Impaired Immune Defense Research Articles

Altered purinergic P2X7 and A2B receptors signaling limits macrophage-mediated host defense in schistosomiasis

BackgroundThe occurrence of co-infections during schistosomiasis, a neglected tropical disease, with other parasites have been reported suggesting an impaired host immune defense. Macrophage purinergic P2X7 receptor (P2X7R) play an important role against intracellular pathogens. Therefore, we investigated the P2X7R-mediated phagocytosis and killing capacity of Leishmania amazonensis by macrophages during schistosomiasis in vitro and in vivo. MethodsSwiss and C57BL/6 (Wild type) and P2X7R−/− were randomized in two groups: control (uninfected) and Schistosoma mansoni-infected. Alternatively, control Swiss and S. mansoni-infected mice were also infected with L. amazonensis. ResultsThe pre-treatment of macrophages with the P2X7R antagonist (A74003) or TGF-β reduced the phagocytosis index, mimicking the phenotype of cells from S. mansoni-infected mice and P2X7R−/− mice. Apyrase also reduced the phagocytosis index corroborating the role of ATP to macrophage activation. Moreover, l-arginine-nitric oxide pathway was compromised, which could explain the reduced killing capacity in response to ATP in vitro and in vivo. We found an increased extracellular nucleotide (ATP, ADP and AMP) hydrolysis along with an increased frequency of F4/80+ CD39+ macrophages from the S. mansoni-infected group. Moreover, the content of adenosine in the cell supernatant was higher in the S. mansoni-infected group in relation to controls. Schistosomiasis also increased the expression of macrophage adenosine A2BR. In good accordance, both ADA and the selective A2BR antagonist restored the phagocytosis index of macrophages from S. mansoni-infected group. ConclusionsAltogether, the altered P2X7R and A2BR signaling limits the role of macrophages to host defense against L. amazonensis during schistosomiasis, potentially contributing to the pathophysiology and clinically relevant co-infections.

The Delayed-Steroid-Strategy (DSS) for Idiopathic Granulomatous Mastitis during the COVID-19 Pandemic: A Case Series

Idiopathic granulomatous mastitis (IGM) is an inflammatory disease. It is often treated with steroids which could result in the recipient having an impaired immune defence and increases risk of getting infections. This could also hinder an adequate immune response post vaccination and render vaccines to be less effective. This was a study to assess the role and outcome of non steroidal anti-inflammatory drugs (NSAIDs) to delay corticosteroid treatment. This strategy aims to allow the patients to achieve complete vaccination with adequate post vaccination response for better COVID-19 protection prior to commencement of steroids. All three newly diagnosed patients with IGM completed their NSAIDs bridging therapy. None of them reported any worsening of disease during that time.

Depletion of mTOR ameliorates CD4+ T cell pyroptosis by promoting autophagy activity in septic mice

A reduction in the number of CD4+ T cells is a central part of the immunosuppression phase of sepsis and leads to impaired immune defense ability and increased mortality. Pyroptosis, a newly discovered programmed cell death, was confirmed to be an important mechanism of lymphocytopenia in a lot of human diseases and is under the regulation of autophagy. The mammalian target of rapamycin (mTOR) pathway is closely related to CD4+ T-cell survival. Whether the mTOR pathway influences CD4+ T cell pyroptosis by regulating autophagy remains unknown. In this study, a septic mouse model was developed using cecal ligation and puncture (CLP) to explore the degree of pyroptosis and autophagy of CD4+ T cells. T-cell-specific mTOR/TSC1-knockout mice were used to investigate the role of mTOR pathway in the regulation of CD4+ T cell pyroptosis. Bafilomycin, a specific autophagy inhibitor, was used to verify the regulatory effect of autophagy on pyroptosis in septic mice. We observed aggravated pyroptosis in CD4+ T cells in CLP mice accompanied by impaired autophagy activity and an overactivated mTOR signaling pathway. Depletion of mTOR relieved autophagy deficiency and reduced the proportion of pyroptotic CD4+ T cells. In T-cell-specific mTOR-knockout mice treated with bafilomycin, the protective effect of mTOR depletion vanished. This indicated that autophagy negatively regulates CD4+ T cell pyroptosis, which is under the control of the mTOR pathway. Taken together, our findings emphasize the importance of pyroptosis in sepsis-induced lymphopenia and reveal the regulatory effects of the mTOR pathway and the role of autophagy in this regulation.

