Anti-Sm B Cell Differentiation in Ig Transgenic MRL/Mp-<i>lpr</i>/<i>lpr</i>Mice: Altered Differentiation and an Accelerated Response

Santulli-Marotto, Sandra; Qian, Yuping; Ferguson, S E; Clarke, Stephen H.

doi:10.4049/jimmunol.166.8.5292

Cited by 42 publications

(41 citation statements)

References 51 publications

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“…A similar finding was seen in mice expressing the neo-self Ag HEL in the thymus, where HEL-specific B cells were not tolerized, yet partial tolerance to HEL existed in the T cell compartment (43). In contrast to the significant B cell tolerance that exists to the lupusassociated autoantigens DNA and Sm (6,44,45), this finding suggests that even though hLa-or HEL-specific autoreactive B cells are not directly tolerized, the development of humoral autoimmunity is constrained by a deficiency of functional autoreactive Th cells. Under these circumstances, self-reactive B cells are not strictly ignorant, in that they appear to take up endogenous autoantigen constitutively and are capable of Ag presentation to T cells.…”

Section: Anti-hla B Cells and Clonal Ignorancecontrasting

confidence: 46%

“…The data suggest that the maturation of hLa-specific B cells is comparable in the presence and the absence of endogenous expression of hLa autoantigen. This finding is in contrast to the anti-Sm/anti-ssDNA Tg model, where the majority of peripheral autoreactive B cells appeared to be arrested at the T-1 transitional B cell stage (4,6). Overall, therefore, the CD23 and CD24 phenotype data suggest that the presence of the hLa autoantigen in surface IgM levels were examined using three-color FACS analysis of splenic lymphocytes from anti-hLa and hLa ϫ anti-hLa Tg mice.…”

Section: Anti-hla B Cells Mature and Populate The Periphery Normally mentioning

confidence: 59%

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Tolerance through Indifference: Autoreactive B Cells to the Nuclear Antigen La Show No Evidence of Tolerance in a Transgenic Model

Aplin

Keech

Kauwe

et al. 2003

The Journal of Immunology

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Systemic autoimmune diseases are characterized by the production of high titer autoantibodies specific for ubiquitous nuclear self-Ags such as DNA, Sm, and La (SS-B), so the normal mechanisms of B cell tolerance to disease-associated nuclear Ags have been of great interest. Mechanisms of B cell tolerance include deletion, anergy, developmental arrest, receptor editing, and B cell differentiation to the B-1 subtype. However, recent studies in our laboratory have suggested that B cell tolerance to the nuclear autoantigen La is limited in normal mice, and tolerance may reside primarily in the T cell compartment. To test this hypothesis, we created Ig transgenic mice expressing the IgM H chain from an mAb specific for a xenogeneic epitope within human La (hLa). These mice were bred with hLa-transgenic mice that constitutively express hLa in a manner comparable to endogenous mouse La. Between 5–15% of transgenic B cells developing in the absence of hLa were specific for hLa, and these cells were neither depleted nor developmentally arrested in the presence of endogenous hLa expression. Instead, these autoreactive B cells matured normally and differentiated into Ab-forming cells, capable of secreting high titer autoantibody. Additionally, the life span of autoreactive hLa-specific B cells was not reduced, and they were phenotypically and functionally indistinguishable from naive nonautoreactive hLa-specific B cells developing in the absence of hLa. Together these data suggest a lack of intrinsic B cell tolerance involving any known mechanisms indicating that these autoreactive B cells are indifferent to their autoantigen.

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Section: Anti-hla B Cells and Clonal Ignorancecontrasting

confidence: 46%

Section: Anti-hla B Cells Mature and Populate The Periphery Normally mentioning

confidence: 59%

Tolerance through Indifference: Autoreactive B Cells to the Nuclear Antigen La Show No Evidence of Tolerance in a Transgenic Model

Aplin

Keech

Kauwe

et al. 2003

The Journal of Immunology

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“…A defect in the B-1 differentiation might thus be a factor in the loss of tolerance to Sm and provide insight into the low prevalence of the anti-Sm response in murine and human SLE [86]. Furthermore, manipulation of the coreceptors CD19 and CD22 in this system, confirmed that the differentiation of B-1 and tolerance is dependent on the strength of the BCR signalling.…”

