B cell depletion enhances T regulatory cell activity essential in the suppression of arthritis.

Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612, USA.
The Journal of Immunology (Impact Factor: 5.52). 09/2011; 187(9):4900-6. DOI: 10.4049/jimmunol.1101844
Source: PubMed

ABSTRACT The efficacy of B cell-depletion therapy in rheumatoid arthritis has driven interest in understanding the mechanism. Because the decrease in autoantibodies in rheumatoid arthritis does not necessarily correlate with clinical outcome, other mechanisms may be operative. We previously reported that in proteoglycan-induced arthritis (PGIA), B cell-depletion inhibits autoreactive T cell responses. Recent studies in B cell-depletion therapy also indicate a role for B cells in suppressing regulatory mechanisms. In this study, we demonstrate that B cells inhibited both the expansion and function of T regulatory (Treg) cells in PGIA. Using an anti-CD20 mAb, we depleted B cells from mice with PGIA and assessed the Treg cell population. Compared to control Ab-treated mice, Treg cell percentages were elevated in B cell-depleted mice, with a higher proportion of CD4(+) T cells expressing Foxp3 and CD25. On a per-cell basis, CD4(+)CD25(+) cells from B cell-depleted mice expressed increased amounts of Foxp3 and were significantly more suppressive than those from control Ab-treated mice. The depletion of Treg cells with an anti-CD25 mAb concurrent with B cell-depletion therapy restored the severity of PGIA to levels equal to untreated mice. Although titers of autoantibodies did not recover to untreated levels, CD4(+) T cell recall responses to the immunizing Ag returned as measured by T cell proliferation and cytokine production. Thus, B cells have the capacity to regulate inflammatory responses by enhancing effector T cells along with suppressing Treg cells.

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    ABSTRACT: B cells mediate multiple functions that influence immune and inflammatory responses in rheumatoid arthritis. Production of a diverse array of autoantibodies can happen at different stages of the disease, and are important markers of disease outcome. In turn, the magnitude and quality of acquired humoral immune responses is strongly dependent on signals delivered by innate immune cells. Additionally, the milieu of cells and chemokines that constitute a niche for plasma cells rely strongly on signals provided by stromal cells at different anatomical locations and times. The chronic inflammatory state therefore importantly impacts the developing humoral immune response and its intensity and specificity. We focus this review on B cell biology and the role of the innate immune system in the development of autoimmunity in patients with rheumatoid arthritis.
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    Thesis: PhD thesis
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    ABSTRACT: Autoimmune diseases such as rheumatoid arthritis (RA) or multiple sclerosis (MS) are commonly regarded as complex or multifactorial diseases. This complexity regards to effector mechanisms involved in pathologic manifestations, and also to the diversity of genetic and environmental factors that predispose individuals to such diseases. Identification of genetic traits becomes relevant to better understand the progression of these diseases, enabling the development of new therapies. Autoantibody formation against cartilage structures (e.g. collagen type II, CII), anti-citrullinated proteins (ACPA) and anti-Fc domains of other antibodies (rheumatoid factors, RF) are pathogenic and typically observed in RA patients. It is thus important to investigate their role in the disease development. In study I we evaluated the usefulness of a particular outbred stock of mice, the Northport heterogeneous stock (HS), in the study of genetic associations of different animal models. We observed that HS mice were suitable for studying disease models of MS, while being limited to study certain RA models, due to the absence of particular major histocompatibility complex (MHC) alleles. By introducing an arthritis permissive MHC H-2q allele, in study II we made use of the best characterized animal model of RA in mice (collagen-induced arthritis, CIA), and evaluated the genetic associations of autoantibody production during the course of the disease. The genetic associations with RF and ACPA production were evident and clearly distinct from anti-CII antibody responses. Amongst several identified quantitative trait loci (QTLs), we distinguished the Fc gamma receptor (FcγR) and immunoglobulin heavy chain (IgH) loci as the most central QTL regulating autoantibody formation. The Cia9 congenic fragment confirmed our FcγR association, while the involvement of the IgH locus on specific antigen recognition was thoroughly investigated in study III. Here we identified different germ-line polymorphisms controlling the antibody production and recognition of a specific CII epitope, named J1. Finally, in study IV, Cia37 congenic mice were used to investigate the role of vitamin D receptor (VDR) polymorphisms in arthritis susceptibility. The influence of vitamin D on cytokine secretion and the VDR gene expression profile observed, strongly implicate the VDR and vitamin D as regulators of autoimmunity in mice. In summary, several genetic associations as well as mechanistic hypothesis involving autoantibody formation are described in this thesis. We hope these findings can be of use for better understanding the pathology of RA, as well as for the development of new therapeutics to treat RA patients.
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