YAP Inhibition Alleviates Simulated Microgravity-Induced Mesenchymal Stem Cell Senescence via Targeting Mitochondrial Dysfunction.

Weightlessness in space leads to bone loss, muscle atrophy, and impaired immune defense in astronauts. Mesenchymal stem cells (MSCs) play crucial roles in maintaining the homeostasis and function of the tissue. However, how microgravity affects the characteristics MSCs and the related roles in the pathophysiological changes in astronauts remain barely known. Here we used a 2D-clinostat device to simulate microgravity. Senescence-associated-β-galactosidase (SA-β-gal) staining and the expression of senescent markers p16, p21, and p53 were used to evaluate the senescence of MSCs. Mitochondrial membrane potential (mΔΨm), reactive oxygen species (ROS) production, and ATP production were used to evaluate mitochondrial function. Western blot and immunofluorescence staining were used to investigate the expression and localization of Yes-associated protein (YAP). We found that simulated microgravity (SMG) induced MSC senescence and mitochondrial dysfunction. Mito-TEMPO (MT), a mitochondrial antioxidant, restored mitochondrial function and reversed MSC senescence induced by SMG, suggesting that mitochondrial dysfunction mediates SMG-induced MSC senescence. Further, it was found that SMG promoted YAP expression and its nuclear translocation in MSCs. Verteporfin (VP), an inhibitor of YAP, restored SMG-induced mitochondrial dysfunction and senescence in MSCs by inhibiting YAP expression and nuclear localization. These findings suggest that YAP inhibition alleviates SMG-induced MSC senescence via targeting mitochondrial dysfunction, and YAP may be a potential therapeutic target for the treatment of weightlessness-related cell senescence and aging.

Zearalenone disturbs the reproductive-immune axis in pigs: the role of gut microbial metabolites

BackgroundExposure to zearalenone (ZEN, a widespread Fusarium mycotoxin) causes reproductive toxicity and immunotoxicity in farm animals, and it then poses potential threats to human health through the food chain. A systematic understanding of underlying mechanisms on mycotoxin-induced toxicity is necessary for overcoming potential threats to farm animals and humans. The gastrointestinal tract is a first-line defense against harmful mycotoxins; however, it remains unknown whether mycotoxin (e.g., ZEN)-induced toxicity on the reproductive-immune axis is linked to altered gut microbial metabolites. In this study, using pigs (during the three phases) as an important large animal model, we investigated whether ZEN-induced toxicity on immune defense in the reproductive-immune axis was involved in altered gut microbial-derived metabolites. Moreover, we observed whether the regulation of gut microbial-derived metabolites through engineering ZEN-degrading enzymes counteracted ZEN-induced toxicity on the gut-reproductive-immune axis.ResultsHere, we showed ZEN exposure impaired immune defense in the reproductive-immune axis of pigs during phase 1/2. This impairment was accompanied by altered gut microbial-derived metabolites [e.g., decreased butyrate production, and increased lipopolysaccharides (LPS) production]. Reduction of butyrate production impaired the intestinal barrier via a GPR109A-dependent manner, and together with increased LPS in plasma then aggravated the systemic inflammation, thus directly and/or indirectly disturbing immune defense in the reproductive-immune axis. To validate these findings, we further generated recombinant Bacillus subtilis 168-expressing ZEN-degrading enzyme ZLHY-6 (the Bs-Z6 strain) as a tool to test the feasibility of enzymatic removal of ZEN from mycotoxin-contaminated food. Notably, modified gut microbial metabolites (e.g., butyrate, LPS) through the recombinant Bs-Z6 strain counteracted ZEN-induced toxicity on the intestinal barrier, thus enhancing immune defense in the reproductive-immune axis of pigs during phase-3. Also, butyrate supplementation restored ZEN-induced abnormalities in the porcine small intestinal epithelial cell.ConclusionsAltogether, these results highlight the role of gut microbial-derived metabolites in ZEN-induced toxicity on the gut-reproductive-immune axis. Importantly, targeting these gut microbial-derived metabolites opens a new window for novel preventative strategies or therapeutic interventions for mycotoxicosis associated to ZEN.