Section: Role Of Polymorphism In Signalling Molecules In Determining mentioning

confidence: 54%

Recent Progress in the Understanding of B‐Cell Functions in Autoimmunity

Porakishvili

Mageed

Jamin³

et al. 2001

Scand J Immunol

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54:30±38Our early concepts of the normal role of B cells in immunity focused on their ability to produce antibodies (Ab) and in the case of autoimmune diseases autoAbs, some of which were pathogenic. Over the past 10 years, it has became apparent that B cells display a variety of characteristics, other than Ab production, which could contribute to autoimmunity. They normally play a role in the development of lymphoid architecture, regulating T-cell subsets and dendritic cell (DC) function through cytokine production, and in activation of T cells. Receptors editing is also important in B cells which aids in immunity to infection and, possibly, prevention of autoimmunity. Transgenic animal models have now shown that B cells are necessary for many autoimmune diseases although their Ab products are not required in some cases. Negative signalling by CD5 and other molecules, such as CD22, in maintaining tolerance through recruitment of src-homology two domaincontaining protein tyrosine phosphatase-1 has also been documented. In fact, we have now reached a new era whereby the B cell has returned as an important contributor to autoimmune disorders, so that the race is on to characterize signalling regulation via the B-cell receptor and coreceptors. Identification of such molecules and their potential defects should lead to effective ways of controlling the immune response and in particular preventing the development of autoimmune states. The classical view of B cells in the biology of immune responses to infectious and self-antigens (Ag) that they promote immunity primarily by producing Ab turns out to be rather naõ Ève. Indeed, studies over the last few years indicate that this view is far from complete, and suggest that B lymphocytes have extraordinarily diverse functions within the immune system. Furthermore, it is becoming increasingly clear that the pathogenesis of autoimmune diseases cannot solely be accounted for by T cells, and intrinsic abnormalities of B cells have been described in such conditions. In this brief review we highlight some recent observations in the context of B lymphocyte in pathophysiology, and focus on their revival as pivotal players the pathophysiology in autoimmune diseases. Yet, it remains difficult to provide a model of how important B cells are in immunity and autoimmunity.

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“…Previous studies have shown that B cells can display an activated phenotype despite being unresponsive to specific Ags in models of anergy (34,35). To investigate whether B cells expressing hCR2 adopt a similar phenotype, we examined a battery of activation markers on unstimulated B cells in the spleen and blood of hCR2-tg mice.…”

Section: Activation Markers Cd44 and Mhc Class II Are Significantly Imentioning

confidence: 99%

B Cells from Mice Prematurely Expressing Human Complement Receptor Type 2 Are Unresponsive to T-Dependent Antigens

Birrell

Kulik

Morgan

et al. 2005

The Journal of Immunology

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Complement receptor type 2 (CR2/CD21), in association with CD19, plays an important role in enhancing mature B cell responses to opsonized Ags. We have shown that mice expressing a human CR2/CD21 (hCR2/CD21) transgene during the CD43+/CD25− late pro-B cell stage of B cell development demonstrate marked changes in subsequent B cell ontogeny. In the present study, we show that the humoral immune response to the T cell-dependent Ag, sheep RBC, is muted severely in a manner inversely proportional to B cell expression level of hCR2. Individual Ag-specific IgG isotypes vary in the degree to which they are affected but all are reduced while IgM titers are normal. A substantial reduction in germinal centers, both in size and frequency, in the spleens of immunized hCR2 transgenic mice demonstrates a failure to maintain germinal center reaction. However, both IgM expression levels and LPS-proliferative responses appear fully intact in B cells from hCR2-positive mice, suggesting that this alteration in B cell phenotype is different qualitatively from that of specific Ag-defined anergy models. These data suggest that the unresponsiveness to T-dependent Ags displayed by hCR2-positive B cells is linked to an increase in the level of stimulus required to propel the B cell into a fully activated state and thus a normal humoral immune response to Ags. We conclude that this phenotype and these mice may offer an additional means to dissect mechanisms underlying B cell tolerance and Ag responsiveness both in bone marrow and periphery.

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Anti-Sm B Cell Differentiation in Ig Transgenic MRL/Mp-lpr/lprMice: Altered Differentiation and an Accelerated Response

Cited by 42 publications

References 51 publications

Tolerance through Indifference: Autoreactive B Cells to the Nuclear Antigen La Show No Evidence of Tolerance in a Transgenic Model

Tolerance through Indifference: Autoreactive B Cells to the Nuclear Antigen La Show No Evidence of Tolerance in a Transgenic Model

Recent Progress in the Understanding of B‐Cell Functions in Autoimmunity

B Cells from Mice Prematurely Expressing Human Complement Receptor Type 2 Are Unresponsive to T-Dependent Antigens

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