The Role of the Lymphatic System in the Pathogenesis and Treatment of Inflammatory Bowel Disease

Abstract

Although the number of therapeutic options for the treatment of inflammatory bowel disease (IBD) has increased in recent years, patients suffer from decreased quality of life due to non-response or loss of response to the currently available treatments. An increased understanding of the disease's etiology could provide novel insights for treatment strategies in IBD. Lymphatic system components are generally linked to immune responses and presumably related to inflammatory diseases pathophysiology. This review aims to summarize findings on immune-mediated mechanisms in lymphoid tissues linked with IBD pathogenesis and (potential) novel treatments. Enhanced innate and adaptive immune responses were observed in mesenteric lymph nodes (MLNs) and other lymphoid structures, such as Peyer's patches, in patients with IBD and in animal models. Furthermore, the phenomenon of lymphatic obstruction in the form of granulomas in MLNs and lymphatic vessels correlates with disease activity. There is also evidence that abnormalities in the lymphatic stromal components and lymph node microbiome are common in IBD and could be exploited therapeutically. Finally, novel agents targeting lymphocyte trafficking have been added to the treatment armamentarium in the field of IBD. Overall, gut-associated lymphoid tissue plays a key role in IBD immunopathogenesis, which could offer novel therapeutic targets.

Keywords: IBD; Peyer’s patches; lymph nodes; lymphatic obstruction; lymphocyte trafficking; microbiome; stroma.

Figure 1

Adaptive and innate immune cell responses in mesenteric lymph nodes (MLNs) of IBD rodent models: Mature differentiated myeloid DC subsets orchestrate Th1 and Th17 inflammatory responses leading to disease onset, as well as, effector T-cell trafficking, whereas immature myeloid DCs induce immune tolerance by regulatory T-cell (T-reg) cell stimulation. Increased effector T-cell trafficking along with impaired T-reg trafficking to the colonic mucosa is associated with elevated inflammatory responses that can induce colitis. Tolerogenic MLN CD103⁺ DCs shift to a proinflammatory phenotype leading to colitis initiation, while MLN CD103⁻ DCs induce primarily Th17 lymphocyte polarization. Elevated macrophage subsets promote Th1 and Th17 differentiation in MLNs. Both Th1 and Th17 cells are responsible for the disease onset. Activation of effector follicular T-helper cells along with the downregulation of follicular T-regs leads to disease exacerbation. Elevated autoreactive B-lymphocytes can lead to humoral autoimmunity in colitis mice but with no clear function in the disease pathophysiology, while tolerogenic B-cells can attenuate the disease progression. (Figure created with BioRender.com-accessed date: 20 December 2021).

Figure 2

Adaptive and Innate Immune cell responses in MLNs of patients with IBD: Myeloid DC populations promote Th1 and Th17 responses linked with IBD initiation, whereas plasmacytoid DCs (pDCs) demonstrate a tolerogenic phenotype. However, these pDCs cannot alter the disease activity and progression. Basophils and mononuclear phagocytes promote Th17 responses. Th17 to Th1 polarization is a potential pathogenetic mechanism along with elevated effector T-cell trafficking to the colonic mucosa through lymphatic vessels. Reduced numbers of the tolerogenic CD103⁺ DCs in MLNs can further contribute to the disease pathogenesis. (Figure created with BioRender.com-accessed date: 20 December 2021).

Figure 3

Study selection diagram.