Clinical Immunology

The protective effect of interfering TLR9-IRF5 signaling pathway on the development of CVB3-induced myocarditis Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Shu Nie, Boqi Dong, Shuang Gao, Yan Zhou, Wenting Lu, Mingli Fang, Shucheng Hua, Yongli Yu, Liying Wang Abstract Since toll-like receptor 9 (TLR9) or interferon regulatory factor 5 (IRF5) was reported to be associated with the development of myocarditis, we wondered if the TLR9-IRF5 pathway could contribute to the development of coxsackievirus B3 (CVB3)-induced myocarditis. We detected signaling molecules of TLR9-IRF5 pathway in CVB3-infected patients and mice. The results showed that TLR9, IRF5 and its downstream molecules such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were significantly increased, and the increase was correlated with the severity of heart injury during CVB3 infection. In addition, we demonstrated that an AAAG ODN with IRF5 interfering activities significantly decreased the levels of the TLR9-IRF5 pathway molecules in hearts, spleens as well as white blood cells, and alleviated the myocarditis in CVB3-infected mice. The data suggest that interfering TLR9-IRF5 pathway could be an approach to treat CVB3-induced myocarditis.

Reactivation of BK virus after double umbilical cord blood transplantation in adults correlates with impaired reconstitution of CD4+ and CD8+ T effector memory cells and increase of T regulatory cells Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Theodoros Karantanos, Haesook T. Kim, Natalia M. Tijaro-Ovalle, Lequn Li, Corey Cutler, Joseph H. Antin, Karen Ballen, Francisco M. Marty, Chen Sabrina Tan, Jerome Ritz, Ioannis Politikos, Vassiliki Boussiotis Abstract BK virus (BKV), a human polyomavirus that remains latent in renal epithelial cells, can be reactivated after hematopoietic stem cell transplantation (HSCT) leading to hemorrhagic cystitis. The incidence of BK viremia is higher after Umbilical cord blood transplantation (UCBT) than HSCT from adult donors. Data regarding the role of immune recovery after UCBT in BKV reactivation is lacking. We examined the correlation between the development of BK viremia and immune reconstitution in 27 adult recipients of UCBT. The incidence of BK viremia was 52% and developed most frequently within the first 8 weeks after the transplantation, but persisted in seven patients at 6 months, and three patients at 1-year post UCBT. Detection of BK viremia 1 year after transplant was negatively associated with the number of CD8+ cells (p = 0.03) and CD8+CD45RO+ cells (p = 0.05) at 6 months, and the number of CD4+ (p = 0.03) and CD4+CD45RO+ cells (p = 0.03) at 12 months after UCBT. Conversely, BK viremia at 6 and 12 months was positively correlated with the number of T regulatory (Treg) cells at 1 month (p = 0.005 and p = 0.016, respectively). Because UCB Treg have highly potent immunosuppressive function, our findings indicate that sustained BK viremia in UCBT recipients might be associated with the increase of Treg cells early after transplantation, which mediate impaired and delayed reconstitution of CD4+ and CD8+ T effector cells.

The contribution of macrophages to systemic lupus erythematosus Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Chunyan Ma, Yu Xia, Qingrui Yang, Yueran Zhao Abstract As a heterogeneous autoimmune disease associated with severe organ damage, the precise mechanisms of systemic lupus erythematosus (SLE) remain to be clarified. Recent research indicates that innate immunity plays vital roles in SLE. Defects in the phagocytosis of apoptotic cells, aberrant activation and imbalanced polarization of macrophages, have been shown to participate in the pathogenesis of SLE. Treatments targeting these processes may ameliorate the disease activity in lupus models as well as in patients with SLE. Macrophages participate in the initiation of autoimmunity and the development of SLE in multiple levels. Better understanding of this complex disease is the prerequisite for exploring more effective therapies of SLE.

