Post by Max on Jul 19, 2005 8:55:27 GMT -5
Lack of primary IgE response and elevated and sustained secondary IgE responses in subjects exposed to (Ro)accutane
Repeated studies, in both mice and human subjects show the lack of a primary IgE response with elevated and sustained secondary IgE responses during and after 13-cRA exposure [1 and more]. Unstimulated human peripheral B cells express mRNA of the RA receptor alpha, beta, and gamma. Using retinoids with different receptor binding specificity (CD336, CD437, CD2019, CD367), dose-dependent inhibition of IgE synthesis was shown by all four derivates, but was most marked by an RA binding the alpha receptor with high specificity. Taken together, this study shows that RA inhibits IgE production of anti-CD40 + IL-4-stimulated B cells in vitro [2]. Retinoic acid is also found to modulate CD38 and BCR mediated B-cell proliferation [5].
IgE receptors
In horses, the gene Cepsilon is encoding the IgE heavy chain molecule and the gene FcepsilonR1 alpha is coding for the alpha subunit of the IgE receptor molecule [9]. However more isoforms of receptors that bind IgE are known in mammals. The low-affinity immunoglobulin E (IgE) receptor, CD23 (FcepsilonRII), binds both IgE and CD21 and, through these interactions, regulates the synthesis of IgE, the antibody isotype that mediates the allergic response [10].
Induction of an efficient immune-response requires the response of immunocompetent B-cells to the signals from the binding of antigens to the antigen receptor (BCR) as well as other events. Surface molecules such as CD38, CD19 and CD40 are known to function as receptors and costimulators of in the activation of B-cells [5].
CD40 gene expression is regulated by a TATA-less promoter, with Sp1 as a key transcription factor. Two Sp1 binding regions were identified in the mouse CD40 promoter at positions 59 to 50 and 74 to 66. Surprisingly, Sp1-mediated CD40 transcription was reduced following lipopolysaccharide stimulation and was associated with a time-dependent reduction in Sp1 DNA binding activity. This reduction seemed to be mediated by phosphorylation of the Sp1 molecule. CD40 expression in lipopolysaccharide-stimulated cells is up-regulated by NF-B through two distinct sites. One of these sites (128 to 119) was shown to bind p50 and p65 members of the NF-B family, while the other site (562 to 553) bound only p65. Transfectants of p65 were generated using RAW 264 cells, and it was shown that the up-regulation of CD40 mRNA expression was dependent on the presence of the p65 molecule [3].
In mesanglial cells, 10microM ATRA reduced both subunits p50 and p65 of [4]. It is suggested that specific blockade of NF-kappaB activation may be responsible for the growth arrest and apoptosis of BCR-activated immature B-cells [6]. In mice, pharmacological inhibition of PKC isozymes and Ras revealed that the BCR-induced activation of NF-kappaB requires conventional PKCbeta, whereas that of NFAT may involve non-conventional PKCdelta and Ras pathways [7]. PKC delta, is activated during RA exposure in the NB-4 and HL-60 acute myeloid leukemia cell lines as well as the MCF-7 breast cancer cell line [8].
Similiar effects on B-cells are highly likely, as well as dose dependent possible inhibition of PKC delta.
Repeated studies, in both mice and human subjects show the lack of a primary IgE response with elevated and sustained secondary IgE responses during and after 13-cRA exposure [1 and more]. Unstimulated human peripheral B cells express mRNA of the RA receptor alpha, beta, and gamma. Using retinoids with different receptor binding specificity (CD336, CD437, CD2019, CD367), dose-dependent inhibition of IgE synthesis was shown by all four derivates, but was most marked by an RA binding the alpha receptor with high specificity. Taken together, this study shows that RA inhibits IgE production of anti-CD40 + IL-4-stimulated B cells in vitro [2]. Retinoic acid is also found to modulate CD38 and BCR mediated B-cell proliferation [5].
IgE receptors
In horses, the gene Cepsilon is encoding the IgE heavy chain molecule and the gene FcepsilonR1 alpha is coding for the alpha subunit of the IgE receptor molecule [9]. However more isoforms of receptors that bind IgE are known in mammals. The low-affinity immunoglobulin E (IgE) receptor, CD23 (FcepsilonRII), binds both IgE and CD21 and, through these interactions, regulates the synthesis of IgE, the antibody isotype that mediates the allergic response [10].
Induction of an efficient immune-response requires the response of immunocompetent B-cells to the signals from the binding of antigens to the antigen receptor (BCR) as well as other events. Surface molecules such as CD38, CD19 and CD40 are known to function as receptors and costimulators of in the activation of B-cells [5].
CD40 gene expression is regulated by a TATA-less promoter, with Sp1 as a key transcription factor. Two Sp1 binding regions were identified in the mouse CD40 promoter at positions 59 to 50 and 74 to 66. Surprisingly, Sp1-mediated CD40 transcription was reduced following lipopolysaccharide stimulation and was associated with a time-dependent reduction in Sp1 DNA binding activity. This reduction seemed to be mediated by phosphorylation of the Sp1 molecule. CD40 expression in lipopolysaccharide-stimulated cells is up-regulated by NF-B through two distinct sites. One of these sites (128 to 119) was shown to bind p50 and p65 members of the NF-B family, while the other site (562 to 553) bound only p65. Transfectants of p65 were generated using RAW 264 cells, and it was shown that the up-regulation of CD40 mRNA expression was dependent on the presence of the p65 molecule [3].
In mesanglial cells, 10microM ATRA reduced both subunits p50 and p65 of [4]. It is suggested that specific blockade of NF-kappaB activation may be responsible for the growth arrest and apoptosis of BCR-activated immature B-cells [6]. In mice, pharmacological inhibition of PKC isozymes and Ras revealed that the BCR-induced activation of NF-kappaB requires conventional PKCbeta, whereas that of NFAT may involve non-conventional PKCdelta and Ras pathways [7]. PKC delta, is activated during RA exposure in the NB-4 and HL-60 acute myeloid leukemia cell lines as well as the MCF-7 breast cancer cell line [8].
Similiar effects on B-cells are highly likely, as well as dose dependent possible inhibition of PKC delta.
