Schlagwort-Archive: dendritic_cells

Osteopontin bridging air pollution and immunology of allergic inflammation

Ostepopontin (OPN) is a remarkable substance. The many aliases already point towards a multitude of biological functions: SPP1=secreted phosphoprotein 1, BSPI 1=bone sialoprotein-1, CIT, ETA-1, GC110940, nephropontin, osteoprotegerin, uropontin, bone sialoprotein I, early T-lymphocyte activation among others. Osteopontin bridging air pollution and immunology of allergic inflammation weiterlesen

Innate immunity is species-, individual, organ-specific

In a previous paper I have questioned if LPS

nanogram exposure on the pulmonary epithelium will supersede the gram-wise exposure on the gut mucosa.

This may indeed work as now shown by Eyal Raz in a commentary in Nature Immunology where previous TLR studies

typically reproduce the splenic version of innate immunity (the spleen is used here as a metaphor for the sterile internal environment).

In the lung only the alveolar space is thought to be sterile while macrophages should not be in a constant state of activation (as inflammation would compromise gas exchange).

There are now several indicators for a lung-specific regulation of innate immunity: TLR9 is expressed in human plasmacytoid dendritic cells while TLR4 is only on myeloid DCs; TGFB-ß mediated crosstalk between alveolar macrophages and epithelial cells seems to be unique in the lung; in addition indeolamine induction or surfactant production is not found elsewhere. Yea, yea.

Unripe

A key event in the vitamin D hypothesis of allergy induction is the immature state of dendritic cells. So far, maturity has been mainly described in terms of reduced expression of cell surface marker like CD80. A new study in Nature now further unravels how the capacity of DC to present antigen may be disturbed. Ubiquitination – the covalent attachment of ubiquitin polymers – of the MHC II ß chain ceases on maturation allowing the transport from endosomal compartments to the plasma membrane. Immature cells seem to be capable to some level of peptide-MHC interaction (at least for some selected antigens) although this process is greatly enhanced by maturation of DCs. Semi-maturity is believed to be an important inetrim stage where at least an earlier review argued

we propose a model in which steady-state migration and partial maturation (semi-maturation) of DCs is embedded as a major component within immune homeostasis, established for permanent and active tolerance induction against self-antigens derived from peripheral tissues by inducing antigen-specific CD4+ Tr cells. Semi-maturation induced by proinflammatory cytokines, such as TNF-alpha, seems to represent a unique developmental tolerogenic stage for DCs, which is based on the absence of proinflammatory cytokine production, despite high expression of MHC II and costimulatory molecules.

Another interesting study in the J Immunol – coined “alternatively activated dendritic cells” the authors probably talk about the same immature cells (compare with my cartoon summarizing a 2002 paper in Trend Mol Med). These immature DCs secrete high levels of IL10 (a paradox discussed in my most recent paper). In addition these DCs produce low amounts of IL12p70, TLR4 and CCR7. What was new to me, was an impressive list of pharmacological agents that suppress DC development: aspirin (also paracetamol?), corticosteroids, cyclosporine A, rapamycin (also other antibiotics?), and finally mycophenolate mofetil.

There is also an update of the IL10 paradox: Allergic sensitization may be down regulated by CD40 AGONISTs independent of IL10!

Finally, I would like to understand what immature really do after encountering allergen exposure. A new paper in nature immunology says that

immature DC are also thought to carry antigen to lymph nodes and to interact with naive T cells but without a previous maturation stimulus, those interactions result in abortive activation of the T cells, which can be eliminated, rendered unresponsive or induced to differentiate into regulatory T cells.

which still does not answer my question.

Vitamin D actions
vd_immun.png

Yea, yea.