Regulatory and effector B cells: Friends or Foes?

Publication date: Available online 23 November 2018

Source: Journal of Dermatological Science

Author(s): Takashi Matsushita

Abstract

B cells have moved to the center stage in many autoimmune diseases including autoantibody-mediated diseases and T cell-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. B cells play an important role for immune response beyond antibody production through mechanisms like antigen presentation and cytokine production. However, not all B cells positively regulate immune responses. Regulatory B cells negatively regulate immune responses by production of anti-inflammatory cytokines such as IL-10, IL-35, and TGF-β. Regulatory B cells have been found to be decreased and/or functionally impaired in various autoimmune diseases. In contrast, B cells also produce pro-inflammatory cytokines, such as IL-6, IFN-γ and GM ­ CSF. These effector B cells contribute to the pathogenesis of autoimmune diseases. Regulatory and effector B cell balance regulates immune response through the release of cytokines. Furthermore, a protocol that selectively depletes effector B cells while sparing regulatory B cells would represent a potent therapy for autoimmune diseases rather than pan-B cell depletion using anti-CD20 mAb.

https://ift.tt/2RbkNQG

Stat3 activation in epidermal keratinocytes induces Langerhans cell activation to form an essential circuit for psoriasis via IL-23 production

Publication date: Available online 23 November 2018

Source: Journal of Dermatological Science

Author(s): Kimiko Nakajima, Sayo Kataoka, Kenji Sato, Mikiro Takaishi, Mayuko Yamamoto, Hideki Nakajima, Shigetoshi Sano

ABSTRACT

Background

Psoriasis is an inflammatory disease associated with aberrant crosstalk between the epidermis and immune system. However, the role of Langerhans cells (LCs) in psoriasis remains controversial.

Objectives

To elucidate whether LCs are functionally involved in the development of psoriasis using a mouse model.

Methods

Two lines of transgenic mice were used and crossed. They included K5.Stat3C, the psoriasis-model mouse and langerin DTR knock-in (KI) mouse. We performed immunofluorescence staining for LCs in psoriatic lesion of human and model mice. Flow cytometric analyses were performed to compare between dendritic cells (DCs) and LCs in the epidermis and skin-draining lymph nodes (sDLNs). To assess cytokine/chemokine expression in the skin lesion or primary cultured keratinocytes, we performed RT-PCR, microarray analysis or intracellular staining on the flow cytometer.

Results

LCs were activated in psoriatic lesion of patients with psoriasis and K5.Stat3C mice. Compared with non-transgenic mice, K5.Stat3C mice constitutively showed an increased number of LCs in the sDLNs before psoriasis-like lesion developed. Stat3C transgenic keratinocytes expressed an elevated level of IL-1α. Psoriasis-like lesion in K5.Stat3C mice were attenuated in the absence of LCs, indicating that LCs were essential to the development of psoriasis-like lesion. Furthermore, we also recognized that epidermal LCs in psoriatic lesion of not only K5.Stat3C mice but also psoriasis patients produced IL-23.

Conclusions

Our study suggests that Stat3 activation in keratinocytes may impact on LC activation in situ via IL-1α stimulation, at least in part, and that their presence may be essential for the pathogenesis of psoriasis through producing IL-23.

https://ift.tt/2PSv7Ar

Chest radiography or chest CT plus head and neck CT versus 18F-FDG PET/CT for detection of distant metastasis and synchronous cancer in patients with head and neck cancer

Publication date: January 2019

Source: Oral Oncology, Volume 88

Author(s): Yehree Kim, Jong-Lyel Roh, Jae Seung Kim, Jeong Hyun Lee, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim

Abstract

Objectives

Current guidelines recommend chest computed tomography (CT) with locoregional CT/magnetic resonance imaging for patients with head and neck squamous cell carcinoma (HNSCC), and ¹⁸F-fluorodeoxyglucose (FDG) positron-emission tomography (PET)/CT is suggested for stage III–IV patients. However, whole body screening with ¹⁸F-FDG PET/CT may provide better detection of distant metastases and synchronous cancer than conventional imaging. We evaluated the utility of ¹⁸F-FDG PET/CT in detecting distant metastasis and synchronous cancer.

