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Results in Journal Clinical and Experimental Immunology: 15,251

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H. Ebe, I. Matsumoto, H. Kawaguchi, I. Kurata, Y. Tanaka, A. Inoue, Y. Kondo, H. Tsuboi, T. Sumida
Clinical and Experimental Immunology, Volume 191, pp 338-348;

Tumour necrosis factor alpha (TNF)‐α‐induced adipose‐related protein (TIARP) is a negative regulator of inflammation in arthritis model mice. In humans, six‐transmembrane epithelial antigen of prostate 4 (STEAP4) (human counterpart of TIARP) is also expressed in CD14+ monocytes from patients with rheumatoid arthritis (RA). Recently, highly levels of exon 3‐spliced variant STEAP4 (v‐STEAP4) expression have been observed in porcine lung. The aim of this study is to elucidate the expression and functional role of v‐STEAP4, comparing it with that of STEAP4, in the pathogenesis of arthritis. We identified v‐STEAP4 in CD14+ cells. The expression of STEAP4 and v‐STEAP4 was higher in patients with RA than in healthy participants. We also found that STEAP4 and v‐STEAP4 were correlated positively with C‐reactive protein and that their expression was decreased after treatment with an interleukin (IL)‐6 antagonist in patients with RA. To investigate further the role of STEAP4 and v‐STEAP4, we produced STEAP4 and v‐STEAP4 over‐expressing human monocytic cell lines (THP‐1) for functional analysis. In the v‐STEAP4 over‐expressing cells, the production of IL‐6 was suppressed significantly, but TNF‐α was increased significantly through lipopolysaccharide (LPS) stimulation. Immunoblot analysis revealed that phosphorylated (p‐)nuclear factor kappa B (NF‐κB) was increased after LPS stimulation and degradation of nuclear factor kappa B inhibitor alpha (IκBα) was sustained, whereas p‐signal transducer and activator of transcription 3 (STAT‐3) was decreased with v‐STEAP4. We identified specific up‐regulation of v‐STEAP4 in RA monocytes. V‐STEAP4 might play a crucial role in the production of TNF‐α and IL‐6 through NF‐κB and STAT‐3 pathways, resulting in the generation of RA.
D. Kowalczyk, , A. D. B. Webster, M. Zembala
Clinical and Experimental Immunology, Volume 127, pp 507-512;

Intracellular expression of several cytokines was assessed in lymphocytes and monocytes of children with transient hypogammaglobulinaemia of infancy (THI) and selective IgA deficiency (SIgAD). THI was characterized by an increased frequency of CD3+/CD4+ lymphocytes expressing tumour necrosis factor α (TNF-α), TNF-β and interleukin 10 (IL-10), while in SIgAD elevated numbers of these cells containing TNF-α and interferon γ (IFN-γ) were observed. No changes in the number of CD4+ T cells expressing IL-4 in both diseases were noted. The proportion of CD33+ monocytes containing TNF-α both in THI and SIgAD was unchanged. The secretion of IL-12 by peripheral blood mononuclear cells (PBMCs) of patients with THI and SIgAD was significantly elevated and associated with an increased frequency of IL-12 expressing monocytes in THI but not in SIgAD. IL-18 secretion was slightly, but not significantly, elevated in both diseases. Intracellular Th1 and Th2 type cytokines within CD3+/CD4+ lymphocytes were also determined in the normal blood donors that showed high or low production of IgG and IgA in vitro. In low producers of IgG an increased proportion of CD3+/CD4+ cells expressing TNF-α and IFN-γ was found, while in low IgA responders only elevated TNF-α positive CD3+/CD4+ cells were observed. These results suggest that THI and SIgAD may represent diseases with an excessive Th1 type response that is associated with an up-regulation of IL-12 secretion and, at least in THI, elevated numbers of monocytes expressing intracellular IL-12. Up-regulation of IL-12 may be the essential factor in the patomechanism(s) of these diseases as already described in common variable immunodeficiency (CVID).
, M. Horstmann, , S. Plöhn, K. Stähr, S. Mattheis, , S. Lang, U. Flögel, U. Berchner‐Pfannschmidt, et al.
Clinical and Experimental Immunology, Volume 191, pp 255-267;

Experimental models of Graves' hyperthyroid disease accompanied by Graves' orbitopathy (GO) can be induced efficiently in susceptible inbred strains of mice by immunization by electroporation of heterologous human TSH receptor (TSHR) A‐subunit plasmid. In this study, we report on the development of a bona fide murine model of autoimmune Graves' disease induced with homologous mouse TSHR A‐subunit plasmid. Autoimmune thyroid disease in the self‐antigen model was accompanied by GO and characterized by histopathology of hyperplastic glands with large thyroid follicular cells. Examination of orbital tissues showed significant inflammation in extra‐ocular muscle with accumulation of T cells and macrophages together with substantial deposition of adipose tissue. Notably, increased levels of brown adipose tissue were present in the orbital tissue of animals undergoing experimental GO. Further analysis of inflammatory loci by 19F‐magnetic resonance imaging showed inflammation to be confined to orbital muscle and optic nerve, but orbital fat showed no difference in inflammatory signs in comparison to control β‐Gal‐immunized animals. Pathogenic antibodies induced to mouse TSHR were specific for the self‐antigen, with minimal cross‐reactivity to human TSHR. Moreover, compared to other self‐antigen models of murine Graves' disease induced in TSHR knock‐out mice, the repertoire of autoantibodies to mouse TSHR generated following the breakdown of thymic self‐tolerance is different to those that arise when tolerance is not breached immunologically, as in the knock‐out models. Overall, we show that mouse TSHR A‐subunit plasmid immunization by electroporation overcomes tolerance to self‐antigen to provide a faithful model of Graves' disease and GO.
D. De J. Cruz‐González, D. Gómez‐Martin, , L. Baranda, , J. Alcocer‐Varela, R. González‐Amaro,
Clinical and Experimental Immunology, Volume 191, pp 288-300;

Natural killer (NK) cells participate in the regulation of the immune response. However, the immunomodulatory function of NK cells in systemic lupus erythematosus (SLE) is not well understood. The aim of this study was to evaluate the regulatory function of NK cells in SLE patients and to identify the NK cells involved in the pathogenesis of this complex disease. We analysed the expression of NK receptors and co‐stimulatory molecules in peripheral NK cells (CD3CD56+) from SLE patients, as well as the numbers of human leucocyte antigen D‐related (HLA‐DR)/CD11c+ NK cells. In addition, NK cell regulatory function was assessed by the detection of NK cell‐mediated dendritic cell (DC) lysis. We found that SLE patients showed increased numbers of immunoglobulin‐like transcript 2 (ILT2)+, CD86+ and CD134+ NK cells. Furthermore, NK cells from SLE patients induced higher levels of DC lysis. We were able to identify a new subset of NK cells co‐expressing CD11c and HLA‐DR. These atypical NK cells were increased in SLE patients when compared with controls. We have identified an expanded new subset of NK cells in SLE patients. This is the first study, to our knowledge, which demonstrates that NK cells in SLE patients have an altered phenotype with a high expression of receptors characteristic of dendritic cells. Our results suggest that the impairment in the regulatory function of NK cells, together with the increased number of DC‐like NK cells, could play an important role in the development of SLE and highlight the importance of NK cells as a future therapeutic target.
P. Kumar, P. Misra, , A. Saurabh, N. Rishi,
Clinical and Experimental Immunology, Volume 191, pp 318-327;

Visceral leishmaniasis (VL) is a disseminated and lethal disease of reticulo-endothelial system caused by protozoan parasites Leishmania donovani and L. infantum, which are known to induce host T cell suppression. To understand the impact of parasite load on T cell function, the present was focused on parasite load with T cell function in bone marrow of 26 VL patients. We observed significant enrichment of forkhead box protein 3 (FoxP3)+ (P = 0·0003) and interleukin (IL)-10+ FoxP3+ regulatory T cells (Treg) (P = 0·004) in the bone marrow (BM) of patients with high parasite load (HPL) compared with low parasite load (LPL). Concordantly, T effector cells producing interferon (IFN)-γ (P = 0·005) and IL-17A (P = 0·002) were reduced in the BM of HPL. Blocking of Treg-cell derived suppressive cytokines [(IL-10 and transforming growth factor (TGF)-β] rescued the effector T cells and their functions. However, it was observed that TGF-β levels were dominant, favouring Treg cell differentiation. Furthermore, the low ratio of IL-6/TGF-β favours the suppressive milieu in HPL patients. Here we show the change in levels of various cytokines with the parasitic load during active VL, which could be helpful in devising newer immunotherapeutic strategies against this disease.
J. C. Rincon, A. L. Cuenca, S. L. Raymond, B. Mathias, D. C. Nacionales, R. Ungaro, P. A. Efron, , L. L. Moldawer,
Clinical and Experimental Immunology, Volume 191, pp 268-278;

