Rheumatoid arthritis is associated with signaling alterations in naturally occurring autoreactive B-lymphocytes

Abstract

Immune tolerance established during the development of B lymphocytes can be subverted in mature cells and lead to autoimmunity. This study focuses on the recently discovered subset of CD19+CD27−IgD+IgMlow/− B cells that recognize self-antigens and have the capacity to produce autoantibodies, but under normal conditions do not generate autoimmune response due to intrinsic signaling inhibition (a condition known as clonal anergy and characterized by impaired antigen receptor signaling). Phosphorylation of intracellular signaling proteins and Ca2+ responses in anergic B cells were measured by multicolor flow cytometry. Our results demonstrate a distinct phosphoryation pattern for major signal transduction proteins, which distinguishes anergic B cells. Comparison of B cell signaling properties in Rheumatoid Arthritis patients and healthy controls revealed a reversal of pTyr and Ca2+ anergic signaling features in patients, accompanied by phosphorylation decreases of Blnk, Syk, SHP2, CD19. We identified BCR signaling pathway alterations associated with the loss of anergic B cell tolerance in Rheumatoid Arthritis.

B Cell Receptor Signaling-Based Index as a Biomarker for the Loss of Peripheral Immune Tolerance in Autoreactive B Cells in Rheumatoid Arthritis

“…However, RA subjects exhibited substantially increased phosphoprotein responses to BCR stimulation in the CD19 + CD27 − IgD + IgMl low/− B cell subset, as compared to normal controls (total pTyr mean±SE % increase of 121.4±30.6 vs. 22.5±31.0 in RA and control groups, respectively (p = 0.05)), suggesting that the breach of PIT in RA patients occurs regardless of the age (data previously reported [2]). …”

“…We have established the loss of PIT in autoreactive B ND cells as a contributing factor in the development of RA and demonstrated that inhibitory BCR signaling cascades involved in the maintenance of PIT are altered in RA [2]. According to the central hypothesis of our study (Figure 1), in healthy individuals, autoreactive B ND cells that have escaped the mechanisms of central tolerance maintain the peripheral immune tolerance (PIT) to ubiquitous autoantigens through continuous receptor tuning and BCR signaling inhibition, and our results demonstrate that this tolerogenic mechanism is compromised in RA.…”

“…After the recent definitive reports on the postdevelopmantally tolerized autoreactive B ND cell subset in humans [2], [27], [28], new evidence has emerged suggesting that PIT sustained via tolerogenic BCR signaling inhibition is present in a much larger fraction of human B cells than previously thought, and this reflects a state of peripheral immune tolerance induced by the chronic autoantigen stimulation [28]. Recent studies in RA patients also revealed the increased frequency of B cells with PIT producing germline autoreactive antibodies, which recognize nuclear and cytoplasmic structures [29].…”

Regulatory CD4+ T Cells Promote B Cell Anergy in Murine Lupus

“…Autoreactive lupus B cells with an anergic phenotype could have an abnormally prolonged lifespan, being neither activated nor deleted (23). Of interest, a loss of anergy in T3 B cells has been observed in autoimmune diseases such as collageninduced arthritis and rheumatoid arthritis (24)(25)(26), suggesting that the generation and survival of anergic B cells requires a fine control to avert autoimmunity. 2+ flux was measured after BCR stimulation in NZB/W mice (dark gray) and in CW controls (light gray).…”

Stem Cell Therapy in Autoimmune Rheumatic Diseases: a Comprehensive Review

“…The etiology of ARD is unknown. Dysregulation of innate and adaptive immunity [2], breaking of tolerance [3][4][5], production of autoantibodies [6][7][8][9], and generation of autoreactive T and B cells [10][11][12], lead to necrosis, scaring, and organ dysfunction and account for many of the clinical manifestations of ARD [13,14]. Due to the complexity of the pathogenesis, there is no universal therapeutic approach that is effective for all cases of ARD.…”