Type I IFNs play an important, yet poorly characterized, role in systemic lupus erythematosus. To better understand the interplay between type I IFNs and the activation of autoreactive B cells, we evaluated the effect of type I IFN receptor (IFNAR) deficiency in murine B cell responses to common TLR ligands. In comparison to wild-type B cells, TLR7-stimulated IFNAR−/− B cells proliferated significantly less well and did not up-regulate costimulatory molecules. By contrast, IFNAR1−/− B cells did not produce cytokines, but did proliferate and up-regulate activation markers in response to other TLR ligands. These defects were not due to a difference in the distribution of B cell populations or a failure to produce a soluble factor other than a type I IFN. Instead, the compromised response pattern reflected the disruption of an IFN-β feedback loop and constitutively low expression of TLR7 in the IFNAR1−/− B cells. These results highlight subtle differences in the IFN dependence of TLR7 responses compared with other TLR-mediated B cell responses.

We have previously shown that rheumatoid factors produced by Fas-deficient autoimmune-prone mice typically bind autologous IgG2a with remarkably low affinity. Nevertheless, B cells representative of this rheumatoid factor population proliferate vigorously in response to IgG2a/chromatin immune complexes through a mechanism dependent on the sequential engagement of the BCR and TLR9. To more precisely address the role of both receptors in this response, we analyzed the signaling pathways activated in AM14 B cells stimulated with these complexes. We found that the BCR not only serves to direct the chromatin complex to an internal compartment where it can engage TLR9 but also transmits a suboptimal signal that in combination with the signals emanating from TLR9 leads to NF-κB activation and proliferation. Importantly, engagement of both receptors leads to the up-regulation of a group of gene products, not induced by the BCR or TLR9 alone, that include IL-2. These data indicate that autoreactive B cells, stimulated by a combination of BCR and TLR9 ligands, acquire functional properties that may contribute to the activation of additional cells involved in the autoimmune disease process.

No abstract

The three appellants and Betts (along with others) were Aboriginals and had spent 12 December 2012 together consuming alcohol in Presley's premises on Hayles Road in Australia. At approximately 23:00, Betts and Presley left the premises to obtain marijuana, and on their way back to the premises, Betts urinated against a residential property in Grant Street. The deceased, Clifford Hall, was a resident of Grant Street and criticised their behaviour, along with the support of another neighbour, Wayne King. There was an exchange of words between the four men, in which racial slurs were made by the deceased, and the facts at this point become unclear: Betts or Presley was pushed by either Hall or King, and Betts was punched in the face. Upon returning to Presley's premises, Betts informed the remaining two parties of the altercation, and Presley took hold of a baseball bat, suggesting that they should all go back to the scene of the incident. The four men left the premises, Presley armed with a baseball bat and Betts with a knife. A key issue at the original trial was whether the prosecution had established that the appellants knew that Betts was carrying a knife. The appellants, Betts and potentially others, made their way back to Grant Street, where some neighbours, including Hall and King, had gathered. One of the Aboriginal men, who the prosecution alleged to be Smith, was carrying a shovel. Wayne King was struck from behind. He testified that he turned and saw Presley and Betts, each of whom struck him with an object. Witnesses also saw King being kicked and hit by two men while he was lying on the floor. One of these men, Betts, was identified as having a tattoo of a crucifix on his face. Clifford Hall was struck with a shovel, causing him to fall to the ground, where a witness saw him being kicked in the jaw, as well as seeing a hand coming at him and hitting him in the back. The prosecution alleged this to be the fatal knife attack delivered by Betts. As the deceased lay on the ground, he was subject to repeated blows from several Aboriginal men, one of whom was armed with a shovel, and the deceased sustained a scalping wound, consistent with the use of such an object. The appellants subsequently returned to the premises on Hayles Road. Gary Willis, who had been drinking with the appellants and Betts earlier that day, recalled someone saying that a fight had broken out and recalled Betts stating that he thought he had stabbed someone. Presley was seen by a police officer at the Hayles Road premises at approximately 23:30, pacing in an agitated manner. He was subsequently arrested at 00:25 on the 13th December. Betts and Miller were arrested at different premises at 01:52, and Smith was arrested after being found asleep in a car at 05:15. While all the appellants declined to give evidence at the original trial, during his police interview, Betts confessed to stabbing the deceased but claimed to have acted in self-defence. Betts located the knife for the police and a shovel was also seized, both of which contain...