Missed Cell Signals in Lupus: Find Me and Eat Me

June 2, 2014

The biology that underlies the abundance of new treatments for lupus is laid out clearly in a new comprehensive review.

Lisnevskaia L, Murphy G, Isenberg D. Seminar: Systemic lupus erythematosus. The Lancet (2014) Published online May 30. doi:10.1016/S0140-6736(14)60128-8

The 15-plus new biological modifiers described in this article are the results of a better understanding of the mechanisms of the immune system in general,  and lupus in particular. This solid review article highlights a few essentials of biological and clinical significance to lupus, in a way that cuts a clear path through the overwhelming maze of cellular and molecular biology.

Lupus, the authors explain, is associated with defects in apoptotic clearance and the pathogenic effect of the resulting apoptotic debris. Early apoptotic cells express “eat-me” signals, specifically cell-surface proteins such as phosphatidylserine, that prompt immune cells to engulf them. Apoptotic cells also express “find-me” signals, to attract macrophages and dendritic cells. When phagocytes don't correctly remove apoptotic material, it is captured instead by antigen-presenting cells, which leads to development of antinuclear antibodies.

Patients with systemic lupus erythematosus have intense polyclonal B-cell activation, with a population shift towards immature B cells. Memory B cells with increased CD27+/IgD- are less susceptible to immunosuppression. CD27-/IgD- memory B cells are associated with increased disease activity and renal lupus.

T cells, which regulate B-cell responses and infiltrate target tissues, have defects in signaling, adhesion, co-stimulation, gene transcription, and alternative splicing. The cytokines B-lymphocyte stimulator (BLys), interleukin 6, interleukin 17, interleukin 18, type I interferons, and tumor necrosis factor α (TNFα) are involved in the inflammatory process and are potential therapeutic targets.

Among the biological agents, rituximab is suggested for refractory lupus nephritis by American College of Rheumatology and European League Against Rheumatism guidelines, although rituximab missed its endpoints in the EXPLORER and LUNAR trials. Belimumab, an inactivating antibody against BLys, met its primary endpoints in the BLISS trials, although patients with active renal disease or central nervous system involvement were excluded. A trial of atacicept, which blocks the BLys pathway, is ongoing in non-renal lupus. Epratuzumab, an antibody against the B-cell membrane protein CD22, is in phase II trials. Trials of abatacept, a CTLA-4 fusion protein that inhibits T-cell activation, failed their primary endpoint. Several interferon α antagonists are under development.

The article also summarizes both clinical and research perspectives on recent epidemiology and outcomes data, the Systemic Lupus International Collaborating Clinics classification system, environmental factors (including iatrogenic lupus caused by TNFα inhibitors), cardiovascular risk, lupus nephritis (and the difference between European and American recommendations), CNS lupus, antiphospholipid syndrome, and pregnancy.

This review continues a 2013 review series on autoimmunity. See: Autoimmune Rheumatology in Brief: Lancet Reviews and Forecasts.