1225. The Perfect Storm: A Hardy and Lethal Pathogen and a Unit Filled with Immunocompromised Patients with Large Open Wounds. Troubles with Candida Auris in a Burn Intensive Care Unit

Abstract Background C auris is an emerging often multidrug resistant pathogen capable of causing severe morbidity and mortality. C auris has been increasingly isolated from patients in skilled nursing facilities and hospitals, and has been associated with facility outbreaks. A resilient pathogen, C. auris survives harsh disinfectants, desiccation and readily colonizes the environment posing an especially great risk to immunocompromised patients with large open wounds and long lengths of stay. Methods From 7/1/21 - 8/30/21 we noted a cluster of 4 patients with C auris in clinical cultures from the Burn ICU (BICU). A multidisciplinary team involving infection prevention, nursing/medical directors, health and safety, engineering, environmental services, and hospital leadership investigated the cluster as a potential outbreak. Mitigation measures involved a multi-modal response of C auris admission screening, weekly point prevalence testing of all BICU patients, environmental surface cultures, enhanced room cleaning, staff education, hand hygiene and personal protective equipment usage audits. Results 11 cases of C auris were identified on our BICU from 7/1/21 - 2/28/22. 5 (45.5%) cases from clinical isolates, 1 (9.1%) from a BICU point prevalence screen on 12/15/21, 5 (45.5%) as a part of weekly point prevalence screens started on 1/1/22. 6 (54.5%) patients were admitted for burn related injuries, 2 (18.2%) for Steven Johnson Syndrome, 2 (18.2%) for necrotizing wounds, and 1 (9.1%) for COVID-19 pneumonia. Cases occurred in 6/10 rooms in the Burn ICU. One (9.1%) patient expired during this outbreak (not deemed to be from C auris infection). Conclusion Resilient infections like C auris pose a risk of nosocomial transmission and potential high morbidity and mortality to burn patients with impaired immune defense and large open wounds. A multidisciplinary team using targeted interventions including screening, education, enhanced cleaning eradicated the outbreak in our BICU. As of 5/1/22, we went 13 + weeks without identifying a new case. The last patient with C auris was discharged 3/16/22. To prevent future outbreaks, we created a standardized response plan and instituted a universal screening protocol for C auris targeting all patient admissions from skilled nursing facilities and admissions to all ICUs. Disclosures Jorge Paiva Parada, MD MPH, Shionogi: Honoraria.

Application of bioinformatical analysis to identify candidate genes associated with hereditary angioedema

