Recent insights into the genetic basis of systemic lupus erythematosus

Abstract

Many identified genetic risk factors for SLE contribute to the function of the immune system, which has expanded our understanding of disease pathogenesis. We outline the genetic variants in the recently identified SLE-associated loci, the immunologic pathways affected by these gene products, and the disease manifestations linked to these loci. Pathways potentially influenced by SLE risk variants include: apoptosis, DNA degradation and clearance of cellular debris; antigen-presentation; type I interferon, Toll-like receptor and NFκB activation; defective clearance of immune complexes containing nuclear antigens; B- and T-cell function and signaling; and monocyte and neutrophil function and signaling. These identified SLE susceptibility loci are predominantly common variants that have been confirmed among multiple ancestries, suggesting shared mechanisms in disease etiology. Ongoing genetic studies continue the investigation of specific functional variants, and their potential consequences upon immune dysregulation, enhancing our understanding of links between genotypes and specific disease manifestations. The next generation sequencing explores the identification of causal rare variants that may contribute robust genetic effects to developing SLE. Novel insights coming from genetic studies of SLE provide the opportunity to elucidate pathogenic mechanisms as well as contribute to the development of innovative therapeutic targets for this complex disease.

TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice

“…The kidneys, skin, joints, lungs, serous membranes, as well as, the cardiovascular, nervous and musculoskeletal system become targets of inflammation at onset or during the course of the disease (2). The etiology of SLE is unknown, yet genetics, sex, infectious agents, environmental factors, and certain medications may play a role in the initiation of the disease by causing alterations in lymphoid signaling, antigen presentation, apoptosis, and clearance of immune complexes (3,4).…”

Plasma DNA aberrations in systemic lupus erythematosus revealed by genomic and methylomic sequencing

“…The etiology of SLE remains unknown and is multifactorial, involving genetic, epigenetic, environmental, hormonal, and immunologic factors (2,4). Cell death has been regarded as an important event in the pathogenesis of SLE, as it leads to the release of antigens, such as nucleic acids, for immune complex formation, which may trigger a cascade of immune responses against the bodily tissues of the SLE patients (5,6).…”

Experimental modeling of nucleoprotein disposal disorders in systemic lupus erythematosus

“…Согласно наиболее распространенной на данный момент гипотезе, нарушение процессов апоптоза и/или элиминации продуктов распада клеток приводит к значительному повышению содержания дезоксирибонуклеопротеинов и других внутриклеточных молекул во внеклеточном пространстве, что инициирует выработку патогенных аутоантител [3]. Известные факторы риска данного заболевания (генетические, средовые и гормональные) не всегда "вписываются" в существующие концепции патогенеза СКВ [4,5].…”