Development Of Tertiary Lymphoid Tissue Research Articles

Aryl Hydrocarbon Receptor Activity in Intestinal Epithelial Cells in the Formation of Colonic Tertiary Lymphoid Tissues.

After birth, the development of secondary lymphoid tissues (SLTs) in the colon is dependent on the expression of the Aryl Hydrocarbon Receptor (AhR) in immune cells as a response to the availability of AhR ligands. However, little is known about how AhR activity from intestinal epithelial cells (IECs) may influence the development of tertiary lymphoid tissues (TLTs). As organized structures that develop at sites of inflammation or infection during adulthood, TLTs serve as localized centers of adaptive immune responses, and their presence has been associated with the resolution of inflammation and tumorigenesis in the colon. Here, we investigated the effect of the conditional loss of AhR activity in IECs in the formation and immune cell composition of TLTs in a model of acute inflammation. In females, loss of AhR activity in IECs reduced the formation of TLTs without significantly changing disease outcomes nor immune cell composition within TLTs. In males lacking AhR expression in IECs, increased disease activity index, lower expression of functional-IEC genes, increased number of TLTs, increased T-cell density, and lower B- to T-cell ratio was observed. These findings may represent an unfavorable prognosis when exposed to DSS-induced epithelial damage compared to females. Sex and loss of IEC AhR also resulted in changes in microbial populations in the gut. Collectively, these data suggest that the formation of TLTs in the colon is influenced by sex and AhR expression in IECs.

Who am I? (re-)Defining fibroblast identity and immunological function in the age of bioinformatics.

Who am I? (re-)Defining fibroblast identity and immunological function in the age of bioinformatics.

Tumor PDCD1LG2 (PD-L2) Expression and the Lymphocytic Reaction to Colorectal Cancer.

Expression of the immune checkpoint ligand CD274 (programmed cell death 1 ligand 1, PD-L1, from gene CD274) contributes to suppression of antitumor T cell-mediated immune response in various tumor types. However, the role of PDCD1LG2 (PD-L2, CD273, from gene PDCD1LG2) in the tumor microenvironment remains unclear. We hypothesized that tumor PDCD1LG2 expression might be inversely associated with lymphocytic reactions to colorectal cancer. We examined tumor PDCD1LG2 expression by IHC in 823 colon and rectal carcinoma cases within two U.S.-nationwide cohort studies and categorized tumors into quartiles according to the percentage of PDCD1LG2-expressing carcinoma cells. We conducted multivariable ordinal logistic regression analysis to assess the associations of tumor PDCD1LG2 expression with Crohn-like lymphoid reaction, peritumoral lymphocytic reaction, intratumoral periglandular reaction, or tumor-infiltrating lymphocytes, controlling for potential confounders, including microsatellite instability, CpG island methylator phenotype, long-interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Tumor PDCD1LG2 expression was inversely associated with Crohn-like lymphoid reaction (Ptrend = 0.0003). For a unit increase in the three-tiered ordinal categories of Crohn-like lymphoid reaction, a multivariable OR in the highest (vs. lowest) quartile of the percentage of PDCD1LG2-expressing tumor cells was 0.38 (95% confidence interval, 0.22-0.67). Tumor PDCD1LG2 expression was not associated with peritumoral lymphocytic reaction, intratumoral periglandular reaction, tumor-infiltrating lymphocytes, or patient survival (Ptrend > 0.13). Thus, tumor PDCD1LG2 expression is inversely associated with Crohn-like lymphoid reaction to colorectal cancer, suggesting a possible role of PDCD1LG2-expressing tumor cells in inhibiting the development of tertiary lymphoid tissues during colorectal carcinogenesis. Cancer Immunol Res; 5(11); 1046-55. ©2017 AACR.

Intrarenal B Cell Cytokines Promote Transplant Fibrosis and Tubular Atrophy.

Renal transplantation is the optimum treatment for end-stage renal failure. B cells have been identified in chronic allograft damage (CAD) and associated with the development of tertiary lymphoid tissue within the human renal allograft. We performed renal transplantation in mice to model CAD and identified B cells forming tertiary lymphoid tissue with germinal centers. Intra-allograft B220(+) B cells comprised of IgM(high) CD23(-) B cells, IgM(lo) CD23(+) B cells, and IgM(lo) CD23(-) B cells with elevated expression of CD86. Depletion of B cells with anti-CD20 was associated with an improvement in CAD but only when administered after transplantation and not before. Isolated intra-allograft B cells were cultured and shown to synthesize multiple cytokines, the most abundant of these were GRO-α (CXCL1), RANTES (CCL5), IL-6 and MCP-1 (CCL2). Tubular loss was observed with T cell accumulation within the allograft and development of interstitial fibrosis, whilst type III collagen deposition was observed in areas of F4/80(+) macrophages and PDGFR-β(+) and transgelin(+) fibroblasts, all of which were reduced by B cell depletion. We have shown that intra-allograft B cells are key mediators of CAD. B cells possibly contribute to CAD by intra-allograft secretion of cytokines and chemokines.

