TNF signals are dispensable for the generation of CD23+ CD21/35-high CD1d-high B cells in inflamed lymph nodes

Kuzin, Igor; Bouta, Echoe M.; Schwarz, Edward M.; Bottaro, Andrea

doi:10.1016/j.cellimm.2015.04.005

Cited by 7 publications

(6 citation statements)

References 19 publications

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“…In previous work, we described the significant influx of B cells in draining LN and their migration from the follicular area into the LN sinuses [4, 8, 9, 26]. To asses if iNOS plays a role in the LN phenotype described above, we assessed PLN histology from female and male mice (4 and 6 months, respectively).…”

Section: Resultsmentioning

confidence: 99%

iNOS dependent and independent phases of lymph node expansion in mice with TNF-induced inflammatory-erosive arthritis

Bell

Slattery

et al. 2019

Arthritis Res Ther

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IntroductionA pivotal effect of lymphatic vessel (LV) function in joint homeostasis was identified in the tumor necrosis factor-transgenic (TNF-Tg) mouse model of rheumatoid arthritis (RA). Specifically, loss of LV contractions is associated with progressive synovitis and erosions. Furthermore, draining lymph node expansion is a biomarker of arthritic progression, and both macrophages and lymphatic endothelial cells express inducible nitric oxide synthase (iNOS), which disrupts LV contraction and transport of immune cells to the draining lymph nodes. Therefore, to directly assess these relationships, we tested the hypothesis that TNF-Tg mice with global genetic ablation of iNOS (iNOS−/−) will show delayed draining lymph node expansion, maintained LV contractions, and decreased synovitis and erosions.MethodiNOS−/−× TNF-Tg female and male mice, and control littermates (iNOS−/−, TNF-Tg, and WT), were examined with (1) ultrasound to determine popliteal lymph node (PLN) volume and (2) near-infrared imaging (NIR) to assess popliteal LV contraction frequency, and differences between genotypes were assessed at 3, 4, 5, and 6 months of age. Knees and PLN were harvested at 4 months in females and 6 months in males, to assess synovitis, bone erosions, and cellular accumulation in PLN sinuses via histology.ResultsInitially, an increase in PLN volume was observed for both female and male iNOS−/−× TNF-Tg and TNF-Tg compared to their WT and iNOS−/− counterparts at 2 and 3 months, respectively. Subsequently, TNF-Tg PLNs continue to increase in volume, while iNOS−/−× TNF-Tg did not increase in volume from the initial timepoints. WT and iNOS−/− PLN volume was unchanged throughout the experiment. LV contraction frequency was increased at 4 months in females and 5 months in males, in the iNOS−/−× TNF-Tg mice compared to the TNF-Tg. Synovitis and erosions were moderately reduced in iNOS−/−× TNF-Tg versus TNF-Tg knees in females, while no differences in knee pathology were observed in males.ConclusionsGenetic iNOS ablation maintains draining lymph node volume and LV function during TNF-induced inflammatory arthritis and is associated with moderately decreased joint inflammation and damage.

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Section: Resultsmentioning

confidence: 99%

iNOS dependent and independent phases of lymph node expansion in mice with TNF-induced inflammatory-erosive arthritis

Bell

Slattery

et al. 2019

Arthritis Res Ther

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“…It is challenging to determine the underlying mechanisms driving this ILC imbalance, although changes in cytokine production within the LN microenvironment as a consequence of LN activation preceding RA development may be key in the orchestration of ILC differentiation . Interestingly, although evidence is limited, some cytokines altered during LN activation are related to certain ILC subsets.…”

Section: Discussionmentioning

confidence: 99%

Brief Report: Altered Innate Lymphoid Cell Subsets in Human Lymph Node Biopsy Specimens Obtained During the At‐Risk and Earliest Phases of Rheumatoid Arthritis

