Enhanced IL-9 secretion by p66Shc-deficient CLL cells modulates the chemokine landscape of the stromal microenvironment.

The stromal microenvironment is central to chronic lymphocytic leukemia (CLL) pathogenesis. How leukemic cells condition the stroma to enhance its chemoattractant properties remains elusive. Here, we show that mouse and human CLL cells promote the contact-independent stromal expression of homing chemokines. This function was strongly enhanced in leukemic cells from Eµ-TCL1 mice lacking the pro-oxidant p66Shc adaptor, which develop an aggressive disease with organ infiltration. We identified interleukin-9 (IL-9) as the soluble factor, negatively modulated by p66Shc, that is responsible for the chemokine-elevating activity of leukemic cells on stromal cells. IL-9 blockade in Eµ-TCL1/p66Shc-/- mice resulted in a decrease in the nodal expression of homing chemokines, which correlated with decreased leukemic cell invasiveness. IL-9 levels were found to correlate inversely with residual p66Shc in p66Shc-deficient human CLL cells (n = 52 patients). p66Shc reconstitution in CLL cells normalized IL-9 expression and neutralized their chemokine-elevating activity. Notably, high IL-9 expression in CLL cells directly correlates with lymphadenopathy, liver infiltration, disease severity, and overall survival, emerging as an independent predictor of disease outcome. Our results demonstrate that IL-9 modulates the chemokine landscape in the stroma and that p66Shc, by regulating IL-9 expression, fine tunes the ability of leukemic cells to shape the microenvironment, thereby contributing to CLL pathogenesis.

Adipocytokine plasma level changes in a 24-month dietary and physical activity randomised intervention trial in postmenopausal women.

BACKGROUND: Adipocytokines are signaling molecules secreted by adipose tissue contributing to the control of body fat, energy expenditure and secretion of insulin and cytokines. They have been related to the development of obesity, type-2 diabetes, cardiovascular diseases and cancer. Diet and physical activity (PA) may have beneficial effects on their level. We evaluated the effects of a 24-month dietary and/or PA intervention on plasma levels of adipocytokines as a secondary analysis in the DAMA (Diet, physical Activity and Mammography) trial. METHODS: The 234 study participants (healthy postmenopausal women with high breast density, 50-69 years, non-smokers, no hormone therapy) were randomised to four arms: (1) isocaloric dietary intervention mainly based on plant-foods; (2) moderate-intensity PA intervention with at least 1 h/week of supervised strenuous activity; (3) both interventions; (4) general recommendations on healthy dietary and PA patterns. Leptin, resistin and adiponectin were measured at baseline and at the end of the intervention. Analyses were performed using Tobit regression. RESULTS: After 24 months, women randomised to PA intervention (arms #2 + #3) showed significant lower level of leptin (37.5% lower) and resistin (65.6% lower) compared to the control group (arms #1 + #4). No significant differences emerged in adiponectin levels. No significant differences in leptin, resistin and adiponectin levels at follow-up emerged in women randomised to the dietary intervention (arms #1 + #3) in comparison with controls (arms #2 + #4). CONCLUSION: This study supports the effectiveness of PA, even at moderate intensity, in improving the leptin and resistin profile in postmenopausal women. TRIAL REGISTRATION NUMBER: ISRCTN28492718, date of trial registration 17/05/2012.

Serum Interleukin-36 α as a Candidate Biomarker to Distinguish Behçet's Syndrome and Psoriatic Arthritis.

