Red blood cell (RBC) transfusions can result in alloimmunization toward RBC alloantigens that can increase the probability of complications following subsequent transfusion. An improved understanding of the immune mechanisms that underlie RBC alloimmunization is critical if future strategies capable of preventing or even reducing this process are to be realized. Using the HOD (hen egg lysozyme [HEL] and ovalbumin [OVA] fused with the human RBC antigen Duffy) model system, we aimed to identify initiating immune factors that may govern early anti-HOD alloantibody formation. Our findings demonstrate that HOD RBCs continuously localize to the marginal sinus following transfusion, where they colocalize with marginal zone (MZ) B cells. Depletion of MZ B cells inhibited immunoglobulin M (IgM) and IgG anti-HOD antibody formation, whereas CD4 T-cell depletion only prevented IgG anti-HOD antibody development. HOD-specific CD4 T cells displayed similar proliferation and activation following transfusion of HOD RBCs into wild-type or MZ B-cell–deficient recipients, suggesting that IgG formation is not dependent on MZ B-cell–mediated CD4 T-cell activation. Moreover, depletion of follicular B cells failed to substantially impact the anti-HOD antibody response, and no increase in antigen-specific germinal center B cells was detected following HOD RBC transfusion, suggesting that antibody formation is not dependent on the splenic follicle. Despite this, anti-HOD antibodies persisted for several months following HOD RBC transfusion. Overall, these data suggest that MZ B cells can initiate and then contribute to RBC alloantibody formation, highlighting a unique immune pathway that can be engaged following RBC transfusion.

Despite being the first genetic disease described, sickle cell disease (SCD) continues to result in severe complications. Of these complications, acute chest syndrome (ACS), a form of acute lung injury, leads all-cause mortality. However, the pathophysiology of ACS remains incompletely understood, resulting in patients with ACS receiving only supportive measures. Here, we found that ACS is accompanied by activation of the complement pathway, an evolutionarily ancient innate immune system responsible for eliminating microbes. Using a well-defined preclinical model of SCD, hemolysis, a precursor of ACS, not only induced ACS but also drove robust complement activation. Artificial activation of complement alone similarly induced ACS, whereas genetic removal or pharmacological inhibition of complement rendered SCD mice resistant to ACS even after induction of hemolysis. These results demonstrate that complement drives ACS, establishing a link between SCD and this ancient form of immunity that provides an opportunity for targeted treatment of this complication.

From 2010 to 2019, 40.5% fewer senior students from United States (US) allopathic medical schools pursued pathology in the Main Residency Match. To possibly explain this trend, we sought to identify major concerns about pathology which were made during this time. Because the Student Doctor Network (SDN) website is widely used by students at American medical schools during the residency application process, SDN has been shown to influence career decisions. So, the 50 all-time most-viewed SDN pathology threads (as of February 2018) were analyzed. The words "job" and "jobs" were used in the title of 11 of the 50 (22%) threads, which altogether received more than 400,000 views. However, the term "job(s)" was rarely used by 14 other major medical specialties. Seven of the 11 (63.6%) job-related threads were created from 2009 to 2011, corresponding with the start of the decline in medical students pursuing pathology residency. It was reasoned that job-market concerns within SDN threads may have discouraged students from pursuing pathology. To test this hypothesis, 5 pathology residents were asked to read all 11 threads and then complete a survey. Most thread reviewers agreed that commenters, which included medical students, were concerned about the pathology job-market and that medical students who viewed the threads would be less likely to pursue pathology residency. Because more than 85% of SDN users are from the US, the threads likely had a greater impact on American medical students compared to foreign students. In conclusion, job-market concerns over the past decade are so prominent in the SDN pathology forum that they likely contributed to fewer seniors from US allopathic medical schools pursuing pathology residency. As of 2019, there are 12 job-related threads among the 50 all-time most-viewed, including threads created in 2016 and 2017. To improve recruitment, the pathology community should carefully review and address concerns about employment opportunities. Due to conflicting reports, additional studies are needed to determine if a mismatch in workforce supply and demand warrants prompt and thoughtful intervention.