Clinical manifestations and gastrointestinal pathology in 40 patients with autoimmune enteropathy Publication date: October 2019 Source: Clinical Immunology, Volume 207 Author(s): Vincenzo Villanacci, Vassilios Lougaris, Alberto Ravelli, Elisabetta Buscarini, Tiziana Salviato, Paolo Lionetti, Marianna Salemme, Stefano Martelossi, Costantino De Giacomo, Diego Falchetti, Gloria Pelizzo, Gabrio Bassotti Abstract Autoimmune enteropathy (AIE) is a rare condition that may affect pediatric and adult patients, frequently associated with primary immunodeficiencies. We performed a retrospective study on clinical and histological findings from 40 AIE patients. Histological presentation showed a prevalent celiac disease pattern (50%), followed by the mixed pattern (35%), independently of age, chronic active duodenitis (10%), and GVHD-like pattern (5%). Patients with primary immunodeficiencies (24/40) presented mainly with the celiac disease pattern (72.2% versus 22.2%; p < .0001), while patients without primary immunodeficiencies presented with a mixed histological pattern (61.1% versus 13.6%; p < .0001). Our study shows that the prevalent histological presentation is the celiac disease-like pattern, independently of age, and, for the first time, that the histological presentation of AIE differs significantly between patients with and without primary immunodeficiencies. These findings may be helpful for more precise and timely diagnosis and management of this rare disorder.

M2a and M2b macrophages predominate in kidney tissues and M2 subpopulations were associated with the severity of disease of IgAN patients Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Wenxue Hu, Jieshan Lin, Xingji Lian, Feng Yu, Wei Liu, Yanhua Wu, Xiaowu Fang, Xinling Liang, Wenke Hao Abstract M2 macrophages play important roles during the injury and repair phases in kidney. Our aims are to investigate the distribution of M2 subpopulations and the correlation with clinicopathological features of IgA nephropathy (IgAN) patients. In this study, renal samples from 49 IgAN patients were detected by immunofluorescence. The markers of M2 macrophages, including M2a (CD206+/CD68+), M2b (CD86+/CD68+) and M2c (CD163+/CD68+) were identified. We found M2a and M2b macrophages were the predominant subpopulations in kidney tissues of IgAN. M2a macrophages were mainly distributed in tubulointerstitium with renal lesions like segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis. However, there were larger numbers of M2c in glomeruli with minor lesions. Moreover, M2a and M2c macrophages were inversely correlated with the clinical and pathologic features, respectively. These results suggest M2 subpopulations were involved in the progression of IgAN, and M2a and M2c macrophages might show different properties to participate in the pathogenesis of IgAN.

Evaluation of the frequency of invariant natural killer T (iNKT) cells in nasal polyps Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Mohammad Fereidouni, Afshin Derakhshani, Simon Yue, Saeed Nasseri, Reza Farid Hosseini, Mehdi Bakhshaee, Fatemeh Vahidian, Mark A. Exley Abstract Nasal polyps (NP) are associated with inflamed mucosa of unknown etiology. The role of T cells in nasal polyposis is unclear. Invariant natural killer T cells (iNKT) can promote Th2 responses and have been implicated in some types of asthma. As there are shared inflammatory pathways involved in asthma and NPs, we evaluated the frequency of iNKT in 17 patients with NPs, but without asthma. A median of 6% polyp cells were T lymphocytes, of which iNKT were 0 to 2.38% (mean 0.674%). In the matched group (n = 10), iNKT in NPs was significantly higher than PBMCs (1.057% vs 0.155%, P < 0.05). Relative expression of Vα24 to TCR-beta genes in polyps (n = 14) was higher than blood in matched samples (n = 4). The presence of greater proportions of iNKT in NPs than in blood suggests that iNKT may play a role in the pathogenesis of nasal polyposis.

A novel simplified method of generating cytomegalovirus-specific cytokine-induced killer cells of high specificity and superior potency with GMP compliance Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Yen Hoon Luah, Kirubavathy Sundar Raj, Mickey B.C. Koh, Yeh Ching Linn Abstract We describe a method of rendering polyclonal cytokine-induced killer cells (CIK) specific against cytomegalovirus (CMV), focusing on GMP compliance. Peripheral blood mononuclear cells (PBMNC) are stimulated with pooled CMV peptides pp65 and IE-1 for 16–24 h and the reactive T cell subset which up-regulate CD137 is further co-stimulated with anti-CD137, followed by expansion in G-Rex flasks under standard CIK culture condition. This method generates a large number CMV-specific CIK with superior potency compared to published method currently in clinical trials. The cytotoxicity as measured by chromium release assay correlates with the upregulation of CD107a upon peptide re-challenge as measured by flow cytometry. CMV-CIK at maturity consist of mainly late effector memory CD8 T cells and have a skewed TCR repertoire with preferential expansion of a few families. Such CMV-CIK retain their function after freezing and thawing. CMV-CIK thus generated is ready for clinical trial against drug-resistant CMV disease.

