Adhesion of Human B Cells to Germinal Centers in Vitro Involves VLA-4 and INCAM-110

Freedman, AS; Munro, J M; Rice, Gregory E.; Bevilacqua, Michael P.; Morimoto, Chikao; McIntyre, BW; Rhynhart, Kurt K.; Pober, J S; Nadler, LM

doi:10.1126/science.1697696

Cited by 281 publications

(133 citation statements)

References 51 publications

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“…VCAM-1 is a cell surface molecule expressed on endothelial cells mostly involved in rolling and homing of lymphocytes to inflammatory sites by binding to its ligand, very late antigen 4 (VLA-4) on T cells [38]. Moreover, VCAM-1 is also expressed on lymphoid DC [39,40] that participate in activation of resting CD4 + T cells [41]. Other important surface molecules such as the mannose receptor (MR) C type 1 and ficolin A were up-regulated, as were complement component 1q subunits (Supplemental Table 1).…”

Section: Resultsmentioning

confidence: 99%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire -/-dendritic cells (DC) activate naive T cells more efficiently than do Aire +/+ DC. Expression array analyses of Aire -/-DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire -/-DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire -/-DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire -/-DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire -/-mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35240_s.pdf IntroductionInactivation of the autoimmune regulator gene (AIRE) [1][2][3] causes autoimmunity in patients with autoimmune polyendocrine syndrome type I (APS I, APECED, OMIM 240300) and in a gene targeted mouse model [4,5]. APS I is a rare monogenic autosomal recessive disease without HLA association [6,7], which is prevalent in isolated populations [8][9][10]. APS I patients develop a progressive loss of tolerance against self antigens and suffer from multiorgan failures due to the immunological destruction of adrenals, parathyroid glands and b cells of the islets of Langerhans [11]. Many of the APS I organ-specific autoantigens have been identified and characterized [12,13]. In addition, as a sign of immune dysfunction, these patients have difficulties clearing Candida albicans infections in mucosal membranes [14]. Functional studies of AIRE suggest a role as a transcription factor and in vitro transactivating studies support this notion [15][16][17][18]. Moreover, the PHD1 domain of AIRE has been suggested to have an E3 ubiquitin ligase activity in cell-free assays [19], findings in variance with a recent report [20]. Aire is highly expressed in a subset of the medullary thymic epithelial cells (mTEC) as well as in DC in the spleen and lymph nodes [21][22][23][24], indicating a potential role in immunological tolerance.To characterize the function of Aire, we previously engineered an Aire-deficient mouse targeting the most common APS I mutation [4]. Aire-deficient mice develop multiple organ-specific autoantibodies and lymphocytic infiltrates, thus mimicking some of the features of human APS I [4]. Subsequently, the role of Aire in negative selection was demonstrated [5]. These findings were further supported using TCR transgenic mic...

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Section: Resultsmentioning

confidence: 99%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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“…A frozen section assay [11][12][13][14][15][16]19,20 was used to determine whether human B-CLL cells bind to distinct histologic compartments of human tonsils. Previously, clinically relevant data were provided with this assay by demonstrating that the in situ binding pattern of lymphoma cells was an indicator for the capacity of the tumor cells to metastasize in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Germinal centers of secondary lymphoid organs are filled with a dense network of antigen presenting follicular dendritic cells (FDCs) 13,[22][23][24] which have been identified as ligands for binding of B and T cells in vitro and in situ. [13][14][15][16]20,25,26 Interestingly, in situ binding of CLL cells was not mediated by integrin ␣ L ␤2, although this antigen was differentially expressed by these cells and has been shown to mediate germinal center binding of activated T cells. 16 Possibly, the affinity of integrin ␣ L ␤2 on CLL cells towards their respective ligands was too low to be detected by this assay.…”

Section: Discussionmentioning

confidence: 99%

“…The finding that peripheral blood B cells did not show anti-CD19-induced homotypic aggregation is consistent with earlier reports indicating that normal B cells need appropriate stimuli to exert binding in vitro. 13,14 We identified the adhesion pair integrin ␣ L /ICAM-1 and CD21 as the molecules that mediate the anti-CD19-induced aggregation of B-CLL cells. Interestingly, combinations of these mAbs blocked aggregation in more cases than individual antibodies did.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][14][15][16] Normal human tonsils, obtained from routine tonsillectomies, were snap frozen, cut (8 m), placed on microscope slides and dried overnight. B-CLL cells were applied at 2.4 × 10 7 cells/ml in 300 l adhesion medium (containing 2.4 mM MgCl 2 ) on tissue sections within a 2-cm diameter circle marked with a water-repellent 'Pap-pen' (Dako, Carpinteria, CA, USA) and were incubated under rotation (70 revolutions per min) for 20 min at room temperature.…”

Section: Frozen Section Binding Assaymentioning

confidence: 99%

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Differential adhesion pattern of B cell chronic lymphocytic leukemia cells

Behr

Korinth²,

Schriever³

1998

Leukemia

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Intercellular adhesion molecule-1 (ICAM-1) staining of reactive and neoplastic follicles. ICAM-1 expression of neoplastic follicle differs from that of reactive germinal center and is independent of follicular dendritic cells

Ree

Khan

Elsakr

et al. 1993

Cancer

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Background. Intercellular adhesion molecule‐1 (ICAM‐1) is expressed on follicular dendritic cells (FDC), and the ICAM‐1/LFA‐1 pathway is essential for affinity selection of activated B‐cells in germinal centers (GC). The expression of ICAM‐1 has been studied by immunostaining methods in GC, but not in neoplastic follicles (NF). Methods. The authors studied the expression of ICAM‐1 by the avidin‐biotin‐peroxidase complex (ABC) method with frozen sections in GC of reactive nodes (n = 22) and NF of follicular lymphomas (n = 19), in comparison with FDC staining. Results. GC stained uniformly for ICAM‐1, with staining intensity varying little from node to node, and follicular borders were well demarcated from the surroundings. Endothelial cells within GC did not stain whereas those outside stained strongly. In contrast, NF stained variably from tumor to tumor, and in any given tumor. Characteristically, follicular borders were not demarcated, and stained areas were difficult to define due to the lack of demarcation, with the exception of large cell type with diffuse areas (n = 2). Endothelium of intrafollicular vessels stained prominently (12 of 19), and appeared to contribute to the staining intensity of the follicles. FDC staining revealed a meshwork pattern in GC which was similar to that of ICAM‐1. The FDC meshwork pattern was present in 15 tumors. The pattern was remarkably uniform with sharply defined borders, which contrasted starkly to the variable staining and lack of follicular borders in the ICAM‐1 stain of the same tumors. Conclusions. The staining pattern of follicles for ICAM‐1 was similar to that for FDC in reactive nodes, but distinct from the latter in follicular lymphomas. An appropriate expression of ICAM‐1 appears to be essential for normal GC, as the alteration of the expression coincides with the malignant transformation of GC. The altered expression of ICAM‐1 may be useful in distinguishing NF from reactive GC.

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Adhesion of Human B Cells to Germinal Centers in Vitro Involves VLA-4 and INCAM-110

Cited by 281 publications

References 51 publications

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Differential adhesion pattern of B cell chronic lymphocytic leukemia cells

Intercellular adhesion molecule-1 (ICAM-1) staining of reactive and neoplastic follicles. ICAM-1 expression of neoplastic follicle differs from that of reactive germinal center and is independent of follicular dendritic cells

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