Plasma Cells in the Mucosa of Patients with Inflammatory Bowel Disease Produce Granzyme B and Possess Cytotoxic Activities

Cupi, Maria Laura; Sarra, Massimiliano; Marafini, Irene; Monteleone, Ivan; Franzè, Eleonora; Ortenzi, Angela; Colantoni, Alfredo; Sica, Giuseppe; Sileri, Pierpaolo; Rosado, M. Manuela; Carsetti, Rita; MacDonald, Thomas T.; Pallone, Francesco; Monteleone, Giovanni

doi:10.4049/jimmunol.1302238

Cited by 69 publications

(39 citation statements)

References 35 publications

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“…Administration of DSS for 6 consecutive days led to colitis as evidenced by body weight loss, diarrhea, shortening of the colon, and histopathological alterations, which was greatly ameliorated by Hyp. It has been reported that the overactivation of inflammatory response is a critical mediator associated with the onset of colitis . The concentrations of Hyp in the serum or colonic tissues were greater in Hyp supplementation and Hyp plus DSS co‐treatment groups as compared with that of controls.…”

Section: Discussionmentioning

confidence: 89%

Hydroxyproline Attenuates Dextran Sulfate Sodium‐Induced Colitis in Mice: Involvment of the NF‐κB Signaling and Oxidative Stress

Dai

Sun

et al. 2018

Molecular Nutrition Food Res

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Section: Discussionmentioning

confidence: 89%

Hydroxyproline Attenuates Dextran Sulfate Sodium‐Induced Colitis in Mice: Involvment of the NF‐κB Signaling and Oxidative Stress

Dai

Sun

et al. 2018

Molecular Nutrition Food Res

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“…In the current study, it has been shown that CD19 + CD27 + CD38 + plasma cells, the major B cell component in periodontitis tissues, expressed RANKL. Moreover, gut plasma cells in patients with inflammatory bowel disease were demonstrated to be positive for granzyme B (62). However, no granzyme B-positive plasma cells were detected in periodontitis tissues.…”

Section: Discussionmentioning

confidence: 99%

Human Memory B Cells in Healthy Gingiva, Gingivitis, and Periodontitis

Mahanonda

Champaiboon

Subbalekha

et al. 2016

The Journal of Immunology

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The presence of inflammatory infiltrates with B cells, specifically plasma cells, is the hallmark of periodontitis lesions. The composition of these infiltrates in various stages of homeostasis and disease development is not well documented. Human tissue biopsies from sites with gingival health (n = 29), gingivitis (n = 8), and periodontitis (n = 21) as well as gingival tissue after treated periodontitis (n = 6) were obtained and analyzed for their composition of B cell subsets. Ag specificity, Ig secretion, and expression of receptor activator of NF-κB ligand and granzyme B were performed. Although most of the B cell subsets in healthy gingiva and gingivitis tissues were CD19+CD27+CD38− memory B cells, the major B cell component in periodontitis was CD19+CD27+CD38+CD138+HLA-DRlow plasma cells, not plasmablasts. Plasma cell aggregates were observed at the base of the periodontal pocket and scattered throughout the gingiva, especially apically toward the advancing front of the lesion. High expression of CXCL12, a proliferation-inducing ligand, B cell–activating factor, IL-10, IL-6, and IL-21 molecules involved in local B cell responses was detected in both gingivitis and periodontitis tissues. Periodontitis tissue plasma cells mainly secreted IgG specific to periodontal pathogens and also expressed receptor activator of NF-κB ligand, a bone resorption cytokine. Memory B cells resided in the connective tissue subjacent to the junctional epithelium in healthy gingiva. This suggested a role of memory B cells in maintaining periodontal homeostasis.

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“…We cannot exclude that BAFF may have modulated the anti-tumor activity of B lymphocytes in MDR1A deficiency ex-vivo. Future studies will need to identify the specific B cell subset-derived immune responses against CAC in MDR1A deficiency, which may include several tumoricidal mechanisms, such as production of granzyme B [82] and anti-tumor antibodies [83]. It is possible that colonic MDR1A KO B cells represent the cellular source of enhanced cytotoxic TNFSF10 in the inflamed tumor microenvironment [84].…”

Section: Discussionmentioning

confidence: 99%

MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis

et al. 2017

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Patients with Ulcerative Colitis (UC) have an increased risk to develop colitis-associated colorectal cancer (CAC). Here, we found that protein expression of ABCB1 (ATP Binding Cassette Subfamily B Member 1) / MDR1 (multidrug resistance 1) was diminished in the intestinal mucosa of patients with active UC with or without CAC, but not in non-UC patients with sporadic colon cancer. We investigated the consequences of ABCB1/MDR1 loss-of-function in a common murine model for CAC (AOM/DSS). Mice deficient in MDR1A (MDR1A KO) showed enhanced intratumoral inflammation and cellular damage, which were associated with reduced colonic tumor size and decreased degree of dysplasia, when compared to wild-type (WT). Increased cell injury correlated with reduced capacity for growth of MDR1A KO tumor spheroids cultured ex-vivo. Gene expression analysis by microarray demonstrated that MDR1A deficiency shaped the inflammatory response towards an anti-tumorigenic microenvironment by downregulating genes known to be important mediators of cancer progression (PTGS2 (COX2), EREG, IL-11). MDR1A KO tumors showed increased gene expression of TNFSF10 (TRAIL), a known inducer of cancer cell death, and CCL12, a strong trigger of B cell chemotaxis. Abundant B220+ B lymphocyte infiltrates with interspersed CD138+ plasma cells were recruited to the MDR1A KO tumor microenvironment, concomitant with high levels of immunoglobulin light chain genes. In contrast, MDR1A deficiency in RAG2 KO mice that lack both B and T cells aggravated colonic tumor progression. MDR1A KO CD19+ B cells, but not WT CD19+ B cells, suppressed growth of colonic tumor-derived spheroids from AOM/DSS-WT mice in an ex-vivo co-culture system, implying that B-cell regulated immune responses contributed to delayed tumor development in MDR1A deficiency. In conclusion, we provide first evidence that loss of ABCB1/MDR1 function may represent an essential tumor-suppressive host defense mechanism in CAC.

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Plasma Cells in the Mucosa of Patients with Inflammatory Bowel Disease Produce Granzyme B and Possess Cytotoxic Activities

Cited by 69 publications

References 35 publications

Hydroxyproline Attenuates Dextran Sulfate Sodium‐Induced Colitis in Mice: Involvment of the NF‐κB Signaling and Oxidative Stress

Hydroxyproline Attenuates Dextran Sulfate Sodium‐Induced Colitis in Mice: Involvment of the NF‐κB Signaling and Oxidative Stress

Human Memory B Cells in Healthy Gingiva, Gingivitis, and Periodontitis

MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis

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