B cells from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal transduction events.

Liossis, S.-N.; Kovacs, Birgit; Dennis, Greg; Kammer, Gary M.; Tsokos, George C.

doi:10.1172/jci119073

Cited by 207 publications

(146 citation statements)

References 78 publications

Supporting

Mentioning

136

Contrasting

Unclassified

Order By: Relevance

“…The inability to properly terminate activation may therefore result in inappropriate responses. In this regard, it has been shown in SLE that B cells have abnormal Ag receptor-mediated early signal transduction events [68]. The authors showed that following the Ag receptor ligation, Ca 21 responses and PTK phosphorylation were abnormally high compared with other autoimmune diseases and controls.…”

Section: B-cell Signallingmentioning

confidence: 98%

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

Porakishvili

Mageed

Jamin³

et al. 2001

Scand J Immunol

View full text Add to dashboard Cite

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.

show abstract

Section: B-cell Signallingmentioning

confidence: 98%

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

Porakishvili

Mageed

Jamin³

et al. 2001

Scand J Immunol

View full text Add to dashboard Cite

show abstract

“…Altered expression of B cell receptor (BCR)-signaling molecules, such as CD19, CD22, CD45, Lyn, SHIP, and SHP-1, has been described in human autoimmune conditions (19)(20)(21)(22). It has also been reported that B lymphocytes from SLE patients exhibit abnormal intracellular calcium mobilization after BCR stimulation (23).…”

mentioning

confidence: 99%

Association of a four–amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: Molecular and functional analysis

Otsuka

Horiuchi

Yoshizawa

et al. 2004

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To investigate whether polymorphism(s) or mutation(s) in the hematopoietic cellspecific Lyn substrate 1 (HS1) gene are involved in the pathogenesis of systemic lupus erythematosus (SLE).Methods. The entire coding region of the HS1 gene was analyzed by reverse transcriptase-polymerase chain reaction/single-strand conformational polymorphism analysis. HS1-transfected WEHI-231 cells or B lymphocytes from patients with SLE were studied for apoptosis, activation, and proliferation by flow cytometric analysis and MTT assay.Results. We identified a glutamic acid-prolineglutamic acid-proline insertion between codons 366 and 367 (EPEP366-367ins) and 2 amino acid substitutions (A235T and E361K). The genotype frequency among individuals homozygous for the EPEP؉ allele was 0.184 in 201 patients with SLE but only 0.098 in 184 healthy individuals (P ‫؍‬ 0.016). The allele frequency of EPEP366-367ins was 0.408 in patients with SLE; this frequency was significantly higher than that in healthy controls (0.312) (P ‫؍‬ 0.006). WEHI-231 cells transfected with EPEP؉ HS1 were 100-fold more sensitive to B cell receptor (BCR)-mediated apoptosis than were those transfected with HS1 without EPEP. B lymphocytes from SLE patients with the EPEP؉ allele were significantly more apoptotic without BCR stimulation and less activated after BCR stimulation than were those from SLE patients without the EPEP allele. Conclusion. These results suggest that HS1 with the EPEP insertion polymorphism transmits accelerated signals from BCR and is involved in the pathogenesis of SLE.Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the presence of a variety of autoantibodies. Various genetic and environmental factors, including B cell hyperactivity, T cell dysfunction, and cytokine dysregulation, initiate immune activation in SLE that culminates in organ inflammation and damage (1-9). It has been considered that B cells are innocent bystanders that are activated secondarily by autoreactive T lymphocytes. However, recent evidence from the study of human SLE and its murine models suggests that B lymphocytes are intrinsically defective and are primarily essential for the maintenance of activated/memory T cells by presenting antigens to T cells.B cells from mice deficient in Lyn (10-12), CD22 (13-16), SHP-1 (17,18) exhibit a hyperreactive phenotype and produce autoantibodies. Indeed, Lyn-deficient mice demonstrate activation of autoreactive B cells and subsequent SLE-like symptoms, such as the production of anti-double-stranded DNA (anti-dsDNA)

show abstract

“…There are indications that abnormal B cell signaling may contribute to autoimmune diseases in humans as well. In patients with lupus, stimulation of circulating B cells through their surface IgM (sIgM) produces significantly higher Ca 2ϩ fluxes as compared with similarly induced responses of B cells from patients with other systemic rheumatic diseases (40). The overall level of sIgM-initiated protein tyrosyl phosphorylation was also significantly enhanced in peripheral B lymphocytes, and correlated with the augmented BCR-mediated, free Ca 2ϩ responses.…”

Section: Bcr Signaling Alterations In Humansmentioning

confidence: 99%