bphs. However, the location of Bphs, together with physiologic effects it shares with Tnfr1 activation, suggest that Bphs may prove to be another member of the TNF receptor superfamily.

The existence of immunoregulatory genes conferring dominant resistance to autoimmunity is well documented. In an effort to better understand the nature and mechanisms of action of these genes, we utilized the murine model of autoimmune orchitis as a prototype. When the orchitis-resistant strain DBA/2J is crossed with the orchitis-susceptible strain BALB/cByJ, the F1 hybrid is completely resistant to the disease. By using reciprocal radiation bone marrow chimeras, the functional component mediating this resistance was mapped to the bone marrow-derived compartment. Resistance is not a function of either low-dose irradiation- or cyclophosphamide (20 mg/kg)-sensitive immunoregulatory cells, but can be adoptively transferred by primed splenocytes. Genome exclusion mapping identified three loci controlling the resistant phenotype. Orch3 maps to chromosome 11, whereas Orch4 and Orch5 map to the telomeric and centromeric regions of chromosome 1, respectively. All three genes are linked to a number of immunologically relevant candidate loci. Most significant, however, is the linkage of Orch3 to Idd4 and Orch5 to Idd5, two susceptibility genes which play a role in autoimmune insulin-dependent type 1 diabetes mellitus in the nonobese diabetic mouse.

Experimental allergic orchitis (EAO) can be induced actively and passively in mice by either immunization with mouse testicular homogenate (MTH) in conjunction with the appropriate adjuvants or by transferring CD4+ T cells isolated from sensitized donors into non-immunized, naive recipients. The distribution of inflammatory lesions seen in active and passive EAO are markedly different. In active EAO maximal disease is observed in the seminiferous tubules, whereas in passive EAO lesions occur primarily in the straight tubules, rete testis, and ductus efferentes. These observations suggest that different immunopathogenic mechanisms and/or aspermatogenic autoantigens may be responsible for the distinct histopathologic profiles. Two murine testis-specific aspermatogenic autoantigens (mAP1 and mAP2) were partially purified from MT acetone powder by extraction in 7-M urea under reducing conditions, gel filtration, ion-exchange chromatography, and preparative isoelectric focusing from pH 3 to 10. In gel filtration on Sephacryl S-400 in 7-M urea, mAP1 is confined to the V0 peak, while mAP2 is in the major included peak. mAP1 has an isoelectric point of 4.4-4.9, is sensitive to both pronase and DNase but not RNase, and is active at a minimal dose of 250-500 micrograms (dry wt). Dose-response bioassays for active and passive EAO revealed that mAP1 preferentially elicits active disease, whereas mAP2 is most effective at eliciting passive disease. These results support the concept that the different histopathologic profiles seen in active and passive EAO are, in part, the result of different immunopathologic responses elicited by separate aspermatogenic autoantigens.

Experimental allergic orchitis is an organ-specific autoimmune disease characterized by inflammatory infiltrates associated with the seminiferous tubules of the testes. Orchitis is often, but not always, accompanied by aspermatogenesis in susceptible strains of mice. In this study, various strains of H-2 congenic mice were used to examine the relationship between orchitis and aspermatogenesis, and as a result, a genetic predisposition to spontaneous aspermatogenesis has been defined. A high correlation was seen between orchitis and aspermatogenesis in B10.D2/nSnJ mice, however, the two conditions were uncorrelated in C57BL/10J mice. Subsequent analysis of C57BL/10J congenic strains showed their aspermatogenesis to be spontaneous, rather than due to either testis-specific antigen or adjuvants. Further studies using other H-2 congenic strains revealed that the aspermatogenesis seen in C57BL/10J mice is linked to H-2 and influenced by C57BL/10J background genes. Finally, spontaneous aspermatogenesis was shown not to be a function of differences in the level of testicular testosterone.

Pertussis toxin (PTX) is the primary component responsible for eliciting the majority of biological activities associated with Bordetella pertussis, including the induction of several tissue-adjuvant models of organ-specific autoimmune disease. PTX, when administered in vivo, enhances vascular permeability, which is made manifest by a concomitant increase in sensitivity to a variety of agents and treatments affecting the vascular bed. One such agent is histamine, and the response to PTX, as measured by hypersensitivity following vasoactive amine challenge, is genetically controlled by the Bphs locus. Susceptibility to the induction of both experimental allergic encephalomyelitis (EAE) and experimental allergic orchitis (EAO) in mice is associated with, and in the latter case linked to, a susceptible allele at this locus. We report here the mapping of the Bphs locus to mouse chromosome 6, telomeric of Tcrb and centromeric of Prp (D6Nds8). This region also contains a number of loci of immunologic relevance including Igk, Ly-2, Ly-3, Il-5r, Ly-35, Ly-4, and Tnfr-2.