Consensus?. Treat active TB after renal transplantation with the same therapy as general population (Evidence level B) If rifampin is used, monitor blood levels of calcineurin inhibitors and rapamycin. Use rifabutin as an alternative (Evidence level C). Risk factors for Post-TxTB. DM
Alexander Usorov, MD
Streptomycin was used successfully in 1944, which led to
Nobel Prize in 1952
1946 –pts with lupus vulgaris were treated with Vitamin D2 and 18 out
of 32 were cured (Dowling et al in Lancet 1947: 919-922)
Human TLRs and their ligands. TLR 2 heterodimerizes with TLR1 and TLR6 to recognize triacyl- and diacyl-lipopeptides. TLR4 and TLR5 ligands are LPS and flagellin, respectively. These TLRs are supposed to recognize products derived from bacteria. By contrast, TLR3 recognizes viral dsRNA, whereas TLR8 recognizes viral ssRNA. TLR9 recognizes DNA from both bacteria and viruses. TLR7 and TLR10 have no known natural ligand; however, TLR7 can be stimulated by synthetic compounds such as imiquimod. TLR signaling is mediated via two different adapters, MyD88 and TRIF, which lead to activation of NF-κB and IRF3, respectively. MyD88 interacts directly with TLR5, TLR7, TLR8 and TLR9. TLR2–TLR1, TLR2–TLR6 and TLR4 associate with MyD88 through TIRAP; it is unclear how MyD88 associates with TLR10. TRIF directly associates with TLR3, but requires TRAM to interact with TLR4.
Upregulation of macrophage 1α,25(OH)2D synthesis following administration of pharmacologic doses of vitamin D in active Mycobacterium tuberculosis infection. In the granuloma both IFNγ and ligation of macrophage TLR2/1 by M. tuberculosis induces macrophage expression of 25(OH)D-1α-hydroxylase. Administration of pharmacologic doses of vitamin D results in increased circulating concentrations of free 25(OH)D, which is metabolised by upregulated 1α-hydroxylase to 1α,25(OH)2D. This may either act in a paracrine manner to modulate immune responses in the granuloma, or, if produced at high concentration, may enter the systemic circulation and induce hypercalcemia.
Human TLR2–TLR1-induced antimicrobial mechanism against intracellular mycobacteria. TLR2–TLR1 stimulation results in the upregulation of the expression of Cyp27B1 and of VDR. Cyp27B1 converts inactive vitamin D (25D3) into its active form (1,25D3). The intracellular pool of 25D3 is shuttled into the cell via the vitamin D binding protein (DBP). Once activated, 1,25D3 can then bind to and activate the VDR, and induce transcription of antimicrobial factors, including the antimicrobial peptide cathelicidin (Cath.). The cathelicidin peptide can then traffic into intracellular compartments harboring mycobacteria. Whether or not cathelicidin has a role in the TLR-induced antimicrobial activity is still unclear. However, the cathelicidin peptide has been demonstrated to kill Mycobacterium tuberculosisdirectly. Therefore, cathelicidin probably has an important role in the TLR2–TLR1-mediated antimicrobial activity, but is probably not the only effector. The induction of host-defense mechanisms by TLR2–TLR1 depends on the amount of 25D3 present in the serum. Abbreviation: RIP, rest in peace.