Behçet's syndrome (BS) is a rare systemic vasculitis characterized by different clinical manifestations. As no specific laboratory tests exist, the diagnosis relies on clinical criteria, and the differential diagnosis with other inflammatory diseases can be challenging. Indeed, in a relatively small proportion of patients, BS symptoms include only mucocutaneous, articular, gastrointestinal, and non-typical ocular manifestations, which are frequently found also in psoriatic arthritis (PsA). We investigate the ability of serum interleukin (IL)-36α-a pro-inflammatory cytokine involved in cutaneous and articular inflammatory diseases-to differentiate BS from PsA. A cross-sectional study was performed on 90 patients with BS, 80 with PsA and 80 healthy controls. Significantly lower IL-36α concentrations were found in patients with BS as compared to PsA, although in both groups IL-36α was significantly increased compared to healthy controls. An empirical cut-off of 420.6 pg/mL displayed a specificity of 0.93, with a sensitivity of 0.70 (AUC 0.82) in discriminating PsA from BS. This cut-off displayed a good diagnostic performance also in BS patients lacking highly specific BS manifestations. Our results indicate that IL-36α might be involved in the pathogenesis of both BS and PsA, and might be a candidate biomarker to support the differential diagnosis of BS.

The Helicobacter pylori CagY Protein Drives Gastric Th1 and Th17 Inflammation and B Cell Proliferation in Gastric MALT Lymphoma.

BACKGROUND: the neoplastic B cells of the Helicobacter pylori-related low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma proliferate in response to H. pylori, however, the nature of the H. pylori antigen responsible for proliferation is still unknown. The purpose of the study was to dissect whether CagY might be the H. pylori antigen able to drive B cell proliferation. METHODS: the B cells and the clonal progeny of T cells from the gastric mucosa of five patients with MALT lymphoma were compared with those of T cell clones obtained from five H. pylori-infected patients with chronic gastritis. The T cell clones were assessed for their specificity to H. pylori CagY, cytokine profile and helper function for B cell proliferation. RESULTS: 22 of 158 CD4+ (13.9%) gastric clones from MALT lymphoma and three of 179 CD4+ (1.7%) clones from chronic gastritis recognized CagY. CagY predominantly drives Interferon-gamma (IFN-γ) and Interleukin-17 (IL-17) secretion by gastric CD4+ T cells from H. pylori-infected patients with low-grade gastric MALT lymphoma. All MALT lymphoma-derived clones dose dependently increased their B cell help, whereas clones from chronic gastritis lost helper activity at T-to-B-cell ratios greater than 1. CONCLUSION: the results obtained indicate that CagY drives both B cell proliferation and T cell activation in gastric MALT lymphomas.

USF1 defect drives p53 degradation during Helicobacter pylori infection and accelerates gastric carcinogenesis.

OBJECTIVE: Helicobacter pylori (Hp) is a major risk factor for gastric cancer (GC). Hp promotes DNA damage and proteasomal degradation of p53, the guardian of genome stability. Hp reduces the expression of the transcription factor USF1 shown to stabilise p53 in response to genotoxic stress. We investigated whether Hp-mediated USF1 deregulation impacts p53-response and consequently genetic instability. We also explored in vivo the role of USF1 in gastric carcinogenesis. DESIGN: Human gastric epithelial cell lines were infected with Hp7.13, exposed or not to a DNA-damaging agent camptothecin (CPT), to mimic a genetic instability context. We quantified the expression of USF1, p53 and their target genes, we determined their subcellular localisation by immunofluorescence and examined USF1/p53 interaction. Usf1-/- and INS-GAS mice were used to strengthen the findings in vivo and patient data examined for clinical relevance. RESULTS: In vivo we revealed the dominant role of USF1 in protecting gastric cells against Hp-induced carcinogenesis and its impact on p53 levels. In vitro, Hp delocalises USF1 into foci close to cell membranes. Hp prevents USF1/p53 nuclear built up and relocates these complexes in the cytoplasm, thereby impairing their transcriptional function. Hp also inhibits CPT-induced USF1/p53 nuclear complexes, exacerbating CPT-dependent DNA damaging effects. CONCLUSION: Our data reveal that the depletion of USF1 and its de-localisation in the vicinity of cell membranes are essential events associated to the genotoxic activity of Hp infection, thus promoting gastric carcinogenesis. These findings are also of clinical relevance, supporting USF1 expression as a potential marker of GC susceptibility.

