Th1-Biased Tertiary Lymphoid Tissue Supported by CXC Chemokine Ligand 13-Producing Stromal Network in Chronic Lesions of Autoimmune Gastritis

Lymphotoxin β-receptor (LTβR) and TNF receptor-1 (TNFR1) are important for the development of secondary lymphoid organs during embryonic life. The significance of LTβR and TNFR1 for the formation of lymphoid tissue during adult life is not well understood. Immunohistochemistry, morphometry, flow cytometry, and laser microdissection were used to compare wild-type, LTβR−/−, TNFR1−/− spleens with splenic tissue that has been newly formed 8 wk after avascular implantation into adult mice. During ontogeny, LTβR is sufficient to induce formation of the marginal zone, similar-sized T and B cell zones, and a mixed T/B cell zone that completely surrounded the T cell zone. Strikingly, in adult mice, the formation of splenic compartments required both LTβR and TNFR1 expression, demonstrating that the molecular requirements for lymphoid tissue formation are different during embryonic and adult life. Thus, interfering with the TNFR1 pathway offers the possibility to selectively block the formation of ectopic lymphoid tissue and at the same time to spare secondary lymphoid organs such as spleen and lymph nodes. This opens a new perspective for the treatment of autoimmune and inflammatory diseases.

Section: Discussionmentioning

confidence: 87%

TNF Receptor-1 Is Required for the Formation of Splenic Compartments during Adult, but Not Embryonic Life

Milićević¹,

Klaperski

Nohroudi

et al. 2011

“…T zone FRCs and follicular FDCs are closely associated with the corresponding lymphocyte subsets. In addition, both of these types of stromal cells are induced in chronic inflammatory diseases, even in ectopic lymphoid tissues (30,33,40,41). Therefore, we would suggest that the existence of mature lymphocytes induces the differentiation and maintenance of these stromal cells.…”

Section: Discussionmentioning

confidence: 99%

Organizer-Like Reticular Stromal Cell Layer Common to Adult Secondary Lymphoid Organs

Katakai

Suto

Sugai

et al. 2008

Self Cite

216

282

Mesenchymal stromal cells are crucial components of secondary lymphoid organs (SLOs). Organogenesis of SLOs involves specialized stromal cells, designated lymphoid tissue organizer (LTo) in the embryonic anlagen; in the adult, several distinct stromal lineages construct elaborate tissue architecture and regulate lymphocyte compartmentalization. The relationship between the LTo and adult stromal cells, however, remains unclear, as does the precise number of stromal cell types that constitute mature SLOs are unclear. From mouse lymph nodes, we established a VCAM-1+ICAM-1+MAdCAM-1+ reticular cell line that can produce CXCL13 upon LTβR stimulation and support primary B cell adhesion and migration in vitro. A similar stromal population sharing many characteristics with the LTo, designated marginal reticular cells (MRCs), was found in the outer follicular region immediately underneath the subcapsular sinus of lymph nodes. Moreover, MRCs were commonly observed at particular sites in various SLOs even in Rag2−/− mice, but were not found in ectopic lymphoid tissues, suggesting that MRCs are a developmentally determined element. These findings lead to a comprehensive view of the stromal composition and architecture of SLOs.

“…Such ectopic lymph node structures have been described in the target organs of several other human autoimmune diseases, including Sjogren's syndrome, diabetes, gastritis, and rheumatoid arthritis (43)(44)(45)(46). Our present findings extend these reports and highlight the potential contribution of distinct subsets of B cells to ongoing inflammation, both within the target organs of human autoimmune diseases and in the periphery, where they may elaborate chemokines, produce factors that promote lymphoneogenesis, act as APCs, and regulate the local immune response through the expression of effector cytokines.…”

Section: Discussionmentioning

confidence: 99%

Distinct Effector Cytokine Profiles of Memory and Naive Human B Cell Subsets and Implication in Multiple Sclerosis

Duddy

Niino

Adatia

et al. 2007

583

594

Although recent animal studies have fuelled growing interest in Ab-independent functions of B cells, relatively little is known about how human B cells and their subsets may contribute to the regulation of immune responses in either health or disease. In this study, we first confirm that effector cytokine production by normal human B cells is context dependent and demonstrate that this involves the reciprocal regulation of proinflammatory and anti-inflammatory cytokines. We further report that this cytokine network is dysregulated in patients with the autoimmune disease multiple sclerosis, whose B cells exhibit a decreased average production of the down-regulatory cytokine IL-10. Treatment with the approved chemotherapeutic agent mitoxantrone reciprocally modulated B cell proinflammatory and anti-inflammatory cytokines, establishing that the B cell cytokine network can be targeted in vivo. Prospective studies of human B cells reconstituting following in vivo depletion suggested that different B cell subsets produced distinct effector cytokines. We confirmed in normal human B cell subsets that IL-10 is produced almost exclusively by naive B cells while the proinflammatory cytokines lymphotoxin and TNF-α are largely produced by memory B cells. These results point to an in vivo switch in the cytokine “program” of human B cells transitioning from the naive pool to the memory pool. We propose a model that ascribes distinct and proactive roles to memory and naive human B cell subsets in the regulation of memory immune responses and in autoimmunity. Our findings are of particular relevance at a time when B cell directed therapies are being applied to clinical trials of several autoimmune diseases.