Complement component C5a Promotes Expression of IL-22 and IL-17 from Human T cells and its Implication in Age-related Macular Degeneration

Abstract

BackgroundAge related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly populations worldwide. Inflammation, among many factors, has been suggested to play an important role in AMD pathogenesis. Recent studies have demonstrated a strong genetic association between AMD and complement factor H (CFH), the down-regulatory factor of complement activation. Elevated levels of complement activating molecules including complement component 5a (C5a) have been found in the serum of AMD patients. Our aim is to study whether C5a can impact human T cells and its implication in AMD.MethodsHuman peripheral blood mononuclear cells (PBMCs) were isolated from the blood of exudative form of AMD patients using a Ficoll gradient centrifugation protocol. Intracellular staining and enzyme-linked immunosorbent assays were used to measure protein expression. Apoptotic cells were detected by staining of cells with the annexin-V and TUNEL technology and analyzed by a FACS Caliber flow cytometer. SNP genotyping was analyzed by TaqMan genotyping assay using the Real-time PCR system 7500.ResultsWe show that C5a promotes interleukin (IL)-22 and IL-17 expression by human CD4+ T cells. This effect is dependent on B7, IL-1β and IL-6 expression from monocytes. We have also found that C5a could protect human CD4+ cells from undergoing apoptosis. Importantly, consistent with a role of C5a in promoting IL-22 and IL-17 expression, significant elevation in IL-22 and IL-17 levels was found in AMD patients as compared to non-AMD controls.ConclusionsOur results support the notion that C5a may be one of the factors contributing to the elevated serum IL-22 and IL-17 levels in AMD patients. The possible involvement of IL-22 and IL-17 in the inflammation that contributes to AMD may herald a new approach to treat AMD.

C5a receptor signalling in dendritic cells controls the development of maladaptive Th2 and Th17 immunity in experimental allergic asthma

“…In this setting, C5a drives Th17-cell differentiation by a strictly IL-6-dependent mechanism. 30,38,39 In future studies, it will be important to delineate the signaling pathways activated by the complex allergens like HDM and the cross talk between C5aR, C5L2, and TLRs in the context of C5aR and C5L2 deficiencies. As we and others have shown before, cross-regulation exists between the different anaphylatoxin receptors 14,40 that can affect the signaling program in different DC subsets ultimately defining the production of cytokines that regulate the lineage commitment of naive Th cells.…”

“…44 An anti-apoptotic role for C5a has also been shown for human T cells. 39 Together, the available data suggest a complex, antiapoptotic role for C5a on T cells. Importantly, C5aR deficiency on T cells seems to affect steady state survival 20 and early T-cell apoptosis during T-cell expansion, 44 whereas C5aR deficiency in antigen-presenting cells, at least in BMDCs, promotes accelerated T-cell apoptosis during the contraction phase.…”

Immuno-modulatory Effect of IFN-gamma in AMD and its Role as a Possible Target for Therapy

“…Th17 cells have been characterized as a subclass of T cells and implicated in numerous autoimmune disorders including diabetes, autoimmune encephalomyelitis, autoimmune uveitis, and thyroiditis [43]. Recently Th17 cell specific cytokines, IL-17 and IL-22 are found to be elevated in serum of AMD patients, further implicating Th17 cells in the pathogenesis of AMD [70]. The upregulation of IL-17 is believed to be mediated by complement activation product C5a [70].…”

Akt-Dependent Enhanced Migratory Capacity of Th17 Cells from Children with Lupus Nephritis

“…This finding suggests that the abundant levels of C5a observed in children with active LN might be involved in Th17 immune responses in children with LN under certain conditions. A role of C5a in Th17 immune responses was also recently described in murine autoimmune arthritis (52) and in age-related macular degeneration (53). mTORC1 is located downstream of Akt, and mTOR activity is enhanced in lupus T cells (13).…”