Antibody-independent functions of B cells: a focus on cytokines.

Cytokine production by B cells is important for multiple aspects of immunity. B cell-derived cytokines, including lymphotoxin, are essential for the ontogenesis, homeostasis and activation of secondary lymphoid organs, as well as for the development of tertiary lymphoid tissues at ectopic sites. Other B cell-derived cytokines, such as interleukin-6 (IL-6), interferon-γ and tumour necrosis factor, influence the development of effector and memory CD4(+) T cell responses. Finally, B cells can regulate inflammatory immune responses, primarily through their provision of IL-10 and IL-35. This Review summarizes these various roles of cytokine-producing B cells in immunity and discusses the rational for targeting these cells in the clinic.

Tertiary lymphoid tissue with germinal centers and T follicular helper cells in immunologically privileged retinas of mice with chronic autoimmune uveitis (P4172)

Abstract Mice transgenic for a retina-specific T cell receptor develop spontaneous autoimmune uveitis. In contrast to induced models of uveitis the disease is prolonged and the mice display distinct retinal lesions that resemble tertiary lymphoid tissue. Here we investigate these lesions for presence of germinal center (GC) and T follicular helper cell (TfH) markers. Retinas were immunohistochemically stained for CD4+ T cells, CD8+ T cells, and B cells, as well as the GC markers PNA and GL-7. The retinal lesions stained positively for CD4+ T cells and B cells and also for PNA and GL-7. Laser capture microdissection was then used to isolate the retinal lesions and microarray analysis was performed to assess expression of GC- and TfH-associated genes. The microdissected lesions consistently showed upregulation of germinal center markers and T follicular helper cell markers with a 4 fold increase in Btla, Fas, and CXCL13, a 3.5 fold increase in CXCR5, and a doubling in CXCR4 compared to control retina. Heat map analysis revealed a similar gene expression profile of the retinal lesions to that of germinal centers present in 5 day-immunized spleen and lymph nodes. We conclude that despite the immunologically privileged status enjoyed by the eye, chronic autoimmune uveitis precipitates development of tertiary lymphoid tissue in the retina, expressing genes and immunological markers characteristic of GC and TfH.

Investigation of the role of B lymphocytes and tertiary lymphoid tissue in a murine model of renal chronic allograft damage

BackgroundNodular B-lymphocyte rich infiltrates have been identified in chronically rejected renal allografts and biopsies of acute transplant rejection, and this has been associated with the development of tertiary lymphoid tissue (TLT). However their significance is unclear, with conflicting published data. We aim to investigate the role and significance of B-lymphocyte infiltrates and the development of TLT in a murine model of renal chronic allograft damage. MethodsWe used congenic strains with donor C57bl/6-BM12 mice kidneys transplanted into C57bl/6 recipients, this being a single MHC-II mismatch. Using immunohistochemistry we investigated the presence of B lymphocytes within the allograft. In addition we investigated other markers of chronic allograft damage in this model including lymphatic expansion, microvessel rarefication, and fibrosis. FindingsNodular aggregates of B cells appearing to be TLT developed over 12 weeks; however, in some allografts we observed a scattered B-cell pattern. The B-cell infiltrate of the allograft cortex increased progressively with a significant increased density by 12 weeks compared with 5 days after transplantation. Microvessels were counted with a 25-point graticule, and there was a significant difference between allograft and native kidney cortex (p<0·01) with both time and transplant kidney being responsible for the effect. There was a significant difference in the number of lymphatic vessels at 12 and 8 weeks compared with 5 days (p<0·05). Similar to findings in chronic allograft nephropathy, the expanded lymphatics were seen both in the tubulointerstitium and in the perivascular regions. The B-lymphocyte phenotype was explored and shown by immunofluoresence to form germinal centres and IgG-positive plasma cell (CD138+) differentiation. InterpretationWe have shown that this strain combination closely models that of chronic rejection of the renal allograft. Furthermore, we have identified the progressive infiltration and expansion of the B-lymphocytes compartment within the allograft cortex. This work has provided the basis for further investigation of B-lymphocyte depletion and the prospects of identifying a regulatory B lymphocyte. FundingKidney Research UK.

