Lactobacillus plantarum NCIMB8826 ameliorates inflammation of colon and skin in human APOC1 transgenic mice.

Genetic predisposition and environmental factors, including the gut microbiota, have been suggested as major factors in the development and progression of atopic dermatitis. Hyperlipidemic human APOC1(+/+) transgenic mice display many features of human atopic dermatitis, such as scaling, lichenification, excoriations, and pruritus, along with a disturbed skin barrier function. Cytokine analysis of serum shows an increase of various pro-inflammatory cytokines, including interleukin (IL)-12p40, IL-6, and IL-1α, but lower levels of interferon-γ. These mice also display aspects of colitis evident from macroscopic and histological abnormalities. Genome-wide transcriptome analysis of the intestine shows up-regulation of several genes associated with mast cells and eosinophils and this observation was confirmed by demonstrating increased numbers of IgE(+) and FcRε(+) mast cells in the colon and in the skin. Oral treatment with Lactobacillus plantarum NCIMB8826 resulted in decreased numbers of mast cells in the colon. Moreover, this L. plantarum strain ameliorated skin pathology, evident from improved skin barrier integrity, absence of skin thickening, and less excoriations. These results suggest that modulation of intestinal immune homeostasis contributes to the suppression of atopic dermatitis.

High mobility group box1 (HMGB1) in relation to cutaneous inflammation in systemic lupus erythematosus (SLE).

SUMMARY: Photosensitivity is characteristic of systemic lupus erythematosus (SLE). Upon ultraviolet B (UVB) exposure, patients develop inflammatory skin lesions in the vicinity of sunburn cells (SBCs). High mobility group box 1 (HMGB1) is released from apoptotic and activated cells and exerts inflammatory actions through ligation to its receptors. METHODS: Eleven SLE patients and 10 healthy controls (HCs) were exposed to UVB. Skin biopsies were taken before and at one, three and 10 days after irradiation. Sections were stained for SBC, HMGB1, CD3, CD68, interferon-induced protein MxA and cleaved caspase 3. In vitro experiments with UVB-irradiated keratinocytes were also performed. Higher numbers of cells that had released HMGB1 were seen in the skin of SLE patients compared to HCs before and after irradiation. HMGB1-negative nuclei correlated with the presence of SBCs, and with the number of cleaved caspase 3 positive cells in lupus skin. RESULTS: HMGB1 release is increased in the skin of SLE patients compared to HCs. Upon UVB exposure, HMGB1 release further increases in SLE patients and is related to the number of apoptotic cells. Our data suggest that HMGB1, probably released from apoptotic keratinocytes, contributes to the development of inflammatory lesions in the skin of SLE patients upon UVB exposure.

Type I interferons are involved in the development of ultraviolet B-induced inflammatory skin lesions in systemic lupus erythaematosus patients.

OBJECTIVE: To investigate the involvement of type I interferons and endothelial cell adhesion molecules in the development of ultraviolet B (UVB)-induced systemic lupus erythaematosus (SLE) skin lesions. METHODS: A total of 19 SLE patients and 13 controls were irradiated with two minimal erythaemal doses(MED) of UVB. Subsequently, skin biopsies were analysed (immuno) histologically over 10 days, for expression of IFNalpha-induced MxA, numbers of plasmacytoid dendritic cells (pDC), and expression of endothelial cell adhesion molecules, namely E-selectin, ICAM-1, and L-selectin ligand. Additionally, MxA expression was compared to its expression in nine established cutaneous lupus erythaematosus(CLE) lesions of SLE patients. RESULTS: Before irradiation IFNalpha-induced MxA was expressed at significantly higher levels in non-lesional skin of SLE patients compared to healthy controls. In patients developing infiltrates upon UVB irradiation, MxA expression increased further, reaching expression levels similar to or exceeding levels in CLE-skin lesions. In these patients, MxA expression was sustained up to day 10, in contrast to patients not developing infiltrates in whom expression decreased. No noteworthy numbers of plasmacytoid dendritic cells (pDC) were detected in nonirradiated skin or at any time after UVB exposure in SLE patients or controls. MxA expression correlated with influx of T-cells and monocytes/macrophages, and with expression of E-selectin and ICAM-1. CONCLUSION: Development of UVB-induced SLE skin lesions involves a skewing towards production of Th1-associated cytokines, such as IFNalpha. In turn, this may lead to up-regulation of E-selectin and ICAM-1 resulting in recruitment of T-cells and macrophages.

