Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus

Baumann, Irith; Kolowos, Wasilis; Voll, Reinhard; Manger, Bernhard; Gaipl, Udo S.; Neuhuber, Winfried; Kirchner, Thomas; Kalden, Joachim R.; Herrmann, Martin

doi:10.1002/1529-0131(200201)46:1<191::aid-art10027>3.0.co;2-k

Cited by 509 publications

(309 citation statements)

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“…3c). The presence of an elevated steady-state number of apoptotic cells in these mutant mice is likely to contribute to the development of autoimmune disease 45 , as unremoved apoptoticcell debris presents danger signals and autoantigens 46,47 , and elevated numbers of apoptotic cells are often seen in the germinal centres of lymph nodes and other lymphoid organs in human autoimmune syndromes 48,49 . At the same time, apoptotic cells are known to have multiple immunomodulatory -but generally immunosuppressive -effects on APCs [50][51][52] .…”

Section: Tam Regulation Of Phagocytosismentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

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Section: Tam Regulation Of Phagocytosismentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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“…In addition, several groups have reported defective processing, and FcR-dependent clearance, of ICs and apoptotic cells in lupus patients [116][117][118]. Further indications of deficient removal of apoptotic material in SLE patients include the associations between relative or absolute deficiencies of certain components of the classical complement pathway (C1q, C1r, C1s, C4 or C2) and the occurrence of SLE [119,120].…”

Section: Sle and The Waste Disposal Hypothesismentioning

confidence: 99%

Pathogenic implications for autoantibodies against C-reactive protein and other acute phase proteins

Sjöwall

Wetterö

2007

Clinica Chimica Acta

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Systemic lupus erythematosus (SLE) is a systemic rheumatic disease characterized clinically by multiorgan involvement and serologically by the occurrence of antinuclear antibodies. SLE patients may present with multiple autoantibodies to cytoplasmic and cell surface antigens as well as to circulating plasma proteins. Another feature of SLE is that serum levels of C-reactive protein (CRP) often remain low despite high disease activity and despite high levels of other acute phase proteins and interleukin-6, i.e. the main CRP inducing cytokine. Apart from its important role as a laboratory marker of inflammation, CRP attracts increasing interest due to its many intriguing biological functions, one of which is a role as an opsonin contributing to the elimination of apoptotic cell debris, e.g. nucleosomes, thereby preventing immunization against autoantigens. Recently, autoantibodies against CRP and other acute phase proteins have been reported in certain rheumatic conditions, including SLE. Although the presence of anti-CRP autoantibodies does not explain the failed CRP response in SLE, antibodies directed against acute phase proteins have several implications of pathogenetic interest. This paper thus highlights the biological and clinical aspects of native and monomeric CRP and anti-CRP, as well as autoantibodies against mannose-binding lectin, serum amyloid A and serum amyloid P component. © 2006 Elsevier B.V. All rights reserved

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“…Defects in the scavenging process of apoptotic cells have been postulated to play a crucial role in the development and expression of autoimmunity in humans (32)(33)(34)(35). SLE is a prototypic systemic autoimmune disease.…”

Section: Apoptosis and Autoimmunitymentioning

confidence: 99%

“…In a recent study, we investigated the fate of apoptotic B cells in the germinal centers of the lymph nodes of patients with SLE (35). In a subgroup of these patients, apoptotic cells were not properly cleared from the germinal centers by tingible body macrophages.…”

Section: Apoptosis and Autoimmunitymentioning

confidence: 99%

“…Here, these autoantigens may provide a survival signal for autoreactive B cells accidentally generated in the germinal centers during the process of somatic hypermutation. These unjustified survival signals may then override an important initial control mechanism of B cell tolerance (35). Therefore, impaired uptake of apoptotic material may contribute to the loss of B and T cell tolerance observed in patients with SLE (33,35) (Figure 1).…”

Section: Apoptosis and Autoimmunitymentioning

confidence: 99%

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