Decreased phagocytosis of apoptotic cells in diseased SLE mice

Licht, Ruud; Dieker, Jürgen; Jacobs, Cor; Tax, W.J.M.; Berden, Jo H. M.

doi:10.1016/j.jaut.2003.11.003

Cited by 112 publications

(91 citation statements)

References 35 publications

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“…Apoptotic cells are the unique source of nucleosomes, which are formed through cleavage of chromatin by nucleases [26][27][28]. At physiological condition, apoptotic cells, which maintain their membrane integrity for a certain time, have to be cleared quickly and efficiently by phagocytes in order to prevent the release of tissue-damaging intracellular constituents [29].…”

Section: Discussionmentioning

confidence: 99%

DNase1 activity in systemic lupus erythematosus patients with and without nephropathy

et al. 2009

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Section: Discussionmentioning

confidence: 99%

DNase1 activity in systemic lupus erythematosus patients with and without nephropathy

et al. 2009

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“…Most importantly, it was reported that the clearance of apoptotic material by phagocytes is impaired in both lupus mice and patients. 17,18 We showed the accumulation of apoptotic debris in germinal centres (GC) of patients with SLE. 19 In normal lymph nodes, apoptotic nuclei can almost exclusively be detected inside tingible body macrophages (TBM), which often displayed an altered morphology in patients with SLE.…”

Section: Impaired Clearance Of Apoptotic Cells In Slementioning

confidence: 99%

Apoptosis in the pathogenesis of systemic lupus erythematosus

Muñoz

Bavel

Franz

et al. 2008

Lupus

189

141

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Systemic lupus erythematosus (SLE) is a prototype inflammatory autoimmune disease resulting from autoimmune responses against nuclear autoantigens. During apoptosis many lupus autoantigens congregate inside the cells and are susceptible to modifications. Modified nuclear constituents are considered foreign and dangerous. Therefore, apoptotic cells have to has to be efficiently removed to avoid the accumulation of apoptotic debris and the subsequently development of autoimmune responses. Hence, apoptosis and clearance of apoptotic cells/material are considered key processes in the aetiology of SLE. Clearance deficiencies may account for the development of autoimmunity by inducing a loss of tolerance in lymphoid tissues. Furthermore, phagocytosis of apoptotic cells may lead to a pro-inflammatory response in the presence of autoantibodies. This may sustain inflammatory conditions and the pathology found in overt lupus.

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“…Ingestion of apoptotic cells reduces the secretion of proinflammatory cytokines by DCs and MΦs, inhibiting their maturation and controlling the activation of T cells and autoimmune responses to apoptotic cells [116][117][118][119][120][121]. Decreased clearance of apoptotic cells and defects in phagocytosis by MΦs in SLE patients and lupus-prone mice may lead to autoimmunity [69,108,[122][123][124]. The increase in apoptotic cells and antigens could dysregulate DCs and MΦs, triggering a chronic anti-inflammatory response that downregulates the production of cytokines important for B cell tolerance [45,107].…”

Section: Apoptotic Cells: Dangerous In Deathmentioning

confidence: 99%

The regulation of autoreactive B cells during innate immune responses

Vilen

Rutan

2008

Immunol Res

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Systemic lupus erythematosus (SLE) highlights the dangers of dysregulated B cells and the importance of initiating and maintaining tolerance. In addition to central deletion, receptor editing, peripheral deletion, receptor revision, anergy, and indifference, we have described a new mechanism of B cell tolerance wherein dendritic cells (DCs) and macrophages (MΦs) regulate autoreactive B cells during innate immune responses. In part, DCs and MΦs repress autoreactive B cells by releasing IL-6 and soluble CD40L (sCD40L). This mechanism is selective in that IL-6 and sCD40L do not affect Ig secretion by naïve cells during innate immune responses, allowing immunity in the absence of autoimmunity. In lupus-prone mice, DCs and MΦs are defective in secretion of IL-6 and sCD40L and cannot effectively repress autoantibody secretion suggesting that defects in DC/MΦ-mediated tolerance may contribute to the autoimmune phenotype. Further, these studies suggest that reconstituting DCs and MΦs in SLE patients might restore regulation of autoreactive B cells and provide an alternative to immunosuppressive therapies. KeywordsSystemic lupus erythematosus; B cell tolerance; Autoimmunity; Dendritic cell; Macrophage; Smith antigen Learning tolerance: a B cell's storyA diverse B cell repertoire is critical in combating pathogens, but inherent in generating diversity is the threat of autoimmunity. In the bone marrow, central tolerance mechanisms such as deletion or receptor editing remove high-affinity autoreactive B cells before they exit to the periphery [1][2][3][4][5][6][7][8][9][10]. Those that escape are subject to receptor revision [8,[11][12][13][14], peripheral deletion [15,16], or a shortened lifespan because they fail to enter B cell follicles [17][18][19][20][21][22]. In rare cases, autoreactive B cells are fully functional but indifferent to their specific antigen [23][24][25]. Finally, many low-affinity autoreactive B cells are maintained in an unresponsive state known as anergy. Anergic B cells do not receive sufficient activation signals to differentiate into plasma cells or secrete immunoglobulin (Ig) in response to antigenic or mitogenic stimulation [26][27][28][29]. Their proliferative responses to B cell receptor (BCR) or toll-like receptor (TLR) signaling as well as their lifespans vary in different models [18,[30][31][32][33][34][35]. Some anergic B cells transduce BCR-derived signals [30, 32,[36][37][38][39][40], while others exhibit desensitized BCRs [30, 33,41]. Quiescence is dependent on chronic exposure to self-antigen and occupancy of the BCR [42,43] The affinity and avidity of the antigen-BCR interaction determines whether developing B cells will be deleted, edited, anergized, or ignored [46]. Self-reactive B cells that survive these developmental checkpoints tend to bind self-antigens with low affinity and they remain anergic in the absence of costimulation by cognate T cells. Many of the early transgenic (Tg) models expressed BCRs with high affinities. However, concerns were raised that these models...

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Decreased phagocytosis of apoptotic cells in diseased SLE mice

Cited by 112 publications

References 35 publications

DNase1 activity in systemic lupus erythematosus patients with and without nephropathy

DNase1 activity in systemic lupus erythematosus patients with and without nephropathy

Apoptosis in the pathogenesis of systemic lupus erythematosus

The regulation of autoreactive B cells during innate immune responses

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