Adrian Y. S. Lee

CC Chemokine Ligand 20 and Its Cognate Receptor CCR6 in Mucosal T Cell Immunology and Inflammatory Bowel Disease: Odd Couple or Axis of Evil?

Chemokines and their cognate receptors have been identified as major factors initiating and governing cell movement and interaction. These ligands and their receptors are expressed on a wide variety of cells and act during steady-state migration as well as inflammatory recruitment. CCR6 is a non-promiscuous chemokine receptor that has only one known chemokine ligand, CCL20, and is present on B and T cells as well as dendritic cells (DCs). Two CD4+ T cell populations with opposing functions present in the intestines and the mesenteric lymph nodes express CCR6: the pro-inflammatory TH17 and regulatory Treg cells. CCL20 is also present in the intestine and is strongly up-regulated after an inflammatory stimulus. Interestingly, this ligand is also expressed by TH17 cells, which opens up the possibility of autocrine/paracrine signaling and, consequently, a self-perpetuating cycle of recruitment, thereby promoting inflammation. Recently, CCR6 has been implicated in inflammatory bowel disease (IBD) by genome wide association studies which showed an association between SNPs in the genomic region of the CCR6 gene and the inflammation. Furthermore, recent research targeting the biological function of CCR6 indicates a significant role for this chemokine receptor in the development of chronic IBD. It is therefore possible that IBD is facilitated by a disordered regulation of TH17 and Treg cells due to a disruption in the CCL20-CCR6 axis and consequently disturbed mucosal homeostasis. This review will summarize the literature on CCL20-CCR6 in mucosal immunology and will analyze the role this receptor-ligand axis has in chronic IBD.

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

BackgroundKnowledge 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.MethodsTo 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.ResultsA 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.ConclusionsThis 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.

Parafibromin expression in breast cancer: a novel marker for prognostication?

Background: Parafibromin is a novel protein product of HRPT2, a recently identified tumour suppressor gene. Mutations of the HRPT2 gene are common in parathyroid carcinomas, and these exhibit reduced protein expression. Parafibromin expression in breast cancer has not been previously studied. Aims: To determine the distribution of parafibromin in breast cancer tissues, and correlate its expression with conventional pathological parameters. Methods: Tissue microarrays were constructed from archival paraffin embedded breast cancer samples. Sections cut from tissue microarray blocks were subjected to immunohistochemistry. Immunopositivity for parafibromin and intensity-percentage scores were derived by blinded evaluation. Findings were correlated with clinicopathological parameters. Results: 163 breast cancers were assessed. Larger tumours were less likely to express parafibromin than smaller ones, with the association approaching statistical significance (p = 0.05). Staining intensity correlated inversely with tumour size (p = 0.016) and pathological stage (p = 0.008); as did parafibromin intensity-percentage score with pathological stage (p = 0.03), lymphovascular invasion (p = 0.03) and cerbB2 intensity-percentage score (p = 0.04). Conclusion: Parafibromin in breast cancer, as in parathyroid tumours, appears to have tumour suppressor functions, with loss of protein expression associated with adverse pathological parameters. These findings may indicate a potential role of parafibromin as a prognostic marker in breast cancer.

Effect of Neuraminidase on the Phagocytosis of Heterologous Red Cells by Mouse Peritoneal Macrophages

Summary The degree of ingestion of opsonized heterologous red cells by mouse peritoneal macrophages was greatly increased if the red cells were treated with neuraminidase before opsonization. An opsonin specific for the enzyme-treated red cells was shown to be present in normal mouse serum.

CCR6 and CCL20: emerging players in the pathogenesis of rheumatoid arthritis.

