B-Cell Kinase Lyn Deficiency in Patients with Systemic Lupus Erythematosus

Liossis, Stamatis–Nick C.; Solomou, Elena E.; Dimopoulos, Meletios-Athanasios; Panayiotidis, Panayiotis; Mavrikakis, Myron; Sfikakis, Petros P.

doi:10.2310/6650.2001.34042

Cited by 121 publications

(101 citation statements)

References 35 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the case of the T cell receptor, the zeta chain of the CD3 complex is aberrantly expressed in a subset of SLE patients, which has been implicated in tolerance disruption (48,49). In fact, the phosphorylation patterns of several proteins of T and B lymphocytes are altered in patients with SLE (20)(21)(22)47,50), which suggests that signaling pathways, including protein kinases and phosphatases, are defective in these patients.…”

Section: Discussionmentioning

confidence: 99%

“…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) antibodies, splenomegaly, and glomerulonephritis (11,12). 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%

See 1 more Smart Citation

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

Section: Discussionmentioning

confidence: 99%

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

show abstract

“…In further studies, the content of Lyn, CD45, and SHP-1 in lupus B cells was found to be significantly altered in patients (41,42). Investigation of gene polymorphisms in the Japanese population suggested that CD22 could be considered a candidate susceptibility gene for autoimmune diseases (43).…”

Section: Bcr Signaling Alterations In Humansmentioning

confidence: 93%

“…Investigation of gene polymorphisms in the Japanese population suggested that CD22 could be considered a candidate susceptibility gene for autoimmune diseases (43). Although the function of the CD22/Lyn signaling-inhibitor complex was not addressed (41,42), it is likely that the decreased expression of Lyn in SLE B cells may contribute to the B cell overactivity. Consistent with studies in rodents showing that a 20% overexpression of CD19 induced autoantibody production in normal mice, expression of CD19 and CD21 levels were shown to be 20% higher on B cells from patients with systemic sclerosis compared with healthy individuals (17).…”

Section: Bcr Signaling Alterations In Humansmentioning

confidence: 99%

B lymphocyte signaling pathways in systemic autoimmunity: Implications for pathogenesis and treatment

Zouali¹,

Sármay

2004

Arthritis & Rheumatism

View full text Add to dashboard Cite

“…In this respect, a recent study of Lyn expression has shown about two-thirds of patients with SLE have reduced levels of Lyn in their B lymphocytes. 72 …”

Section: B-lymphocytesmentioning

confidence: 99%

Immunopathology and the gene therapy of lupus

Mageed

Prud’homme

2003

Gene Ther

View full text Add to dashboard Cite

B-Cell Kinase Lyn Deficiency in Patients with Systemic Lupus Erythematosus

Abstract: Decreased expression of Lyn in some patients with SLE represents a B-cell defect that may enhance our understanding of SLE molecular pathogenesis by providing rational therapeutic targets.

Cited by 121 publications

References 35 publications

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

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

B lymphocyte signaling pathways in systemic autoimmunity: Implications for pathogenesis and treatment

Immunopathology and the gene therapy of lupus

Contact Info

Product

Resources

About