Clinical Immunology

Cis-regulatory genetic variants in the CCR5 gene and natural HIV-1 control in black South Africans Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Gemma W. Koor, Maria Paximadis, Anabela C.P. Picton, Fidan Karatas, Shayne A. Loubser, Weijing He, Sunil K. Ahuja, Richard E. Chaisson, Neil Martinson, Osman Ebrahim, Caroline T. Tiemessen Abstract Studies have investigated CCR5 haplotypes (HHA, HHB, HHC, HHD, HHE, HHF*1, HHF*2, HHG*1, HHG*2), defined by seven 5′UTR single nucleotide polymorphisms (SNPs), CCR2-V64I and CCR5Δ32, in HIV-1 disease. CCR5 cis-regulatory regions were sequenced, CCR2-V64I and CCR5Δ32 genotyped, and compared in HIV-1-infected black South Africans: 71 HIV-1 controllers (23 elite controllers, 37 viraemic controllers (VCs), 11 high viral load long-term non-progressors) and 74 progressors. The HHE haplotype and 3′UTR +2919 T > G SNP heterozygosity were underrepresented in total controllers and VCs vs. progressors (p = .004; p = .007 and p = .002, pbonferroni = 0.032; p = .004, respectively). Possession of the +2919 T > G SNP (dominant mode) was associated with HIV-1 progression (controllers vs. progressors: p = .001, pbonferroni = 0.016). The +2919 T > G SNP is in linkage disequilibrium (LD; r2 = 0.73) with two 5′UTR SNPs (−2459G > A and -2135 T > C; r2 = 1: 5′UTR-2SNP-hap). The 5′UTR-2SNP-hap was lower in total controllers and VCs vs. progressors (p = .003, pbonferroni = 0.048; p = .01, respectively). Results suggest -2459G > A, −2135 T > C, and + 2919 T > G as key CCR5 variants in HIV-1 control.

Interference of canakinumab with commercial IL-1β ELISAs Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Mary Linge, Christian M. Hedrich, Angela Rösen-Wolff, Stefan Winkler

Elevated oxidized lipids, anti-lipid autoantibodies and oxidized lipid immune complexes in active SLE Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Yujin Ye, Tianfu Wu, Ting Zhang, Jie Han, Deena Habazi, Ramesh Saxena, Chandra Mohan Abstract Background Here, we explore the serum levels of anti-oxidized lipid autoantibodies as well as immune complexes in patients with SLE and determine their correlation with disease. Methods Serum levels of oxidized-LDL immune complexes, autoantibodies to dsDNA, ox-LDL, MDA-LDL, 9-HODE, 13-HODE and POVPC were detected by ELISA in 64 SLE patients and 9 healthy controls. Results Active SLE patients exhibited increased serum levels of autoantibodies compared to healthy controls, including anti-MDA-LDL-IgG (p = .003), anti-ox-LDL-IgG (p = .004), anti-9-HODE-IgG (p = .001), anti-13-HODE-IgG (p = .0003), anti-POVPC-IgG (p = .001) and ox-LDL-IC (p = .003). Serum anti-ox-LDL-IgG was positively correlated with SLEDAI (r = 0.34; p = .01), and negatively with C3 (r = −0.40; p = .01). Anti-9-HODE-IgG and anti-POVPC-IgG were positively correlated with SLEDAI and negatively with C4. Conclusions Active SLE patients exhibit significantly increased serum levels of IgG anti-oxidized-lipid autoantibodies. Coordinated elevation of oxidized lipids, autoantibodies to these lipids, and immune complexes of these lipid-antibody components could potentially serve as pathogenic drivers and serum markers of SLE disease activity.

Candidiasis associated with very early onset inflammatory bowel disease: First IL10RB deficient case from the National Iranian Registry and review of the literature Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Reza Yazdani, Bobak Moazzami, Seyedeh Panid Madani, Nasrin Behniafard, Gholamreza Azizi, Majid Aflatoonian, Hassan Abolhassani, Asghar Aghamohammadi Abstract Defects in interleukin-10 (IL10) and interleukin-10 receptors (IL10R) are closely related to very early onset (infantile) inflammatory bowel disease (VEO-IBD). In the present study, we report a novel homozygous null mutation within interleukin-10 receptor B (IL10RB) gene in a child presenting with severe VEO-IBD. In accordance with previous reports, our patient manifested with chronic diarrhea, failure to thrive, intermittent fever and multiple anal ulcers associated with Candidiasis. Homozygous null mutation within IL10RB gene (c.92C > T, p.S31P) affecting the extracellular domain of protein was discovered in this patient. In conclusion, the diagnosis of IL-10R gene mutations should always be considered as a possible cause of refractory diarrhea and failure to thrive. Mutation analysis could help detect the genetic defects associated with these clinical manifestations and to determine the most appropriate treatment option for patients affected by this disease.

