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Mucosal B cells and their function
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Jo Spencer, Edward N. Janoff, Per Brandtzaeg
Migration to different anatomical destinations is a feature of mucosal B-cell responses, allowing cells to migrate or home from local inductive to appropriate effector sites. The ability of the GALT-derived B cells in blood to home via the lymphatics to the intestinal lamina propria is imprinted on B cells through binding of the vitamin A derivative retinoic acid to the B-cell retinoic acid receptor (RAR). Retinoic acid is generated by dendritic cells and macrophages exposed to pathogen-associated molecular patterns from the intestinal lumen via the activity of induced retinal dehydrogenase 1 (RALDH1). RAR activation upregulates the expression of the integrin α4β7 that mediates lymphocyte homing to the gut lamina propria by specific binding to its ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1), constitutively expressed by mucosal postcapillary endothelial cells. Binding of retinoic acid to B-cell RAR also results in the induction of chemokine receptor CCR9 which mediates preferential homing and retention in the small intestinal mucosa, because epithelial cells produce the CCR9 ligand CCL25. Migration of plasma cells to different destinations involves complex combinations of chemokines and their receptors to guide the plasmablasts to the effector sites. For example, B-cell migration to the colon is favored by the expression of CCR10 on B cells controlled by the production by colonic epithelium of CCL28 but is also dependent on high expression of the homing receptor α4β7 to bind to colonic endothelial MAdCAM-1 to gain entry. These motifs allow plasmablasts to migrate to the colonic microenvironment.
Molecular Mimicry between Betaine Aldehyde Dehydrogenase of Leptospira and Retinal Dehydrogenase 1 of Human Lens: A Potential Trigger for Cataract Formation in Leptospiral Uveitis Patients
Published in Ocular Immunology and Inflammation, 2021
Sivakumar Rathinam, Irene Daniel, Dharmalingam Kuppamuthu, Jeya Maheshwari Jayapal
One of the cross-reacting proteins, retinal dehydrogenase 1, is homologous to a leptospiral protein. Human retinal dehydrogenase 1 protein sequence shared ~50–58% similarity with betaine aldehyde dehydrogenase protein from many Leptospira species/serovars. This suggests that antibodies that cross-reacted with retinal dehydrogenase 1 might be specific to leptospiral infection. Lens retinal dehydrogenase 1 is an important defense enzyme that detoxifies endogenous as well as exogenous lipid derived aldehydes such as 4-hydroxynonenal and malonaldehyde generated due to oxidative stress.13 Retinal dehydrogenase 1 has been shown to play a critical role in protection against oxidative stress-induced cytotoxicity in human lens epithelial cells, and in addition, inhibition of retinal dehydrogenase accelerates opacification in rat lens.14 Retinal dehydrogenase 1 transgenic knockout mice also develop lens opacities later on in life.15 All these reports show that inhibition of the function of this protein can compromise lens transparency.
Quasidominance in autosomal recessive RDH12-Leber congenital amaurosis
Published in Ophthalmic Genetics, 2020
Ruben Jauregui, Ahra Cho, Christine L. Xu, Akemi J. Tanaka, Janet R. Sparrow, Stephen H. Tsang
The gene retinol dehydrogenase 12 (RDH12) encodes for a protein that is a member of the family of retinol dehydrogenases that localize to the inner segments of the rod and cone photoreceptors (5). Proposed roles for the protein RDH12 include the conversion of all-trans retinal (vitamin A) to all-trans retinol during the regeneration of photopigment and protection of the retina from excessive all-trans retinal accumulation (5,6). A study in 2004 described RDH12 as encoding a non-redundant retinal dehydrogenase, whose loss of function leads to childhood-onset severe retinal dystrophy; this contrasts to the mild visual impairment that patients with pathogenic variants in RDH5 present with, causing the disease fundus albipunctatus (7). Pathogenic variants in RDH12 are estimated to cause 2.7–10% of LCA/EOSRD cases (1,8).
Tripterine and all-trans retinoic acid (ATRA) – loaded lipid-polymer hybrid nanoparticles for synergistic anti-arthritic therapy against inflammatory arthritis
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2021
Jichao Li, Zeng Zhang, Xiaohan Huang
Anti-inflammatory effect of individual ATRA and TRI and nanoparticles-based ATLP were examined (Figure 4(a–c)). To this end, RAW264.7 cells were activated with LPS and then treated with respective formulations. The treatment with LPS significantly increased the expression of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β). As expected, treatment of TRI and ATRA significantly decreased the expression of all three tested pro-inflammatory cytokines. Both TRI and ATRA showed strong inhibitory effects on the expressions of TNF-α, IL-6 and IL-1β. ATLP exhibited the strongest inhibitory effects than that of free TRI or ATRA implying the synergistic effect of dual components in the lipid-polymer hybrid nanoparticles. It has been reported that TRI controls the inflammation via the regulation of NF-κB, JAK/STAT, and PI3K/AKT pathways [43,44]. Whereas, ATRA has shown anti-inflammatory responses in several autoimmune disorders such as RA. ATRA is oxidized into retinoic acid by retinal dehydrogenase. The biological function of retinoic acid is mediated by nuclear receptors RARs and RXRs. Consistent with this published information, we have observed in our study that ATRA could potentially inhibit the expression of pro-inflammatory cytokines contributing to the anti-arthritic effect [45]. The combination of ATRA with TRI produced a strongest anti-inflammatory effect in the LPS-stimulated RAW264.7 cells. It is possible that co-loading of the two therapeutics in a lipid-polymer hybrid nanoparticles that would allow a controlled and pH-responsive release of drugs could contribute to the synergistic anti-inflammatory effect [46].