The high mortality in neonatal sepsis has been related to both quantitative and qualitative differences in host protective immunity. Pretreatment strategies to prevent sepsis have received inadequate consideration, especially in the premature neonate, where outcomes from sepsis are so dismal. Aluminium salts-based adjuvants (alum) are used currently in many paediatric vaccines, but their use as an innate immune stimulant alone has not been well studied. We asked whether pretreatment with alum adjuvant alone could improve outcome and host innate immunity in neonatal mice given polymicrobial sepsis. Subcutaneous alum pretreatment improves survival to polymicrobial sepsis in both wild-type and T and B cell-deficient neonatal mice, but not in caspase-1/11 null mice. Moreover, alum increases peritoneal macrophage and neutrophil phagocytosis, and decreases bacterial colonization in the peritoneum. Bone marrow-derived neutrophils from alum-pretreated neonates produce more neutrophil extracellular traps (NETs) and exhibit increased expression of neutrophil elastase (NE) after in-vitro stimulation with phorbol esters. In addition, alum pretreatment increases bone marrow and splenic haematopoietic stem cell expansion following sepsis. Pretreatment of neonatal mice with an alum-based adjuvant can stimulate multiple innate immune cell functions and improve survival. These novel findings suggest a therapeutic pathway for the use of existing alum-based adjuvants for preventing sepsis in premature infants.
, G. N. de Graav, M. Dieterich, , ,
Clinical and Experimental Immunology, Volume 191, pp 363-372;

Blockade of the CD80/86‐CD28 pathway by belatacept after kidney transplantation is associated with an increased risk of rejection compared with standard, calcineurin inhibitor (CNI)‐based therapy. CD28 T cells, which express CD57, are not susceptible to belatacept treatment. High numbers of CD4+CD57+programmed death 1 (PD‐1) T cells pretransplantation have been associated with a higher chance of rejection, although conflicting data have been reported. To investigate the working mechanism behind this possible higher chance of rejection, we studied the expression of co‐inhibitory molecules (CD223, CD244 and PD‐1), proliferative capacity and cytotoxic potential of fluorescence activated cell sorted (FACS) CD4+CD57+PD‐1 and CD8+CD57+PD‐1 T cells, and their CD57 control populations, after alloantigen stimulation. The effect of belatacept on the cytotoxic capacity of pretransplantation peripheral blood mononuclear cells from 20 patients who received belatacept post‐transplantation was also tested. Expression of co‐inhibitory molecule CD223 increased by approximately 10‐fold after allogeneic stimulation in all four T cell subsets. Proliferation and up‐regulation of CD244 and PD‐1 was observed for CD4+CD57PD‐1 T cells after allogeneic stimulation, but no up‐regulation of these markers occurred on CD8+ T cells or CD4+CD57+PD‐1 T cells. However, CD4+CD57+PD‐1 T cells and, to a lesser extent, CD8+CD57+PD‐1 T cells displayed higher cytotoxicity as indicated by granzyme B expression. Belatacept inhibited the cytotoxic potential of CD4+CD57+PD‐1 T cells (median of inhibition 31%, P< 0·01) and CD8+CD57+PD‐1 T cells (median of inhibition 10%, P< 0·05). In conclusion, alloantigen‐activated CD4+CD57+PD‐1 T cells exhibited a less proliferative but more cytotoxic profile than their CD57 counterparts. Their cytotoxic capacity can be inhibited partly by belatacept and was not associated with development of rejection after kidney transplantation.
K. Sharif, V. Vieira Borba, G. Zandman‐Goddard,
Clinical and Experimental Immunology, Volume 191, pp 149-150;

Summary: Ferritin, which was only discovered in the last century, has stirred a formidable debate. Ferritin has long been appreciated as a non-specific acute-phase reactant. Several years ago, we hypothesized the contributory role of ferritin as a pathogenic molecule rather than being a product of inflammation. The latest emerging evidence provides support to this notion. Such revelation provides a step forward towards the understanding of disease conditions associated with hyperferritinaemia, and hence provide new targets for treatment modalities.
A. Stubbs, C. Bangs, B. Shillitoe, , , M. Thomas, H. Alachkar, , E. McDermott, , et al.
Clinical and Experimental Immunology, Volume 191, pp 212-219;

Immunoglobulin replacement therapy enhances survival and reduces infection risk in patients with agammaglobulinemia. We hypothesized that despite regular immunoglobulin therapy some patients will experience ongoing respiratory infections and develop progressive bronchiectasis with deteriorating lung function. 139 (70%) of 199 patients aged 1 to 80 years from nine cities in the UK with agammaglobulinemia currently listed on the UKPID registry were recruited to this retrospective case study and their clinical and laboratory features analyzed. 94% were male of whom 78% had BTK gene mutations. All patients were on immunoglobulin replacement therapy and 52% had commenced therapy by the time they were two years old. 60% were also taking prophylactic oral antibiotics. 56% of patients had radiological evidence of bronchiectasis, which developed between the ages of 7 to 45 years. Multi-variate analysis showed that three factors were significantly associated with bronchiectasis: reaching 18 years old (relative risk (95% CI) 14.2 (2.7 – 74.6)), history of pneumonia (3.9 (1.1 – 13.8)) and IVIG rather than SCIG (3.5 (1.2 – 10.1)), while starting immunoglobulin replacement after reaching two years old, gender and recent serum IgG concentration were not significantly associated. Independent of age, patients with bronchiectasis had significantly poorer lung function (predicted FEV1 74% (50 – 91)) than those without this complication (92% (84 – 101)) (p < 0.001). We conclude that despite immunoglobulin replacement therapy, many patients with agammaglobulinemia can develop chronic lung disease and progressive impairment of lung function.
Fengyun Chu, Yan Hu, Ya Zhou, Mengmeng Guo, Jia Lu, Wen Zheng, Hualin Xu, Juanjuan Zhao,
Clinical and Experimental Immunology, Volume 191, pp 166-179;

Recent evidence showed that microRNA-126 (miR-126) has been involved in the development and function of immune cells, which contributed to the pathogenesis of related clinical diseases. However, the potential role of miR-126 in the development and function of CD4+T cells remains largely unknown. Here we firstly found that the activation and proliferation, as well as the expression of IFN-γ, of CD4+T cells from miR-126 knockdown (KD) mice using miRNA-Sponge technique were enhanced significantly in vitro, compared with those in CD4+T cells from wild type (WT) mice. To further monitor the possible effect of miR-126 deficiency on the function of CD4+T cells in vivo, we used dextran sulfate sodium (DSS)-induced murine model of acute autoimmune colitis and found that miR-126 deficiency could elevate the pathology of colitis. Importantly, the proportion of CD4+T cells in splenocytes increased significantly in miR-126KD mice. Moreover, the expression levels of CD69 and CD44 on CD4+T cells increased obviously and CD62L expression decreased significantly. Of note, adoptive cell transfer assay showed that the pathology of colitis was more serious in CFSE-labeled miR-126KD CD4+T cells transferred group, compared with that in CFSE-labeled WT CD4+T cells transferred group. Consistently, the expression levels of CD69 and CD44 on CFSE+ cells increased significantly. Furthermore, both the proliferation and IFN-γ secretion of CFSE+ cells also increased significantly in CFSE-labeled miR-126KD CD4+T cells transferred group. Mechanistic evidence showed that the expression of insulin receptor substrate 1 (IRS-1), as a functional target of miR-126, was elevated in CD4+T cells from miR-126KD mice, accompanied by altered transduction of ERK, AKT and NF-κB pathway. Our data revealed a novel role in which miR-126 was an intrinsic regulator in the function of CD4+T cells, which provided preliminary basis for further exploring on the role of miR-126 in the development, function of CD4+T cells and related clinical diseases.
L M A Janssen, T Macken, M C W Creemers, J F M Pruijt, J J J Eijk,
Clinical and Experimental Immunology, Volume 191, pp 203-211;

Summary: Isolated decreased serum-immunoglobulin (Ig)M has been associated with severe and/or recurrent infections, atopy and autoimmunity. However, the reported high prevalence of clinical problems in IgM-deficient patients may reflect the skewed tertiary centre population studied so far. Also, many papers on IgM deficiency have included patients with more abnormalities than simply IgM-deficiency. We studied truly selective primary IgM deficiency according to the diagnostic criteria of the European Society for Immunodeficiencies (ESID) (true sIgMdef) by reviewing the literature (261 patients with primary decreased serum-IgM in 46 papers) and analysing retrospectively all patients with decreased serum-IgM in a large teaching hospital in 's-Hertogenbosch, the Netherlands [1 July 2005–23 March 2016; n = 8049 IgM < 0·4 g/l; n = 2064 solitary (IgG+IgA normal/IgM < age-matched reference)]. A total of 359 of 2064 (17%) cases from our cohort had primary isolated decreased serum-IgM, proven persistent in 45 of 359 (13%) cases; their medical charts were reviewed. Our main finding is that true sIgMdef is probably very rare. Only six of 261 (2%) literature cases and three of 45 (7%) cases from our cohort fulfilled the ESID criteria completely; 63 of 261 (24%) literature cases also had other immunological abnormalities and fulfilled the criteria for unclassified antibody deficiencies (unPAD) instead. The diagnosis was often uncertain (possible sIgMdef): data on IgG subclasses and/or vaccination responses were lacking in 192 of 261 (74%) literature cases and 42 of 45 (93%) cases from our cohort. Our results also illustrate the clinical challenge of determining the relevance of a serum sample with decreased IgM; a larger cohort of true sIgMdef patients is needed to explore fully its clinical consequences. The ESID online Registry would be a useful tool for this.
, , P Müller, D Gustafsson, T K Nilsson
Clinical and Experimental Immunology, Volume 191, pp 240-251;

