Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS) and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease.

Keywords: Human genetics; Lupus; Mouse models; SLE; Susceptibility genes.

Fig. 1.

Multi-organ involvement in systemic lupus erythematosus. The characteristic appearance of antinuclear antibodies in the sera is a hallmark of lupus. Clinically, inflammation in lupus can affect the skin (rashes), CNS (neuropsychiatric disorders), lungs (serositis), joints (arthritis) and kidney (glomerulonephritis). Blood disorders such as anemia and thrombocytopenia can also be present. Hyperproliferation of immune populations can lead to an enlargement of the spleen (splenomegaly). A proper diagnosis of SLE requires four parameters linked to these phenotypes to be met, where at least one is clinical (e.g. the presence of a malar rash) and one is immunological (e.g. a positive for serum antinuclear antibodies).

Fig. 2.

SLE: the many players involved in systemic autoimmunity and tissue destruction. Presentation of unknown antigens by MHC molecules leads to priming of CD4⁺ T cells. These cells then help B cells in autoreactive germinal centers undergo class switching, affinity maturation and differentiation into plasma cells that secrete high levels of soluble autoantibodies of the IgG isotype. These autoantibodies form immune complexes by binding autoantigens, and fix complement or engage Fcγ receptors on several different cell types. This can support inflammation and tissue destruction through the recruitment of inflammatory cells to tissues. Apoptotic cells from damaged tissues can be taken up by phagocytes, which present novel autoantigens, supporting further priming and autoreactivity. Engagement of TLRs by environmental triggers such as viral infection or DNA damage by UV rays contribute to the process by inducing the secretion of IFN-I and other cytokines, supporting lymphocyte autoreactivity as well as tissue destruction. APC, antigen-presenting cell; TCR, T-cell receptor. Bold text shows cellular functions that have lupus susceptibility genes related to them (see Fig. 3).

Fig. 3.

Lupus susceptibility genes in humans and mice. Genetic studies in humans and mice have found genes involved in different aspects of the disease. Human genes and their murine homologs are listed underneath headings that denote their function in the cell. See the main text for references.