Interleukin 28 is a potential therapeutic target for sepsis Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Qin Luo, Yi Liu, Shuang Liu, Yibing Yin, Banglao Xu, Ju Cao Abstract Identification of new therapeutic targets for the treatment of sepsis is imperative. We report here that cytokine IL-28 (IFN-λ) levels were elevated in clinical and experimental sepsis. Neutralization of IL-28 protected mice from lethal sepsis induced by cecal ligation and puncture (CLP), which was associated with improved bacterial clearance and enhanced neutrophil infiltration. Conversely, administration of recombinant IL-28 aggravated mortality, facilitated bacterial dissimilation and limited neutrophil recruitment, in the model of sepsis induced by CLP. This study defines IL-28 as a detrimental mediator during sepsis and identifies a potential therapeutic target for the immune therapy in sepsis.

Delay expression of NKp30 on NK cells correlates with long-term mycophenolate mofetil treatment and higher EBV viremia post allogenic hematological stem cells transplantation Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Xing-Xing Yu, Xun-Hong Cao, Hong Yan, Xue-Yi Luo, Xiao-Su Zhao, Yu-Qian Sun, Yu Wang, Lan-Ping Xu, Xiao-Hui Zhang, Ying-Jun Chang, Xiao-Jun Huang, Xiang-Yu Zhao Abstract Mycophenolate mofetil (MMF) is an immunosuppressive agent that is widely used in graft-versus-host disease prophylaxis because of its inhibitory function on T cells and B cells. However, the effect of MMF on natural killer cell reconstitution after allogenic hematological transplantation is largely unknown. The present study examined the effects of different MMF administration durations after haploidentical allo-HSCT on NK cell reconstitution. Ninety patients were enrolled in this study and defined into two groups in term of MMF duration. We found that MMF patients in the long-term MMF group were associated with a poor reconstitution of NK cells and a significantly lower cytotoxicity from day 30 to day 180 post-transplantation. Especially, the long-term MMF group inhibits reconstitution of NKp30 NK subsets, which correlated with higher risk of EBV viremia. Multivariate analysis showed that a better reconstitution of NKp30 cells was associated with lower EBV viremia (HR0.957, p = .04). In vitro experiments demonstrated that the active metabolite of MMF, mycophenolic acid (MPA), inhibited the proliferation and cytotoxicity of NK cells from healthy donors or patients at day 30 post-transplantation. In summary, our findings demonstrated that long-term MMF administration delayed the quality and quantity of NK cells, especially NKp30 subpopulations, which was associated with decreased EBV viremia post allogeneic HSCT.

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.

When neonatal inflammation does not mean infection: an early-onset mevalonate kinase deficiency with interstitial lung disease Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Carlo Pietrasanta, Francesca Minoia, Sofia Torreggiani, Andrea Ronchi, Marco Gattorno, Stefano Volpi, Isabella Ceccherini, Fabio Mosca, Giovanni Filocamo, Lorenza Pugni Abstract Systemic inflammation in neonates is attributable to an infection in almost all cases. When inflammation persists, an autoinflammatory disease should be promptly suspected. We report here a case of mevalonate kinase deficiency (MKD) that presented at birth with mild symptoms and signs suggestive for a perinatal infection, together with the uncommon finding of interstitial lung disease. An extensive diagnostic work-up, performed after ineffective antibiotic treatment, demonstrated high levels of mevalonic acid in urine (7024 mM/M of creatinine, normal value <0.1). Next-generation sequencing showed a rare c.709A > T (p.T237S) homozygous mutation in the MVK gene, consistent with MKD. Treatment with anakinra led to a prompt resolution of symptoms and a sharp drop in serum inflammatory markers. The patient is now six months-old, currently undergoing evaluation for hematopoietic stem-cell transplantation. To our knowledge, this is the first case of MKD presenting within the first week of life with interstitial lung disease.

Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections Publication date: August 2019 Source: Clinical Immunology, Volume 205 Author(s): Svetlana O. Sharapova, Emma Haapaniemi, Inga S. Sakovich, Larysa V. Kostyuchenko, Agnes Donkó, Alina Dulau-Florea, Oksana Malko, Anastasia V. Bondarenko, Maria V. Stegantseva, Thomas L. Leto, Vedat Uygun, Gulsun Tezcan Karasu, Steven M. Holland, Amy P. Hsu, Olga V. Aleinikova Abstract Here we describe a 10-year-old girl with combined immunodeficiency presenting as recurring chest infections, lung disease and herpetic skin infections. The patient experienced two hematopoietic stem cell transplantations and despite full chimerism, she developed bone marrow aplasia due to adenovirus infection and died at post-transplant day 86. Immunologic investigation revealed low numbers of TRECs/KRECs, a severe reduction of memory B cells, absence of isohemagglutinins, and low IgG levels. Whole exome sequencing (WES) identified a novel heterozygous mutation in RAC2(c.275A > C, p.N92 T). Flow cytometric investigation of neutrophil migration demonstrated an absence of chemotaxis to fMLP. Cell lines transfected with RAC2 [N92 T] displayed characteristics of active GTP-bound RAC2 including enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA. Our findings broaden the clinical picture of RAC2 dysfunction, showing that some individuals can present with a combined immunodeficiency later in childhood rather than a congenital neutrophil disease.

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.