Summary: A child, 2 years with the ‘hypercalprotectinaemia with hyperzincaemia’ clinical syndrome, presented with atypical symptoms and signs, notably persistent fever of approximately 38°C, thrombocythaemia of > 700 × 109/l and a predominance of persistent intestinal symptoms. In an effort to find a cure by identifying the dysregulated pathways we analysed whole-genome mRNA expression by the Affymetrix HG U133 Plus 2·0 array in blood on three occasions 3–5 months apart. Major up-regulation was demonstrated for the Janus kinase/signal transducer and activators of transcription (JAK/STAT) pathway including, in particular, CD177, S100A8, S100A9 and S100A12, accounting for the thrombocytosis; a large number of interleukins, their receptors and activators, accounting for the febrile apathic state; and the high mobility group box 1 (HMBG1) gene, possibly accounting for part of the intestinal symptoms. These results show that gene expression array technology may assist the clinician in the diagnostic work-up of individual patients with suspected syndromal states of unknown origin, and the expression data can guide the selection of optimal treatment directed at the identified target pathways.
, E. Alicot,
Clinical and Experimental Immunology, Volume 191, pp 151-165;

Defining how self-antigens are perceived by the immune system is pivotal to understand how tolerance is maintained under homeostatic conditions. Clinically relevant, natural autoantigens targeted by autoantibodies, in e.g. systemic lupus erythematosus (SLE), commonly have an intrinsic ability to engage not only the B cell receptor (BCR), but also a co-stimulatory pathway in B cells, such as the Toll-like receptor (TLR)-7 pathway. Here we developed a novel mouse model displaying inducible expression of a fluorescent epidermal neo-autoantigen carrying an OT-II T cell epitope, B cell antigen and associated ribonucleic acids capable of stimulating TLR-7. The neo-autoantigen was expressed in skin, but did not drain in intact form into draining lymph nodes, even after ultraviolet B (UVB)-stimulated induction of apoptosis in the basal layer. Adoptively transferred autoreactive B cells were excluded follicularly and perished at the T–B border in the spleen, preventing their recirculation and encounter with antigen peripherally. This transitional check-point was bypassed by crossing the reporter to a BCR knock-in line on a C4-deficient background. Adoptively transferred OT-II T cells homed rapidly into cutaneous lymph nodes and up-regulated CD69. Surprisingly, however, tolerance was not broken, as the T cells subsequently down-regulated activation markers and contracted. Our results highlight how sequestration of intracellular and peripheral antigen, the transitional B cell tolerance check-point and T cell regulation co-operate to maintain immunological tolerance in vivo.
Clinical and Experimental Immunology, Volume 191, pp 253-254;

Summary: Cytokine storm syndromes are a clinically heterogeneous group of conditions resulting from a maladaptive host response to an inflammatory trigger. These syndromes lead to rapid progression of immune-mediated damage to healthy tissues resulting in life-threatening multi-system organ failure. Prompt recognition of disease and medical intervention to limit damage to healthy tissues is essential to prevent cytokine storm morbidity and mortality. However, the diagnosis of cytokine storm syndromes is challenging, given the clinical heterogeneity in disease presentations. Therefore, expeditious and readily available tests to diagnose disease and differentiate between the various types of cytokine storm syndromes are of clinical utility. The recently published work of Shimizu and colleagues brings us closer to making this a reality.
, Susanne Kricke, Elizabeth Ralph, Nathaniel Gilmour, Kimberly C. Gilmour
Clinical and Experimental Immunology, Volume 191, pp 198-202;

Summary: Assessment of thymic output by measurement of naive T cells is carried out routinely in clinical diagnostic laboratories, predominantly using flow cytometry with a suitable panel of antibodies. Naive T cell measurements can also be made using molecular analyses to quantify T cell receptor excision circle (TRECs) levels in sorted cells from peripheral blood. In this study we have compared TRECs levels retrospectively with CD45RA+CD27+ T cells and also with CD45RA+CD31+ T cells in 134 patient samples at diagnosis or during follow-up. Both panels provide naive T cell measurements that have a strongly positive correlation with TRECs numbers and are suitable for use with enumerating naive T cell levels in a clinical laboratory.
P. C. Rodríguez, D. M. Prada, , L. E. Aira, C. Molinero, A. M. López, J. A. Gómez, I. M. Hernández, J. P. Martínez, Y. Reyes, et al.
Clinical and Experimental Immunology, Volume 191, pp 229-239;

Summary: Itolizumab is a humanized anti-CD6 monoclonal antibody (mAb) that has previously shown encouraging results, in terms of safety and positive clinical effects, in a 6-week monotherapy clinical trial conducted in rheumatoid arthritis (RA) patients. The current Phase I study evaluated the safety and clinical response for a longer treatment of 12 itolizumab intravenous doses in subjects with active RA despite previous disease-modifying anti-rheumatic drug (DMARD) therapy. Twenty-one subjects were enrolled into four dosage groups (0·1, 0·2, 0·4 and 0·8 mg/kg). Efficacy end-points including American College of Rheumatology (ACR)20, ACR50 and ACR70 response rates and disease activity score in 28 joints (DAS28) were monitored at baseline and at specific time-points during a 10-week follow-up period. Itolizumab was well tolerated up to the highest tested dose. No related serious adverse events were reported and most adverse events were mild. Remarkably, itolizumab treatment did not produce lymphopenia and, therefore, was not associated with infections. All patients achieved a clinical response (ACR20) at least once during the study. Eleven subjects (55%) achieved at least a 20% improvement in ACR just 1 week after the first itolizumab administration. The clinical response was observed from the beginning of the treatment and was sustained during 24 weeks. The efficacy profile of this 12-week treatment was similar to that of the previous study (6-week treatment). These results reinforce the safety profile of itolizumab and provide further evidence on the clinical benefit from the use of this anti-CD6 mAb in RA patients.
J. Schwarz, V. Scheckenbach, H. Kugel, B. Spring, J. Pagel, C. Härtel, J. Pauluschke‐Fröhlich, A. Peter, C. F. Poets, , et al.
Clinical and Experimental Immunology, Volume 191, pp 328-337;

Summary: Preterm delivery is the leading cause of perinatal morbidity and mortality. Among the most important complications in preterm infants are peri- or postnatal infections. Myeloid-derived suppressor cells (MDSC) are myeloid cells with suppressive activity on other immune cells. Emerging evidence suggests that granulocytic MDSC (GR-MDSC) play a pivotal role in mediating maternal–fetal tolerance. The role of MDSC for postnatal immune-regulation in neonates is incompletely understood. Until the present time, nothing was known about expression of MDSC in preterm infants. In the present pilot study, we quantified GR-MDSC counts in cord blood and peripheral blood of preterm infants born between 23 + 0 and 36 + 6 weeks of gestation (WOG) during the first 3 months of life and analysed the effect of perinatal infections. We show that GR-MDSC are increased in cord blood independent of gestational age and remain elevated in peripheral blood of preterm infants during the neonatal period. After day 28 they drop to nearly adult levels. In case of perinatal or postnatal infection, GR-MDSC accumulate further and correlate with inflammatory markers C-reactive protein (CRP) and white blood cell counts (WBC). Our results point towards a role of GR-MDSC for immune-regulation in preterm infants and render them as a potential target for cell-based therapy of infections in these patients.
Clinical and Experimental Immunology, Volume 191, pp 189-197;

