Defects in Germinal Center Selection in SLE

Woods, Megan; Zou, Yong; Davidson, Anne

doi:10.3389/fimmu.2015.00425

Cited by 38 publications

(41 citation statements)

References 94 publications

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“…On the other hand, our study raises the possibility that supplemental oxygen could be utilized to suppress GCs which produce pathogenic antibodies such as in systemic lupus erythematosus (33). We view this study as opening the door to further investigations of the functional role of hypoxia within the GC microenvironment.…”

Section: Discussionmentioning

confidence: 96%

Germinal Center Hypoxia Potentiates Immunoglobulin Class Switch Recombination

Abbott

Thayer

Labuda

et al. 2016

The Journal of Immunology

131

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Germinal centers (GCs) are anatomic sites where B cells undergo secondary diversification to produce high affinity, class switched antibodies. We hypothesized that proliferating B cells in GCs create a hypoxic microenvironment that governs their further differentiation. Using molecular markers, we found GCs to be predominantly hypoxic. Compared to normoxia (21% O2), hypoxic culture conditions (1% O2) in vitro accelerated class switching and plasma cell formation and enhanced expression of GL-7 on B and CD4+ T cells. Reversal of GC hypoxia in vivo by breathing 60% O2 during immunization resulted in reduced frequencies of GC B cells, T follicular helper (TFH) cells and plasmacytes, as well as lower expression of ICOS on TFH. Importantly, this reversal of GC hypoxia decreased antigen-specific serum IgG1 and reduced the frequency of IgG1+ B cells within the antigen specific GC. Taken together, these observations reveal a critical role for hypoxia in GC B cell differentiation.

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Section: Discussionmentioning

confidence: 96%

Germinal Center Hypoxia Potentiates Immunoglobulin Class Switch Recombination

Abbott

Thayer

Labuda

et al. 2016

The Journal of Immunology

131

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“…Indeed, generation of autoantibodies and lupus pathogenesis has been associated with the aberrant expansion and dysregulation of several T H effector subsets including T H -17 and follicular T helper (T FH ) cells [2–4]. Moreover, in addition to well-known abnormalities in germinal center B cells and plasma cells [5, 6], premature accumulation of CD11c + Tbet + B cells has recently been shown to accompany the development of autoimmune disorders like SLE. The regulatory mechanisms that prevent the inappropriate accumulation and pathogenicity of CD11c + Tbet + B cells are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Regulation of systemic autoimmunity and CD11c + Tbet + B cells by SWEF proteins

Manni

Ricker

Pernis

2017

Cellular Immunology

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Recent studies have revealed the existence of a T-bet dependent subset of B cells, which expresses unique phenotypic and functional characteristics including high levels of CD11c and CD11b. In the murine system this B cell subset has been termed Age/autoimmune-associated B cells (ABCs) since it expands with age in non-autoimmune mice and it prematurely accumulates in autoimmune-prone strains. The molecular mechanisms that promote the expansion and function of ABCs are largely unknown. This review will focus on the SWEF proteins, a small family of Rho GEFs comprised of SWAP-70 and its homolog DEF6, a newly identified risk variant for human SLE. We will first provide an overview of the SWEF proteins and then discuss the complex array of biological processes that they control and the autoimmune phenotypes that spontaneously develop in their absence, highlighting the emerging involvement of these proteins in regulating ABCs. A better understanding of the pathways controlled by the SWEF proteins could help provide new insights into the mechanisms responsible for the expansion of ABCs in autoimmunity and potentially guide the design of novel therapeutic approaches.

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“…63 In contrast, in many of the other mouse models of lupus, autoantibody production is dependent on T cells and/or seems to depend on GC responses. [64][65][66][67][68] For example, in Fcgr2b −/− mice, which spontaneously develop lupus-like autoantibodies, GC B cells were shown to include anti-nuclear antigen-specific cells. 44 Moreover, in the B6.nba2 lupus-like mice, AID was shown to be required for generation of anti-nuclear antibodies and they originated from B cells with no detectable self-reactivity, 69 strongly suggestive of a GC origin.…”

Section: Events Leading To Production Of Autoantibodiesmentioning

confidence: 99%

Germinal centers and autoimmune disease in humans and mice

DeFranco

2016

Immunol Cell Biol

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Antibodies are involved in the pathogenesis of many autoimmune diseases. While the mechanisms underlying the antibody response to infection or vaccination are reasonably well understood, we still have a poor understanding of the nature of autoimmune antibody responses. The most well studied are the anti-nuclear antibody responses characteristic of systemic lupus erythematosus and studies over the past decade or so have demonstrated a critical role for signaling by TLR7 and/or TLR9 in B cells to promote these responses. These TLRs can promote T cell-independent extrafollicular antibody responses with a heavy chain class switch and a low degree of somatic mutation, but they can also strongly boost the germinal center response that gives rise to high affinity antibodies and long-lived plasma cells. TLRs has been shown to enhance affinity maturation in germinal center responses to produce high affinity neutralizing antibodies in several virus infection models of mice. While more data is needed, it appears that anti-nuclear antibodies in mouse models of lupus and in lupus patients can be generated by either pathway, provided there are genetic susceptibility alleles that compromise B cell tolerance at one or another stage. Limited data in other autoimmune diseases suggests that the germinal center response may be the predominant pathway leading to autoantibodies in those diseases. A better understanding of the mechanisms of autoantibody production may ultimately be helpful in the development of targeted therapeutics for lupus or other autoimmune diseases.

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Defects in Germinal Center Selection in SLE

Cited by 38 publications

References 94 publications

Germinal Center Hypoxia Potentiates Immunoglobulin Class Switch Recombination

Germinal Center Hypoxia Potentiates Immunoglobulin Class Switch Recombination

Regulation of systemic autoimmunity and CD11c + Tbet + B cells by SWEF proteins

Germinal centers and autoimmune disease in humans and mice

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