Pathogenesis of human systemic lupus erythematosus: recent advances

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with manifestations derived from the involvement of multiple organs including the kidneys, joints, nervous system and hematopoietic organs. Immune system aberrations, as well as heritable, hormonal and environmental factors interplay in the expression of organ damage. Recent contributions from different fields have developed our understanding of SLE and reshaped current pathogenic models. Here, we review recent findings that deal with (i) genes associated with disease expression; (ii) immune cell molecular abnormalities that lead to autoimmune pathology; (iii) the role of hormones and sex chromosomes in the development of disease; and (iv) environmental and epigenetic factors thought to contribute to the expression of SLE. Finally, we highlight molecular defects intimately associated with the disease process of SLE that might represent ideal therapeutic targets and disease biomarkers.

Figure 1. SLE-associated loci and genes

The approximate position of SLE-associated loci (red squares) and genes (arrows) in the human genome is shown. Additional studies will identify the risk alleles responsible for these associations. This will allow a more comprehensive understanding of disease pathogenesis and the selection of better biomarkers and therapeutic targets. *FCGR stands for FCGR2A, FCGR3B, and FCGR3A; COMP stands for C2, and C4A, and C4B.

Figure 2. Altered signaling and gene transcription in T cells

(A) Factors present in SLE sera (e.g. auto-antibodies, cytokines) and constitutive defects in signaling molecules alter T cell signaling events. This results in profound changes in the activation of transcription factors (i.e. more NFAT and CREM activation; less CREB phosphorylation and AP-1 activation) and subsequently in the function of T cells. (B) T cells from SLE patients produce increased amounts of pro-inflammatory cytokines such as IL-17. Shown are T cells from a patient with SLE, stimulated with anti-CD3 and anti-CD28, and stained with anti-IL-17 (green) and a nuclear dye (DAPI; blue) after permeabilization (white bar represents 5 μm). (C) CD3+ CD4- CD8- (double negative) T cells are expanded in patients with SLE and infiltrate affected kidneys. Shown is a dense T cell infiltrate from a renal biopsy of a patient with SLE stained with anti-CD3 (green) and anti-CD4 and CD8 (red). Green cells are double negative T cells and yellow cells are CD4 and CD8 T cells.

Figure 3. Activated dendritic cells induce inflammation upon exposure to apoptotic and necrotic debris

Dendritic cells from patients with SLE are activated by T cell co-stimulatory molecules (i.e. CD40L), inflammatory cytokines, and nucleic acid-containing immune complexes. Activated DCs produce increased amounts of pro-inflammatory cytokines (e.g. IL-6, IFN-α) that amplify the immune response. Apoptotic material is not recognized as anti-inflammatory and contributes to DC activation.