Primary immunodeficiencies (PID) are a heterogeneous group of hereditary diseases that lead to impaired immune defense. Often, the diagnosis cannot be made without identifying mutations that lead to the development of the disease. For many PIDs, there is no clear understanding of the etiology, pathogenesis, and genes involved. There is an obvious need to identify candidate genes potentially capable of leading to the development of PIDs.Hereditary angioedema (HAE) is a rare genetically determined disease, accompanied by recurrent edema of soft tissues and submucosal membranes, posing a threat to the life of patients. Diagnosis is based on the clinical presentation, family history, laboratory values of C1-esterase inhibitor, complement component 4, complement component 1q, antibodies to C1 and genetic testing for a number of mutations in the genes SERPING1, F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6. However, pathogenesis may involve other genes in which the negative effect of mutations has not yet been studied. HAE is a non-monogenic disease that may involve an extensive network of genes. It seems important to determine the groups of the most probable candidate genes presumably involved in the development of pathology.Aim – to identify, using bioinformatics analysis, candidate genes for the development/pathogenesis of HAE and to reveal their biological context.The analysis was based on a group of genes, mutations in which are significantly associated with HAE: SERPING1, F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6. To analised genetic and protein–protein networks and identify the biological context of the selected candidate genes, a number of web resources were used: HumanNetv3, GeneMania, FUMA GWAS in the GENE2FUNC mode.One hundred potential candidate genes in which mutations can be associated with HAE have been identified. The biological context of the identified genes was determined. The data of the biological context, genetic and protein-protein interactions made it possible to exclude a number of genes from the list of the most likely participants in pathogenesis and divide the remaining ones into groups with a greater or lesser potential for involvement. The group of the most likely HAO candidate genes includes PLAT, HRG, SERPINA1, SERPINF2, MASP2, GRB14, C1QBP, DOK2, KLKB1, F11, TEK, KLK10, KRT1, APOH, CPB2, F2.The results obtained can provide significant assistance in the study of the HAE molecular mechanism, as well as in the diagnosis and prognosis of the disease course. The identified candidate genes have the potential to serve as diagnostic biomarkers for patients with unexplained angioedema.The use of bioinformatic methods makes it possible to determine the list of candidate genes that are presumably involved in the disease pathogenesis or aggravate its course, and to obtain up-to-date information about the biological context of the identified genes. Understanding the genetic underpinnings and pathophysiology of PID may help define new diagnostic and therapeutic targets.

Interleukin-17 Genes Polymorphisms are Significantly Associated with Cutaneous T-cell Lymphoma Susceptibility.

Tumour microenvironment has an important effect on the progression of cutaneous T-cell lymphomas. Using PCR with sequence-specific primers, this study analysed single-nucleotide polymorphisms in the interleukin-17 genes of 150 patients with cutaneous T-cell lymphoma. GG homozygote rs8193036 A/G of interleukin-17A gene occurred less commonly in the cutaneous T-cell lymphoma group; however, patients with this single-nucleotide polymorphism experience significantly intense pruritus. Conversely, the rs2397084 AG heterozygote of interleukin-17F is more common in the lymphoma population. In addition, there were significant differences in the frequencies of interleukin-17 genotypes when comparing early (Ia to IIa) and advanced stages (IIb, III and IV) of this neoplasms. A similar result has been shown in comparison between Sézary syndrome and mycosis fungoides. The current data may serve as a possible explanation for the increased bacterial infection rates in the course of cutaneous T-cell lymphoma, especially caused by Staphylococcus aureus. In summary, specific single-nucleotide polymorphisms occur with different frequencies between cutaneous T-cell lymphoma and healthy patients. Moreover, genetic predisposition of several interleukin-17 single-nucleotide polymorphisms may be a factor causing impaired immune defence in cutaneous lymphomas.

SARS-CoV-2 Morbidity in the CNS and the Aged Brain Specific Vulnerability

The infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be the cause of a fatal disease known as coronavirus disease 2019 (COVID-19) affecting the lungs and other organs. Particular attention has been given to the effects of the infection on the brain due to recurring neurological symptoms associated with COVID-19, such as ischemic or hemorrhagic stroke, encephalitis and myelitis, which are far more severe in the elderly compared to younger patients. The specific vulnerability of the aged brain could derive from the impaired immune defenses, from any of the altered homeostatic mechanisms that contribute to the aging phenotype, and from particular changes in the aged brain involving neurons and glia. While neuronal modifications could contribute indirectly to the damage induced by SARS-CoV-2, glia alterations could play a more direct role, as they are involved in the immune response to viral infections. In aged patients, changes regarding glia include the accumulation of dystrophic forms, reduction of waste removal, activation of microglia and astrocytes, and immunosenescence. It is plausible to hypothesize that SARS-CoV-2 infection in the elderly may determine severe brain damage because of the frail phenotype concerning glial cells.

