Search

Soluble IgM forms a predominantly pentameric complex that also contains a small polypeptide J chain. While the IgM pentamer has various immune functions to defend against foreign pathogens, it also behaves as a carrier of the circulating apoptosis inhibitor of macrophage (AIM, also called CD5L). The binding to IgM pentamer protects AIM from renal excretion, leading to high serum AIM levels. When AIM dissociates from IgM, it becomes functionally active and facilitates the repair of a variety of diseases including acute kidney injury and hepatocellular carcinoma. Since the precise manner of AIM-IgM pentamer binding remains unknown, we examined the structure using a latest single-particle negative-stain electron microscopy. Surprisingly, the IgM pentamer shapes “one-piece missing” hexagon containing one large gap, which is markedly different from the textbook prediction of a symmetric pentagon model. A single AIM molecule stably fits into the gap, cross-bridging two IgM-Fc through a disulfide bond and a charge-based interaction. We also found that the association of AIM with IgM pentamer not only inactivates AIM but also progresses inflammatory immune-complex formation in certain autoimmune diseases such as IgA nephropathy. Thus, our current findings of the bona fide structure of the AIM/IgM pentamer complex provides an important insight into the releasing mechanism of AIM from IgM, which could be the basis for the development of new therapeutic strategies against multiple diseases, via the increase of active AIM as well as the disruption of immune-complex formation.

It has been of much interest whether there is functional redundancy between the constitutively signaling pre-Talpha/TCRbeta (pre-TCR) and ligated TCRalphabeta complexes, which independently operate the two distinct checkpoints during thymocyte development, i.e., the pre-TCR involved in beta-selection at the CD4(-)CD8(-) double-negative stage and the TCRalphabeta being crucial for positive/negative selection at the CD4(+)CD8(+) double-positive stage. We found that the pre-TCR expressed on double-positive cells in TCRalpha-deficient (TCRalpha(-/-)) mice produced a small number of mature CD8(+) T cells. Surprisingly, when pre-Talpha was overexpressed, resulting in augmentation of pre-TCR expression, there was a striking increase of the CD8(+) T cells. In addition, even in the absence of up-regulation of pre-TCR expression, a similar increase of CD8(+) T cells was also observed in TCRalpha(-/-) mice overexpressing Egr-1, which lowers the threshold of signal strength required for positive selection. In sharp contrast, the CD8(+) T cells drastically decreased in the absence of pre-Talpha on a TCRalpha(-/-) background. Thus, the pre-TCR appears to functionally promote positive selection of CD8(+) T cells. The biased production of CD8(+) T cells via the pre-TCR might also support the potential involvement of signal strength in CD4/CD8 lineage commitment.

Peptidylarginine deiminase 4 (PAD4) functions as a transcriptional co-reporessor by catalyzing the conversion of arginine to citrulline residues of histone H3. Although the high expression of PAD4 in the bone marrow may suggest its involvement in the hematopoiesis, its precise contribution remains unclear. Here we found that PAD4 is highly expressed in the hematopoietic stem and multipotent cells (Lineage-Sca1+c-kit+; termed LSK cells). Microarray and RT-qPCR analysis showed that the mRNA level of c-myc in PAD4-deficient (PADI4-/-) LSK cells was increased compared to PADI4+/+ LSK cells. Chromatin immunoprecipitation assay showed that in LSK cells, PAD4 targeted to the upstream of c-myc gene, suggesting that PAD4 might catalyze the citrullination and reduce the arginine methylation in histone H3. Furthermore, PAD4 was associated with the transcription factor LEF1 as well as histone deacetylase 1 (HDAC1). These results indicated that PAD4 suppressed c-Myc expression by histone citrullination acting as a suppressor complex with LEF1 and HDAC1 in LSK cells. Supporting these findings, PADI4-/- LSK cells showed an advanced proliferation in a cell-autonomous fashion, resulting in increase in number compared to PADI4+/+ LSK cells. Together, our results strongly suggest that PAD4 regulates the proliferation of LSK cells via controlling c-Myc expression, implying that PAD4 may be involved in pathogenesis of some myeloproliferative diseases.

AIM (apoptosis inhibitor of macrophage), a member of scavenger receptor cysteine-rich super family (SRCR-SF), is a secreted protein solely produced by tissue macrophages with a direct regulation by a nuclear receptor liver X receptor/ retinoid X receptor (LXR/RXR) heterodimers. AIM circulates in blood at the concentration of 10-100 μg/mL in human. We have reported that AIM is involved in the metabolic syndromes such as atherosclerosis and insulin resistance, mediated by its functions: inhibition of apoptosis in macrophages and induction of lipolysis in adipocytes, respectively. It has been well-known that AIM binds to IgM in blood. However, its physiological significance has not been yet elucidated. In this study, we found that AIM-IgM complex intensely reinforces the stability of AIM protein in blood, and in the meantime, AIM supports the function of IgM. The AIM-IgM interaction enables the maturation of immunity, transition from innate-like immunity mediated by IgM, to adaptive immunity brought about by IgG. These new observations suggest that the modern life style, such as a continuous high-fat diet, may result in an excessive increase of AIM in blood, and appears to affect not only innate-like but also adaptive immunity by supporting the function of IgM. This may cause various disorders based on chronic inflammation including metabolic and autoimmune diseases.