Vitiligo is a multifactorial polygenic disorder with a complex pathogenesis, linked with both genetic and non-genetic factors. The precise modus operandi for vitiligo pathogenesis has remained elusive. Theories regarding loss of melanocytes are based on autoimmune, cytotoxic, oxidant-antioxidant and neural mechanisms. Reactive oxygen species (ROS) in excess have been documented in active vitiligo skin. Numerous proteins in addition to tyrosinase are affected. It is possible that oxidative stress is one among the main principal causes of vitiligo. However, there also exists ample evidence for altered immunological processes in vitiligo, particularly in chronic and progressive conditions. Both innate and adaptive arms of the immune system appear to be involved as a primary event or as a secondary promotive consequence. There is speculation on the interplay, if any, between ROS and the immune system in the pathogenesis of vitiligo. The article focuses on the scientific evidences linking oxidative stress and immune system to vitiligo pathogenesis giving credence to a convergent terminal pathway of oxidative stressautoimmunity-mediated melanocyte loss.

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The peptide editor HLA-DM (DM) mediates exchange of peptides bound to major histocompatibility (MHC) class II molecules during antigen processing; however, the mechanism by which DM displaces peptides remains unclear. Here we generated a soluble mutant HLA-DR1 with a histidine-to-asparagine substitution at position 81 of the β-chain (DR1βH81N) to perturb an important hydrogen bond between MHC class II and peptide. Peptide-DR1βH81N complexes dissociated at rates similar to the dissociation rates of DM-induced peptide-wild-type DR1, and DM did not enhance the dissociation of peptide-DR1βH81N complexes. Reintroduction of an appropriate hydrogen bond (DR1βH81N βV85H) restored DM-mediated peptide dissociation. Thus, DR1βH81N might represent a `post-DM effect' conformation. We suggest that DM may mediate peptide dissociation by a `hit-and-run' mechanism that results in conformational changes in MHC class II molecules and disruption of hydrogen bonds between βHis81 and bound peptide.Shortly after being synthesized in the antigen-presenting cell, major histocompatibility complex (MHC) class II αβ heterodimers form nonameric assemblies with invariant chain (Ii) in the endoplasmic reticulum and are then transported through the Golgi complex to the endocytic pathway 1, 2. During transport through the endocytic pathway, most Ii is removed from MHC class II molecules by low pH and acid proteases3, leaving a proteolytic fragment of Ii called `CLIP' bound to MHC class II molecule4. CLIP acts as a `placeholder' for the MHC class II groove, inhibiting conformational changes that render the groove closed5 -13 , and it must be removed to allow binding of exogenous peptides to nascent MHC class II complexes. Human HLA-DM (called `DM' here), or H2-M in mice, is a nonclassical HLA molecule that is critical in the displacement of CLIP 14-17. In addition to displacing CLIP, DM transiently interacts with empty MHC class II molecules to generate a peptide-receptive conformation and is active in the selection of specific peptide-MHC class II complexes during antigen processing18 -26. The two concurrent hypotheses for the recognition of certain peptide-MHC class II by DM relate to the intrinsic affinity between MHC class II © 2006 Nature Publishing Group Correspondence should be addressed to S.S-N (ssadegh@jhmi.edu).. 4 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Immunology website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Immunol. Author manuscript; available in PMC 2011 January 12. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript and the peptide 22,27,28 or to subtle structural variations among different peptide-MHC complexes 25,[29][30][31][32] , whereby structurally flexible complexes are susceptible to DM-induced dissociation, and `rigid' complexes are resistant to DM 25 . Although those studies may have brought greater understanding of the crite...

Many candidate vaccines are effective in animal models of genital herpes simplex virus type 2 (HSV-2) infection. Among them, clinical trials showed moderate protection from genital disease with recombinant HSV-2 glycoprotein D (gD2) in alum-monophosphoryl lipid A adjuvant only in HSV women seronegative for both HSV-1 and HSV-2, encouraging development of additional vaccine options. Therefore, we undertook direct comparative studies of the prophylactic and therapeutic efficacies and immunogenicities of three different classes of candidate vaccines given in four regimens to two species of animals: recombinant gD2, a plasmid expressing gD2, and dl5-29, a replication-defective strain of HSV-2 with the essential genes UL5 and UL29 deleted. Both dl5-29 and gD2 were highly effective in attenuating acute and recurrent disease and reducing latent viral load, and both were superior to the plasmid vaccine alone or the plasmid vaccine followed by one dose of dl5-29. dl5-29 was also effective in treating established infections. Moreover, latent dl5-29 virus could not be detected by PCR in sacral ganglia from guinea pigs vaccinated intravaginally. Finally, dl5-29 was superior to gD2 in inducing higher neutralizing antibody titers and the more rapid accumulation of HSV-2-specific CD8؉ T cells in trigeminal ganglia after challenge with wild-type virus. Given its efficacy, its defectiveness for latency, and its ability to induce rapid, virus-specific CD8؉ -T-cell responses, the dl5-29 vaccine may be a good candidate for early-phase human trials.