Programmed death-1 (PD-1) and interactions with PD-L1 play critical roles in the tumor evasion of immune responses through different mechanisms including inhibition of effector T cell proliferation, reducing cytotoxic activity, induction of apoptosis in tumor-infiltrating T cells, and regulatory T cells (Treg) expansion. Effective blockade of immune checkpoints can therefore potentially eliminate these detrimental effects. The aim of this study was to investigate the effect of anti-PD-1 antibody, pembrolizumab, on various Treg subpopulations. Peripheral blood mononuclear cells (PBMC) from healthy donors (HD) and primary breast cancer patients (PBC) were treated in vitro with pembrolizumab, which effectively reduced PD-1 expression in both cohorts. We found that PD-1 was expressed mainly on CD4+CD25+ T cells, and pembrolizumab had a greater effect on PD-1 expression in CD4+CD25- T cells, compared to CD4+CD25+ cells. In addition, pembrolizumab did not affect the expression levels of Treg-related markers including CTLA-4, CD15s, LAP and Ki-67. Moreover, we report that CD15s is mainly expressed on FoxP3-Helios+ Treg in HD, but it is expressed on FoxP3+Helios- Treg subset in addition to FoxP3-Helios+ Treg in PBC. Pembrolizumab did not affect the levels of FoxP3+/-Helios+/- Treg subsets in both cohorts. Taken together, our study suggests that pembrolizumab does not affect Treg or change their phenotype or function but rather blocks signaling via PD-1/PD-L1 axis in activated T cells.
, Paola Cipriani, , , , Francesco Carubbi, Francesco Ciccia, , Giovanni Triolo, Roberto Giacomelli
Clinical and Experimental Immunology, Volume 191, pp 220-228;

Summary: Macrophage activation syndrome (MAS) is hyperinflammatory life-threatening syndrome, associated typically with high levels of serum ferritin. This is an iron storage protein including heavy (H) and light (L) subunits, categorized on their molecular weight. The H-/L subunits ratio may be different in tissues, depending on the specific tissue and pathophysiological status. In this study, we analysed the bone marrow (BM) biopsies of adult MAS patients to assess the presence of: (i) H-ferritin and L-ferritin; (ii) CD68+/H-ferritin+ and CD68+/L-ferritin+; and (iii) interleukin (IL)-1β, tumour necrosis factor (TNF) and interferon (IFN)-γ. We also explored possible correlations of these results with clinical data. H-ferritin, IL-1β, TNF and IFN-γ were increased significantly in MAS. Furthermore, an increased number of CD68+/H-ferritin+ cells and an infiltrate of cells co-expressing H-ferritin and IL-12, suggesting an infiltrate of M1 macrophages, were observed. H-ferritin levels and CD68+/H-ferritin+ cells were correlated with haematological involvement of the disease, serum ferritin and C-reactive protein. L-ferritin and CD68+/L-ferritin+ cells did not correlate with these parameters. In conclusion, during MAS, H-ferritin, CD68+/H-ferritin+ cells and proinflammatory cytokines were increased significantly in the BM inflammatory infiltrate, pointing out a possible vicious pathogenic loop. To date, H-ferritin and CD68+/H-ferritin+ were associated significantly with haematological involvement of the disease, suggesting biomarkers assessing severity of clinical picture.
, A Moreno-Olivera, Y Kelly, P O'Hara, S Murray, A Kennedy, N Conlon, J Scott, , F B Hickey, et al.
Clinical and Experimental Immunology, Volume 191, pp 180-188;

Summary: Innate lymphocyte populations, such as innate lymphoid cells (ILCs), γδ T cells, invariant natural killer T (iNK T) cells and mucosal-associated invariant T (MAIT) cells are emerging as important effectors of innate immunity and are involved in various inflammatory and autoimmune diseases. The aim of this study was to assess the frequencies and absolute numbers of innate lymphocytes as well as conventional lymphocytes and monocytes in peripheral blood from a cohort of anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis (AAV) patients. Thirty-eight AAV patients and 24 healthy and disease controls were included in the study. Patients with AAV were sampled both with and without immunosuppressive treatment, and in the setting of both active disease and remission. The frequencies of MAIT and ILC2 cells were significantly lower in patients with AAV and in the disease control group compared to healthy controls. These reductions in the AAV patients remained during remission. B cell count and frequencies were significantly lower in AAV in remission compared to patients with active disease and disease controls. Despite the strong T helper type 2 (Th) preponderance of eosinophilic granulomatosis with polyangiitis, we did not observe increased ILC2 frequency in this cohort of patients. The frequencies of other cell types were similar in all groups studied. Reductions in circulating ILC2 and MAIT cells reported previously in patients with AAV are not specific for AAV, but are more likely to be due to non-specific manifestations of renal impairment and chronic illness. Reduction in B cell numbers in AAV patients experiencing remission is probably therapy-related.
D. Mesquita, , M. F. Franco, L. A. Reis, S. F. Perazzio, F. V. Mesquita, V. Da Silva Ferreira, ,
Clinical and Experimental Immunology, Volume 191, pp 50-59;

The objective of this study was to evaluate the frequency of CD4+ T cell subsets in peripheral blood mononuclear cells (PBMC), urine and renal tissue from patients with lupus nephritis (LN). PBMC and urinary cells were collected from 17 patients with active LN, 20 disease controls (DC) with primary glomerulonephritis and 10 healthy controls (HC) and were analysed by flow cytometry with markers for T helper type 1 (Th1), Th2, Th17 and regulatory T cells (Treg) cells. T cell subsets were assessed by immunohistochemistry from LN biopsy specimens from 12 LN patients. T cell subtypes in PBMC were re-evaluated at 6 months of therapy. CD4+ T cells were decreased in PBMC in LN compared with DC and HC (P = 0·0001). No differences were observed in urinary CD4+ T cell subsets between LN and DC. The frequency of urinary Th17 cells was higher in patients with non-proliferative than in proliferative LN (P = 0·041). CD3+ and T-box 21 ( Tbet+ ) cells were found in glomeruli and interstitium of LN patients, while forkhead box protein 3 (FoxP3), retinoid-related orphan receptor gamma (ROR-γ) and GATA binding protein 3 (GATA-3) were present only in glomeruli. Th1 cells in PBMC were correlated negatively with urinary Th1 cells (Rho = –0·531; P = 0·028) and with Tbet in renal interstitium (Rho = –0·782; P = 0·004). At 6 months, LN patients showed an increase in Th17 cells in PBMC. In conclusion, the inverse association between Th1 cells from PBMC and urinary/renal tissue indicate a role for Th1 in LN pathophysiology. Urinary Th17 cells were associated with less severe LN, and Th17 increased in PBMC during therapy. Urinary CD4+ T cells were not different between LN and DC.
, P. Fitch, S. E. M. Howie
Clinical and Experimental Immunology, Volume 191, pp 32-41;

Only mismatch repair (MMR)-deficient colorectal cancer (CRC) appears to respond well to programmed death (PD)-1 inhibition at the present time. Emerging evidence suggests a role for micro-environmental factors such as CD25+ cells modulating response to PD-1 inhibition. In the ApcMin/+ model of familial adenomatous polyposis (MMR-proficient CRC), increased Cyclooxygenase-2 (Cox-2) expression by cells which include alternatively activated mononuclear phagocytes promotes intestinal tumorigenesis by mechanisms which may include immune suppression. To gain insight into this, we compared regulatory T cell (Treg) populations between ApcMin/+ and wild-type mice prior to and after the phase of increased intestinal Cox-2-dependent prostaglandin E2 (PGE2) production. There was no difference in systemic Treg function or numbers between ApcMin/+ and wild-type mice. However, increased numbers of small intestinal CD25+ Tregs were observed with increased Cox-2 activity in the absence of any difference in the expression of Tgf-β or Tslp between ApcMin/+ and wild-type mice. Cox-2 inhibitor therapy (Celecoxib) reversed the increase in ApcMin/+ intestinal CD25+ Treg numbers, without decreasing numbers of CD25+ systemic Tregs. Forkhead box protein 3 (FoxP3+) and Cox-2+ cells were co-localized to the interstitium of adenomas of Apcmin/+ mice. These results suggest selective dependence of an ‘activated Treg’ phenotype on paracrine Cox-2 activity in ApcMin/+ small intestine. For therapeutic potential, further studies are required to evaluate the relevance of these findings to human cancer as well as the functional significance of CD25+ intestinal Tregs in cancer.
L. Cheng, S.‐J. Gou, H.‐Y. Qiu, L. Ma,
Clinical and Experimental Immunology, Volume 191, pp 116-124;

The complement system activation is involved in the development of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). The study aimed to investigate the expression of complement regulatory proteins (CRPs) CD46, CD55 and CD59 in kidneys of 51 AVV patients. The expression of CD46, CD55 and CD59 in kidneys was detected by immunohistochemistry and double immunofluorescence staining. The immunohistochemical examination revealed that expression of the three CRPs could be detected in the glomeruli and tubules of both AAV patients and normal controls. The expression levels of the three CRPs in glomeruli of patients with AAV were significantly lower than those of normal controls. The scores of CD46 and CD55 expression in the tubules of AAV patients were significantly lower than those of normal controls, while there was no significant difference between the scores of CD59 expression in tubules of AAV patients and those of normal controls. Among AAV patients, the expression level of CD46 in glomeruli correlated inversely with the proportion of normal glomeruli, while it correlated with tubular atrophy in renal interstitium (r = –0·305, P = 0·026; r = 0·330, P = 0·023, respectively). The expression levels of CD55 and CD59 in glomeruli correlated with the proportion of total crescents (r = 0·384, P = 0·006; r = 0·351, P = 0·011, respectively). Double immunofluorescence staining indicated that all three CRPs were expressed on endothelial cells, podocytes and mesangial cells in glomeruli. The expression levels of the three CRPs were dysregulated in kidneys of patients with AAV. The expression levels of CD46, CD55 and CD59 were associated with the severity of renal injury of AAV patients.
J. Romo‐Tena, , L. Aparicio‐Vera, J. Alcocer‐Varela,
Clinical and Experimental Immunology, Volume 191, pp 42-49;