Interleukin-17/Interleukin-21 and Interferon-γ producing T cells specific for ß2 Glycoprotein I in atherosclerosis inflammation of systemic lupus erythematosus patients with antiphospholipid syndrome.

Systemic lupus erythematosus is frequently associated with antiphospholipid syndrome. Patients with lupus-antiphospholipid syndrome are characterized by recurrent arterial/venous thrombosis, miscarriages, and persistent presence of autoantibodies against phospholipid-binding proteins, such as ß2-Glycoprotein I. We investigated the cytokine production induced by ß2-Glycoprotein I in activated T cells that infiltrate in vivo atherosclerotic lesions of lupus-antiphospholipid syndrome patients. We examined the helper function of ß2-Glycoprotein I-specific T cells for tissue factor production, as well as their cytolytic potential and their helper function for antibody production. Lupus-antiphospholipid syndrome patients harbor in vivo activated CD4+ T cells that recognize ß2-Glycoprotein I in atherosclerotic lesions. ß2-Glycoprotein I induces T-cell proliferation and expression of both Interleukin-17/Interleukin-21 and Interferon-γ in plaque-derived T-cell clones. ß2-Glycoprotein I-specific T cells display strong help for monocyte tissue factor production, and promote antibody production in autologous B cells. Moreover, plaque-derived ß2-Glycoprotein I-specific CD4+ T lymphocytes express both perforin-mediated and Fas/FasLigand-mediated-cytotoxicity. Altogether, our results indicate that ß2-Glycoprotein I is able to elicit a local Interleukin-17/Interleukin-21 and Interferon-γ inflammation in lupus-antiphospholipid syndrome patients that might lead, if unabated, to plaque instability and subsequent arterial thrombosis, suggesting that the T helper 17/T helper 1 pathway may represent a novel target for the prevention and treatment of the disease.

LMW-PTP targeting potentiates the effects of drugs used in chronic lymphocytic leukemia therapy.

BACKGROUND: Low molecular weight protein tyrosine phosphatase (LMW-PTP) is overexpressed in different cancer types and its expression is related to more aggressive disease, reduced survival rate and drug resistance. Morin is a natural polyphenol which negatively modulates, among others, the activity of LMW-PTP, leading to the potentiation of the effects of different antitumoral drugs, representing a potential beneficial treatment against cancer. METHODS: LMW-PTP levels were measured by immunoblot analysis both in CLL cells from patients and in chronic lymphocytic leukemia (CLL)-derived Mec-1 cells. Cell viability was assessed in Mec-1 cells treated with morin alone or in combination with either fludarabine or ibrutinib or following siRNA-mediated LMW-PTP knockdown. Furthermore, the expression levels of VLA-4 and CXCR4 were assessed by both qRT-PCR and flow cytometry and both adhesion to fibronectin-coated plates and migration toward CXCL12 were analyzed in Mec-1 cells treated with morin alone or in combination with fludarabine or ibrutinib. RESULTS: We observed that LMW-PTP is highly expressed in Mec-1 cells as well as in leukemic B lymphocytes purified from CLL patients compared to normal B lymphocytes. Morin treatment strongly decreased LMW-PTP expression levels in Mec-1 cells and potentiated the anticancer properties of both fludarabine and ibrutinib by increasing their apoptotic effects on leukemic cells. Moreover, morin negatively regulates adhesion and CXCL12-dependent migration of Mec-1 cells by affecting VLA-4 integrin expression and CXCR4 receptor recycling. CONCLUSIONS: Morin treatment in CLL-derived Mec-1 cell line synergizes with conventional anticancer drugs currently used in CLL therapy by affecting leukemic cell viability and trafficking.

The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis.