The therapeutic targeting of pro‐inflammatory TNF with neutralising biological anti‐TNF agents, often in combination with other disease‐modifying anti‐rheumatic drugs, such as the purine synthesis inhibitor methotrexate has been the first major break‐through in the treatment of chronic inflammatory diseases in decades. There are however, side effects and disadvantages of these treatments, such as general immunosuppression as well as therapy resistance in a large proportion of patients. This evokes the wish for other, more specialised forms of treatments. The targeting of chemokines and their receptors to disrupt cell movement specifically has been seen as a promising avenue of therapy for a considerable time. We will discuss one particular chemokine and its receptor, the C‐C chemokine ligand CCL20 and the C‐C chemokine receptor CCR6, and summarise its genetic and biological role in rheumatoid arthritis (RA). CCR6 has been associated with RA in genome‐wide association studies and has been shown to be an interesting candidate for a therapeutic approach, considering its and CCL20s expression patterns within the tissue as well as the immune system.

The relationship between CCR6 and its binding partners: Does the CCR6-CCL20 axis have to be extended?

Chemokines and their receptors are vital for the trafficking of immune cells. In an orchestrated fashion, up- and down-regulation of chemokines and their receptors contribute to both immune system homeostasis as well as inflammation. The CC chemokine, CCL20 and its cognate receptor, CCR6, are described as one of the few chemokine-receptor pairs that show exclusivity. In our review, we analyze observations which indicate that CCR6 does not have CCL20 as an exclusive ligand as once appreciated. For example, attempts to study the pair, utilizing mainly CCR6-deficient mice, are confounded by a family of non-chemokine ligands known as β-defensins that can bind to CCR6 and potentially can activate the cell. Therefore, a review of the activities of other potential binding partners of CCR6 is essential for interpretation of the current literature on this matter and for an understanding of their involvement in basic immunology and pathology.

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.

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.

CCR6/CCL20 chemokine axis in human immunodeficiency virus immunity and pathogenesis

Recent studies in human immunodeficiency virus (HIV) have garnered interest for the role of CC chemokine receptor 6 (CCR6) and its known ligands, CC chemokine ligand 20 (CCL20) and human β-defensins, in viral entry, dissemination and antiviral immunity. Several studies have suggested that CCR6 may also act as a weak co-receptor of HIV entry, in addition to the canonical CXC chemokine receptor 4 (CXCR4) and CCR5. However, the pathogenic significance has yet to be demonstrated as the observations for preferential infection of CD4+CCR6+ over CD4+CCR6- T cells appear to be independent of CCR6 expression. This indicates means for preferential infection other than CCR6 co-receptor use. Attention has also turned to the inadvertent role of the CCR6/CCL20 axis in attracting key immune cells, including TH17 cells and dendritic cells, to sites of infection and propagating the virus to other sites of the body. This review article will summarize the latest evidence that the CCR6/CCL20 chemokine axis is playing an important role in HIV pathogenesis and immunity. Further work with in vivo studies is needed to establish the biological and, hence, therapeutic significance of these findings.

A review of the role and clinical utility of anti-Ro52/TRIM21 in systemic autoimmunity

Anti-Ro52/tripartite motif-containing 21 (TRIM21) is a ubiquitous antibody found in a number of systemic autoimmune conditions including Sjögren’s syndrome, systemic lupus erythematosus and systemic sclerosis, appearing in about half of these patients. Once coupled with its closely related antibody, anti-Ro60 as the anti-SSA antibody, anti-Ro52 is emerging as a unique antibody with direct pathogenic disease involvement and distinct clinical properties. As a result, recent attention has turned to this antibody and its clinical associations and utility. There is a suggestion of anti-Ro52 being associated with more clinical and laboratory markers of disease; however, marked disagreements occur about its association with various clinical entities such as interstitial lung disease and Raynaud’s phenomena. Nevertheless, with a relative paucity of studies about these across the systemic autoimmunity paradigm, limited confidence can be invested in these conclusions. Although the antibody holds great potential as a biomarker, further studies examining its clinical utility are needed. This paper will review the mechanisms of Ro52 as an autoantigen and the clinical associations of anti-Ro52 in human autoimmunity.