The Regulation of FasL Expression—A Distinguishing Feature Between Monocytes and T Lymphocytes/NK Cells with Possible Implications for SLE

Monocytes and lymphocytes from patients with systemic lupus erythematosus (SLE) had a higher cell surface expression of FasL than the corresponding cells from healthy individuals. Inhibitors of metalloproteases upregulated the surface expression of FasL in peripheral blood lymphocytes (PBL), indicating that a metalloprotease is responsible for the cleavage of FasL. The level of sFasL in serum was slightly increased in the patient group compared to the controls. Therefore, the possible contribution of various mononuclear cell types to the release of FasL was analyzed. Isolated NK cells and T lymphocytes released FasL into the medium and the release was prevented by inhibitors of metalloproteases. In contrast, isolated monocytes did not release FasL. FasR expression was elevated in patients with inverted CD4/CD8 ratio, while FasL expression showed no relationship to CD4/CD8 ratio. The absence of FasL release by isolated cells and a high level of surface expression of FasL distinguish monocytes and T lymphocytes/NK cells.     

AQP1 and AQP3, psoriasin, and nitric oxide synthases 1-3 are inflammatory mediators in erythema toxicum neonatorum

Erythema toxicum neonatorum is a common, inflammatory skin reaction in healthy newborn infants characterized by an accumulation of activated immune cells in the lesions. Its etiology and physiologic significance are still unclear. The purpose of this study was to extend the search for possible inflammatory mediators of the rash. We performed immunohistochemistry on punch biopsy cryosections from lesions of four, 1-day-old infants and from four matched controls without rash, using antibodies against the water channel proteins aquaporin-1 (AQP1) and aquaporin-3 (AQP3), psoriasin, and the nitric oxide synthase (NOS) enzymes, neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). All sections from the lesions showed a dense, nodular cellular infiltrate located near the hair follicle. The vessels in the dermis showed a high incidence of AQP1 and eNOS. Strong staining for AQP1, AQP3, and psoriasin, as well as nNOS, iNOS, and eNOS were seen in the entire epidermal layer. The infiltrate in the dermis contained numerous cells expressing AQP1, AQP3, nNOS, iNOS, and eNOS. Double immunofluorescence staining showed that AQP3 was located in CD1a-expressing Langerhans cells and other dendritic cells in the dermis, as well as in CD14-expressing macrophages, CD15-expressing neutrophils, and EG2-expressing eosinophils surrounding the hair follicle. Our findings show that AQP1 and AQP3, psoriasin, and NOSs are involved in the activation of the skin immune system at birth.     

Up‐regulation of cytokines and chemokines predates the onset of rheumatoid arthritis

Objective

To identify whether cytokines, cytokine‐related factors, and chemokines are up‐regulated prior to the development of rheumatoid arthritis (RA).

Methods

A nested case–control study was performed in 86 individuals who had donated blood samples before experiencing any symptoms of disease (pre‐patients) and 256 matched control subjects (1:3 ratio). In 69 of the pre‐patients, blood samples were also obtained at the time of the diagnosis of RA. The plasma levels of 30 cytokines, related factors, and chemokines were measured using a multiplex system.

Results

The levels of several of the cytokines, cytokine receptors, and chemokines were significantly increased in individuals before disease onset compared with the levels in control subjects; i.e., those representing signs of general immune activation (interleukin‐1β [IL‐1β], IL‐2, IL‐6, IL‐1 receptor antagonist, and tumor necrosis factor), activation of Th1 cells (interferon‐γ, IL‐12), Th2 cells (IL‐4, eotaxin), Treg cells (IL‐10), bone marrow–derived factors (IL‐7, granulocyte–macrophage colony‐stimulating factor, and granulocyte colony‐stimulating factor), as well as chemokines (monocyte chemotactic protein 1 and macrophage inflammatory protein 1α). The levels were particularly increased in anti–cyclic citrullinated peptide antibody– and rheumatoid factor–positive individuals, and the concentration of most of these increased further after disease onset. The concentration of IL‐17 in individuals before disease onset was significantly higher than that in patients after disease onset. Individuals in whom RA subsequently developed were discriminated from control subjects mainly by the presence of Th1 cells, Th2 cells, and Treg cell–related cytokines, while chemokines, stromal cell–derived cytokines, and angiogenic‐related markers separated patients after the development of RA from individuals before the onset of RA.

Conclusion

Individuals in whom RA later developed had significantly increased levels of several cytokines, cytokine‐related factors, and chemokines representing the adaptive immune system (Th1, Th2, and Treg cell–related factors); after disease onset, the involvement and activation of the immune system was more general and widespread.

     

Increased expression of HMGB-1 in the skin lesions of erythema toxicum

Abstract:  At birth, commensal microbes penetrate into the skin of the human newborn, eliciting an acute rash, erythema toxicumn neonatorum . Histologically, the rash is characterized by an upregulation of proinflammatory activity and a local recruitment of immunocytes, including macrophages. High mobility group box chromosomal protein 1, a nuclear and cytosolic protein, is also a pro-inflammatory cytokine released by macrophages in response to microbial stimulation. Here, we reasoned that macrophages but also keratinocytes might upregulate this protein in response to the first colonization and that high mobility group box chromosomal protein 1 might play a role as a proinflammatory mediator in the development and progression of erythema toxicum . Punch biopsy specimens from 1-day-old healthy infants, seven with and four without erythema toxicum were analyzed with indirect immunohistochemistry and two different antihigh mobility group box chromosomal protein 1 antibodies, immunofluorescence, nuclear counterstaining, confocal and immunoelectron imaging. We found relocation of nuclear high mobility group box chromosomal protein 1 into the cytoplasm in keratinocytes and macrophages in erythema toxicum. Cytoplasmatic high mobility group box chromosomal protein 1 was also found in melanocytes and did neither co-locate with lysosomal-associated membrane proteins nor with melanosomes. We speculate that terrestrial adaptation triggers the induction of the endogenous "danger signal" high mobility group box chromosomal protein 1 in the skin of the newborn infant, perhaps in response to the first commensal colonization and that this signal may contribute to alert the immune system and promote a protective immune response.