Highlight of 2023: CAR T cells driving precision therapy for autoimmune disease.

CAR T cell therapy is showing remarkable results in autoimmune disease with treatment-refractory patients showing durable drug-free remission. Here, we highlight five key papers from 2023 that are driving the development of CAR T cells to improve precision, safety, efficacy and accessibility for the treatment of autoantibody-associated autoimmune diseases.

Fostering pathology as a medical discipline among medical students and graduates.

Dwindling interest in pathology as a career is a notable concern among medical students and graduates. Proposed reasons include the lack of exposure during their medical education and the unfavourable view of the discipline. This article discusses the barriers for adoption of pathology as a career and strategies to overcome this.

CC chemokine receptor 6 (CCR6) in the pathogenesis of systemic lupus erythematosus.

The CC chemokine receptor 6 (CCR6) and its sole chemokine ligand, CCL20, are an intriguing pair that have been implicated in a growing number of inflammatory, autoimmune and malignant disease processes. Recent observations have also highlighted this chemokine axis in the regulation of humoral immune responses. Through this review article, we explore the emerging links of CCR6-CCL20 with an archetypal autoimmune disease of humoral dysregulation: systemic lupus erythematosus (SLE). CCR6 is expressed prominently on several immune cells involved in the pathogenesis of SLE, such as dendritic cells and T-helper 17 cells. CCR6's expression is correlated with disease activity and serological markers of disease severity, suggesting a possible role in disease pathogenesis. However, there are numerous holes in our understanding of the functions of CCR6 and CCL20, and future studies are required to determine if there are any diagnostic, prognostic or monitoring roles for these important molecules.

Haematopoietic stem cell transplantation for severe combined immunodeficiency: Long-term health outcomes and patient perspectives.

AIM: To examine the long-term follow-up and health outcomes of patients who have undergone haematopoietic stem cell transplant (HSCT) for severe combined immunodeficiency (SCID). METHODS: Through a structured questionnaire, we examined follow-up arrangements and long-term health outcomes in 22 children who have had a successful HSCT for SCID during the period of 1984-2012 at the Sydney Children's Hospital, Sydney, Australia. RESULTS: Most children considered themselves healthy and 'cured' from SCID. Whilst many children enjoy relatively good bio-social health outcomes, specific negative health outcomes and absenteeism from school were perceived negatively. Two-thirds of children see their general practitioner or specialist regularly; however, there did not appear to be consistency with the nature of this follow-up. CONCLUSION: The findings from our study highlight the complex bio-psychosocial health needs of post-HSCT SCID children and encourage SCID centres to consider a multidisciplinary approach to their follow-up. Further studies into the determinants of patients' perceptions of their health are needed.

Early CCR6 expression on B cells modulates germinal centre kinetics and efficient antibody responses.

The CC-chemokine receptor 6 (CCR6) can be detected on naive and activated B cells. Counterintuitively, its absence accelerates the appearance of germinal centres (GCs) and increases the production of low-affinity antibodies. The detailed mechanism of CCR6 function during the humoral response has remained elusive, but previously we identified a distinct CCR6high B-cell population in vivo early after antigenic challenge. In this study, we defined this population specifically as early, activated pre-GC B cells. In accordance, we show that CCR6 is upregulated rapidly within hours on the protein or mRNA level after activation in vitro. In addition, only activated B cells migrated specifically towards CCL20, the specific ligand for CCR6. Lack of CCR6 increased the dark zone/light zone ratio of GC and led to decreased antigen-specific IgG1 and IgG2a antibody generation in a B-cell intrinsic manner in mixed bone marrow chimeras. In contrast, antigen-specific IgM responses were normal. Hence, CCR6 negatively regulates entry of activated, antigen-specific pre-GC B cells into the GC reaction.

Evaluating for immunodeficiency in children with recurrent infection.

BACKGROUND: Children have infections more frequently than adults. It may, therefore, be difficult to identify the rare child with immunodeficiency among the many who have recurrent infections but who have a normal immune system. OBJECTIVE: The focus of this article will be on differentiating normal children from those with childhood primary immunodeficiency, through thorough clinical evaluation, and outlining some of the more important immunodeficiency diagnoses. DISCUSSION: When investigating for immunodeficiency, the best available diagnostic tool is a thoughtful clinician with a good working knowledge of what is normal in terms of frequency and severity of childhood infection.

Emerging correlations between measures of population well-being, suicide and homicide: a look at global and Australian data.

OBJECTIVE: Our aim was (1) to examine global and Australian data with a view to determining the presence of an inverse relationship between suicide and homicide rates, and (2) to examine global Human Development Index (HDI) values and suicide and homicide rates, with a view to determining any statistical relationship. METHOD: Suicide and homicide rates and HDI values were available for 102 countries, and suicide and homicide rates were available for the states and territories of Australia. The three data sets had non-normal distributions, and the non-parametric Spearman's ρ was used for correlation statistics with α = 0.05. RESULTS: We found a weak, statistically significant inverse relationship between the suicide and homicide rates of 102 countries (ρ = -0.244, p = 0.014). No relationship was established for the Australian values, however. As anticipated, we found a significant negative correlation between homicide and HDI values. We unexpectedly demonstrated a positive correlation between suicide rates and HDI values. CONCLUSION: The notion that suicide and homicide have an inverse relationship now has some scientific support; but additional research is warranted to characterise and explain this relationship. The unexpected finding of a positive correlation between suicide rates and HDI values requires further examination.

Retention of knowledge and perceived relevance of basic sciences in an integrated case-based learning (CBL) curriculum.

BACKGROUND: Knowledge and understanding of basic biomedical sciences remain essential to medical practice, particularly when faced with the continual advancement of diagnostic and therapeutic modalities. Evidence suggests, however, that retention tends to atrophy across the span of an average medical course and into the early postgraduate years, as preoccupation with clinical medicine predominates. We postulated that perceived relevance demonstrated through applicability to clinical situations may assist in retention of basic science knowledge. METHODS: To test this hypothesis in our own medical student cohort, we administered a paper-based 50 MCQ assessment to a sample of students from Years 2 through 5. Covariates pertaining to demographics, prior educational experience, and the perceived clinical relevance of each question were also collected. RESULTS: A total of 232 students (Years 2-5, response rate 50%) undertook the assessment task. This sample had comparable demographic and performance characteristics to the whole medical school cohort. In general, discipline-specific and overall scores were better for students in the latter years of the course compared to those in Year 2; male students and domestic students tended to perform better than their respective counterparts in certain disciplines. In the clinical years, perceived clinical relevance was significantly and positively correlated with item performance. CONCLUSIONS: This study suggests that perceived clinical relevance is a contributing factor to the retention of basic science knowledge and behoves curriculum planners to make clinical relevance a more explicit component of applied science teaching throughout the medical course.