Treatment Strategies and Challenges in the Co-Management of Type 2 Diabetes and Tuberculosis

Despite rapid advances in the healthcare field, diabetes mellitus (DM) and tuberculosis (TB) continues to be a global burden that affects millions of people every year. The association between DM and TB has been known for an extended period. The last 15 years, however, have seen an increased number of studies showing that diabetes (both type 1 and type 2) increases the risk of tuberculosis because of impaired immune defences and likewise, TB may induce hyperglycemia and therefore increase the risk of DM. When DM and TB co-exist as dual diseases, it complicates management strategies as treatment outcomes are affected. In developing countries where the epidemic of DM and TB is rapidly growing, the presence of a concomitant disease becomes a challenge to the affected nation and could also impact DM and TB control on a global scale. This review brings together information on what is currently known about T2DM and TB as a double epidemic, the recommended treatment strategies, and the challenges involved in disease management. Furthermore, we address the future perspectives of the co-management of T2DM and TB and what can be done to overcome the shortcomings of currently available guidelines.

Pseudomonas aeruginosa Pneumonia: Evolution of Antimicrobial Resistance and Implications for Therapy.

Pseudomonas aeruginosa (PA), a non-lactose-fermenting gram-negative bacillus, is a common cause of nosocomial infections in critically ill or debilitated patients, particularly ventilator-associated pneumonia (VAP), and infections of urinary tract, intra-abdominal, wounds, skin/soft tissue, and bloodstream. PA rarely affects healthy individuals, but may cause serious infections in patients with chronic structural lung disease, comorbidities, advanced age, impaired immune defenses, or with medical devices (e.g., urinary or intravascular catheters, foreign bodies). Treatment of pseudomonal infections is difficult, as PA is intrinsically resistant to multiple antimicrobials, and may acquire new resistance determinants even while on antimicrobial therapy. Mortality associated with pseudomonal VAP or bacteremias is high (> 35%) and optimal therapy is controversial. Over the past three decades, antimicrobial resistance (AMR) among PA has escalated globally, via dissemination of several international multidrug resistant "epidemic" clones. We discuss the importance of PA as a cause of pneumonia including health care-associated pneumonia, hospital-acquired pneumonia, VAP, the emergence of AMR to this pathogen, and approaches to therapy (both empirical and definitive).

Connecting Metabolism to Mastitis: Hyperketonemia Impaired Mammary Gland Defenses During a Streptococcus uberis Challenge in Dairy Cattle.

β-hydroxybutyrate (BHB) has been associated with disease incidence in early lactation dairy cattle, but such associations do not demonstrate causation. Therefore, the objective of this study was to examine the effects of BHB during an intramammary Streptococcus uberis challenge. A secondary objective was to elucidate the mechanisms behind BHB effects on cytokine transcript abundance using the RAW 264.7 cell line. Late lactation multiparous dairy cows (n = 12) were continuously infused intravenously with either BHB to induce hyperketonemia (target concentration: 1.8 mM) or with saline (CON) for 72 h during a S. uberis intramammary challenge. Body temperature, dry matter intake (DMI), milk production, and milk S. uberis cfu were measured daily until one week post-challenge. Blood samples were collected during infusion to assess changes in metabolism (glucose, insulin, glucagon, NEFA, and cortisol) and systemic inflammation (IL-1β and SAA). Mammary biopsies were conducted at 72 h post-challenge to assess transcript abundance of inflammation-associated genes. BHB-infused cows exhibited a delayed febrile response, noted by a lesser vaginal temperature during the final day of infusion, followed by a greater vaginal temperature 6 d post-challenge. Consequently, BHB-infused cows had greater S. uberis cfu on d 4, 6, and 7 as compared to CON. Accordingly, BHB-infused cows consumed less DM, produced less milk, had reduced blood glucose, and had increased cortisol concentrations, however, no effects were seen on other systemic parameters or transcript abundance of inflammation-related genes in mammary tissue. To elucidate mechanisms behind the impaired immune defenses, RAW 264.7 cells were transfected with a GPR109A siRNA for 24 h and then treated with or without 1.8 mM BHB and challenged or left unchallenged with S. uberis for an additional 3 h. Transfection with siRNA reduced Gpr109a by 75%. Although BHB treatment did not significantly increase Il10, GPR109A knockdown as compared to the scrambled control reduced Il10 by 90% in S. uberis challenged macrophages treated with BHB, suggesting that macrophage immune responses to S. uberis can be altered via a GPR109A-dependent mechanism. Taken together, these data suggest that BHB altered the immune response promoting tolerance toward S. uberis rather than resistance.

