Magrita Prinslo (1896), Magdalena Retief (1938) and Mies Julie (2012): from historical Afrikaner Mothers of the Nation to a modern Afrikanermeisie (girl): a postcolonial reading of Farber’s Mies Julie

Afrikaans and Theory of Literatur

B-cell cross-presentation of autologous antigen precipitates diabetes

For autoimmune conditions like type 1 diabetes to progress, self-reactive CD8⁺ T cells would need to interact with peptide-antigen cross-presented on the surface of antigen-presenting cells in a major histocompatibility complex (MHC) class I-restricted fashion. However, the mechanisms by which autoantigen is cross-presented remain to be identified. In this study, we show cross-presentation of islet-derived autoantigens by B cells. B cells engage self-reactive CD8⁺ T cells in the pancreatic lymph node, driving their proliferative expansion and differentiation into granzyme B⁺interferon-γ⁺lysosomal-associated membrane protein 1⁺ effector cells. B-cell cross-presentation of insulin required proteolytic cleavage and endosomal localization and was sensitive to inhibitors of protein trafficking. Absent B-cell MHC class I, or B-cell receptor restriction to an irrelevant specificity, blunted the expansion of self-reactive CD8⁺ T cells, suggesting B-cell antigen capture and presentation are critical in vivo events for CD8 activation. Indeed, the singular loss of B-cell MHC class I subverted the conversion to clinical diabetes in NOD mice, despite the presence of a pool of activated, and B cell-dependent, interleukin-21-expressing Vβ4⁺CD4⁺ T cells. Thus, B cells govern the transition from clinically silent insulitis to frank diabetes by cross-presenting autoantigen to self-reactive CD8⁺ T cells.Eliana Mariño, Bernice Tan, Lauren Binge, Charles R. Mackay and Shane T. Gre

G protein-coupled receptor 43 modulates neutrophil recruitment during acute inflammation

Fermentation of dietary fibre in the gut yields large amounts of short chain fatty acids (SCFAs). SCFAs can impart biological responses in cells through their engagement of 'metabolite-sensing' G protein-coupled receptors (GPCRs). One of the main SCFA receptors, GPR43, is highly expressed by neutrophils, which suggests that the actions of GPR43 and dietary fibre intake may affect neutrophil recruitment during inflammatory responses in vivo. Using intravital imaging of the small intestine, we found greater intravascular neutrophil rolling and adhesion in Gpr43-/-mice in response to LPS at 1 h. After 4 h of LPS challenge, the intravascular rolling velocity of GPR43-deficient neutrophils was reduced significantly and increased numbers of neutrophils were found in the lamina propria of Gpr43-/-mice. Additionally, GPR43-deficient leukocytes demonstrated exacerbated migration into the peritoneal cavity following fMLP challenge. The fMLP-induced neutrophil migration was significantly suppressed in wildtype mice that were treated with acetate, but not in Gpr43-/-mice, strongly suggesting a role for SCFAs in modulating neutrophil migration via GPR43. Indeed, neutrophils of no fibre-fed wildtype mice exhibited elevated migratory behaviour compared to normal chow-fed wildtype mice. Interestingly, this elevated migration could also be reproduced through simple transfer of a no fibre microbiota into germ-free mice, suggesting that the composition and function of microbiota stemming from a no fibre diet mediated the changes in neutrophil migration. Therefore, GPR43 and a microbiota composition that allows for SCFA production function to modulate neutrophil recruitment during inflammatory responses

Baseline parameters are comparable between wildtype and <i>Gpr43</i>^{<i>−/−</i>}mice.

<p>The number of circulating leukocytes (<b>A</b>) and neutrophils (<b>B</b>) in the peripheral blood of wildtype and <i>Gpr43</i>^{<i>−/−</i>}mice were quantitated. Bone marrow leukocytes (<b>C</b>) and neutrophils (<b>D</b>) isolated from wildtype and <i>Gpr43</i>^{<i>−/−</i>}mice were quantitated. N ≥ 8 per group. Baseline cell surface expression of L-selectin (<b>E</b>), and PMA-induced L-selectin shedding (<b>F</b>) and respiratory burst (<b>G</b>) was measured and compared between wildtype and <i>Gpr43</i>^{<i>−/−</i>}bone marrow neutrophils. N ≥ 4 mice per group or independent <i>in vitro</i> experiments performed in duplicates, N.S. denote not statistical significant, <i>t</i> test.</p

Acetate reduces neutrophil migration via a mechanism mediated by GPR43.

<p>The total number of leukocytes in the peritoneal cavity was quantified in wildtype and <i>Gpr43</i>^{<i>−/−</i>}mice at 24 h following sham or cecal ligation and puncture (CLP; (<b>A</b>)), or at 2 h after saline, fMLP or fMLP + acetate (<b>B</b>). The peritoneal neutrophil numbers of acetate-treated wildtype and <i>Gpr43</i>^{<i>−/−</i>}mice at 2 h after saline or fMLP treatment were also measured (<b>C</b>). N ≥ 3 mice per group, **<i>p</i> < 0.01, *<i>p</i> < 0.05 vs corresponding Sham or Saline group, <i>t</i> test. ##<i>p</i> < 0.01, #<i>p</i> < 0.05 vs treated Wildtype, <i>t</i> test. <i>&p <</i> 0.05 vs fMLP-treated Wildtype, <i>t</i> test. N.S denotes not statistically significant vs fMLP-treated <i>Gpr43</i>^{<i>−/−</i>}.</p

Exacerbated intestinal inflammation in <i>Gpr43</i>^{<i>−/−</i>}mice in response to LPS.

<p>(<b>A</b>) Representative histological images of jejunum of wildtype and <i>Gpr43</i>^{<i>−/−</i>}mice following 4 h of saline or LPS challenge. Neutrophils are denoted by the black arrowheads. Scale bar = 100 μm. (<b>B</b>) Histological quantification of neutrophils in the (<b>i</b>) duodenum, (<b>ii</b>) jejunum and (<b>iii</b>) ileum of wildtype and <i>Gpr43</i>^{<i>−/−</i>}mice following 4 h of saline or LPS challenge. N ≥ 5 mice per group, **<i>p</i> < 0.01, *<i>p</i> < 0.05 vs corresponding Saline group, <i>t</i> test. #<i>p</i> < 0.05 vs Wildtype, <i>t</i> test.</p

GPR43 deficiency induces migration, accelerated neutrophil rolling and adhesion following 1 h of LPS challenge.

<p>Neutrophils were isolated from the bone marrow of wildtype and <i>Gpr43</i>^{<i>−/−</i>}mice, and analysed for chemotaxis towards increasing concentration of CXCL1 (<b>A</b>) and LPS (<b>B</b>). N ≥ 4 independent <i>in vitro</i> experiments performed in duplicates, ***<i>p</i> < 0.001, *<i>p</i> < 0.05 vs Wildtype, 2-way ANOVA. Intravital microscopy was utilised to visualise and quantitate the number of intravascular neutrophils that were rolling (<b>C</b>) or adherent (<b>D</b>) following 1 h of saline or LPS challenge in wildtype and <i>Gpr43</i>^{<i>−/−</i>}mice. N ≥ 5 mice per group, ***<i>p</i> < 0.001, **<i>p</i> < 0.01 vs corresponding Saline group, <i>t</i> test. #<i>p</i> < 0.05 vs Wildtype, <i>t</i> test.</p