Ectopic lymphoid tissue alters the chemokine gradient, increases lymphocyte retention and exacerbates murine ileitis

BackgroundThe earliest endoscopically-evident lesion in Crohn's disease is the aphthous ulcer, which develops over ectopic lymphoid tissues (ie, inducible lymphoid follicles (ILF), tertiary lymphoid tissue (TLT)) in the chronically inflamed...

CXCR5‐ and CCR7‐dependent lymphoid neogenesis in a murine model of chronic antigen‐induced arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with unknown etiology and only partially defined pathogenesis. The aim of this study was to establish a murine model of chronic arthritis in which the development of tertiary lymphoid tissue, a hallmark of human RA, is locally induced, and to characterize the roles of the homeostatic chemokine receptors CXCR5 and CCR7 in this process. We developed a modified model of chronic antigen-induced arthritis (AIA) in mice with a strong bias toward inflammation. Disease pathology was assessed up to 9 months in wild-type, CXCR5-deficient, and CCR7-deficient mice by determination of knee joint swelling and cellular and humoral immune responses, as well as by histologic analysis of arthritic knee joints. In this novel model of AIA, mice developed organized ectopic lymphoid follicles with topologically segregated B cell and T cell areas, high endothelial venules, and germinal center formation within the chronically inflamed synovial tissue. Analysis of the initiation and progression of AIA in wild-type, CXCR5-/-, and CCR7-/- mice revealed a reduction of acute inflammatory parameters in both knockout strains as well as significantly reduced joint destruction in CXCR5-/- mice. Most importantly, the development and organization of tertiary lymphoid tissue were significantly impaired in CXCR5-deficient and CCR7-deficient mice. Our results suggest that an inflammatory microenvironment efficiently triggers lymphoid neogenesis in autoimmune diseases such as RA. Moreover, the generation of autoreactive tertiary lymphoid tissues, which is entirely dependent on homeostatic chemokines, may in turn maintain local aberrant chronic immune responses.

Chemokines and Autoimmune Diseases

Autoimmune diseases are caused by a misdirection of the host immune system against the self. After the triggering of self-reactivity, two successive phases, i.e. the acute / deterioration phase and subsequent chronic phase are observed during the course of manifestation and maintenance of autoimmune symptoms. Not only inflammatory chemokines but also homeostatic chemokines are involved in effector cells migration and the development of tertiary lymphoid tissue in the target tissue. In the acute / deterioration phase, Th1-associated chemokines and a vicious cycle of type 1 immune responses are crucial for the destruction of the tissue. Subsequently, homeostatic chemokines play important roles in organizing ectopic lymphoid tissue for sustaining autoreactivity in the chronic phase. If they are only correctly directed toward invasive pathogens, immune responses are, essentially, an evolutionally acquired function of the adaptive immune system, which is quite efficient for eradicating non-self. However, if self-components accidentally happen to become the target of the host immune system, a serious situation ensues. For clinical treatment, both inflammatory and homeostatic chemokines would be promising targets in the different phases of autoimmune diseases. Keywords: chemokines, autoimmune diseases, homeostatic

Role of B cells in the pathogenesis of rheumatoid arthritis: potential implications for treatment.

In patients with rheumatoid arthritis, chronic inflammation in affected joints may lead to the development of tertiary lymphoid tissue. A micro-environment is generated in the synovial membrane which supports the activation and differentiation of B cells into plasma cells. Through a process of affinity maturation, plasma cells may be generated locally which secrete antibodies of high affinity. Rheumatoid arthritis is characterised by autoantibodies specific for self immunoglobulin. These rheumatoid factors form large antigen/antibody complexes which may enhance the process of joint destruction. The poor prognosis of rheumatoid factor-positive patients is indicitive of the critical role of immunoglobulin complexes in the continuous stimulation of the immune system and thus of the inflammatory processes. In general, treatment of patients with rheumatoid arthritis aims at suppressing inflammation. The currently most successful reagents are those which interfere with the network of cytokines, such as tumour necrosis factor or interleukin-1 receptor antagonists. Only recently have immunosuppressive therapies targeted directly at the B cell response been developed. These first studies suggest that therapies which directly affect the humoral immune response are of great therapeutic potential in the treatment of patients with rheumatoid arthritis.