Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players

Abstract

Systemic lupus erythematosus (SLE) is a complex disease resulting from inflammatory responses of the immune system against several autoantigens. Inflammation is conditioned by the continuous presence of autoantibodies and leaked autoantigens, e.g. from not properly cleared dying and dead cells. Various soluble molecules and biophysical properties of the surface of apoptotic cells play significant roles in the appropriate recognition and further processing of dying and dead cells. We exemplarily discuss how Milk fat globule epidermal growth factor 8 (MFG-E8), biophysical membrane alterations, High mobility group box 1 (HMGB1), C-reactive protein (CRP), and anti-nuclear autoantibodies may contribute to the etiopathogenesis of the disease. Up to date knowledge about these key elements may provide new insights that lead to the development of new treatment strategies of the disease.

High prevalence of autoantibodies to C-reactive protein in patients with chronic hepatitis C infection: association with liver fibrosis and portal inflammation

“…This could indicate that anti-CRP antibodies in HCV patients may partially be targeted against native epitopes of CRP and not to hidden neo-epitopes (monomeric) CRP as is the case in lupus. Potential pathogenic roles for anti-CRP include impaired clearance of immune complexes and apoptotic debris as well as loss of complement-inhibitory effects of CRP in solution [14,[39][40][41][42]; both scenarios could result in advanced damage in targeted organs [16,37,[43][44][45].…”

The Role of HMGB1 in the Pathogenesis of Inflammatory and Autoimmune Diseases

“…Furthermore, apoptotic cells are swiftly recognized and removed by phagocytic cells such as macrophages. As a result, intracellular material including HMGB1 can be shielded from the immune system, making apoptosis immunologically "silent" (43,44).…”

C-reactive protein, immunoglobulin G and complement co-localize in renal immune deposits of proliferative lupus nephritis

“…A number of promiscuous serum proteins involved in pathogen recognition and initiation of the immune responses, including C1q, C-reactive protein (CRP), serum amyloid P component (SAP), pentraxin-3 (PTX3), mannan-binding lectin, galectin-3 and β2-glycoprotein I, can opsonize apoptotic debris and thereby facilitate their removal via the RES as described above [11,12]. These evolutionarily highly conserved pattern recognition molecules (PRMs) are pivotal components of the innate immune system and are of great interest in relation to the pathogenesis of lupus.…”

“…These evolutionarily highly conserved pattern recognition molecules (PRMs) are pivotal components of the innate immune system and are of great interest in relation to the pathogenesis of lupus. The affinity of CRP and other pentraxins for cell nuclear antigens, their ability to activate the classical complement pathway and their affinity for Fc-receptors is thought provoking in relation to deficient 'waste disposal' and ANA formation in SLE, where a CRP response is often low or absent despite raised interleukin 6 in disease flares [11][12][13]. Homozygous deficiency of C1q and C1r/C1s is associated with a very high risk to develop lupus (≥90%), whereas heterozygous genetic deficiency of C1 components appears not to be associated with decreased serum levels of C1q or an increased risk of developing SLE [14].…”