Modulation of human monocytes by the pathogenic fungus Candida albicans

As part of the normal flora in the human body C. albicans acts as an opportunistic microbe but can also cause superficial and systemic infections. As a part of cellular immune defense mechanisms, monocytes directly phagocytose, release extracellular DNA traps (MoETs), and secrete cytokines in response to C. albicans. The cytokine secretion by monocytes is enhanced by complement activation in the human serum. However, Candida albicans has the ability to bind human complement regulators onto its surface to evade complement attack. One of these regulators is complement factor H which inhibits further complement activation, limiting recognition and contact with immune cells and enhancing the survival of the pathogenic fungus. The bound factor H modulates cytokine secretion of monocytes in similar pattern when bound onto apoptotic HUVEC cells, which is known to be immunologically silent. This modulation of cytokine secretion creates a favorable condition for the pathogen to survive. Moreover, the secreted cytokines by factor H-modulated monocytes also strong enough to induce differentiation of naive T cells into induced regulatory T cells which dampens further immune reaction. Taken together, this study shows a new immune evasion mechanism by C. albicans by modulating human monocytes response by utilizing human complement regulator. ..

Anaphylatoxins Activate Ca2+, Akt/PI3-Kinase, and FOXO1/FoxP3 in the Retinal Pigment Epithelium

Purpose: The retinal pigment epithelium (RPE) is a main target for complement activation in age-related macular degeneration (AMD). The anaphylatoxins C3a and C5a have been thought to mostly play a role as chemoattractants for macrophages and immune cells;here, we explore whether they trigger RPE alterations. Specifically, we investigated the RPE as a potential immunoregulatory gate, allowing for active changes in the RPE microenvironment in response to complement. Design: In vitro and in vivo analysis of signaling pathways. Methods: Individual activities of and interaction between the two anaphylatoxin receptors were tested in cultured RPE cells by fluorescence microscopy, western blot, and immunohistochemistry. Main outcome measures: Intracellular free calcium, protein phosphorylation, immunostaining of tissues/cells, and multiplex secretion assay. Results: Similar to immune cells, anaphylatoxin exposure resulted in increases in free cytosolic Ca2+, PI3-kinase/Akt activation, FoxP3 and FOXO1 phosphorylation, and cytokine/chemokine secretion. Differential responses were elicited depending on whether C3a and C5a were co-administered or applied consecutively, and response amplitudes in co-administration experiments ranged from additive to driven by C5a (C3a + C5a = C5a) or being smaller than those elicited by C3a alone (C3a + C5a < C3a). Conclusion: We suggest that this combination of integrative signaling between C3aR and C5aR helps the RPE to precisely adopt its immune regulatory function. These data further contribute to our understanding of AMD pathophysiology