Murine lupus in MRL/<i>lpr</i> mice lacking CD4 or CD8 T cells

Koh, David; Ho, Alexandra; Rahemtulla, Amin; Fung-Leung, Wai-Ping; Griesser, Henrik; Mak, T. W.

doi:10.1002/eji.1830250923

Cited by 134 publications

(81 citation statements)

References 28 publications

(12 reference statements)

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“…Indeed, the evidence that autoantibody production in murine lupus is T cell dependent is quite solid, stemming initially from the demonstration that neonatal thymectomy of lupus-prone mice led to abrogation of IgG anti-double-stranded DNA synthesis and glomerulonephritis, and to improved mortality (13). Similar results were obtained after treatment of these animals with antibodies that depleted total T cells (14) or that selectively depleted CD4+ cells (15), findings that were confirmed in genetic studies by neonatal elimination of CD4+ or T cell receptor (TCR) alp+ T cells in lupus-prone mice using homologous recombination (gene knockouts) (16)(17)(18). It should be noted, however, that these latter experiments demonstrated that non-alp T cells, including ylS T cells, do have the capacity to support autoantibody production, although such antibodies have markedly reduced pathogenicity; it is not known if they are somatically hypermutated (18,19).…”

Section: T Cells Are Required For Autoantibody Synthesis In Murine Ansupporting

confidence: 58%

Self antigens and epitope spreading in systemic autoimmunity

Craft

Fatenejad

1997

Arthritis & Rheumatism

131

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Section: T Cells Are Required For Autoantibody Synthesis In Murine Ansupporting

confidence: 58%

Self antigens and epitope spreading in systemic autoimmunity

Craft

Fatenejad

1997

Arthritis & Rheumatism

131

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Section: Arresting and Silencing Sm-specific B Cellsmentioning

confidence: 99%

“…Early studies showed a critical role for T cells in disease because thymectomized MRL/lpr mice failed to develop lupus-like disease [95]. Subsequently, it was shown that defects in central deletion and the number and function of T-regulatory cells allow CD4 + Thelper cells to activate autoreactive B cells, induce terminal differentiation and autoantibody production [96][97][98][99][100][101].Dysregulation of the innate immune system is apparent in MRL/lpr mice [39]. ICs containing RNA or chromatin stimulate RF-specific B cells through TLR7 and TLR9 to secrete anti-Sm and anti-chromatin [38,39].…”

mentioning

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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“…Another possibility is that the lack of conventional MHC class I-restricted CD8 + T cells is responsible for the increased skin disease in g 2m-deficient MRL-lpr mice. However, CD8-deficient MRL-lpr mice have no increase in skin disease, at least until 16 weeks of age [13]. A third possibility is that a deficiency in regulatory CD1d-dependent natural killer T (NKT) cells is responsible for the increased skin disease in g 2m-deficient MRL-lpr mice.…”

Section: Introductionmentioning

confidence: 99%

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

et al. 2004

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Mechanisms responsible for the development of autoimmune skin disease in humans and animal models with lupus remain poorly understood. In this study, we have investigated the role of CD1d, an antigen-presenting molecule known to activate natural killer T cells, in the development of inflammatory dermatitis in lupus-susceptible MRL-lpr/lpr mice. In particular, we have established MRL-lpr/lpr mice carrying a germ-line deletion of the CD1d genes. We demonstrate that CD1d-deficient MRL-lpr/lpr mice, as compared with wild-type littermates, have more frequent and more severe skin disease, with increased local infiltration with mast cells, lymphocytes and dendritic cells, including Langerhans cells. CD1d-deficient MRL-lpr/ lpr mice had increased prevalence of CD4 + T cells in the spleen and liver and of TCR § g + B220 + cells in lymph nodes. Furthermore, CD1d deficiency was associated with decreased T cell production of type 2 cytokines and increased or unchanged type 1 cytokines. These findings indicate a regulatory role of CD1d in inflammatory dermatitis. Understanding the mechanisms by which CD1d deficiency results in splenic T cell expansion and cytokine alterations, with increased dermal infiltration of dendritic cells and lymphocytes in MRL-lpr/lpr mice, will have implications for the pathogenesis of inflammatory skin diseases.

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Murine lupus in MRL/lpr mice lacking CD4 or CD8 T cells

Cited by 134 publications

References 28 publications

Self antigens and epitope spreading in systemic autoimmunity

Self antigens and epitope spreading in systemic autoimmunity

The regulation of autoreactive B cells during innate immune responses

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

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