Reduced uptake of apoptotic cells by macrophages in systemic lupus erythematosus: correlates with decreased serum levels of complement.

BACKGROUND: Defects in phagocytosis of apoptotic cells have a role in the pathogenesis of autoimmune diseases. Decrease of phagocytosis of apoptotic cells occurs in systemic lupus erythematosus (SLE). Factors underlying this decrease are, presently, unknown. OBJECTIVE: To analyse the expression of relevant membrane receptors of monocyte derived macrophages (MDM) from patients with SLE and assess their ability to phagocytose apoptotic cells in comparison with MDM from healthy controls. Additionally, to compare phagocytosis in the presence of SLE sera with that in normal human serum (NHS). METHODS: Human peripheral blood monocytes were isolated from patients and controls, and cultured for 7 days to obtain MDM. Membrane expression of CD14, CD18, CD36, and CD51/61 was measured. MDM were incubated with apoptotic Jurkat cells in the presence of NHS or serum from patients with active or inactive disease. RESULTS: No differences in phagocytosis capacity were found between MDM from patients and controls. Membrane expression of the respective receptors was comparable in patients and controls. However, when MDM from controls were incubated with apoptotic cells in patient serum, phagocytosis was significantly decreased in comparison with incubation in NHS. This effect depended on the patients' disease activity and could be reversed by addition of NHS. Reduced uptake of apoptotic cells was associated with decreased levels of complement C1q, C4, and C3, but not with levels of complement factor B. CONCLUSIONS: Reduced uptake of apoptotic cells by MDM from patients with SLE is not an intrinsic defect but is serum dependent and associated with decreased levels of C1q, C4, and C3.

Skin sensitivity to UVB irradiation in systemic lupus erythematosus is not related to the level of apoptosis induction in keratinocytes.

OBJECTIVES: Accumulation of apoptotic cells has been suggested to be involved in the pathogenesis of systemic lupus erythematosus (SLE). As sunlight exposure is one of the factors that can trigger disease activity, we hypothesized that UV light may induce increased numbers of apoptotic cells in SLE. METHODS: Fourteen SLE patients and 16 controls were irradiated with UVB to determine their minimal erythemal dose (MED). Subsequently, skin was irradiated with 1 MED and 2 MED, respectively, and after 24 h skin biopsies were analysed immunohistologically for the number of apoptotic cells and presence of pyknotic nuclear debris. RESULTS: MED was significantly decreased in SLE patients and the presence of decreased MED was associated with a history of butterfly rash. Decreased MED was not related to other skin-related ACR criteria or to autoantibody specificities. No differences were detected in the numbers of apoptotic keratinocytes between patients and controls or in the amount of pyknotic nuclear debris following 1 and 2 MED irradiation, respectively. Absolute UVB doses were correlated with the number of apoptotic keratinocytes; dose-responses did not differ significantly between patients and controls. CONCLUSIONS: Increased sensitivity of SLE patients to UVB, although associated with a history of malar rash, is not related to increased induction of apoptosis or increased levels of secondary necrosis in the skin. Thus, compared with controls, UVB-induced apoptosis is not increased in SLE patients under physiological conditions.

The alternatively spliced CD64 transcript FcgammaRIb2 does not specify a surface-expressed isoform.

Three highly homologous genes (A, B and C) and six transcripts have been identified for the class I human IgG receptor (CD64). The hFcgammaRIa1 isoform encodes the prototypic high-affinity receptor for IgG. The alternatively spliced hFcgammaRIb2 transcript was postulated to exist as a second surface-expressed CD64 isoform on myeloid cells. In this report we assessed this proposed role for hFcgammaRIb2 in detail. As CD64 monoclonal antibodies might not recognize hFcgammaRIb2, we tagged the receptor with an hemagglutinin tag and transfected hFcgammaRIb2tag in the presence of FcR gamma-chain into IIA1.6 cells. Both transcript and protein of hFcgammaRIb2tag were clearly present in transfectants. However, in contrast to the (control) hFcgammaRIa1tag, no surface expression of hFcgammaRIb2tag was detectable with a tag-specific monoclonal antibody. Confocal scan laser microscopy revealed hFcgammaRIb2tag to be retained in the endoplasmic reticulum, resulting in absent plasma membrane expression. These results show hFcgammaRIb2 neither to be surface expressed, nor to represent a separate CD64 isoform. This finding, furthermore, implicates that other FcR transcripts defined at the mRNA level may not represent true FcR isoforms either.