Membrane Ig-mediated triggering of B cell tolerance and B cell clonal expansion: Implications for rheumatoid factor production in rheumatoid synovitis

Mongini, Patricia K. A.; Rudich, Steven M.

doi:10.1007/bf00197185

Cited by 3 publications

(1 citation statement)

References 121 publications

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“…Further experiments based on 2D electrophoresis techniques are necessary and should focus on selected material such as the pannus area, histologically defined areas of the synovial membrane or isolated or cloned Tor B-lymphocytes [57,58] taken from human synovial membrane or mouse model systems [59] or focus on the demonstration of cytokines or monokines involved in the pathogenesis of RA [60]. These approaches may be helpful in pin-pointing subtle differences in the protein pattern between RA and osteoarthritis patients.…”

Section: Discussionmentioning

confidence: 97%

Two-dimensional electrophoresis of synovial tissue, synovial fluid and serum in patients with rheumatoid arthritis and related diseases

et al. 1990

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Using the technique of two-dimensional (2D) electrophoresis with consecutive silver staining, we investigated samples of serum, synovial fluid and synovial tissue obtained from 19 patients suffering from rheumatoid arthritis (RA) or non-RA arthritis. From these experiments we have drawn the following conclusions. 2D electrophoresis of serum, synovial fluid and synovial tissue extracts taken from patients suffering from joint diseases is a reproducible method. Repeated runs of the same sample reveal an essentially constant protein spot pattern. The time period between surgery and tissue preparation did not influence the number of protein spots when less than 15 h was involved. The protein spot number is always lower in synovial fluid than in either synovial tissue or serum in RA and non-RA patients. The mean value for the number of spots is 68 for the inflamed tissue irrespective of the cause of arthritis (RA and non-RA group taken together) and 47 for the control group. This difference is significant. We were able to definitely identify 7 spots in the tissue extract. We did not find RA-specific protein spots in either serum, synovial fluid or tissue extracts from the synovial membrane. The only significant difference between RA patients and either non-RA or control group patients concerning the protein spot pattern is the increased size of the immunoglobulin spot (mainly IgG) in RA. In addition, we discuss possible reasons for failure of the 2D electrophoresis technique to detect disease-specific protein patterns.

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Section: Discussionmentioning

confidence: 97%

Two-dimensional electrophoresis of synovial tissue, synovial fluid and serum in patients with rheumatoid arthritis and related diseases

et al. 1990

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Affinity requirements for induction of sequential phases of human B cell activation by membrane IgM-cross-linking ligands.

Mongini

Blessinger

Dalton

1991

The Journal of Immunology

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The affinity of Ag interaction with a B cell's membrane IgM (mIgM) receptors has long been considered to play a critical role in the in vivo clonal selection of B lymphocytes. This study has examined a possible basis for this affinity selection at the level of Ag induction of sequential B cell activation phenomena, i.e., elevated membrane class II MHC expression (G0* excitation), G1 entry, and S phase entry. Functional experiments with model bivalent Ag, i.e., a group of murine mAb of diverse intrinsic binding affinities for human IgM, revealed that the minimal affinity requisites for inducing the above phenomena vary significantly. At a ligand concentration of 100 micrograms/ml, the induction of increased class II MHC expression, G1 entry, and S phase had minimal affinity thresholds of Ka approximately 0.2 to 2 x 10(6) M-1; approximately 7 x 10(6) M-1; and approximately 1 x 10(8) M-1, respectively. Pulsing studies revealed that whereas high affinity ligand was essential at later periods in the prolonged (greater than 24 h) signaling period that leads to S phase entry, mAb with significantly lower affinity were competent at signaling during the first 24 h. Because all but the lowest affinity ligand (Ka = 2 x 10(5) M-1) could effectively modulate mIgM, and furthermore, because B cells show a substantial increase in surface area during activation, it appears likely that one factor contributing to the higher affinity requirements for induction of late activation phenomena is a progressive decrease in the density of mIgM on the responsive B cells. These studies suggest that whereas only a small proportion of B cells, i.e., those with relatively high affinity for an antigenic epitope, will be triggered to clonally expand on encountering a paucivalent Ag in the absence of T cell help, a much wider spectrum of the B cell repertoire will be triggered to a state of partial activation. How the presence of ancillary T cells and cytokines may facilitate the full clonal expansion of these latter cells is discussed.

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Human B cell activation. Effect of T cell cytokines on the physicochemical binding requirements for achieving cell cycle progression via the membrane IgM signaling pathway.

Mongini

Highet²,

Inman³

1995

The Journal of Immunology

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Given the range of mIg-binding affinities expressed by Ag-specific B cells, the ligand:receptor affinity threshold for achieving full B cell activation via the mIgM-mediated signaling pathway is quite high. Several recombinant, or semi-purified, cytokines were found to reduce the very high mIgM:ligand affinity threshold for induction of human B cell S phase entry by bivalent, affinity-diverse anti-IgM mAbs without notably affecting the lower affinity threshold for G1-related RNA synthesis. Two-stage culture experiments suggested that one major means by which IL-4, IL-2, and low m.w. B cell growth factor lower the affinity threshold for S phase entry is an indirect one, i.e., rescue of B cells whose mIg engagements with Ag are of sufficient affinity for achieving G1 entry, but of insufficient affinity for initiating the late-phase mIgM-mediated signals needed for the G1-->S phase transition. IL-4 had additional effects in early G1. In contrast to the above cytokines, IFN-gamma, did not function as an independent cell cycle progression factor, but rather required the concomitant presence of mIgM-cross-linking ligand for enhancement. A greater potential of multivalent anti-IgM-dextran conjugates to trigger S phase entry in the absence of cytokines was found to reflect a greater potential for initiating mIgM signals during the late phase in B cell activation. The results indicate that progression of mIgM receptor-activated B cells past a G1-->S phase restriction point is dependent upon continued signal transduction via either the mIgM receptor and/or a cytokine receptor signaling pathway. When mIgM-engaging ligands are ineffective at initiating late-phase signals, due to limited size and binding site valency and/or affinity, ancillary signal transduction through cytokine receptors becomes most relevant.

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Membrane Ig-mediated triggering of B cell tolerance and B cell clonal expansion: Implications for rheumatoid factor production in rheumatoid synovitis

Cited by 3 publications

References 121 publications

Two-dimensional electrophoresis of synovial tissue, synovial fluid and serum in patients with rheumatoid arthritis and related diseases

Two-dimensional electrophoresis of synovial tissue, synovial fluid and serum in patients with rheumatoid arthritis and related diseases

Affinity requirements for induction of sequential phases of human B cell activation by membrane IgM-cross-linking ligands.

Human B cell activation. Effect of T cell cytokines on the physicochemical binding requirements for achieving cell cycle progression via the membrane IgM signaling pathway.

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