T cells from systemic lupus erythematosus (SLE) patients display a wide array of anomalies in peripheral immune tolerance mechanisms. The role of ubiquitin ligases such as Cbl-b has been described recently in these phenomena. However, its role in resistance to suppression phenotype in SLE has not been characterized, which was the aim of the present study. Thirty SLE patients (20 with active disease and 10 with complete remission) and 30 age- and sex-matched healthy controls were recruited. Effector (CD4+CD25) and regulatory (CD4+CD25+) T cells (Tregs) were purified from peripheral blood mononuclear cells (PBMCs) by magnetic selection. Suppression assays were performed in autologous and allogeneic co-cultures and analysed by a flow cytometry assay. Cbl-b expression and lysine-63 (K63)-specific polyubiquitination profile were assessed by Western blotting. We found a defective Cbl-b expression in Tregs from lupus patients in contrast to healthy controls (1·1 ± 0·9 versus 2·5 ± 1·8, P = 0·003), which was related with resistance to suppression (r = 0·633, P = 0·039). Moreover, this feature was associated with deficient K63 polyubiquitination substrates and enhanced expression of phosphorylated signal transducer and activation of transcription 3 (pSTAT-3) in Tregs from lupus patients. Our findings support that Cbl-b modulates resistance to suppression by regulating the K63 polyubiquitination profile in lupus Tregs. In addition, defective K63 polyubiquitination of STAT-3 is related to increased pSTAT-3 expression, and might promote the loss of suppressive capacity of Tregs in lupus patients.
, A. Sankiewicz, , E. Gorodkiewicz, ,
Clinical and Experimental Immunology, Volume 191, pp 125-132;

The aim of this study was to determinate the immunoproteasome concentration in the blood plasma of children with appendicitis, and its correlation with circulating proteasome and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1). Twenty-seven children with acute appendicitis, managed at the Paediatric Surgery Department, were included randomly into the study (age 2 years 9 months up to 14 years, mean age 9·5 ± 1 years). There were 10 girls and 17 boys; 18 healthy, age-matched subjects, admitted for planned surgeries served as controls. Mean concentrations of immunoproteasome, 20S proteasome and UCHL1 in the blood plasma of children with appendicitis before surgery 24 h and 72 h after the appendectomy were higher than in the control group. The immunoproteasome, 20S proteasome and UCHL1 concentrations in the blood plasma of patients with acute appendicitis were highest before surgery. The immunoproteasome, 20S proteasome and UCHL1 concentration measured 24 and 72 h after the operation decreased slowly over time and still did not reach the normal range (P< 0·05). There was no statistical difference between immunoproteasome, 20S proteasome and UCHL1 concentrations in children operated on laparoscopically and children after classic appendectomy. The immunoproteasome concentration may reflect the metabolic response to acute state inflammation, and the process of gradual ebbing of the inflammation may thus be helpful in the assessment of the efficacy of treatment. The method of operation – classic open appendectomy or laparoscopic appendectomy – does not influence the general trend in immunoproteasome concentration in children with appendicitis.
, C. Maβlo, C. A. Müller, A. Tahedl, J. Volkind, Y. Nowak, V. Umansky, J. Esterlechner, , C. Ganss, et al.
Clinical and Experimental Immunology, Volume 191, pp 74-83;

ATP binding cassette subfamily B member 5 (ABCB5) has been identified as a tumour-initiating cell marker and is expressed in various malignancies, including melanoma. Moreover, treatment with anti-ABCB5 monoclonal antibodies has been shown to inhibit tumour growth in xenotransplantation models. Therefore, ABCB5 represents a potential target for cancer immunotherapy. However, cellular immune responses against ABCB5 in humans have not been described so far. Here, we investigated whether ABCB5-reactive T cells are present in human melanoma patients and tested the applicability of ABCB5-derived peptides for experimental induction of human T cell responses. Peripheral blood mononuclear cells (PBMNC) isolated from blood samples of melanoma patients (n = 40) were stimulated with ABCB5 peptides, followed by intracellular cytokine staining (ICS) for interferon (IFN)-γ and tumour necrosis factor (TNF)-α. To evaluate immunogenicity of ABCB5 peptides in naive healthy donors, CD8 T cells were co-cultured with ABCB5 antigen-loaded autologous dendritic cells (DC). ABCB5 reactivity in expanded T cells was assessed similarly by ICS. ABCB5-reactive CD8+ T cells were detected ex vivo in 19 of 29 patients, melanoma antigen recognised by T cells (MART-1)-reactive CD8+ T cells in six of 21 patients. In this small, heterogeneous cohort, reactivity against ABCB5 was significantly higher than against MART-1. It occurred significantly more often and independently of clinical characteristics. Reactivity against ABCB5 could be induced in 14 of 16 healthy donors in vitro by repeated stimulation with peptide-loaded autologous DC. As ABCB5-reactive CD8 T cells can be found in the peripheral blood of melanoma patients and an ABCB5-specific response can be induced in vitro in naive donors, ABCB5 could be a new target for immunotherapies in melanoma.
, D. Koftori, L. Chen, P. Bowness
Clinical and Experimental Immunology, Volume 191, pp 11-18;

The association between carriage of the human leucocyte antigen (HLA)-B*51 allele and development of Behçet's disease (BD) has been known since the early 1970s, but the exact mechanisms responsible for its role in pathogenesis remain much-debated. In an effort to explain the disease process, it has been suggested that BD constitutes one of a newly termed group of diseases, the ‘MHC-I-opathies’. Other MHC-I-opathies include ankylosing spondylitis and HLA-B*27-associated spondyloarthropathies and HLA-C*0602-associated skin psoriasis. Recent work analysing the peptidome of HLA-B*51 suggests that altered peptide presentation by HLA-B*51 is vital to the disease process. In this review, we argue that immune receptor interactions with HLA-B*51 or the HLA-B*51-peptide complex could lead to development of inflammation in BD. The evidence for CD8+ T cell involvement is weak, and based on emerging studies it seems more likely that natural killer (NK) or other cell interactions, perhaps mediated by leucocyte immunoglobulin-like receptor (LILR) or killer immunoglobulin-like receptor (KIR) receptors, are culpable in pathogenesis. HLA misfolding leading directly to inflammation is another hypothesis for BD pathogenesis that deserves greater investigation. Ultimately, greater understanding of HLA-B*51's unique role in BD will probably lead to improved development of therapeutic strategies.
D. Feng, Y. Wang, Y. Liu, L. Wu, X. Li, Y. Chen, C. Xu, ,
Clinical and Experimental Immunology, Volume 191, pp 107-115;

Summary: In the pathological process of acute kidney injury (AKI), innate immune receptors are essential in inflammatory response modulation; however, the precise molecular mechanisms are still unclear. Our study sought to demonstrate the inflammatory response mechanisms in renal tubular epithelial cells via Toll-like receptor-4 (TLR-4) and dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin 1 (DC-SIGN) signalling. We found that DC-SIGN exhibited strong expression in renal tubular epithelial cells of human acute renal injury tissues. DC-SIGN protein expression was increased significantly when renal tubular epithelial cells were exposed to lipopolysaccharide (LPS) for a short period. Furthermore, DC-SIGN was involved in the activation of p65 by TLR-4, which excluded p38 and c-Jun N-terminal kinases (JNK). Interleukin (IL)-6 and tumour necrosis factor (TNF)-α expression was decreased after DC-SIGN knock-down, and LPS induced endogenous interactions and plasma membrane co-expression between TLR-4 and DC-SIGN. These results show that DC-SIGN and TLR-4 interactions regulate inflammatory responses in renal tubular epithelial cells and participate in AKI pathogenesis.
, B. R. Shivakumar, A. E. Postlethwaite, K. A. Hasty
Clinical and Experimental Immunology, Volume 191, pp 84-95;

