Immune complexes in systemic lupus erythematosus

Introduction

Immune complexes (ICs) are products of immune reactions that are formed by binding between antigen and antibody through non-covalent interactions. ICs play important roles in the clearance of pathogens. However, the production of autoantibodies and formation of ICs against autoantigens induce tissue injuries. Systemic lupus erythematosus (SLE) is an autoimmune disease, in which nucleic acid-containing IC deposition causes inflammation and tissue damage in multiple organs through activation of complement and engagement of Fcγ receptors (FcγRs). In addition, recent studies have shown the association of neutrophil extracellular traps (NETs) and Toll-like receptors (TLRs) with the ICs in the pathogenesis of SLE.

Basic immunochemistry of ICs

The formation of ICs is dependent on the ratio between the amounts of antigen and antibody. Because one molecule of antibody, IgG, for example, has two binding sites for antigens and one antigen usually possesses many epitopes to which antibodies bind, lattice ICs are formed by the binding of antigens with antibodies. Mixing antigen and antibody in vitro results in the formation of ICs. When that amount of antibodies is in excess of that of antigens (zone of antibody excess) or the amount of antigens is in excess of that of antibodies (zone of antigen excess), small-lattice soluble ICs are formed ( Fig. 29.1 ). When the antigen-antibody ratio is optimal (zone of equivalence), large-lattice ICs are formed, which tend to precipitate.

Generation of autoantibodies and ICs in SLE

The mechanisms underlying the generation of autoantibodies against nucleic acids and of the formation of ICs in SLE are shown in Fig. 29.2 In SLE patients, an impaired clearance of apoptotic cells or inefficient degradation of NETs are associated with the production of autoantibodies against nuclear antigens. Under physiological conditions, apoptotic cells are opsonized and rapidly phagocytosed by macrophages. However, in SLE patients, extracellular nucleic acids from apoptotic cells or NETs are not efficiently cleared due to the decreased activity of endonucleases, such as DNase1, and due to the defective engulfment function of macrophages for apoptotic materials.

Immature conventional dendritic cells (cDCs) are activated by extracellular nucleic acids, which bind to TLR7 or TLR9—RNA for TLR7 and CpG motifs for TLR9. Activated mature cDCs present nucleic acids antigens to the relevant T helper cells. Then, activated T helper cells interact with nucleic acid-specific B cells, which in turn, transform into plasma cells to produce anti-nucleic acid antibodies, such as anti-dsDNA antibodies and anti-RNP antibodies. These antibodies bind to nucleic acids in the circulation to form ICs, which become deposited in tissues and trigger an inflammatory response. Circulating antibodies also bind to predeposited antigens in the tissues or to extracellular nucleic acids from apoptotic cells or NETs in the tissues.

IFN-α production from pDCs induced by ICs through TLRs

ICs enhance autoantibody production by stimulating the plasmacytoid dendritic cells (pDCs) to produce interferon (IFN)-α. ICs formed by combining apoptotic or necrotic cell materials with purified IgG from SLE patients in vitro, induce IFN-α production by pDCs. Especially, ICs from SLE patients’ sera containing autoantibodies to small nuclear RNPs efficiently stimulate pDCs to secrete type I IFNs. ICs formed by binding of nucleic acids with autoantibodies trigger the TLR signaling pathway in the pDCs. DNA or RNA-containing ICs act as vehicles to deliver nucleic acids to the endosomes, where they are recognized by nucleic acid-sensing TLRs, such as TLR7 and TLR9. ICs containing nucleic acids engage FcγRIIa and are delivered into the endosomal compartment, where the nucleic acids stimulate TLR7 and TLR9 to induce IFN-α production ( Fig. 29.2 ).

High mobility group box 1 protein (HMGB1), which is a chromatin-binding protein that is abundantly localized in the cell nucleus and released from the apoptotic cells or necrotic cells, also plays an important role in the delivery of nucleic acids to TLRs. HMGB1 binds to DNA-containing ICs in the serum and stimulates IFN-α production through the TLR9-MyD88 pathway involving the multivalent immunoglobulin receptor RAGE (receptor for advanced glycation end product) in the pDCs ( Fig. 29.2 ). NETs released from the neutrophils of SLE patients contain large amounts of HMGB1 as well as DNA.

IFN-α secreted from the pDCs stimulates upregulation of co-stimulatory molecules in the conventional DCs, as well as production of B cell-activating factor of the tumor necrosis factor family (BAFF) and other proinflammatory cytokines, including interleukin-6 (IL-6). IFN-α, BAFF and IL-6 promote differentiation of B-cells into plasma cells. Thus, there is a positive feedback loop for the production of autoantibodies and activation of pDC by ICs ( Fig. 29.2 ).

Along with pDCs, B cells are also activated by endogenous RNA and DNA in the form of ICs. B cell receptors drive the uptake of ICs and stimulate TLR7 and TLR9 to induce B cell proliferation. HMGB1 bound to DNA-containing ICs also activate DNA or induce chromatin-reactive B cells to proliferate, via the mediation of RAGE and TLR9 ( Fig. 29.2 ).