Tandem Mass Tag (TMT) Proteomic Analysis of Saliva in Horses with Acute Abdominal Disease.

Simple SummaryThis study shows for the first time the variation of the salivary proteome in horses with acute abdominal disease (AAD) compared with healthy horses through a high-throughput proteomic approach. A total of 118 proteins were identified, and 17 showed significant changes between the two groups. The changes observed in proteins were closely related to an impaired primary immune defense and antimicrobial capacity in the mucosa, and one salivary protein (lactoferrin) was successfully verified. These results may increase the background and knowledge of saliva composition in horses with AAD and further understanding of the physiopathological changes occurring in the organism in this disease.The aim of this study was to investigate the changes in the salivary proteome in horses with acute abdominal disease (AAD) using a tandem mass tags (TMT)-based proteomic approach. The saliva samples from eight horses with AAD were compared with six healthy horses in the proteomic study. Additionally, saliva samples from eight horses with AAD and eight controls were used to validate lactoferrin (LF) in saliva. The TMT analysis quantified 118 proteins. Of these, 17 differed significantly between horses with AAD and the healthy controls, 11 being downregulated and 6 upregulated. Our results showed the downregulation of gamma-enteric smooth muscle actin (ACTA2), latherin isoform X1, and LF. These proteins could be closely related to an impaired primary immune defense and antimicrobial capacity in the mucosa. In addition, there was an upregulation of mucin 19 (MUC19) and the serine protease inhibitor Kazal-type 5 (SPINK5) associated with a protective effect during inflammation. The proteins identified in our study could have the potential to be novel biomarkers for diagnosis or monitoring the physiopathology of the disease, especially LF, which decreased in the saliva of horses with AAD and was successfully measured using a commercially available immunoassay.

From the Editor's Desk...

From the Editor's Desk...

Vitamin D, Zinc and Ear Nose Throat Disorders: Novel Findings

Vitamin D and Zinc (Zn) play a crucial role in human biochemistry. Over the last decade, there has been a better understanding on the significant role of vitamin D and zinc in ear, nose, and throat disorders. They are responsible for regulating mucosal immunity. Although vitamin D recognized as a key micronutrient, there is a pervasive vitamin D deficiency globally. Zinc as a critical trace element in human metabolism, facilitates the antioxidant activity and toxin excretion, plays a vital role in hearing system, acts as a cofactor in many enzymes. Zinc tasks in diseases related to mucosal defense, control of seasonal allergic rhinitis and healing of scar tissues. Zinc is an abundant intracellular trace element. Even though a mild zinc deficiency can manifest with serious clinical pictures like impaired immune defense.

Tuberculosis in patients with systemic lupus erythematosus-a 37-year longitudinal survey-based study.

