Immune Complexes Present in the Sera of Autoimmune Mice Activate Rheumatoid Factor B Cells

Rifkin, Ian R.; Leadbetter, Elizabeth A.; Beaudette, Britte C.; Kiani, Cornelia; Monestier, Marc; Shlomchik, Mark J.; Marshak‐Rothstein, Ann

doi:10.4049/jimmunol.165.3.1626

Cited by 73 publications

(66 citation statements)

References 54 publications

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“…This initiation, though stochastic in the population, correlates well with the presence of IgG2a ICs, but not IgG2a alone, strongly implicating this as the natural autoantigen. Moreover, IgG2a anti-chromatin levels, but not IgG2a alone, also correlate with conversion, extending earlier in vitro data (25,29) by implicating a unique role for chromatin-containing ICs in activating RF B cells in vivo. Taken together, our work provides a comprehensive window into the early events of the spontaneous activation of an autoAb response.…”

Section: Discussionsupporting

confidence: 71%

“…AM14 B cells are stimulated to proliferate in vitro much more efficiently by IgG2a anti-chromatin/chromatin-containing ICs than by various control ICs, likely a result of signaling via TLR9 (25,29). Unlike total IgG2a levels (Fig.…”

Section: Converted Mice Have Higher Levels Of Igg2a a Immune Complexementioning

confidence: 99%

“…Anti--alkaline phosphatase and anti-IgG2a-alkaline phosphatase (Southern Biotechnology Associates) were used as secondary Abs. IgG2a ICs were measured using a C1q binding assay previously described (25), with anti-IgG2a as the secondary Ab. 22 and our unpublished observation).…”

Section: Elisas Elispot Assays and Ic Detectionmentioning

confidence: 99%

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Visualizing the Onset and Evolution of an Autoantibody Response in Systemic Autoimmunity

William

Euler

Leadbetter

et al. 2005

The Journal of Immunology

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The onset of systemic autoimmunity is variable, making it difficult to identify early events. In this study, we show in rheumatoid factor (RF) Ig-transgenic autoimmune-prone mice that the appearance of RF B cells in blood signifies the onset of RF B cell activation in spleen, providing a novel window into the initiation of an autoantibody response. This allowed us to study the early and late phases of spontaneous induction of the B cell autoimmune response. Using this approach we showed that extensive Ab-forming cell generation in spleen, accompanied by somatic hypermutation, occurred despite the lack of an early germinal center response. The onset of the RF response correlated with the levels of IgG2a-containing immune complexes but not total IgG2a. By identifying the time of onset in individual mice, we were able to track progression of disease. We found remissions of RF Ab-forming cell production in some mice, suggesting that at the clonal level, chronic autoantibody responses are dynamic and episodic, much like acute pathogen responses. Surprisingly, there was little accumulation of long-lived plasma cells in bone marrow of mice with long-standing RF responses in spleen. These studies are among the first to define the early events of a spontaneous B cell autoimmune response.

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Section: Discussionsupporting

confidence: 71%

Section: Converted Mice Have Higher Levels Of Igg2a a Immune Complexementioning

confidence: 99%

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Visualizing the Onset and Evolution of an Autoantibody Response in Systemic Autoimmunity

William

Euler

Leadbetter

et al. 2005

The Journal of Immunology

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“…For example, concomitant ligation of the BCR and TLR9 by chromatin:IgG immune complexes (ICs) activates RF-specific B cells in the absence of T cell help or overt TLR stimulation [38,59,60]. Signaling through both the BCR and TLR9 is necessary to activate NF-κB in these B cells [37].…”

Section: A Short History Of Smmentioning

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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“…nucleoproteins released during apoptosis), are expressed in large quantities in the vicinity of the germinal center [25]. If B lymphocytes are antigenindependent, the tolerance mechanisms involve Toll-like receptors (TLR7 and TLR9) and dendritic cells [26,27].…”

Section: B Lymphocyte Tolerancementioning

confidence: 99%

A brief insight into systemic lupus erythematosus pathogenesis

Azoicai¹,

Căruntu²

2016

Arch Clin Cases

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Systemic lupus erythematosus is an autoimmune disease which afflicts many systems. The precise pathogenesis is still unclear, but strong evidences sustain a multifactorial mechanism, based on the interaction of various genetic, epigenetic, environment, hormonal and immune-regulatory factors. Nowadays, the research interest focuses on cellular and molecular alterations, as results of the complexity of apoptotic process and immune responses acting as initiators and leading to tissue injury. The paper points out on key pathogenic cells, molecules and processes involved in SLE pathogenesis, namely B and T lymphocytes, mast cells, apoptosis, complement system and oxidative stress.

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Immune Complexes Present in the Sera of Autoimmune Mice Activate Rheumatoid Factor B Cells

Cited by 73 publications

References 54 publications

Visualizing the Onset and Evolution of an Autoantibody Response in Systemic Autoimmunity

Visualizing the Onset and Evolution of an Autoantibody Response in Systemic Autoimmunity

The regulation of autoreactive B cells during innate immune responses

A brief insight into systemic lupus erythematosus pathogenesis

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