Methods

This prospective study enrolled 740 consecutive patients with previously untreated HNSCC diagnosed between September 2010 and December 2015. Synchronous cancer was histologically confirmed and distant metastases were confirmed by biopsy or serial imaging follow-ups. McNemar test was used to compare the true-positive detection rates of chest radiography (CXR) + head and neck CT (hnCT) (A) versus ¹⁸F-FDG PET/CT (C) and chest CT + hnCT (B) versus ¹⁸F-FDG PET/CT.

Results

Distant metastases and synchronous cancer were found in 23 (3.1%) and 55 (7.4%) patients, respectively. A, B, and C detected distant metastases in 10 (1.3%), 19 (2.6%), and 21 (2.8%) patients, respectively. The absolute differences were 1.5% (A versus C, P = 0.003) and 0.3% (B versus C, P = 0.687). A, B, and C detected synchronous cancer in 15 (2.0%), 22 (2.9%), and 36 (4.9%) patients, respectively. The absolute differences were 2.8% (A versus C, P < 0.001) and 1.4% (B versus C, P = 0.013).

Conclusions

¹⁸F-FDG PET/CT detected more distant metastases and synchronous cancer than CXR + hnCT and more synchronous cancer than chest CT + hnCT.

https://ift.tt/2zn2vFi

Reproductive history and risk of nasopharyngeal carcinoma: A population-based case–control study in southern China

Publication date: January 2019

Source: Oral Oncology, Volume 88

Author(s): Rui-Mei Feng, Ellen T. Chang, Zhiwei Liu, Qing Liu, Yonglin Cai, Zhe Zhang, Guomin Chen, Qi-Hong Huang, Shang-Hang Xie, Su-Mei Cao, Yu Zhang, Jingping Yun, Wei-Hua Jia, Yuming Zheng, Jian Liao, Yufeng Chen, Longde Lin, Ingemar Ernberg, Guangwu Huang, Yi Zeng

Abstract

Objects

Nasopharyngeal carcinoma (NPC) incidence exhibits a remarkable sex disparity, with higher risk among males. Whether this pattern can be partly explained by female reproductive history is unclear.

Methods

A population-based case–control study of NPC was conducted in southern China between 2010 and 2014, including 674 histopathologically verified female NPC cases and 690 female controls randomly selected from population-based registries. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression after adjusting for potential confounders.

Results

Women who had 3, 4, or ≥5 pregnancies compared with 2 pregnancies were at significantly increased risk for NPC (ORs 1.56, 1.45 and 1.88, respectively). History of deliveries was similarly associated with a greater risk of NPC. These positive associations were more prominent in women who were younger than 50 years, had less than 10 years of education, or were white-collar workers. Increasing time since menopause was associated with a diminished NPC risk (P_trend = 0.010). Women more than 15 years after menopause had a 0.35-fold (95% CI: 0.16–0.75) NPC risk compared with those 0–3 years after menopause.

Conclusion

Contrary to our hypothesis, a history of pregnancy or delivery increased the risk of NPC and the risk decreased with increasing time since menopause. However, the non-linear relationship and no consistent risk patterns across strata indicate that the observed associations are unlikely to be causal, and may at least partially be ascribed to residual confounding by socioeconomic factors.

https://ift.tt/2P1eZY7

Immune microenvironment and evasion mechanisms in adenoid cystic carcinomas of salivary glands

Publication date: January 2019

Source: Oral Oncology, Volume 88

Author(s): Carla Mosconi, José Alcides Almeida de Arruda, Ana Caroline Rodrigues de Faria, Gabriella Alves Quixabeira Oliveira, Henrique Moura de Paula, Felipe Paiva Fonseca, Ricardo Alves Mesquita, Tarcília Aparecida Silva, Elismauro Francisco Mendonça, Aline Carvalho Batista

Abstract

Objectives

The objective of the present study was to investigate the expression of immune checkpoints (PD-L1, PD-L2, PD-1 and CTLA-4), immune inhibitory molecule HLA-G, markers of tumor-infiltrating lymphocytes (TIL) and dendritic cells (DC), as well as its association with clinicopathological features of adenoid cystic carcinomas (ACC) of the salivary glands.

