Molecular Mechanisms of Immune Complex Pathophysiology

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Background

Immune complexes (ICs) are formed to clear undesired material from the circulation in normal course and are elevated during disease pathologies. Elevated levels of ICs opsonized by complement activation by-products are present during viral infections such as H1N1, HIV, Hepatitis C, autoimmunity, and malignancies as well as during acute humoral rejection. The IC formation and their defective clearance trigger inflammatory response. ICs trigger complement activation and generate inflammatory mediators such as C3a and C5a anaphylotoxins. Complement opsonized ICs deposit at vascular sites, trigger proinflammatory response by releasing cytokines via Fc-receptor and/or complement receptor engagement. Antibodies present in the ICs by bind to activating or inhibitory Fc receptors (FcRs), which trigger effector function and regulate cellular responses. Myeloid cells express both activating and inhibitory FcRs. Complement opsonized ICs interact and regulate B-cell responses. ICs activate macrophages and produce proinflammatory cytokines. In macrophages, FcR ligation by ICs synergized with TLR signaling trigger potent cellular response. DNA/RNA containing ICs engage FcγRIIa on plasmacytoid dendritic cells, simultaneously with TLR7 and TLR9 signaling produce IFN-α. IFN-α is a major driver of SLE pathology. Uptake of ICs by dendritic cells also facilitate antigen cross-presentation.

The mechanisms that contribute to peripheral tolerance breakdown in systemic autoimmune disorder such as SLE are not fully understood. T-cell membrane costimulators of positive CD28, ICOS and negative regulators CTLA4, PD1 regulate immune homeostasis. In diseases that demonstrate IC formation and complement activation also show hyperactive CD4+ T-cell response. However, a mechanistic correlation between these two immune responses has never been examined. The engagement of T-cell receptor (TCR) by pep-MHC present on antigen presenting cells (APCs) and a co-signal from CD28 is a prerequisite for the activation of naïve CD4+ Tcells. These cells upon receiving a cytokine signal trigger differentiation of effector Tcell populations. Canonical TCR activation requires signaling via ζ-chain-ZAP-70. Surprisingly CD4+ T-cells also express γ-chain, a signaling unit of activating FcRs, which are present as γ-γ dimer or γ-ζ heterodimer within TCR complex. In activated CD4+ T-cell phosphorylated γ-chain co-localizes with phosphorylated Syk kinase. In SLE T-cells, a rewiring of TCR signaling by Syk is observed. Recently Syk has been targeted for therapy in both SLE and RA. Those CD4+ T-cells that in addition to canonical ζ-chainZAP-70 signal receive additional positive co-stimulation from γ-chain-Syk signal will overcome the negative co-stimulation from PD1 and CTLA-4. These events during autoimmune pathology could prevent immune contraction, which will result in continuous perpetuation of autoimmune response.

Transplant rejection originally considered as cell mediated response, now has shown to involve humoral response and complement system. Complement influences renal graft viability and transplant out come. A role for membrane attack complex (MAC) in ischemia-reperfusion injury and to lesser extent of C5a in shown. Antibody mediated rejections have gathered momentum. Both C3d and C4d are used as a marker for transplant rejection. C3aR and C5aR signaling at immunological synapse modulate TH1 response. We established a role for Fc receptor responses in driving TH1 and TH17 responses. Cumulative, these observations suggest a negative influence of complement and FcRs on T-cell responses to alloantigens.

In this topic we will highlight the new pathways by which ICs and complement synergism with other lymphocyte signals drive autoimmunity and also discuss their role in transplant rejection. Since FcRs driven mechanisms has been implicated in both old and new therapeutic intervention, we will entertain new ideas and unconventional findings.

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