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

Cyril Seillet,Edwin D Hawkins,Marc Pellegrini,Philippe Bouillet,Michael D Stutz,Joel Rimes,Gabrielle T Belz,Ben Roediger,Elysa Carr,Lachlan Whitehead,Derek Lacey

doi:10.1111/imcb.12197

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.

Highlights

Tertiary lymphoid organs (TLO) such as bronchusassociated lymphoid tissue (BALT) are follicular aggregates containing primarily B and T cells.[1]
IBALT is a normal feature of certain mammals while it is absent from healthy mice and humans
The formation of structured inducible bronchusassociated lymphoid tissue (iBALT), containing many B cell follicles separated by well-defined T cell areas, required that LPS be administered soon after birth

Summary

Introduction

Tertiary lymphoid organs (TLO) such as bronchusassociated lymphoid tissue (BALT) are follicular aggregates containing primarily B and T cells.[1] Unlike secondary lymphoid organs such as Peyer’s patches and nasal-associated lymphoid tissue, the development of BALT is not preprogrammed and commences after birth. BALT can be induced in a number of pathological situations such as chronic inflammation, infection or autoimmunity, and for this reason is often referred to as inducible BALT (iBALT). While some of these clusters are only poorly organized aggregates containing mostly B cells, others have a complex structure containing B cells, T cells, follicular dendritic cells and specialized stroma, reminiscent of the lymphoid follicles found in secondary lymphoid organs. The causes underlying TLO development have not been completely elucidated but a number of chemokines (CXCL13, CCL19, CCL21) and their iBALT and bone marrow lymphoid nodules in TNF-overexpressing mice receptors (CXCR5, CCR7) have been implicated in the development of iBALT.[1]

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