Steady-state generation of mucosal IgA+ plasmablasts is not abrogated by B-cell depletion therapy with rituximab

Abstract

IntroductionPlasmablasts are an immediate product of B-cell activation that home either to the bone marrow or to the mucosa to secrete antibody as terminally differentiated plasma cells. [1][2][3] In healthy persons, B cells and antibodies protect from pathogens, whereas loss of immunologic tolerance and malignant transformation result in the generation of autoreactive B cells and autoantibody production and development of lymphoma, respectively. Direct targeting of B cells by the chimeric anti-human CD20 antibody rituximab (RTX) has been developed for the treatment of rheumatoid arthritis (RA) and B-cell malignancies. 4,5 However, not all patients respond to RTX therapy, and the efficiency of B-cell depletion in lymphoid tissues as well as the susceptibility of different B-cell subtypes remain of central interest, in particular related to individual unresponsiveness.In RA, depletion of peripheral CD20 ϩ B cells reduces, but does not eliminate, autoimmunity, indicated by subsequent flares and continuous production of autoantibodies. 6 Persisting (auto-) antibodies in patients treated with RTX reflect the continued presence of antibody-secreting cells, whereas it remains unclear whether those are long-lived, CD20 Ϫ plasma cells, eg, residing in the bone marrow, or whether they have been generated de novo from B cells not depleted by RTX. In this context, germinal center B cells of the Peyer patches and peritoneal B1 B cells resisted to RTX treatment in human cd20 tg mice. 7 Depletion of B cells from human lymphoid tissues of systemic immunity, for example, the spleen and lymph nodes by RTX has been described in individual cases. [8][9][10] Thus, the efficiency of global or selective B-cell depletion remains of interest, in particular whether there is a distinct susceptibility of B-cell subsets to RTX within gut-associated lymphoid tissues (GALT).Here, we demonstrate the continued presence of dividing and migratory plasmablasts expressing a mucosal phenotype in the peripheral blood of patients with RA consistent with steady-state plasmablasts 1 after treatment with RTX. These data show that a subset of chronically activated mucosal B lymphocytes carrying highly mutated V H gene rearrangements and secreting antimicrobial immunoglobulin A (IgA) are not deleted by RTX. This reflects the robustness of humoral mucosal immunity during B-cell depletion with RTX and underscores the independent regulation of mucosal immune responses in steady state. The resistance of some mucosal B cells to RTX is apparently not stringently related to RA pathogenesis but could represent a mechanism underlying enhanced RTX resistance in some mucosa-associated lymphoid tissue lymphoma cases. 11,12 Methods A detailed description of the patients, samples, and methods are available as supplemental Methods (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). An Inside Blood analysis of this article appears at the front of this issue.The online version of this article contains a data supplement....

Antibody repertoire analysis in polygenic autoimmune diseases

“…In a study of patients with active SLE given rituximab, clonally related B‐cells were found to be persistent in all seven patients, but not found in any of the four age‐matched healthy controls 53. This is consistent with preferential depletion of naïve and CD20 high B‐cells, with the surviving B‐cell population consisting of CD20 low B‐cells, including plasmablasts60 and mucosal IgA + plasmablasts that are not removed by B‐cell depletion therapy. As yet, however, there has been no large‐scale analysis of BCR usage in a large number of patients on ‘standard‐of‐care’ non‐B‐cell depleting therapy.…”

“…Within the IgG memory B‐cell population, there was no significant change in IGHV, D or J gene usage, CDR3 region length or charge before and after therapy. However, the frequencies of clonally expanded IgG memory B‐cells significantly increased after therapy, corresponding to preferential depletion of naïve and CD20 high B‐cells, with the remainder low‐level B‐cell population consisting of CD20 low B‐cells, including plasmablasts 60. However, further studies are required to determine the differences between therapies and if there are B‐cell repertoire features associated with remission and long‐term outcome.…”

Pragmatic Treatment of Patients With Systemic Lupus Erythematosus With Rituximab: Long‐Term Effects on Serum Immunoglobulins

“…Early recovery in serum IgA levels suggests that the IgA plasma cell pool was rapidly replenished. It has previously been reported that circulating IgA+ plasmablasts can remain detectable early after rituximab, suggesting resistance to depletion of switched IgA+ precursor B cells, likely in the mucosal microenvironment and/or early regeneration 52. Serum IgG levels, despite showing a longer “lag” when compared with the recovery of serum IgA levels, was apparently also sustainable, attaining pretreatment levels in most patients by 12 months after rituximab.…”

Optimising treatment in rheumatoid arthritis: a review of potential biological markers of response

“…Notably, another recent report90 demonstrated that precursors of CD19+/IgA+ plasma blasts, which are continuously circulating in ‘steady state’,91 were not completely depleted by rituximab. While there was no relation to RA disease activity, these plasma blasts can produce protective mucosal IgA consistent with the lack of increased mucosal infections during rituximab treatment.…”