Redox Enzymes of the Thioredoxin Family as Potential and Novel Markers in Pemphigus.

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease affecting both skin and mucous membranes. Its pathogenesis is related to IgG autoantibodies primarily targeting the cellular adhesion protein desmoglein (Dsg) 3, one of the major desmosome components. Impaired redox regulation is considered a major player in the pathogenesis of autoimmune diseases such as pemphigus by enhancing inflammation and breakdown of immunological tolerance by structural protein modifications. Despite many recent advances, local and systemic redox profiles that characterize the immune response in pemphigus are virtually unknown but potentially crucial in further advancing our understanding of redox-dependent modifications that eventually lead to clinical manifestation. Here, we have analyzed the individual expression pattern of four major redox enzymes that are members of the thioredoxin (Trx) fold superfamily (peroxiredoxins (Prxs) 1 and 4, glutaredoxin (Grx) 2, and Trx1) in serum and PBMCs as well as their distribution in the skin of pemphigus patients compared to healthy controls. We show that in groups of five pemphigus patients, Prx1 is upregulated in both serum and PBMCs, while its epithelial distribution remains within the spinous epithelial layer. Expression of Grx2 and Prx4 is both reduced in serum and PBMCs, while their distinct and similar expression in the skin changes from an even distribution throughout the basal layer (healthy) to ubiquitous nuclear localization in pemphigus patients. In PV patients, Trx1 is secreted into serum, and cellular distribution appears membrane-bound and cytosolic compared to healthy controls. We furthermore showed that a 3D ex vivo human skin model can indeed be used to reproduce similar changes in the protein levels and distribution of redox enzymes by application of cold atmospheric plasma. Deciphering the relationship between redox enzyme expression and autoimmunity in the context of pemphigus could be critical in elucidating key pathogenic mechanisms and developing novel interventions for clinical management.

Metabolic syndrome and the seminal cytokine network in morbidly obese males.

Given the increasing prevalence of metabolic syndrome (MetS) in males of reproductive age, the objective of this prospective case-controlled study was to investigate the impact of subacute systemic inflammation associated with MetS on seminal cytokines and standard sperm parameters in comparison with healthy men. Between 2011 and 2014, we recruited 27 patients with MetS out of 41 obese patients screened from an internal outpatient clinic. Twenty-seven age-matched healthy controls were enrolled from 54 men requesting vasectomy in a urological outpatient clinic. A multiplex analysis was performed to quantify simultaneously the level of 30 cytokines (Eotaxin, FGF, Fraktalkine, GCSF, GMCSF, Granzyme A, IFN-γ, IL-1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-21, IP-10, I-TAC, MCP-1, MIG, MIP-1α, MIP-1ß, RANTES, TNF-α, and VEGF) in each 50 µL of blood and seminal plasma during the andrological work-up. Semen analysis was performed according to the WHO (Global status report on noncommunicable diseases, 2010) recommendations, including standard sperm parameters as well as peroxidase-positive leukocytes and polymorphonuclear elastase. Blood levels of C-reactive protein, interleukins 6 and 10 were elevated in MetS (p > 0.001). Two-way hierarchical cluster analysis showed characteristic cytokine networks in semen greatly differing from those in blood, but not between MetS and controls. No deterioration of semen analysis was evident in men diagnosed with MetS. Our results suggest that there is no transmission of the systemic inflammation associated with MetS into semen based on cytokine profiles and that MetS does not impair standard semen parameters to a clinically significant extent.

[Seminal cytokines: is quantification useful in urogenital disorders?]. / Zytokine im Ejakulat : Ist die Bestimmung bei urogenitalen Erkrankungen sinnvoll?

Cytokines are cellular messengers which play a key role in many biological conditions such as immune defence and reproduction. During recent years analysis of seminal cytokines has become of increasing interest in various pathologies. To evaluate the current role of seminal cytokines we performed a systematic literature search within the framework of our focus group "Male Infertility during Infection and Inflammation - MIBIE". Out of 581 manuscripts we identified 124 original articles which investigated a total of 31 different cytokines. These studies can be categorized according to the following three topics: infertility, infections and chronic prostatitis. The current analysis demonstrates that seminal cytokine profiles are not associated with either semen quality or fertility; however, cytokines might be beneficial for diagnosis and monitoring therapy in patients with urogenital infections/inflammation. Further studies are needed to clarify if a single cytokine or a combination of different cytokines is necessary to evaluate different pathologies.

Thiol redox control via thioredoxin and glutaredoxin systems.

The Trx (thioredoxin) and Grx (glutaredoxin) systems control cellular redox potential, keeping a reducing thiol-rich intracellular state, which on generation of reactive oxygen species signals through thiol redox control mechanisms. Here, we give a brief overview of the human Trx and Grx systems. The main part focuses on our current knowledge about mitochondrial Grx2, which facilitates mitochondrial redox homoeostasis during oxidative stress-induced apoptosis.