Peripheral blood mononuclear cells taken from patients with scleroderma express increased levels of interleukin (IL)-13. Moreover, the expression of matrix metalloproteinase-1 (MMP-1) from involved scleroderma skin fibroblasts is refractory to stimulation by tumour necrosis factor (TNF)-α. To elucidate the mechanism(s) involved, we examined the effect of IL-13 on TNF-α-induced MMP-1 expression in normal and scleroderma human dermal fibroblast lines and studied the involvement of serine/threonine kinase B/protein kinase B (Akt) in this response. Dermal fibroblast lines were stimulated with TNF-α in the presence of varying concentrations of IL-13. Total Akt and pAkt were quantitated using Western blot analyses. Fibroblasts were treated with or without Akt inhibitor VIII in the presence of IL-13 followed by TNF-α stimulation. MMP-1 expression was analysed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using analysis of variance (anova) or Student's t-test. Upon TNF-α stimulation, normal dermal fibroblasts secrete more MMP-1 than systemic sclerosis (SSc) fibroblasts. This increase in MMP-1 is lost when fibroblasts are co-incubated with IL-13 and TNF-α. IL-13 induced a significant increase in levels of pAkt in dermal fibroblasts, while Akt inhibitor VIII reversed the suppressive effects of IL-13 on the response of cultured fibroblasts to TNF-α, increasing their expression of MMP-1. We show that IL-13 suppresses MMP-1 in TNF-α-stimulated normal and scleroderma dermal fibroblast. Akt inhibitor VIII is able to reverse the suppressive effect of IL-13 on MMP-1 expression and protein synthesis. Our data suggest that IL-13 regulates MMP-1 expression in response to TNF-α through an Akt-mediated pathway and may play a role in fibrotic diseases such as scleroderma.
, J. C. Hartley, C. G. C. Hartley, R. J. Shattock, G. E. Griffin
Clinical and Experimental Immunology, Volume 100, pp 233-238;

SUMMARY: Tuberculosis is characterized by fever, weight loss, a prolonged acute-phase protein response and granuloma formation. These characteristics may partly be due to action of proinflammatory cytokines tumour necrosis factor (TNF), IL-6 and IL-8. We investigated plasma concentrations of these cytokines before and after ex vivo lipopolysaccharide stimulation of whole blood leucocytes from 41 Zambian patients with tuberculosis, 32 of whom were also HIV+. Although patients had a reduced weight, were more anaemic and had higher erythrocyte sedimentation rate compared with controls (all P < 0·0005), clinical and laboratory measurements of disease state were similar in those who died and survivors. In contrast, plasma IL-6 and IL-8 concentrations were higher in patients who died (P < 0·05). There was no detectable cytokine mRNA in unstimulated leucocytes. There was reduced secretion of TNF (P < 0·005 at 2h), IL-6 (P < 0·005 at 8 h) and IL-8 (P < 0·005 at 24 h) after ex vivo stimulation of whole blood leucocytes from patients who died compared with survivors. This was partly due to a soluble inhibitory factor present in plasma. The only additional effect of concurrent infection by HIV with Myco. tuberculosis was decreased IL-6 secretion following ex vivo stimulation of leucocytes. Reduced proinflammatory cytokine release may represent a critical impairment of host immune defences important in determining outcome in tuberculosis.
F. Peyron, N. Burdin, P. Ringwald, J. P. Vuillez, F. Rousset, J. Banchereau
Clinical and Experimental Immunology, Volume 95, pp 300-303;

SUMMARY: IL-10 is a monocyte/lymphocyte derived cytokine which has been shown to inhibit certain cellular immune responses such as delayed hypersensitivity. In particular, the production of tumour necrosis factor (TNF), IL-I and IL-6, which are involved in malaria pathology, are strongly inhibited by IL-10. Accordingly, we examined whether IL-10 could be involved in a human acute parasitic infection such as Plasmodium falciparum malaria. Human IL-10 levels in plasma were determined by two-site ELISA method, taking care to avoid non-specific reactions due to autoantibodies. Fourteen cerebral, 11 severe, and 20 mild malaria cases had mean IL-10 levels of 2812, 2882 and 913 pg/ml, respectively, while 98% of healthy individuals had undetectable (less than 100 pg/ml) circulating IL-10. Thirteen of the 25 cerebral/severe cases had >2000 pg/ml. In 11 hospitalized patients, circulating IL-10 levels were found to return to virtually normal levels 7 days after antimalarial chemotherapy when biological and clinical malaria features had disappeared (mean levels fell from 3880 to 333 pg/ml). Further studies are required to determine whether these elevated levels of IL-10 play a beneficial role by reducing the parasite-induced inflammatory response, or a detrimental one by decreasing the cellular immune responses.
M. M. Stevenson, M.‐F. Tam
Clinical and Experimental Immunology, Volume 92, pp 77-83;

SUMMARY: The induction of T helper cell subsets during the course of non-lethal or lethal blood-stage Plasmodium chabaudi AS infection was investigated using inbred strains of mice which differ in the level of resistance to this intraerythrocytic parasite. Resistant C57B1/6 mice experience a non-lethal course of infection characterized by moderate levels of both parasitaemia and anaemia and resolution of primary acute infection by 4 weeks, while susceptible A/J mice experience lethal infection with fulminant parasitaemia and severe anaemia. T helper subset function was assessed during infection by determining the kinetics of spleen cell production in vitro of the Th1-derived cytokine, interferon-gamma (IFN-γ), and of the Th2-dcrived cytokine, IL-5, using sandwich ELISAs. Spleen cells from resistant C57B1/6 mice were found to produce high levels of IFN-γ within 1 week of infection in response to both the mitogen concanavalin A (Con A) and malaria antigen. Furthermore, CD4+ T cells were found to be the source of I FN-γ while both CD4+ and CD8+ T cells were found to produce IL-5. Decreased IFN-γ production after day 10 was concomitant with significant production of IL-5 between 2 and 3 weeks post infection. In contrast, spleen cells from susceptible A/J mice produced high levels of IL-5 within the first week of infection. In addition, these animals were found to have high serum levels of IL-5. These results, thus, confirm previous observations that resolution of primary blood-stage P. chabaudi infection occurs by sequential activation of Th1 CD4+ T cells followed by activation of the Th2 subset, and in addition, suggest that induction of a strong Th2 response early in infection may lead to a severe and lethal course of malaria.
, V. G. Avdienko, B. V. Nikonenko, , A. M. Moroz, E. Skamene
Clinical and Experimental Immunology, Volume 94, pp 322-329;

SUMMARY: We have studied the impact of distinct haplotypes and of difierent alleles at specific H-2 loci on: (i) the susceptibility to lethal form of experimental tuberculosis; (ii) the level of DTH to mycobacterial antigens: (iii) the efficacy of vaccination with bacille Calmette-Guerin (BCG); and (iv) the IgG production and T cell proliferative response to H37Rv antigens. On the basis of median survival lime (MST) following primary inoculation with lethal dose of Mycobacterium tuberculosis, susceptibility to infection associated with I-Ab and Db alleles. host resistance associated with I-Ak and Dd alleles. Mice bearing a disease-resistant phenotype also developed a vigorous DTH response. Vaccination with BCG before H37Rv infection significantly prolonged the survival time of both resistant and susceptible animals, except in B10.M (H-2f) mice. The latter exhibited intermediate resistance to infection before but slight decrease in the MST following a high-dose BCG vaccination. Distinct H-2 regulation of susceptibility to lethal infection and of BCG vaccination efficacy was confirmed in another relatively resistant H-2f-bearing strain A.CA, in which mortality occurred more rapidly in vaccinated compared with primarily infected animals. The expression of the H-2f haplotype was associated with a low DTH response to tuberculin following vaccination and subsequent lethal infection. The lack of BCG protection against Myco. tuberculosis challenge in B10.M mice associated with the high litre of specific IgG. In addition, these mice exhibited a unique ability to respond to 65-kD antigen by both IgG synthesis and T cell proliferation.
R. Appelberg,
Clinical and Experimental Immunology, Volume 87, pp 379-385;

SUMMARY: Mycobacterium avium is an opportunistic pathogen that infects individuals suffering from chronic lung disease or immunocompromised patients such as AIDS patients. Here we show that a highly virulent isolate of M. avium proliferated as extensively in T cell deficient as in immunocompetent mice. T cell deficient mice allowed a progressive growth of a less virulent AIDS-derived isolate of M. avium while immunocompetent mice arrested the growth of this isolate. Adoptive transfer of T cell enriched spleen cells between congenic strains of mice differing at the Bcg/Ity/Lsh locus showed that only naturally resistant BALB/c. Bcgr (C.D2) mice infected with the highly virulent strain of M. avium or the naturally susceptible BALB/c mice infected with the lower virulence isolate developed protective T cells and that these cells only mediated protection when transferred to naturally susceptible, but not to naturally resistant, mice. Both strains of M. avium proliferated in bone marrow-derived macrophages cultured in vitro and they were both susceptible to the bacteriostatic effects induced in the macrophages by crude lymphokines produced by concanavalin A-stimulated spleen cells.
G. P. Holland, N. Holland, M. W. Steward
Clinical and Experimental Immunology, Volume 82, pp 221-226;

