CXCR4 and CXCR5 orchestrate dynamic germinal center reactions and may contribute to the pathogenesis of systemic lupus erythematosus

Wu, Bingxuan; Li, Zhao; Zhang, Xuan

doi:10.1038/s41423-019-0244-y

Cited by 21 publications

(12 citation statements)

References 14 publications

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“…7C). In summary, we observed a clear preference of K3 deficient B cells for CXCR5 over CXCR4 signals and signs of altered motility, consistent with GC formation 36,39 …”

Section: Resultssupporting

confidence: 76%

Kindlin-3 maintains marginal zone B cells but confines follicular B cell activation and differentiation

Härzschel

Krenn

et al. 2021

Journal of Leukocyte Biology

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Integrin-mediated interactions between hematopoietic cells and their microenvironment are important for the development and function of immune cells. Here, the role of the integrin adaptor Kindlin-3 in B cell homeostasis is studied. Comparing the individual steps of B cell development in B cell-specific Kindlin-3 or alpha4 integrin knockout mice, we found in both conditions a phenotype of reduced late immature, mature, and recirculating B cells in the bone marrow. In the spleen, constitutive B cell-specific Kindlin-3 knockout caused a loss of marginal zone B cells and an unexpected expansion of follicular B cells. Alpha4 integrin deficiency did not induce this phenotype. In Kindlin-3 knockout B cells VLA-4 as well as LFA-1-mediated adhesion was abrogated, and short-term homing of these cells in vivo was redirected to the spleen. Upon inducible Kindlin-3 knockout, marginal zone B cells were lost due to defective retention within 2 weeks, while follicular B cell numbers were unaltered. Kindlin-3 deficient follicular B cells displayed higher IgD, CD40, CD44, CXCR5, and EBI2 levels, and elevated PI3K

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“…7C). In summary, we observed a clear preference of K3 deficient B cells for CXCR5 over CXCR4 signals and signs of altered motility, consistent with GC formation 36,39 …”

Section: Resultssupporting

confidence: 76%

Kindlin-3 maintains marginal zone B cells but confines follicular B cell activation and differentiation

Härzschel

Krenn

et al. 2021

Journal of Leukocyte Biology

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“…The observed reduction in CXCR4 expression during the high relapse risk postpartum period is therefore counterintuitive. A possible explanation for this discrepancy may be that during a primary response, CXCR4 high naive mature B cells escape from T FH -mediated selection in the GC light zones of peripheral secondary lymphoid organs 13 , while CXCR4 low memory B cells are more prone to interact with T FH cells and develop into long-lived plasma cells during a recall response in the CNS. CCR6 could facilitate such recall responses 23 and, together with CXCR3, has also been associated with the production of high affinity antibodies 29 .…”

Section: Discussionmentioning

confidence: 99%

“…CCR6 has been reported to promote their development and antigen responsiveness in the light zone 11 , 12 . Therefore, specific aberrancies in chemokine receptor profiles may affect the outgrowth of B cells into memory and plasmablasts/plasma cells 13 . Currently, it remains to be determined whether this is related to relapse risk in MS.…”

Section: Introductionmentioning

confidence: 99%

Pregnancy-induced effects on memory B-cell development in multiple sclerosis

Janssen

Rijvers

Koetzier

et al. 2021

Sci Rep

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In MS, pathogenic memory B cells infiltrate the brain and develop into antibody-secreting cells. Chemokine receptors not only define their brain-infiltrating capacity, but also assist in their maturation in germinal centers. How this corresponds to pregnancy, as a naturally occurring modifier of MS, is underexplored. Here, we aimed to study the impact of pregnancy on both ex vivo and in vitro B-cell differentiation in MS. The composition and outgrowth of peripheral B cells were compared between 19 MS pregnant patients and 12 healthy controls during the third trimester of pregnancy (low relapse risk) and postpartum (high relapse risk). Transitional, and not naive mature, B-cell frequencies were found to drop in the third trimester, which was most prominent in patients who experienced a pre-pregnancy relapse. Early after delivery, these frequencies raised again, while memory B -cell frequencies modestly declined. CXCR4 was downregulated and CXCR5, CXCR3 and CCR6 were upregulated on postpartum memory B cells, implying enhanced recruitment into germinal center light zones for interaction with T follicular helper (TFH) cells. Postpartum memory B cells of MS patients expressed higher levels of CCR6 and preferentially developed into plasma cells under TFH-like in vitro conditions. These findings imply that memory B- cell differentiation contributes to postpartum relapse risk in MS.

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“…NK Cells and SLE SLE is a progressive autoimmune disease with variable clinical manifestations affecting several organs including skin, lungs, blood, heart, and nervous system (43). It is characterized by the presence of nuclear autoantibodies along with abnormally activated T cells and hyperactive B cells, which form immune complexes that lead to inflammation (4,(44)(45)(46).…”

Section: Nk Cells and Autoimmune Diseases Nk Cells And Systemic Autoimentioning

confidence: 99%

NK Cells in Autoimmune Diseases: Protective or Pathogenic?

2021

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Autoimmune diseases generally result from the loss of self-tolerance (i.e., failure of the immune system to distinguish self from non-self), and are characterized by autoantibody production and hyperactivation of T cells, which leads to damage of specific or multiple organs. Thus, autoimmune diseases can be classified as organ-specific or systemic. Genetic and environmental factors contribute to the development of autoimmunity. Recent studies have demonstrated the contribution of innate immunity to the onset of autoimmune diseases. Natural killer (NK) cells, which are key components of the innate immune system, have been implicated in the development of multiple autoimmune diseases such as systemic lupus erythematosus, type I diabetes mellitus, and autoimmune liver disease. However, NK cells have both protective and pathogenic roles in autoimmunity depending on the NK cell subset, microenvironment, and disease type or stage. In this work, we review the current knowledge of the varied roles of NK cell subsets in systemic and organic-specific autoimmune diseases and their clinical potential as therapeutic targets.

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CXCR4 and CXCR5 orchestrate dynamic germinal center reactions and may contribute to the pathogenesis of systemic lupus erythematosus

Cited by 21 publications

References 14 publications

Kindlin-3 maintains marginal zone B cells but confines follicular B cell activation and differentiation

Kindlin-3 maintains marginal zone B cells but confines follicular B cell activation and differentiation

Pregnancy-induced effects on memory B-cell development in multiple sclerosis

NK Cells in Autoimmune Diseases: Protective or Pathogenic?

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