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. 2019 Jan;97(1):29-38.
doi: 10.1111/imcb.12197. Epub 2018 Sep 8.

Constitutive overexpression of TNF in BPSM1 mice causes iBALT and bone marrow nodular lymphocytic hyperplasia

Cyril Seillet  1   2 , Elyas H Arvell  1 , Derek Lacey  1   2 , Michael D Stutz  1   2 , Marc Pellegrini  1   2 , Lachlan Whitehead  1   2 , Joel Rimes  1   2 , Edwin D Hawkins  1   2 , Ben Roediger  3 , Gabrielle T Belz  1   2 , Philippe Bouillet  1   2
Affiliations

Constitutive overexpression of TNF in BPSM1 mice causes iBALT and bone marrow nodular lymphocytic hyperplasia

Cyril Seillet et al. Immunol Cell Biol. 2019 Jan.

Abstract

BPSM1 (Bone phenotype spontaneous mutant 1) mice develop severe polyarthritis and heart valve disease as a result of a spontaneous mutation in the Tnf gene. In these mice, the insertion of a retrotransposon in the 3' untranslated region of Tnf causes a large increase in the expression of the cytokine. We have found that these mice also develop inducible bronchus-associated lymphoid tissue (iBALT), as well as nodular lymphoid hyperplasia (NLH) in the bone marrow. Loss of TNFR1 prevents the development of both types of follicles, but deficiency of TNFR1 in the hematopoietic compartment only prevents the iBALT and not the NLH phenotype. We show that the development of arthritis and heart valve disease does not depend on the presence of the tertiary lymphoid tissues. Interestingly, while loss of IL-17 or IL-23 limits iBALT and NLH development to some extent, it has no effect on polyarthritis or heart valve disease in BPSM1 mice.

Keywords: Arthritis; BPSM1; IL-17; IL-23; NLH; TNF; heart valve disease; iBALT; nodular lymphoid hyperplasia; tertiary lymphoid organs, bronchus-associated.

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Figures

Figure 1
Figure 1
Spontaneous iBALT and NLH in BPSM1 mice. (a) Lung tissue stained with Hematoxylin and Eosin (H&E) showing iBALT in BPSM1 m/+ and BPSM1 m/m mice. Scale bars, 1 mm. (b) H&E‐stained femoral bone marrow showing spontaneous nodular lymphoid hyperplasia in BPSM1 m/+ and BPSM1 m/m mice. Scale bars, 0.5 mm. (c) Confocal image showing the presence B cells (B220), T cells (CD3) and follicular dendritic cells (CD21/CD35) in iBALT of BPSM1 m/+ mice. Scale bar, 50 μm. (d) Confocal image showing the presence of B cells and T cells in bone marrow lymphoid nodules of BPSM1 m/+ mice. Scale bar, 50 μm.
Figure 2
Figure 2
Loss of B cells prevents iBALT and NLH, loss of T cells does not. (a) H&E‐stained lung tissue (left hand panels) and femoral bone marrow (right hand panels) from a) BPSM1  m/+ Mb1 Ki/Ki and (b) BPSM1  m/+ CD3ε −/− mice. Scale bars, 1 mm for lung panels, 0.5 mm for bone marrow panels.
Figure 3
Figure 3
Loss of IL‐17 or IL‐23 influences iBALT and NLH formation in BPSM1 mice. (a) Quantification of iBALT follicles on H&E‐stained lung sections from WT , BPSM1 m/+ , BPSM1 m/m , BPSM1 m/+ IL‐23 −/− and BPSM1 m/+ IL‐17 −/− animals (5 sections per animal, n ≥ 5 animals for each genotype, mean ± s.d.). (b) Dual confocal/2‐photon microscopy showing the presence B cells (B220, green), T cells (CD3, blue), collagen (grey) and follicular dendritic cells (CD21, CD35, red) in nondecalcified femoral bone marrow of BPSM1 m/+ , BPSM1 m/+ IL‐17 −/− and BPSM1 m/+ IL‐23 −/− animals. Red arrows indicate lymphocyte follicles. (c) Magnified picture of the highlighted area in the white rectangle in b. (d) Total number of follicles/section in BPSM1 m/+ , BPSM1 m/+ IL‐17 −/− and BPSM1 m/+ IL‐23 −/− animals as determined from 2 sections of 2 mice per genotype. (e) Mean surface of follicles was calculated by adding the surface of each iBALT detected and dividing by the number of follicles per section. P‐values were calculated using a two‐tailed Student's t‐test performed using Prism (GraphPad) to determine statistical significance.
Figure 4
Figure 4
BPSM1 mice show improved ability to control M. tuberculosis infection. (a) Bacterial burdens in the lungs of BPSM1 +/+ and BPSM1 m/+ mice enumerated 5 weeks postinfection with aerosolized Mtb. (b) Lung histology of mice 5 weeks postinfection. Sections of the left lobe were stained with H&E. Scale bars, 1 mm. (c) Quantitation of the extent of pulmonary inflammation in H&E‐stained lung sections. (d) Immunohistochemical staining of F4/80 in lung inflammatory lesions. Scale bars, 0.2 mm. Graphs show mean and s.e.m. and each point represents one mouse (n = 11 in each group). Data were analyzed by a Student's t‐test (*P < 0.05; **P < 0.01).
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