Radiation-Detoxified Form of Endotoxin Effectively Activates Th1 Responses and Attenuates Ragweed-Induced Th2-Type Airway Inflammation in Mice.

Urbanization with reduced microbial exposure is associated with an increased burden of asthma and atopic symptoms. Conversely, environmental exposure to endotoxins in childhood can protect against the development of allergies. Our study aimed to investigate whether the renaturation of the indoor environment with aerosolized radiation-detoxified lipopolysaccharide (RD-LPS) has a preventative effect against the development of ragweed-induced Th2-type airway inflammation. To explore this, cages of six-week-old BALB/c mice were treated daily with aerosolized native LPS (N-LPS) or RD-LPS. After a 10-week treatment period, mice were sensitized and challenged with ragweed pollen extract, and inflammatory cell infiltration into the airways was observed. As dendritic cells (DCs) play a crucial role in the polarization of T-cell responses, in our in vitro experiments, the effects of N-LPS and RD-LPS were compared on human monocyte-derived DCs (moDCs). Mice in RD-LPS-rich milieu developed significantly less allergic airway inflammation than mice in N-LPS-rich or common environments. The results of our in vitro experiments demonstrate that RD-LPS-exposed moDCs have a higher Th1-polarizing capacity than moDCs exposed to N-LPS. Consequently, we suppose that the aerosolized, non-toxic RD-LPS applied in early life for the renaturation of urban indoors may be suitable for the prevention of Th2-mediated allergies in childhood.

The role of protein kinase C isoenzymes in the pathogenesis of human autoimmune diseases.

The physiological role of protein kinase C (PKC) enzymes in the immune system is presented briefly. From earlier publications of others data were collected how the defects of one/two isoenzymes of PKC system suggested their involvement in the pathogenesis of human autoimmune diseases. Our observations on the defects of seven PKC isoenzymes in the peripheral blood mononuclear cells (PBMC) demonstrate that these molecular impairments are not prerequisits of the pathogenesis of systemic lupus erythematosus (SLE), mixed connective tissue disease and Sjögren's syndrome. However, these defects can modulate the disease activity and symptoms especially in SLE by several pathways. The role of PKC system in other forms of autoimmune diseases is also very small. It was of note that we detected decreased expression of PKC isoenzymes in PBMC of a European white family with an X-linked genetic background showing seasonal undulations in the lupus patient and also in her healthy mother.

[The standardized mortality numbers of patients with gastrointestinal tumors and cardiovascular diseases in four wine regions and in one not-wine region of Hungary between 2000-2010]. / A gastrointestinalis daganatok és szív-ér rendszeri betegségek standardizált halálozási arányszámai Magyarország négy borvidékén és egy nem borvidéken 2000­2010 között.

INTRODUCTION: Eating habits act on mortalities from gastrointestinal tumors and cardiovascular diseases. AIM: To investigate the role of wine drinking on these mortalities in Hungary. METHOD: The standardized mortality data of people from 206,159 subjects died of gastrointestinal tumors and cardiovascular diseases between 2000-2010 were compared in four wine regions: Tokaj (white), Eger (red), Balaton (white), Szekszárd/Villány (red) and in Hódmezovásárhely (not-wine region). RESULTS: The significantly smallest number of tumors (664) occurred in Tokaj, but the cardiovascular mortality here was the highest (5955). On the other hand, the fewest cardiovascular mortality occurred in Szekszárd/Villány (3907), but showing here (831) and in Eger (934) the highest values of tumor death. CONCLUSIONS: The protective effect of red wine on cardiovascular mortality was verified. Surprisingly, the low value of gastrointestinal mortality in "Tokaj" - besides the higher level of selenium in tap water - shows some hidden features of these white wines. Orv Hetil. 2017; 158(25): 992-998.

[Precision and personalized medicine]. / Precíziós és perszonalizált medicina.

