TNF-α (TNF), a pro-inflammatory cytokine is synthesized as a 26 kDa protein, anchors in the plasma membrane as transmembrane TNF (TmTNF), and is subjected to proteolysis by the TNF-α converting enzyme (TACE) to release the 15 kDa form of soluble TNF (sTNF). TmTNF and sTNF interact with 2 distinct receptors, TNF-R1 (p55) and TNF-R2 (p75), to mediate the multiple biologic effects of TNF described to date. Several anti-TNF biologics that bind to both forms of TNF and block their interactions with the TNF receptors are now approved for the treatment of a variety of immune-mediated diseases. Several reports suggest that binding of anti-TNFs to TmTNF delivers an outside-to-inside ‘reverse’ signal that may also contribute to the efficacy of anti-TNFs. Some patients, however, develop anti-TNF drug antibody responses (ADA or immunogenicity). Here, we demonstrate biochemically that TmTNF is transiently expressed on the surface of lipopolysaccharide-stimulated primary human monocytes, macrophages, and monocyte-derived dendritic cells (DCs) and expression of TmTNF on the cell surface is enhanced following treatment of cells with TAPI-2, a TACE inhibitor. Importantly, binding of anti-TNFs to TmTNF on DCs results in rapid internalization of the anti-TNF/TmTNF complex first into early endosomes and then lysosomes. The internalized anti-TNF is processed and anti-TNF peptides can be eluted from the surface of DCs. Finally, tetanus toxin peptides fused to anti-TNFs are presented by DCs to initiate T cell recall proliferation response. Collectively, these observations may provide new insights into understanding the biology of TmTNF, mode of action of anti-TNFs, biology of ADA response to anti-TNFs, and may help with the design of the next generation of anti-TNFs.
The turbulent spectrum of kinetic Alfvén waves in inhomogeneous plasma is investigated in the presence of Landau damping. Inhomogeneities in transverse and parallel directions to the ambient magnetic field are incorporated in the dynamics. Numerical solutions of the equations governing kinetic Alfvén waves in the linear regime are obtained while retaining the effects of Landau damping, which have a significant impact on the frequency spectrum generated by propagating kinetic Alfvén waves. A semi-analytical model developed to elucidate the physics of this process is also described.
We present modeling of laser pulse compression and intensity enhancement during propagation in underdense plasma having relativistic intensity. Pulse duration shortens to less than 5 fs and 11 times intensity enhancement has been reported. Nonlinearity of plasma generates new frequency by self phase modulation which broadens the frequency spectrum of the pulse that in turn shortens the pulse duration. High intensity pulse pushes the velocity of electrons up to relativistic limit which in turn modifies the dielectric constant of plasma. Modification of the refractive index profile causes the self focusing of laser pulse. Pulse duration shortening and intensity enhancement happen in accordance with length of the plasma medium and density of the plasma.
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