Unexpected development of autoimmunity in BAFF-R-mutant MRL-lpr mice.

BAFF-R is the predominant receptor that mediates B-cell activating factor (BAFF)-dependent B-cell signalling and plays a critical role in late-stage B-cell maturation and survival. BAFF has been implicated in the development of autoimmunity and systemic lupus erythematosus (SLE). To define the role of BAFF-R in autoimmunity and SLE, we crossed A/WySnJ mice with MRL-lpr mice and generated BAFF-R-mutant MRL-lpr mice. The BAFF-R mutation markedly impaired the development of immature, mature and marginal zone B cells in the spleens of MRL-lpr mice. Unexpectedly, the BAFF-R mutation in MRL-lpr mice did not result in decreased autoantibody production, hypergammaglobulinaemia or immune complex-mediated glomerulonephritis. Rather, the ability of BAFF-R-mutant lpr splenic B cells to produce immunoglobulins in vitro was not decreased, although germinal centre formation, antibody response and B-cell proliferation were impaired. Further studies found increased numbers of B cells in the bone marrow of BAFF-R-mutant MRL-lpr mice compared to the BAFF-R-intact lupus mice. ELISPOT analysis revealed that BAFF-R-mutant MRL-lpr mice had more antibody-secreting cells in their bone marrow than the control mice. Thus, these findings could explain the development of autoimmunity and hypergammaglobulinaemia observed in BAFF-R-mutant MRL-lpr mice.

Bradykinin B2 receptors mediate pulmonary sympathetic afferents induced reflexes in rabbits.

Endogenous bradykinin (BK) is an established mediator of pulmonary inflammation, yet its role in lung disease is unclear. In the rabbit, injecting BK into the lung parenchyma elicits reflex hyperpnea, tachypnea, hypotension, and bradycardia by stimulating pulmonary sympathetic afferents. To further explore bradykinin effects, breathing pattern (phrenic nerve and abdominal muscle activities) and hemodynamics (blood pressure and heart rate) were examined in anesthetized, open-chest, and mechanically ventilated rabbits. Three receptor agonists [bradykinin, selective B(1) (des-Arg(9)-BK), and selective B(2) (Tyr(8)-BK)], as well as three B(2) receptor antagonists, B6029 (N alpha-Adamantaneacetyl)-Bradykinin, B(1)650 (D-Arg-[Hyp(3), Thi(5,8), D-Phe(7)]-Bradykinin, or Hoe-140 (D-Arg-[Hyp(3), Thi(5), D-Tic(7), Oic(8)] bradykinin), were used to identify the responsible receptor subtype. In both intact and vagotomized rabbits, injecting BK or a selective B(2) agonist into the lung elicited similar cardiopulmonary responses. These reflex responses were greatly attenuated or blocked by pre-injecting B(2) antagonists into the right atrium or into the lung parenchyma. In contrast, the B(1) agonist elicited fewer cardiopulmonary effects in intact rabbits and had no effect in vagotomized rabbits. We conclude that BK stimulates pulmonary sympathetic afferents [Soukhova, G., Wang, Y., Ahmed, M., Walker, J., Yu, J., 2003. Bradykinin stimulates respiratory drive by activating pulmonary sympathetic afferents in the rabbit. J. Appl. Physiol. 95, 241-249.; Wang, Y., Soukhova, G., Proctor, M., Walker, J., Yu, J., 2003. Bradykinin causes hypotension by activating pulmonary sympathetic afferents in the rabbit. J. Appl. Physiol. 95, 233-240.], eliciting a characteristic cardiopulmonary reflex via B(2) receptors.

Endocarditis and hemorrhagic stroke caused by Cunninghamella bertholletiae infection after kidney transplantation.

Cunninghamella bertholletiae is a saprophytic fungus found in soil. Infection with this organism is extremely rare, occurring almost exclusively in immunosuppressed hosts. There have been only three previous cases of infection with this fungus reported in solid-organ recipients. We report an unusual case of disseminated Cunninghamella infection in a woman who had received a renal transplant. A 48-year-old woman received a living-related kidney transplant for focal segmental glomerulonephritis. She was treated with plasmapheresis and muromonab-CD3 (OKT3) for two episodes of rejection. Because of recurrent focal segmental glomerulonephritis with diuretic-resistant edema, she underwent transplant nephrectomy, was restarted on hemodialysis, and had her immunosuppression stopped. Shortly thereafter, the patient presented with pulmonary infiltrates and hemorrhagic stroke with a rapidly fatal course. Autopsy revealed widely disseminated C bertholletiae involving the central nervous system, lungs, and heart. This is the first reported case of endocarditis caused by this organism. Diagnosis of this fungal infection is often difficult. Because the few patients who have survived this infection seemed to have been diagnosed early, it is important for clinicians caring for transplant patients to be aware of this invasive infection. Successful treatment requires prompt diagnosis and high-dose amphotericin B.