The author describes the concept of "personalized medicine" and the newly introduced "precision medicine". "Precision medicine" applies the terms of "phenotype", "endotype" and "biomarker" in order to characterize more precisely the various diseases. Using "biomarkers" the homogeneous type of a disease (a "phenotype") can be divided into subgroups called "endotypes" requiring different forms of treatment and financing. The good results of "precision medicine" have become especially apparent in relation with allergic and autoimmune diseases. The application of this new way of thinking is going to be necessary in Hungary, too, in the near future for participants, controllers and financing boards of healthcare. Orv. Hetil., 2016, 157(44), 1739-1741.

[Short history of laboratory diagnostics of allergy in Hungary, current possibilities and future perspectives]. / Az allergia laboratóriumi diagnosztikájának rövid hazai története, a jelen lehetoségei és a jövo perspektívája.

Up to know the indications for the optimal applications of laboratory diagnosis of allergic diseases have become widely known. Measurements of allergy specific IgE and various tests of cell mediated immunity are included in the practice. It can be stated that measurements of total serum IgE and allergen specific IgE (kU/l and RAST classes) can be maintained further in the Hungarian practice with the expected continuous participation of all laboratories in the external quality control program (QualiCont). However, it is also apparent that regional introduction of the urgent "molecular (component) based allergy diagnostics" has become necessary for efficient allergen specific immunotherapy in Hungary. In cases of the allergen specific cell mediated immunologic reactions, allergen induced cell proliferation and cytokine release measurements are recommended. However, it is also obvious that application of these measurements in clinical practice need correct financial support from health care authorities.

The immunomodulatory role of bile acids.

Enzymatic oxidation of cholesterol generates numerous distinct bile acids which function both as detergents that facilitate the digestion and absorption of dietary lipids and as hormones that activate five distinct receptors. Activation of these receptors alters gene expression in multiple tissues, leading to changes not only in bile acid metabolism but also in glucose homeostasis, lipid and lipoprotein metabolism, energy expenditure, intestinal motility, bacterial growth, inflammation, and in the liver-gut axis. This review focuses on the present knowledge regarding the physiologic and pathologic role of bile acids and their immunomodulatory role, with particular attention to bacterial lipopolysaccharides (endotoxins) and bile acid and immunological disorders. The specific role that bile acids play in the regulation of innate immunity, various systemic inflammations, inflammatory bowel diseases, allergy, psoriasis, cholestasis, obesity, metabolic syndrome, alcoholic liver disease, and colon cancer will be reviewed.

The in vitro treatment with vitamin D3 is ineffective on the expression of PKC isoenzymes, but decreases further the impaired production of IL-2 in the T lymphocytes of SLE patients.

The objective of the study was to investigate the possibility whether the in vitro treatment with vitamin D3 can restore the impaired expression of protein kinase C (PKC) isoenzymes and IL-2 production in the lymphocytes of patients with systemic lupus erythematosus (SLE). Purified T lymphocytes from 14 patients with SLE and 13 healthy controls were cultured for 48 h in the presence and absence of 1 and 100 nM doses of vitamin D3. The expressions of various PKC isoenzymes were tested by Western blot analysis, and the amounts of various cytokines were detected by ELISA in the culture supernatants. Neither the low (1 nM) nor the high (100 nM) doses of vitamin D3 (1α,-25-dihydroxyvitamin) applied in vitro for 48 h were able to restore the decreased expression of PKC isoenzymes in the T cells of SLE patients. However, 100 nM of vitamin D3 significantly increased the release of IL-10, but suppressed the production of IL-2, IL-6, interferon γ and TNF α in the culture supernatants of both groups. As the low production of IL-2 is one of the main pathologic features of SLE, we recommend to avoid the use of high doses of vitamin D3 for treatment of lupus patients with vitamin D3 deficiency.

[Ten years' experience in the research of abdominal compartment syndrome (2004-2014)]. / Tíz év tapasztalata a hasi kompartmentszindróma kutatásában (2004-2014).