Th17 cells have been casually associated to the pathogenesis of autoimmune disease. We have previously demonstrated that Rai/ShcC, a member of the Shc family of adaptor proteins, negatively regulates Th17 cell differentiation and lupus autoimmunity. In this study, we have investigated the pathogenic outcome of the Th17 bias associated with Rai deficiency on multiple sclerosis development, using the experimental autoimmune encephalomyelitis (EAE) mouse model. We found that, unexpectedly, EAE was less severe in Rai(-/-) mice compared with their wild-type counterparts despite an enhanced generation of myelin-specific Th17 cells that infiltrated into the CNS. Nevertheless, when adoptively transferred into immunodeficient Rai(+/+) mice, these cells promoted a more severe disease compared with wild-type encephalitogenic Th17 cells. This paradoxical phenotype was caused by a dampened inflammatory response of astrocytes, which were found to express Rai, to IL-17. The results provide evidence that Rai plays opposite roles in Th17 cell differentiation and astrocyte activation, with the latter dominant over the former in EAE, highlighting this adaptor as a potential novel target for the therapy of multiple sclerosis.

Intra-tumoral IFN-γ-producing Th22 cells correlate with TNM staging and the worst outcomes in pancreatic cancer.

PDAC (pancreatic ductal adenocarcinoma) is the fifth leading cause of cancer-related death. The causes of this cancer remain unknown, but increasing evidence indicates a key role of the host immune response and cytokines in human carcinogenesis. Intra-tumoral IL (interleukin)-22 levels have been shown to be elevated in PDAC patients. However, little is known regarding the expression and clinical relevance of Th22 cells in human PDAC and, furthermore, which TILs (tumour-infiltrating lymphocytes) are the main producers of IL-22 is unknown. In the present study, we characterized the functional proprieties of the different subsets of IL-22-producing TILs and analysed their relationship with the TNM staging system and patient survival. We have demonstrated for the first time that, in PDAC patients, the T-cells co-producing IFN-γ (interferon γ) and exerting perforin-mediated cytotoxicity are the major intra-tumoral source of IL-22. In addition, isolated Th22 cells were able to induce apoptosis, which was antagonized by IL-22. Finally, we observed that the IL-22-producing T-cells were significantly increased in tumour tissue and that this increase was positively correlated with TNM staging of PDAC and poorer patient survival. These novel findings support the dual role of the anti-tumour immune system and that IL-22-producing cells may participate in PDAC pathogenesis. Therefore monitoring Th22 levels could be a good diagnostic parameter, and blocking IL-22 signalling may represent a viable method for anti-PDAC therapies.

Autoantibodies against ß1-Adrenergic Receptors: Response to Cardiac Resynchronization Therapy and Renal Function.

BACKGROUND: Cardiac resynchronization therapy (CRT) nonresponse remains a major clinical problem. Autoantibodies specific for the ß1-adrenergic (ß1-AAbs) and muscarinic (M2-AAbs) receptors are found in patients with chronic heart failure (HF) of various etiologies. MATERIALS AND METHODS: We retrospectively analyzed 73 HF patients (median age 67 years, 84% males, New York Heart Association II-IV, in sinus rhythm, left ventricular ejection fraction <35%) who received CRT defibrillator (CRT-D) from 2010 to 2013. ß1-AAbs and M2-AAbs were measured by enzyme-linked immunosorbent assay. Echocardiography was used to assess CRT response (reduction >15% in left ventricular end-systolic volume at 6 months follow-up). Renal function (RF) parameters (creatinine [Cr], blood urea nitrogen [BUN], estimated glomerular filtration rate [eGFR Modified Diet in Renal Disease], cystatin C [Cys-C], and neutrophil gelatinase-associated lipocalin [NGAL]) were also evaluated. RESULTS: A significantly higher percentage of patients positive for ß1-AAbs (OD sample/OD reference ratio >2.1) in nonresponders than in responder patients was observed (57% vs 27%, P = 0.004). No influence of M2-AAbs on CRT-D response was demonstrated. ß1-AAbs were predictive of a poor CRT-D response (odds ratio [OR] [95% confidence interval (CI)] 3.64 [1.49-8.88], P = 0.005), also after adjustment for RF parameters (OR [95% CI] 4.95 [1.51-16.26], P = 0.008) observed to influence CRT-D response (Cr P = 0.03, BUN P = 0.009, Cys-C P = 0.02). The positive rates of ß1-AABs in patients with abnormal blood level of Cr, eGFR, Cys-C, and NGAL were significantly higher than those with normal levels (P = 0.03, P = 0.02, P = 0.001, P = 0.007, respectively). CONCLUSIONS: Our study suggests that (1) the evaluation of ß1-AAb is useful to identify responders to CRT-D; (2) the presence of ß1-AAbs is in relationship with elevated renal function parameters.