Infections are one of the most common causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). SLE patients have a higher risk of tuberculosis (TB) infection due to impaired immune defence. To investigate the demographics, clinical characteristics and outcomes of patients with SLE and concomitant TB. Medical records of SLE patients with TB who were admitted to Peking Union Medical College (PUMC) Hospital in 1983-2019 were retrospectively reviewed. Age- and sex-matched SLE inpatients without TB were randomly selected as controls. Clinical and laboratory features and treatment were analysed and compared, and subjects were followed up to assess their outcome. Of the 10469 SLE inpatients, 249 (2.4%) were diagnosed with TB. Compared with controls, SLE/TB+patients exhibited higher frequency of prior haematologic, mucocutaneous and musculoskeletal system involvement, and prior treatment with potent glucocorticoid/immunosuppressive agents (GC/ISA). Arthritis and alopecia, positive T-SPOT.TB test and lymphocytopenia were more common in SLE/TB+patients. SLE/TB+patients with lupus before TB (SLE→TB) had higher risk of miliary TB (22.8%) and intracranial TB (16.5%) than SLE/TB+patients with lupus after TB (TB→SLE). SLE/TB+patients exhibited shorter long-term survival than SLE/TB- patients; those with poorer in-hospital outcomes had more severe lymphocytopenia and had received less treatment with ISAs. Systemic lupus erythematosus patients treated vigorously with GC/ISA should be alerted of increased risk of TB infection, especially miliary and intracranial TB. Positive T-SPOT.TB and lymphocytopenia served as discriminatory variables between SLE/TB+and SLE/TB- patients. Lymphocytopenia was associated with poorer outcomes in SLE/TB+patients.

P0510INFLAMMATORY BOWEL DISEASE IN KIDNEY TRANSPLANTATION:CASE REPORT

Abstract Introduction Kidney transplantation has become the treatment of choice for chronic end-stage renal disease because it improves not only the quality of life of patients but also their survival rate. However, several complications can be observed in transplant patients such as immune rejection, infections and recurrence of initial nephropathy etc. Case summary A 21-year-old man diagnosed with chronic end-stage renal failure 5 years ago with a renal biopsy showing an aspect of proliferative glomerulonephritis. The study of the alternate complementary path show a C3 low level, C4 and CH50 normal level, H factor and I factor was normal too. The patient presented purpuric skin lesions with a biopsy of granular deposits of C3. We started extra renal purification by peritoneal dialysis and the patient had, one year later, a kidney transplant from his mother. Ten month later, we have notice a progressive renal function decline with an aspect of proliferative membranous glomerulonephritis with deposits predominant of c3 in graft biopsy. The diagnosis of the recurrence of the initial nephropathy was made but the treatment was delayed by the onset of cutaneous leishmaniosis. Few months later the patient was presented with diarrhea lasting more than a month, which led us to do a colonoscopy, which objectified an aspect of chronic inflammatory bowel disease evoking earlier a Crohn's disease. Therefore, we stopped tacrolimus and put the patient on full dose corticosteroid therapy and azathioprine without having a remission, and appearance of skin lesions at the elbow and pelvis evoking pyoderma gangrenosum in skin biopsy. In addition, the patient has presented an ischemic retinal damage probably related to a deregulation of the alternate complement pathway. Discussion The complement system is not only a host defense system against microbes, but also a surveillance system that contributes to maintain tissue homeostasis and tissue repair. However, uncontrolled complement activation can induce tissue damage, and inappropriate activation is involved in the pathogenesis of various conditions like autoimmune diseases, sepsis and transplant and extensive inflammation and tissue damage. The impairment of alternative path can explain the extra-renal manifestation of this patient especially the appearance of inflammatory bowel disease witch can be explained by impaired local immune defense in the gut. Conclusion Immune system abnormalities can occur after kidney transplantation this leads to the appearance of several inflammatory abnormalities such as chronic inflammatory bowel disease which may in our case be due to an abnormality of the alternate pathway of the complement.

Monocytes in Uremia.

