Systemic Lupus Erythematosus (SLE) is a prototypic autoimmune disease affecting any organ system. It most commonly affects the young ladies in the reproductive age group. Our understanding of its pathogenesis has improved considerably which has made translational advances in its management.

Genetic and Environmental factors:

Like any other autoimmune disease, the development of SLE is the result of an interplay between susceptible genetics and environmental factors. Even though the incidence is higher and outcomes of SLE are poorer in low socio-economic classes, genetic factors related to ancestry affect the disease development more. Genetically identical animal models of SLE grown in the same environment have shown marked serological differences proving that inheritable genetic factors contribute more to the development of disease as compared to environmental factors. Hitherto almost 150 susceptibility genes contribute to the activation of the IFN-α pathway and reduced IL-2 production, both responsible for immune dysregulation. 

Among the environmental factors, the most important ones are Ultraviolet light, drugs (Procainamide, Hydralazine), viral infections (EBV, SARS-CoV2), chemical exposure (Pesticides, Mercury), etc. which, along with chance, lead to activation of the immune system against self-antigens. 

Immune dysregulation: 

Environmental triggers in cells cause apoptosis. In genetically susceptible individuals, the products of apoptosis like nuclear antigens are not cleared effectively and are recognized as foreign antigens, leading to immune dysregulation. Cells of the innate immune system like dendritic cells and monocytes present these antigens which maintain the immune response. This manifests in the form of an IFN-α signature more prominent and sustained in the monocytes as compared to lymphocytes. Activation of the innate immune system leads to the perpetuation of the autoimmune response by activation of the adaptive immune system. T cells provide help to B cells in the germinal centers in developing memory B cells and long-lived plasma cells. These activated B-cells produce autoantibodies which are the serological hallmark of SLE. Autoantibody profile of the patients, mainly the presence or absence of antibodies to ribonucleoprotein-targeted autoantibodies (anti-RnP, anti-Sm, anti-Ro, and anti-La) irrespective of the presence or absence of anti-dsDNA antibodies affects immune dysregulation more. Toll-like Receptor – 7 on the plasmacytoid dendritic cells, B-cells, and monocytes acts as a central point for immune activation as it identifies the single-stranded RNA of immune complexes and is responsible for the release of autoantibodies and IFN-α in the circulation, thereby perpetuating the immune response. Under the influence of IFN-α, neutrophils also release neutrophil extracellular traps (NETs) which also provide nucleic acids and augment the immune response. Neutrophilic transcriptomic signature has been particularly associated with the development of lupus nephritis.

Immune Complex deposition and clinical manifestations: 

The antigen-antibody complexes form in the circulation and get deposited in various tissues of the body giving rise to hypocomplementemia and various manifestations like nephritis, joint pain, skin rashes, etc. Since these immune complexes get deposited in small capillaries, most of these manifestations are related to small vessel involvement like nephritis.

Suggested reading:

1. Ghodke-Puranik Y, Olferiev M, Crow MK. Systemic lupus erythematosus genetics: insights into pathogenesis and implications for therapy. Nat Rev Rheumatol. Published online September 4, 2024. doi:10.1038/s41584-024-01152-2
2. Crow MK. Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets. Ann Rheum Dis. 2023;82(8):999-1014. doi:10.1136/ard-2022-223741