Lochner, M. et al. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORgamma t and LTi cells. J. Exp. Med. 208, 125-134

Lymphoid Tissue Development Unit, Institut Pasteur, 75724 Paris, France.
Journal of Experimental Medicine (Impact Factor: 12.52). 01/2011; 208(1):125-134. DOI: 10.1084/jem.20100052
Source: PubMed


The programmed development of lymph nodes and Peyer’s patches during ontogeny requires lymphoid tissue inducer (LTi) cells
that express the nuclear hormone receptor RORγt. After birth, LTi cells in the intestine cluster into cryptopatches, the precursors
of isolated lymphoid follicles (ILFs), which are induced to form by symbiotic bacteria and maintain intestinal homeostasis.
We show that in RORγt-deficient mice, which lack LTi cells, programmed lymphoid tissues, ILFs, and Th17 cells, bacterial containment
requires the generation of large numbers of tertiary lymphoid tissues (tLTs) through the activity of B cells. However, upon
epithelial damage, these mice develop severe intestinal inflammation characterized by extensive recruitment of neutrophils
and IgG+ B cells, high expression of activation-induced deaminase in tLTs, and wasting disease. The pathology was prevented by antibiotic
treatment or inhibition of lymphoid tissue formation and was significantly decreased by treatment with intravenous immunoglobulin
G (IVIG). Our data show that intestinal immunodeficiency, such as an absence in RORγt-mediated proinflammatory immunity, can
be compensated by increased lymphoid tissue genesis. However, this comes at a high cost for the host and can lead to a deregulated
B cell response and aggravated inflammatory pathology.

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    • "This could be due to a deleterious effect of the lipotoxicity induced by the HFD. In addition to the lipotoxicity, the changes in gut microbiota induced by the HFD (Cani et al., 2008) could lead to an immunological stress in RORgt À/À mice, which lack secondary lymphoid organs, which has previously been associated with excessive bacterial burden leading to death (Lochner et al., 2011). This important phenotype is still under investigation. "
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    • "Notably, TLT are induced by ectopic expression of LTα or combined LTα and LTβ in multiple organ systems and these studies have provided considerable insight into the biology of these structures (42, 149, 160). There appear to be multiple routes to TLT formation including those induced by RORγt positive cells such as type III innate lymphoid cells (ILC-3) in the gut as well as RORγt independent events (161). Simple ectopic overexpression of several chemokines is sufficient to culminate in TLT formation (152). "
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    • "Eberl and colleagues identified that mice deficient in RORgt exhibited elevated titers of serum immunoglobulin G (IgG) specific for intestinal commensal bacteria in the steady state (Lochner et al., 2011), indicative of impaired intestinal barrier function and dissemination of commensal bacteria to peripheral tissues. Following induction of epithelial damage with DSS administration, RORgt-deficient mice developed hyperactive B cells that promoted commensal bacteria-dependent intestinal pathology and wasting disease (Lochner et al., 2011). Supporting this, mice deficient in CX 3 CR1 + phagocytes, which are critical for optimal IL-22 responses from RORgt + ILCs, exhibit increased translocation of commensal bacteria to the mesenteric lymph node (mLN) and susceptibility to DSS-induced inflammation (Manta et al., 2012; Medina-Contreras et al., 2011). "
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