Alternative Pathway Involvement in Protoporphyria Patients Related to Sun Exposure.

The homeostasis of tissues in a chronic disease is an essential function of the alternative pathway (AP) of the complement system (CS). However, if not controlled, it may also be detrimental to healthy cells with a consequent aggravation of symptoms. The protoporphyria (PP) is a rare chronic disease that causes phototoxicity in visible light with local skin pain and general malaise. In order to establish if there is a systemic involvement of the CS during sun exposure, we designed a non-invasive method with a serum collection in winter and summer from 19 PP and 13 controls to detect the levels of CS protein: Properdin, Factor H (FH), and C5. Moreover, the global radiation data were collected from the regional agency of environmental protection (ARPA). The results show growing values for every protein in patients with PP, compared to control, in both seasons, in particular in summer compared to winter. To reinforce the evidence, we have estimated the personal exposure of patients based on the global radiation data. The main factors of the AP increased over the season, confirming the involvement of the AP in relation to light exposure. The systemic response could justify the general malaise of patients after long light exposure and can be exploited to elucidate new therapeutic approaches.

[The influence of aromatic amino acid derivatives on the complement system under ionizing radiation].

Activities of the complement classical, alternative and lectin pathways were determined under conditions of X-radiation in the blood of rats treated and none-treated with synthetic Schiffbase aromatic amino acid derivatives, nicotinyl-L-tyrosinate or nicotinyl-L-tryptophanate, before irradiation. In case of activities of the alternative and lectin pathways no significant changes between irradiated animals and none-irradiated control animals were detected. However, the data obtained demonstrate significantly elevated activity of the classical complement cascade in the blood of irradiated animals (1 day after irradiation), as compared to those none-irradiated. This effect was less pronounced in rats treated with nicotinyl-L-tyrosinate or nicotinyl-L-tryptophanate 1 hour before irradiation. Based on the results obtained the ability of nicotinyl-L-tyrosinate and nicotinyl-L-tryptophanate to act as cyto-protectors is concluded.

The alternative complement pathway seems to be a UVA sensor that leads to systemic immunosuppression.

UV wavebands in sunlight are immunomodulatory. About half the amount of UVA within a minimum erythemal dose of sunlight is systemically immunosuppressive, whereas higher doses protect from UVB immunosuppression in mice. We have earlier shown that these responses to UVA are genetically restricted, as they occur in C57BL/6 but not in Balb/c mice. We used gene set enrichment analysis of microarray data and real-time reverse transcriptase (RT)-PCR confirmation to determine the molecular mechanisms associated with UVA immunomodulation. We found upregulation of mRNA for the alternative complement pathway. The core-enriched genes complement component 3, properdin, and complement factor B were all activated by the immunosuppressive dose of UVA only in UVA-responsive C57BL/6 but not in unresponsive BALB/c mice. This therefore matched the genetic restriction and dose responsiveness of UVA immunosuppression. The immune-protective higher UVA dose prevented UVB from downregulating chemokine receptor 7 and IL-12B, and decreased IL-10, supporting the earlier identification of IL-12 and IL-10 in high-dose UVA protection from UVB immunosuppression. Our study has identified activation of the alternative complement pathway as a trigger of UVA-induced systemic immunosuppression and suggests that this pathway is likely to be an important sensor of UVA-induced damage to the skin.

[The state of classical and alternative complement activation pathways in persons who participated in the cleanup of the aftereffects of the accident at the Chernobyl Atomic Power Plant]. / Sostoianie klassicheskogo i al'ternativnogo putei aktivatsii T-limfotsitov u likvidatorov posledstvii avarii na ChAES.

The levels of T-cell activation through classical and alternative pathways were studied in persons participated in cleaning-up operations at Chernobyl N. P. P. Proliferation response of T-cells on the action of monoclonal antibody anti-CD3 (classical activation) as well as response on phytohaemagglutinin was partially decreased just as response on autologic erythrocytes in combination with phorbol 12-myristate-13 acetate (CD2-dependent alternative activation) was completely suppressed in all affected persons. Addition of interleukin 2 did not restore T-cell responses on both anti-CD3 and alternative stimulation. The different degree of decrease of T-cell responses on anti-CD3 and CD2-dependent alternative stimulation is not a result of respective alterations of cell surface CD3 and CD2 expression.

Activation of the alternative complement pathway by 405 nm light in serum from porphyric rat.

Sera from hexachlorobenzene-induced porphyric rats were examined for evidence of complement activation. The serum irradiated in vitro with 405 nm light resulted in a dose-dependent diminution of the total hemolytic activity of the complement. Further, such irradiated serum showed immunoelectrophoretical C3 conversion and chemotactic activity for rat polymorphonuclear leukocytes, and caused increased vascular permeability in vivo. C3 conversion was not induced in serum chelated with EDTA, but occurred in serum chelated with Mg++-EGTA. By sephadex G-75 chromatography, the irradiated serum had potent chemotactic activity eluted near the cytochrome C marker. These studies indicate that the irradiation of porphyric rat serum with 405 nm light induces activation of the complement system via the alternative pathway, with the resultant development of anaphylatoxin.