Silica exposure and chronic virus infection synergistically promote lupus-like systemic autoimmunity in mice with low genetic predisposition Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Rosana Gonzalez-Quintial, Jessica M. Mayeux, Dwight H. Kono, Argyrios N. Theofilopoulos, Kenneth M. Pollard, Roberto Baccala Abstract Considerable evidence indicates that autoimmune disease expression depends on both genetic and environmental factors. Among potential environmental triggers, occupational airway exposure to crystalline silica and virus infections have been linked to lupus and other autoimmune diseases in both humans and mouse models. Here, we hypothesized that combined silica and virus exposures synergize and induce autoimmune manifestations more effectively than single exposure to either of these factors, particularly in individuals with low genetic predisposition. Accordingly, infection with the model murine pathogen lymphocytic choriomenigitis virus (LCMV) in early life, followed by airway exposure to crystalline silica in adult life, induced lupus-like autoantibodies to several nuclear self-antigens including chromatin, RNP and Sm, concurrent with kidney lesions, in non-autoimmune C57BL/6 (B6) mice. In contrast, given individually, LCMV or silica were largely ineffectual in this strain. These results support a multihit model of autoimmunity, where exposure to different environmental factors acting on distinct immunostimulatory pathways complements limited genetic predisposition and increases the risk of autoimmunity above a critical threshold.

Urine macrophages reflect kidney macrophage content during acute tubular interstitial and glomerular injury Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Ping-ping Sun, Xu-jie Zhou, Jian-qun Su, Chen Wang, Xiao-juan Yu, Tao Su, Gang Liu, Su-xia Wang, Jing Nie, Li Yang Abstract Macrophage polarization is a major contributing factor in acute kidney injury (AKI). We aim to determine its biomarker value in differentiating etiologic causes of various intrinsic renal AKI. A total of 205 patients with renal intrinsic AKI were enrolled. Urinary sCD163 was quantified and macrophage subtypes in urine and in renal biopsy were determined. Compared to healthy controls and AKI due to interstitial or tubular injuries (0 pg/μmol), urinary sCD163 was markedly higher in glomerulopathy, especially in diffuse proliferative glomerulonephritis (275.5 pg/μmol) and significantly correlated with cellular crescent formation. Urine sediment analysis of M1/M2 ratio could differentiate acute tubulointerstitial nephritis (M1/M2 > 2.35) from crescentic glomerulonephritis (M1/M2 < 0.27). Urinary sCD163 levels and M2 subtype positively correlated with infiltrated M2 in the glomeruli, whereas urine M1 positively correlated with infiltrated M1 in the interstitium. Of note, urinary sCD163 showed better diagnositic performance in differentiating disease etiologies compared to tradiational urinary biomarkers of AKI (NGAL and KIM-1) and markers of myeloid cells (CD11b) and pan macrophages (CD68). Thus markers of macrophage polarization could be viewed as the noninvasive “liquid biopsy” in the presence of various intrinsic kidney diseases.

Epidermal growth factor receptor mimotope alleviates renal fibrosis in murine unilateral ureteral obstruction model Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Lin Yang, Haoran Yuan, Ying Yu, Nan Yu, Lilu Ling, Jianying Niu, Yong Gu Abstract Macrophages have been recognized as a vital factor that can promote renal fibrosis. Previously we reported that the EGFR mimotope could alleviate the macrophage infiltration in the Sjögren's syndrome-like animal model. In current study, we sought to observe whether the active immunization induced by the EGFR mimotope could ameliorate renal fibrosis in the murine Unilateral Ureteral Obstruction (UUO) model. A series of experiments showed the EGFR mimotope immunization could ameliorate renal fibrosis, reduce the expressions of fibronectin, α-SMA and collagen I and alleviate the infiltrations of F4/80+ macrophages in UUO model. Meanwhile, the EGFR mimotope immunization could inhibit the EGFR downstream signaling. Additionally, the frequency of and F4/80+CD9+/FAS+ macrophages significantly increased in spleen after the EGFR mimotope immunization. These evidence suggested that the EGFR mimotope could alleviate renal fibrosis by both inhibiting EGFR signaling and promoting macrophages apoptosis.