Thrombosis in vasculitis: from pathogenesis to treatment.

In recent years, the relationship between inflammation and thrombosis has been deeply investigated and it is now clear that immune and coagulation systems are functionally interconnected. Inflammation-induced thrombosis is by now considered a feature not only of autoimmune rheumatic diseases, but also of systemic vasculitides such as Behçet's syndrome, ANCA-associated vasculitis or giant cells arteritis, especially during active disease. These findings have important consequences in terms of management and treatment. Indeed, Behçet'syndrome requires immunosuppressive agents for vascular involvement rather than anticoagulation or antiplatelet therapy, and it is conceivable that also in ANCA-associated vasculitis or large vessel-vasculitis an aggressive anti-inflammatory treatment during active disease could reduce the risk of thrombotic events in early stages. In this review we discuss thrombosis in vasculitides, especially in Behçet's syndrome, ANCA-associated vasculitis and large-vessel vasculitis, and provide pathogenetic and clinical clues for the different specialists involved in the care of these patients.

An approach to differential diagnosis of antiphospholipid antibody syndrome and related conditions.

The antiphospholipid antibody syndrome is a systemic, acquired, immune-mediated disorder characterized by episodes of venous, arterial, or microcirculation thrombosis and/or pregnancy abnormalities, associated with the persistent presence of autoantibodies, confirmed at least in two occasions 12 weeks apart, directed to molecular complexes consisting of phospholipids and proteins. Antiphospholipid antibody syndrome should always be considered as a potential diagnosis especially for young patients presenting with a history of thrombotic events, in particular when they occur without any obvious external trigger or any inherited thrombophilic mutation (even if 2006 criteria do not exclude antiphospholipid antibody syndrome in patients with other inherited or acquired prothrombotic conditions), or for women with recurrent pregnancy losses or later fetal deaths. Many other disorders are able to mimic antiphospholipid antibody syndrome, so a broad range of alternative diagnoses should be investigated and ruled out during clinical workup.

Ex vivo analysis of pancreatic cancer-infiltrating T lymphocytes reveals that ENO-specific Tregs accumulate in tumor tissue and inhibit Th1/Th17 effector cell functions.

Pancreatic cancer (PC) is an aggressive disease with dismal prognosis. Surgical resection is the recommended treatment for long-term survival, but patients with resectable PC are in the minority (with a 5-year survival rate of 20 %). Therefore, development of novel therapeutic strategies, such as anti-PC immunotherapy, is crucial. α-Enolase (ENO1) is an enzyme expressed on the surface of pancreatic cancer cells and is able to promote cell migration and cancer metastasis. The capacity of ENO1 to induce an immune response in PC patients renders it a true tumor-associated antigen. In this study, we characterized the effector functions of ENO1-specific T cells isolated from PC patients, and we specifically evaluated the successful role of intra-tumoral T helper 17 (Th17) cells and the inhibitory role of regulatory T (Tregs) cells in respectively promoting or reducing the cancer-specific immune response. In this ex vivo study, we have demonstrated, for the first time, that ENO1-specific Th17 cells have a specific anti-cancer effector function in PC patients, and that there are decreased levels of these cells in cancer compared to healthy mucosa. Conversely, there are elevated levels of ENO1-specific Tregs in PC patients which lead to inhibition of the antigen-specific effector T cells, thus highlighting a possible role in promoting PC progression. These results may be relevant for the design of novel immunotherapeutic strategies in pancreatic cancer.