Rodríguez‐Carrio

Hähnlein

Ramwadhdoebé

et al. 2016

Arthritis & Rheumatology

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Objective Innate lymphoid cells (ILCs) are emerging mediators of immunity, and accumulation of inflammatory ILC populations can occur in inflammatory‐mediated conditions. Since early lymph node (LN) activation has been shown in rheumatoid arthritis (RA), we aimed to investigate the frequency and distribution of ILCs in LN biopsy specimens obtained during the earliest phases of RA. Methods Twelve patients with early RA, 12 individuals with IgM rheumatoid factor and/or anti–citrullinated protein antibodies without arthritis (RA risk group), and 7 healthy controls underwent ultrasound‐guided inguinal LN biopsy. ILC subsets and the expression of vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) by LN endothelial cells and fibroblasts were analyzed by flow cytometry. Results Although no differences in the frequencies of total ILCs (Lin−CD45 +/low CD127+) were found, the distribution of the ILC subpopulations differed among groups. RA patients showed lower numbers of lymphoid tissue–inducer (LTi) cells (c‐Kit+NKp44− ILCs) and increased ILC1 (c‐Kit−NKp44− ILCs) and ILC3 (c‐Kit+NKp44+ ILCs) numbers compared with controls ( P < 0.001, P < 0.050, and P < 0.050, respectively). Individuals at risk of RA exhibited an increased frequency of ILC1 compared with controls ( P < 0.01). LTi cells paralleled the expression of adhesion molecules on endothelial cells and fibroblasts. Conclusion Our findings indicate that during the at‐risk and earliest phases of RA, the ILC distribution in LN changes from a homeostatic profile toward a more inflammatory profile, thereby providing evidence of a role for ILCs in RA pathogenesis.

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“…Further investigations regarding the existence and possible role of the Bin population in pulmonary manifestations in the TNF-Tg model were performed. Flow cytometric analysis interrogating the phenotype of these B cell accumulations was performed (45,64), defining follicular B cells (CD21/ 35 low CD23 + ), marginal zone B cells (CD21/35 hi CD23 low ), and Bins (CD21 + CD23 hi ). Flow cytometry revealed a different B cell profile in the diseased-untreated TNF-Tg lung than in the one observed in the peripheral lymph node (Fig.…”

Section: B Cell Populations Of the Tnf-tg Lung Are Not Cleared With Amentioning

confidence: 99%

TNF-Induced Interstitial Lung Disease in a Murine Arthritis Model: Accumulation of Activated Monocytes, Conventional Dendritic Cells, and CD21+/CD23− B Cell Follicles Is Prevented with Anti-TNF Therapy

Henkes

McGowan

et al. 2019

The Journal of Immunology

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Interstitial lung disease (ILD) is a well-known extra-articular manifestation of rheumatoid arthritis (RA). RA-associated ILD (RA-ILD) exists on a wide spectrum, with variable levels of inflammatory and fibrotic activity, although all subtypes are regarded as irreversible pathologic conditions. In both articular and pulmonary manifestations, TNF is a significant pathogenic factor. Whereas anti-TNF therapy alleviates joint pathologic conditions, it exacerbates fibrotic RA-ILD. The TNF-transgenic (TNF-Tg) murine model of RA develops both inflammatory arthritis and an ILD that mimics a cellular nonspecific interstitial pneumonia pattern dominated by an interstitial accumulation of inflammatory cells with minimal-to-absent fibrosis. Given the model’s potential to elucidate the genesis of inflammatory RA-ILD, we aim to achieve the following: 1) characterize the cellular accumulations in TNF-Tg lungs, and 2) assess the reversibility of inflammatory ILD following anti-TNF therapy known to resolve TNF-Tg inflammatory arthritis. TNF-Tg mice with established disease were randomized to anti-TNF or placebo therapy and evaluated with imaging, histology, and flow cytometric analyses, together with wild-type controls. Flow cytometry of TNF-Tg versus wild-type lungs revealed significant increases in activated monocytes, conventional dendritic cells, and CD21+/CD23− B cells that are phenotypically distinct from the B cells in inflamed nodes, which are known to accumulate in joint-draining lymph nodes. In contrast to human RA-ILD, anti-TNF treatment significantly alleviated both joint and lung inflammation. These results identify a potential role for activated monocytes, conventional dendritic cells, and CD21+/CD23− B cells in the genesis of RA-ILD, which exist in a previously unknown, reversible, prefibrotic stage of the disease.

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TNF signals are dispensable for the generation of CD23+ CD21/35-high CD1d-high B cells in inflamed lymph nodes

Cited by 7 publications

References 19 publications

iNOS dependent and independent phases of lymph node expansion in mice with TNF-induced inflammatory-erosive arthritis

iNOS dependent and independent phases of lymph node expansion in mice with TNF-induced inflammatory-erosive arthritis

Brief Report: Altered Innate Lymphoid Cell Subsets in Human Lymph Node Biopsy Specimens Obtained During the At‐Risk and Earliest Phases of Rheumatoid Arthritis

TNF-Induced Interstitial Lung Disease in a Murine Arthritis Model: Accumulation of Activated Monocytes, Conventional Dendritic Cells, and CD21+/CD23− B Cell Follicles Is Prevented with Anti-TNF Therapy

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