SUMMARY: Interferon-gamma (IFN-γ), the tetrapeptide tuftsin and the synthetic nonapeptide from interleukin-1 beta (IL-1 β) (amino acids 163–171) have previously been shown to act on macrophages and/or T cells and to enhance antibody titres to T cell-dependent antigens. The ability of these immunomodulatory agents to potentiate antibody affinity in addition to antibody titre has been studied in a line of mice that fail to demonstrate normal maturation of antibody affinity (low N/M mice). The results presented here confirm that each of the agents potentiate antibody levels following simultaneous injection with a T cell-dependent antigen but demonstrate that only IFN-γ is able to enhance antibody affinity in these mice. The observation that IFN-γ can enhance both antibody affinity and antibody levels suggests that it could be an important adjuvant for vaccine use.
G. Pastorelli, F. Rousset, J. Pene, C. Peronne, M. G. Roncarolo, P. A. Tovo, J E DE Vries
Clinical and Experimental Immunology, Volume 82, pp 114-119;

SUMMARY: Neonatal B cells have been considered immature because of their impaired capacity to produce immunoglobulins in response to polyclonal activators in vitro. Here we demonstrate that cord blood mononuclear cells (MNC) produce normal levels of IgE in vitro when cultured in the presence of interleukin-4 (IL-4), indicating that the B cells are mature in their capacity to switch to IgE-producing cells. However, in contrast to adult peripheral blood T cells, cord blood T cells failed to produce detectable levels of IL-4 upon activation by phytohaemagglutinin (PHA) concanavalin A (Con A) or combinations of PHA and the phorbol ester TPA. Interferon-gamma (IFN-γ) production by cord blood T cells following activation by Con A or PHA was also strongly reduced. However, high levels of IFN-γ, significantly higher than those produced by adult T cells, were synthesized in response to combinations of PHA and TPA, indicating that IFN-γ production by cord blood T cells is not intrinsically defective. In contrast, cord blood T cells produced levels of IL-2 that were significantly higher than those obtained by adult T cells tested in parallel. Collectively, our data indicate that the minimal levels of IgE production measured in cord blood (< 1 U/ml) are not due to immaturity of the cord blood B cells, but may be associated with the failure of cord blood T cells to produce detectable levels of IL-4, which has been shown to be responsible for induction of IgE synthesis both in vitro and in vivo.
E. C. Ebert
Clinical and Experimental Immunology, Volume 82, pp 81-85;

SUMMARY: Human intraepithelial lymphocytes (IEL) proliferate minimally in response to phytohaemagglutinin (PHA), but produce as much interleukin-2 (IL-2) as do peripheral blood lymphocytes (PBL). The addition of sheep erythrocytes during activation of IEL with PHA markedly augments both T cell functions. This study evaluates the ability of IEL to produce interferon-gamma (IFN-γ) and to develop suppressor and cytotoxic activities when stimulated with mitogens in the presence or absence of sheep erythrocytes. PHA-activated IEL produced as much IFN-γ as did PHA-activated peripheral blood CD8+ T lymphocytes. IEL activated by concanavalin A (Con A) demonstrated less suppressor activity directed against T cell proliferation than did Con A-activated peripheral blood CD8+ T lymphocytes. IEL generated less mitogen-induced cellular cytotoxicity and lymphokine-activated killer cell activity than did peripheral blood CD8+ T lymphocytes. The addition of sheep erythrocyte lysates during mitogen stimulation of IEL markedly enhanced their proliferation and lymphokine production but did not affect their suppressor or cytotoxic activities.
C. Chizzolini, , A. Geinoz, D. Schrijvers
Clinical and Experimental Immunology, Volume 79, pp 95-99;

SUMMARY: Interferon (IFN) alpha and gamma were measured by radio-immunoassays in supernatanls fromcultures of peripheral blood mononuclear cells (PBMC) or purified T cell subsets incubated witheither Plasmodium falciparum schizonl-enriched malaria antigen (mAg). uninfected red blood cells(RBC) or pokeweed mitogen (PWM). Cell donors were 24 clinically immune, healthy African adultnative residents of a P. falciparum-endemic region, Haut-Ogooué, Gabon, and seven non-immune. European temporary residents with a history of a single to a few malaria infections during theprevious 1 to 9 months. When PBMC were cultured in medium alone or with RBC antigen no or lowtitres of IFN-γ were detected. PBMC proliferation and IFN-γ production observed in the presence ofmAg were dose dependent and significantly correlated. When cultured with mAg. PBMC from non-immune Europeans produced significantly higher levels of IFN-γ than did PBMC from clinicallyimmune Africans. No such difference was found when PBMC were cultured with PWM. The mAg-induced IFN-γ production was due mainly to CD4+ T cells and was not enhanced by CDS+ T celldepletion. No IFN-α was detected in culture supernatants. Thus. P. falciparum antigens are able toinduce in vitro production of IFN-γ by CD4+ Tcells; however, in this sample, individuals consideredlo be clinically resistant to malaria were low producers of IFN-γ.
T. T. Macdonald, P. Hutchings, M.‐Y. Choy, S. Murch, A. Cooke
Clinical and Experimental Immunology, Volume 81, pp 301-305;

SUMMARY: The spot-ELISA technique has been used to enumerate the frequency of cells secreting tumor necrosis factor-alpha (TNF-α) and interferon-γ (IFN-γ), isolated from biopsies of normal intestine and from biopsies of children with inflammatory bowel disease. TNF-α production was undetectable in six out of 12 biopsies from normal intestine and in the other six biopsies it ranged from 60 to 580 TNF-α-secreting cells/106 isolated intestinal cells. In contrast, cells isolated from biopsies of children with Crohn's disease (n= 9) all showed elevated frequencies of TNF-á-secreting cells (500–12 000 secreting cells/106 cells). In ulcerative colitis, four out of eight children had increased production of TNF-α and in children with indeterminate colitis two out of three had elevated levels. There was no correlation between plasma TNF-α levels and the number of intestinal cells secreting TNF-α. In controls and all groups of patients IFN-γ-secreting cells were uncommon. These results suggest that TNF-α is an important mediator of inflammation in the human gut, and, furthermore, may play a role in the growth failure frequently seen in children with inflammatory bowel disease.
X.‐D. Yang, J. Gasser, U. Feige
Clinical and Experimental Immunology, Volume 81, pp 189-194;

SUMMARY: Adjuvant arthritis in Lewis rats is a model of T cell-mediated autoimmune arthritis resembling human rheumatoid arthritis. A nonapeptide from the 65-kD heat-shock protein of Mycobacterium bovis BCG, amino acid sequence 180–188, has been described to carry the dominant immunogenic epitope(s) for both arthritis-protective and arthritogenic T cell clones. Here we demonstrate that immunizations with the synthetic nonapeptide completely protected rats against adjuvant arthritis induced by M. tuberculosis. Interestingly, deletion of the N-teminal threonine of the nonapeptide resulted in loss of the protective activity. Pretreatments with the nonapeptide resulted in an immune response to the nonapeptide and to M. tuberculosis. After immunizations with the synthetic nonapeptide, only low titres of nonapcptidc-spccific antibodies were produced, whereas a significant cellular immune response to the nonapeptide was observed. In addition, the protection was transferable to naive rats by spleen T cells. These findings document the requirement of a T cell-specific immune response to the dominant epitope of the 65-kD mycobacterial heat-shock protein for the protection against adjuvant arthritis and suggest the feasibility of immune intervention in autoimmune arthritis through the use of synthetic peptides.
N. Lahat, H. Bitterman, N. Yaniv, A. Kinarty
Clinical and Experimental Immunology, Volume 102, pp 655-659;

SUMMARY: We investigated the secretion of TNF-α by monocytes and macrophages derived from the peripheral blood, spleen, and lungs after a single exposure to a therapeutic profile of hyperbaric oxygen (HBO). Rats were exposed for 90 min to either 100% oxygen at 0 28 MPa (2–8 atmospheres absolute) or air. Immediately after exposure, mononuclear cells were isolated from blood, spleen, and lungs and cultured for 18h. The secretion of TNF-α from the cultured monocytes/macrophages was determined with and without stimulation with lipopolysaccharide (LPS). Exposure to hyperbaric oxygen induced a significant increase in the spontaneous ex vivo secretion of TNF-α (without LPS) by mononuclear cells from the blood, spleen, and lung (P < 0 05 from air controls). Stimulation with LPS after exposure to HBO induced a significant increase in TNF-α secretion by lung and spleen macrophages compared with air controls (P<005). However, absolute TNF-α levels were not significantly higher than those achieved ‘spontaneously’ in macrophages exposed to HBO without LPS. Stimulation with LPS induced a marked increase in secretion of TNF-α from blood monocytes after exposure to air, but not after exposure to HBO. These results provide evidence in support of a role played by TNF-α in mediating HBO effects on different tissues and their immune responses.
J. N. Jarvis, M. M. Diebold, M. K. Chadwell, M. Iobidze, H. T. Moore
Clinical and Experimental Immunology, Volume 100, pp 514-518;