TpF1 from Treponema pallidum activates inflammasome and promotes the development of regulatory T cells.

Human syphilis is a multistage disease, with diverse and wide-ranging manifestations caused by Treponema pallidum. Despite the fact that a cell-mediated immune response takes part in the course of syphilis, T. pallidum often manages to evade host immunity and, in untreated individuals, may trigger chronic infection. With this study, we demonstrate for the first time, to our knowledge, that Treponema pallidum induces a regulatory T (Treg) response in patients with secondary syphilis and we found that the miniferritin TpF1, produced by the bacterium, is able to expand this response and promote the production of TGF-ß. Accordingly, TpF1 stimulates monocytes to release IL-10 and TGF-ß, the key cytokines in driving Treg cell differentiation. Interestingly, we also found that TpF1 stimulates monocytes to synthesize and release several proinflammatory cytokines, such as TNF-α, IL-6, and IL-1ß, the latter following the activation of the multiprotein complex inflammasome. Collectively, these data strongly support a central role for TpF1 both in the inflammation process, which occurs in particular during the early stage of syphilis, and in the long-term persistence of the spirochete within the host by promoting Treg response and TGF-ß production.

Increased IL-17A Serum Levels and Gastric Th17 Cells in Helicobacter pylori-Infected Patients with Gastric Premalignant Lesions.

Background:Helicobacter pylori infection is characterized by an inflammatory infiltrate that might be an important antecedent of gastric cancer. The purpose of this study was to evaluate whether interleukin (IL)-17 inflammation is elicited by gastric T cells in Helicobacter pylori patients with gastric intestinal metaplasia and dysplasia (IM/DYS). We also investigated the serum IL-17A levels in Helicobacter pylori patients with gastric intestinal metaplasia and dysplasia, and patients with Helicobacter pylori non-atrophic gastritis (NAG). Methods: the IL-17 cytokine profile of gastric T cells was investigated in six patients with IM/DYS and Helicobacter pylori infection. Serum IL-17A levels were measured in 45 Helicobacter pylori-infected IM/DYS patients, 45 Helicobacter pylori-infected patients without IM/DYS and in 45 healthy controls (HC). Results: gastric T cells from all IM/DYS patients with Helicobacter pylori were able to proliferate in response to Helicobacter pylori and to produce IL-17A. The Luminex analysis revealed that IL-17A levels were significantly increased in Helicobacter pylori IM/DYS patients compared to healthy controls and to Helicobacter pylori gastritis patients without IM/DYS (452.34 ± 369.13 pg/mL, 246.82 ± 156.06 pg/mL, 169.26 ± 73.82 pg/mL, respectively; p < 0.01, p < 0.05). Conclusions: the results obtained indicate that Helicobacter pylori is able to drive gastric IL-17 inflammation in IM/DYS Helicobacter pylori-infected patients, and that IL-17A serum levels are significantly increased in Helicobacter pylori-infected patients with IM/DYS.

SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly.

CTL-mediated killing of virally infected or malignant cells is orchestrated at the immune synapse (IS). We hypothesized that SARS-CoV-2 may target lytic IS assembly to escape elimination. We show that human CD8+ T cells upregulate the expression of ACE2, the Spike receptor, during differentiation to CTLs. CTL preincubation with the Wuhan or Omicron Spike variants inhibits IS assembly and function, as shown by defective synaptic accumulation of TCRs and tyrosine phosphoproteins as well as defective centrosome and lytic granule polarization to the IS, resulting in impaired target cell killing and cytokine production. These defects were reversed by anti-Spike antibodies interfering with ACE2 binding and reproduced by ACE2 engagement by angiotensin II or anti-ACE2 antibodies, but not by the ACE2 product Ang (1-7). IS defects were also observed ex vivo in CTLs from COVID-19 patients. These results highlight a new strategy of immune evasion by SARS-CoV-2 based on the Spike-dependent, ACE2-mediated targeting of the lytic IS to prevent elimination of infected cells.