Monocytes play an important role in both innate immunity and antigen presentation for specific cellular immune defense. In patients with chronic renal failure, as well as those treated with maintenance hemodialysis, these cells are largely dysregulated. There is a large body of literature on monocyte alterations in such patients. However, most of the publications report on small series, there is a vast spectrum of different methods and the heterogeneity of the data prevents any meta-analytic approach. Thus, a narrative review was performed to describe the current knowledge. Monocytes from patients with chronic renal failure differ from those of healthy individuals in the pattern of surface molecule expression, cytokine and mediator production, and function. If these findings can be summarized at all, they might be subsumed as showing chronic inflammation in resting cells together with limited activation upon immunologic challenge. The picture is complicated by the fact that monocytes fall into morphologically and functionally different populations and population shifts interact heavily with dysregulation of the individual cells. Severe complications of chronic renal failure such as impaired immune defense, inflammation, and atherosclerosis can be related to several aspects of monocyte dysfunction. Therefore, this review aims to provide an overview about the impairment and activation of monocytes by uremia and the resulting clinical consequences for renal failure patients.

Cytokine Release Ensuing Interaction Between Human Peripheral Blood Mononuclears and Epstein-Barr Virus Transformed B-CLL Cell Line.

B-cell chronic lymphocytic leukemia (B-CLL) is a common form of leukemia affecting mostly elderly individuals. The course of the disease is usually unremarkable, but because it may proceed with impaired immune defense, B-CLL might be complicated with infections and even death. The leukemic microenvironment containing a number of immune cells, mainly lymphocytes and macrophages capable to produce various molecules including inflammatory cytokines, plays an important role in the development and outcome of the disease. We studied the capacity of Epstein-Barr virus (EBV)-transformed B-cell chronic lymphocytic leukemia (B-CLL) cell line (EHEB) cells, an EBV-transformed line established from a B-CLL patient, to affect the production of inflammatory cytokines by human peripheral blood mononuclear cells (PBMC). PBMC isolated from peripheral blood of healthy donors were incubated either with EHEB cells or with their supernatants and the production of the following cytokines: tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, interferon (IFN)-γ, IL-1ra, and IL-10 were detected using the enzyme-linked immunosorbent assay method. Direct contact of PBMC incubated with EHEB cells induced a marked increase of TNFα, IL-1β, IL-6, IFNγ, and IL-10 release by the immune cells. Yet, incubation of PBMC with EHEB cells' supernatant resulted in a mild production of the same cytokines. The noticeable increased production of inflammatory cytokines by PBMC following direct contact with EHEB cells and to a lesser degree with their supernatants implies the existence of an immune dialogue between these two types of cells. The results support the concept that not only leukemic cells, but also peripheral blood mononuclears could serve as a therapeutic target for B-CLL.

P2.17-14 Impaired Immune Defense in Tumor Micro-Environment Is Associated with Risk of Recurrence in Early Stage Lung Adenocarcinoma

Despite curative surgery with or without chemotherapy, 27-76% of surgically resected early stage lung cancer will unfortunately develop recurrence which is often fatal. Platinum-based adjuvant chemotherapy in NSCLC improves cure rates in only 5% of patients at the cost of significant toxicities. Developing biomarkers to select high risk patients and strategies to reduce recurrence in early stage lung cancer are critical. Thirty surgically resected primary lung adenocarcinomas from 16 patients with lung cancer recurrence and 14 patients without recurrence in 4 years were included in this study. Among these 30 patients, 27 have either stage I or II. RNA sequencing (694 genes and 14 key immuno-oncology (IO) pathways) was determined using nanoString technology and RNA from primary tumors from recurrent versus non-recurrent patients. Chemokines including CCL18, CCL23, CXCL1, CXCL2, CCL26 and chemokine receptors CXCR2, CX3CR1 and TNFRSF10C were significantly decreased in tumors from patients who had recurrence versus those from patients without recurrence. By contrast, genes related to cancer associated fibroblasts in the stromal microenvironment such as LRRC15 and genes involved in release of cancer cell antigens were significantly increased in adenocarcinomas from recurrent patients. Our results suggest that recurrence in early stage lung adenocarcinoma might be related to impaired immune defense such as decreased immune cell trafficking and antigen release in tumor micro-environment. Further study with larger sample size is warranted.