SUMMARY: Data published from In vitro studies have shown that IgM-rheumatoid factor (RF)-bearing immune complexes possess several biological features that may contribute to their pathogenicity. However, no studies have demonstrated that such complexes exist at sites of inflammation in children with rheumatoid disease. We used two methods of sequential column chromatography to purify immune complexes from synovial fluids of children with JRA. We demonstrate that high molecular weight complexes contain IgM-RF, have not bound C4 in vivo, but activate the classical pathway in vitro. In contrast, complexes which have bound C3 in vivo do not contain IgM- RF and are weak complement activators in vitro.
, , R. Thorpe
Clinical and Experimental Immunology, Volume 96, pp 1-7;

SUMMARY: Although the immunopathology of most autoimmune diseases has been well defined, the mechanisms responsible for the breakdown of self-tolerance and which lead to the development of systematic and organ-specific autoaggression are still unclear. Evidence has accumulated which supports a role for a disregulated production of cytokines by leucocytes and possibly other cells in the pathogenesis of some autoimmune diseases. However, due to the complexity and heterogeneity of cytokine effects in the regulation of the immune response, it is difficult to determine whether abnormalities in the patterns of cytokine production are primary or secondary to the pathological process. Confusion is also caused by the fact that the biological activities of cytokines are multiple and often overlapping, and consequently it is difficult to focus on a unique effect of any one cytokine. Characterization of the potential and actual involvement of cytokines is important not only for a better understanding of the pathogenesis of autoimmune conditions, but particularly because of the implications for the development of immunotherapeutic strategies for the prevention and treatment of the diseases.
A. Ishizaka, Y. Sakiyama, M. Nakanishi, K. Tomizawa, E. Oshika, K. Kojima, Y. Taguchi, , S. Matsumoto
Clinical and Experimental Immunology, Volume 79, pp 392-396;

SUMMARY: Using murine monoclonal antibodies against human IgG subclasses, specific and sensitive ELISAs assay to quantify the four human IgG subclasses in cell culture supernaUints were established. The effect of human recombinant interleukin-4 (IL-4) on the regulation of IgG subclasses by normal peripheral blood lymphocytes was investigated. In addition to the enhancement of lgE synthesis. IL-4 preferentially induced IgG4 synthesis in vitro, whereas IL-4 had no effect on IgGl, IgG2, and IgG3 synthesis. IL-4-induced IgG4 production was blocked in a dose-dependent manner by recombinant interferon-gamma and anti-human IL-4 monoclonal antibody. Collectively, this data indicates that IL-4 plays an important regulatory role in both IgG subclass and IgE synthesis.
, , J. M. Fernandez‐Rasada, A. Figuera, A. Torres, A. Iriondo,
Clinical and Experimental Immunology, Volume 82, pp 145-150;

SUMMARY: Some patients undergoing bone marrow transplantation (BMT) persistently present increased proportions of circulating CD57+ T cells. We analysed the cell surface phenotype in peripheral blood mononuclear cells (PBMC) from 69 allogeneic and 11 autologous BMT recipients. In parallel samples from 49 patients, the proliferative response to T cell mitogens was assessed, either in the presence or absence of exogenous interleukin-2 (IL-2). PBMC samples from long-term allogeneic BMT patients with increased proportions of CD57+ cells displayed significantly (P < 0.001) lower proliferative responses, compared with samples from patients with normal proportions of CD57+ cells and from healthy subjects. Elimination of the CD57+ population by C′-dependent lysis did not normalize the proliferative response. After positive selection by cell sorting. CD57+ cells responded poorly, but in the presence of IL-2 the proliferation appeared to be similar to that displayed by the CD57- subset and still suboptimal compared with normal controls. These data suggest that the hyporesponsiveness to mitogenic stimuli in the presence of exogenous IL-2 of PBMC from allogeneic BMT recipients cannot be simply attributed either to the putative suppressor activity of CD57+ cells, or to a poor proliferative capacity of this subset. Supporting this notion we report that PBMC from long-term autologous BMT recipients containing high proportions of CD57+ T cells respond normally to T cell mitogens.
S. J. Richards, R. A. Jones, B. E. Roberts, D. Patel, C. S. Scott
Clinical and Experimental Immunology, Volume 81, pp 149-155;

We characterized and established relationships between the expression of membrane 2H4 (CD45R A) and UCHL1 (CD45RO) by enriched lymphocyte fractions prepared by selective immunomagnetic depletion of monoclonal antibody‐defined populations. Cell fractions analysed in this study could be divided into two broad groups according to the presence (CD.3+VCD4+CD8, CD3+CD4CD8+ CD3+ CD4 CD8dim+ and CD3+CD4 CD8) or absence (CD3CD4CD8dim+ and CD3 CD4 CD8) of the CD3 antigen. Preliminary studies confirmed a reciprocal relationship for CD45RA and CD45RO expression by major lymphoid components and further showed that the level or intensity of membrane 2H4 staining (2H4+, 2H4int and 2H4) could be directly related to UCHLI expression. As a reflection of their differential functions, the various CD3+ populations examined showed much greater heterogeneity in 2H4 and UCHLI expression. CD3+CD4+CD8 cells generally showed significant proportions of 2H4+, 2H4int and 2H4 components, whereas the CD3+CD4CD8+ population was characterized by a predominance of 2H4+ cells. The results of this current investigation further suggested a higher proportion of dual‐positive (2H4+ UCHL1+) cells and a much greater degree of inter‐individual variation than previously suspected. In contrast to CD3* lymphocytes, natural killer (NK) associated CD3CD4 CD8dim+ and CD3CD4CD8populations were mostly 2H4+ with only minor 2H4int components and very low expression of UCHL1. An additional observation of note was that the proportions of 2H4+ and 2H4 cells comprising the CD4+ CD8 fraction in any given individual was highly correlated (P= 0·002) with the distributions of 2H4+ and 2H4 components within the CD4 CD8+ fraction. This suggests the possible existence of a common control mechanism for the acquisition of immunological memory by distinct lymphocyte populations and further indicates that individual variations in the distribution of 2H4/UCHLI lymphocyte subpopulations may be a direct consequence of immunological experience’ rather than age alone.
N. Pineau, P. Aucouturier, J. C. Brugier, J. L. Preud'Homme
Clinical and Experimental Immunology, Volume 80, pp 420-425;

SUMMARY: The major protein component of seeds from jackfruit is the lectin jacalin. Jackfruit crude extracts are known to stimulate human lymphocytes, but the mitogenic properties of purified jacalin have not been studied in detail so far. Study of the proliferative response of cell populations from normal human peripheral blood to purified jacalin showed it to be mitogenic through an interaction with lymphocytes by its lectin-binding site, as shown by inhibition by IgA. Jacalin failed to stimulate B cells to proliferate and to undergo plasma cell maturation. It induced a proliferation of CD4 (and not CD8) lymphocytes, as shown by phenotypic analysis of cells recovered after culture and by studies of the response of isolated T cell subpopulations. The proliferative response to jacalin was autologous monocyte-dependent. The kinetics of jacalin-induced DNA synthesis, expression of CD25 and interleukin-2 secretion was shifted by comparison with that induced by phytohaemagglutinin. The reason for the restricted responsiveness of CD4T cells is presently unclear; jacalin bound to all blood cells and did not significantly co-cap with CD1, CD2, CD3, CD4, CD8 and CD38, and jacalin response was neither enhanced nor inhibited by antibodies to these surface antigens.
L. Lanza, M. Scudeletti, F. Puppo, O. Bosco, L. Peirano, , E. Fecarotta, G. Vidali, F. Indiveri
Clinical and Experimental Immunology, Volume 103, pp 482-490;

SUMMARY: Glucocorticoid hormones (GCH) regulate, through the apoptotic process, the negative selection of immature T cells in the thymus. Because apoptosis seems to occur also in the maintenance of peripheral tolerance, we have investigated whether GCH may induce apoptosis in human mature lymphocytes. Peripheral blood lymphocytes (PBL) or peripheral CD4+ and CD8+ T cell subsets were cultured in the presence of phytohaemaglutinin (PHA) or PHA and prednisone (PDN) at 10−3-10−12M concentrations for 72, 96 and 120h. Cell cycle and membrane antigen expression were evaluated by flow cytometry and DNA degradation was detected by agarose gel electrophoresis. PDN blocks PBL growth in the G1 phase of cell cycle and inhibits both IL-2 receptor (IL-2R) expression and IL-2 secretion. Apoptosis is clearly increased by PDN in PHA-activated human PBL, and the apoptotic effect of PDN is stronger on CD8+ than on CD4+ T lymphocytes. All these effects are dose- and time-dependent. The addition of exogenous IL-2 did not rescue lymphocytes from PDN-increased apoptosis. These results show that PDN increases apoptosis in mature activated human peripheral blood lymphocytes, suggesting a possible role of GCH in the maintenance of immune tolerance at post-thymic level.
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