Targeting of tumor cells by custom antigen transfer: a novel approach for immunotherapy of cancer.

In the early stages of carcinogenesis, the transformed cells become "invisible" to the immune system. From this moment on, the evolution of the tumor depends essentially on the genotype of the primitive cancer cells and their subsequent genetic drift. The role of the immune system in blocking tumor progression from the earliest stages is largely underestimated because by the time tumors are clinically detectable, the immune system has already completely failed its task. Therefore, a clinical treatment capable of restoring the natural anti-tumor role of the immune system could prove to be the "ultimate weapon" against cancer. Herein, we propose a novel therapeutic approach for the treatment of solid cancer that exploits the capability of activated monocytes to transfer major histocompatibility complex I (MHC-I) molecules bound to antigenic peptides to cancer cells using microvesicles as cargo, making tumor cells target of a "natural" CD8+ T lymphocyte cytotoxic response.

Skin IL-17A and IFN-γ Production Correlate with Disease Severity in Patients with Psoriasis and Streptococcal Infection.

Psoriasis is a multisystemic inflammatory disorder mainly involving the skin and joints, whose etiopathogenesis is still not completely understood. An association with streptococcal throat infection has been suggested. We aim to investigate a correlation between IL-17A and IFN-γ production by T cells infiltrating skin lesions and PASI in 313 patients with psoriasis, compared with that in 252 healthy controls. The phenotype of ß-hemolytic Streptococci-specific infiltrating T cells in skin lesions was evaluated and characterized for IFN-γ, IL-4, and IL-17A production. In addition, PBMCs were tested by ELISpot for IFN-γ and IL-17A after streptococcal antigen exposure. A total of 64 of 313 (20.4%) patients with psoriasis had throat streptococcal infection. Of the 3,868 skin-derived T-cell clones from psoriasis with streptococcal infection, 66% proliferated in response to ß-hemolytic Streptococci antigens. Most ß-hemolytic Streptococci-specific T cells displayed T helper 17 and T helper 1 phenotypes. The levels of IFN-γ and IL-17A secreted by skin-infiltrating T cells of patients with psoriasis significantly correlated with PASI score. In ß-hemolytic Streptococci-positive patients, IFN-γ and IL-17A production by peripheral blood T cells after stimulation with streptococcal antigens was quantified by ELISpot. The results obtained may suggest ELISpot as a useful diagnostic tool to identify patients with psoriasis that may deserve antibiotic treatment.

HP-NAP inhibits the growth of bladder cancer in mice by activating a cytotoxic Th1 response.

Intravesical Bacillus Calmette-Guérin (BCG) is the gold standard treatment for intermediate and high-risk non-muscle-invasive bladder cancer. BCG therapy is the most successful example of immunotherapy in cancer. Unfortunately, the treatment-related side effects are still relevant. Furthermore, non-responder patients are candidate to radical cystectomy in the absence of valuable alternative options. These aspects have prompted the search for newer biological response modifiers (BRM) with a better benefit/side effects ratio. The toll-like receptor (TLR) 2 ligand, Helicobacter pylori protein HP-NAP, has been shown to deserve a potential role as BRM. HP-NAP is capable of driving the differentiation of T helper (Th) 1 cells, both in vitro and in vivo, because of its ability to create an IL-12-enriched milieu. Herein, we report that local administration of HP-NAP decreases tumour growth by triggering tumour necrosis in a mouse model of bladder cancer implant. The effect is accompanied by a significant accumulation of both CD4+ and CD8+ IFN-γ-secreting cells, within tumour and regional lymph nodes. Noteworthy, HP-NAP-treated tumours show also a reduced vascularization due to the anti-angiogenic activity of IFN-γ induced by HP-NAP. Our findings strongly indicate that HP-NAP might become a novel therapeutic "bullet" for the cure of bladder tumours.