Materials and methods

Thirty-six samples from patients with ACC were analyzed immunohistochemically for the expression of PD-L1, PD-L2, PD-1, CTLA-4, HLA-G, CD8, GrB, CD1a and CD83. Positivity of HLA-G, PD-L1 and PD-L2 expression was defined by cut-offs values. CD8⁺ TIL was measured semiquantitatively and also using cut-off values obtained by the ROC curve considering recurrence of the lesion.

Results

ACC showed low CD8⁺, GrB⁺  TIL, CD1a and CD83 populations, as well as scarce positivity for CTLA-4 and PD-1. In contrast, PD-L2 and HLA-G expression was increased, while no PD-L1 expression was detected. Interestingly, cases with lower CD8⁺ TIL density presented greater recurrence rates.

Conclusion

Our findings suggest that the ACC microenvironment exhibits low immunogenicity, represented by low TIL and DC density. Moreover, there seems to be activation of the immune inhibitory proteins/PD-L2 and HLA-G, a scenario that may favor tumor escape from the immune system and partially explain the poor prognosis of ACC.

https://ift.tt/2zn2npi

Identification of the minimal region of peptide derived from ADP-ribosylation factor1 (ARF1) that inhibits IgE-mediated mast cell activation

Publication date: January 2019

Source: Molecular Immunology, Volume 105

Author(s): Ryota Uchida, Tomonori Egawa, Yoshio Fujita, Kazuyuki Furuta, Hiroaki Taguchi, Satoshi Tanaka, Keigo Nishida

Abstract

Mast cells play a pivotal role in allergic reactions and inflammations. Aggregation of the high affinity IgE receptor (FcεRI) eventually leads to the release of granule components such as histamine, as well as the de novo synthesis of inflammatory cytokines and lipid mediators. These substances are involved in the development of allergy and inflammation. Therefore, efficient inhibitors of mast cell activation would be therapeutically beneficial. We previously demonstrated that the synthetic peptide derived from the NH₂-terminal region (2–17: GNIFANLFKGLFGKKE) of a small GTPase ARF1 (ADP-ribosylation factor1) inhibited FcεRI-induced mast cell degranulation. However, detailed structure-activity relationship study of NH₂-terminal portion of ARF1 peptide has not been done. In addition, it is still unclear whether the NH₂-terminal peptide of ARF1 suppresses FcεRI-induced production of cytokines and lipid mediators such as leukotriene C4 (LTC₄) from mast cells.

Here we show that amino acid residues K¹⁰-K¹⁶ are necessary for ARF1 peptide to efficiently inhibit FcεRI-induced activation of bone marrow-derived mast cells (BMMCs), indicated by decreased mast cell degranulation, cytokine secretion and leukotriene release. Furthermore, we show that ARF1 peptide inhibits IgE-mediated passive cutaneous anaphylaxis reaction. Our results suggest that the peptide derived from ARF1 could be developed into a novel anti-allergic agent for therapeutic intervention in allergy and mast cell-related pathologies.

https://ift.tt/2FDv0DX

A complex auxiliary: IL-17/Th17 signaling during type 1 diabetes progression

Publication date: January 2019

Source: Molecular Immunology, Volume 105

Author(s): Zihan Zheng, Feng Zheng

Abstract

Type 1 diabetes (T1D) is an autoimmune disease centered around the loss of the beta cells of the islets of Langerhans, and consequent inability of the islets to produce the insulin necessary to maintain glycemic control. While most therapeutic approaches have been centered on insulin replacement, newer approaches to target the underlying immune response have become an area of focus. However, the immune landscape in T1D is extremely complex, and the roles played by individual cytokines during disease progression are incompletely understood, making the development of immunotherapies very difficult. In this review, we discuss the complex auxiliary role played by IL-17, both around the islet and in peripheral tissues such as the gut and kidney, which might influence T1D progression. Through our re-analysis of the key factors involved IL-17 signaling in recently published single-cell sequencing and sorted-cell bulk sequencing datasets, we find supporting evidence for the general existence of the signaling apparatus in islet endocrine cells. We also explore the emerging evidence of IL-17 serving as an influential factor in diabetic complications that affect distal tissues. While anti-IL-17 therapies are emerging as an option for psoriasis and other autoimmune disorders, we highlight here a number of questions that would need to be addressed before their potential applicability to treating T1D can be fully evaluated.

https://ift.tt/2r1Zs0F