Intra-abdominal hypertension and abdominal compartment syndrome are frequent findings among severe surgical ill patients. In spite of the fast diagnostic methods and effective therapeutic procedures the mortality is high. The causing factors lead to increased intra-abdominal pressure and abdominal compartment syndrome. It can be defined as adverse physiologic consequences that occur as a result of an acute increase in the intra-abdominal pressure. The most common causes are retroperitoneal haemorrhage, pancreatitis, bowel obstruction, tense ascites, peritonitis and serious visceral edema due to massive fluid resuscitation. The affected systems are cardiovascular, respiratory, renal, central nervous systems, splanchnic organs, and finally the whole body. The diagnostic method is the intra-abdominal pressure monitoring. The bases of the treatment are adequate fluid resuscitation, non-surgical management and decompression. The authors review the topic including the international and Hungarian references based on their ten years experience.

Enalapril Is Superior to Lisinopril in Improving Endothelial Function without a Difference in Blood-Pressure-Lowering Effects in Newly Diagnosed Hypertensives.

Angiotensin-converting enzyme (ACE) inhibitors are the primarily chosen drugs to treat various cardiovascular diseases, such as hypertension. Although the most recent guidelines do not differentiate among the various ACE inhibitory drugs, there are substantial pharmacological differences. GOAL: Here, we tested if lipophilicity affects the efficacy of ACE inhibitory drugs when used as the first therapy in newly identified hypertensives in a prospective study. METHODS: We tested the differences in the cardiovascular efficacy of the hydrophilic lisinopril (8.3 ± 3.0 mg/day) and the lipophilic enalapril (5.5 ± 2.3 mg/day) (n = 59 patients). The cardiovascular parameters were determined using sonography (flow-mediated dilation (FMD) in the brachial artery, intima-media thickness of the carotid artery), 24 h ambulatory blood pressure monitoring (peripheral arterial blood pressure), and arteriography (aortic blood pressure, augmentation index, and pulse wave velocity) before and after the initiation of ACE inhibitor therapy. RESULTS: Both enalapril and lisinopril decreased blood pressure. However, lisinopril failed to improve arterial endothelial function (lack of effects on FMD) when compared to enalapril. Enalapril-mediated improved arterial endothelial function (FMD) positively correlated with its blood-pressure-lowering effect. In contrast, there was no correlation between the decrease in systolic blood pressure and FMD in the case of lisinopril treatment. CONCLUSION: The blood-pressure-lowering effects of ACE inhibitor drugs are independent of their lipophilicity. In contrast, the effects of ACE inhibition on arterial endothelial function are associated with lipophilicity: the hydrophilic lisinopril was unable to improve, while the lipophilic enalapril significantly improved endothelial function. Moreover, the effects on blood pressure and endothelial function did not correlate in lisinopril-treated patients, suggesting divergent mechanisms in the regulation of blood pressure and endothelial function upon ACE inhibitory treatment.

Standardized data on the incidence and mortality of female and male breast cancers in Hungary between 2000 and 2016. / A noi és a férfiemlorák standardizált incidencia- és mortalitásadatai Magyarországon 2000 és 2016 között.

Összefoglaló. Bevezetés: A rákbetegségek incidencia- (gyakorisági) értékei világszerte, így Magyarországon is folyamatosan növekednek. Az emlorákok elofordulása és kórlefolyása a két nemben azonban sajátosan különbözik. Célkituzés: Célul tuztük ki, hogy megvizsgáljuk és értékeljük a noi és a férfiemlorák incidencia- és mortalitási (halálozási) adatait Magyarországon 2000 és 2016 között. Módszer: A Központi Statisztikai Hivatalból és a Nemzeti Rákregiszterbol származó adatok standardizált, 100 000 fore számított feldolgozása. Eredmények: Magyarországon a vizsgált idoszakban az emlorákok gyakoriságának növekedése megközelítoleg ugyanolyan mértéku (39%) volt, mint az összes ráké (34%). Az emelkedés jelentos: a 2016-ban 8,7% részarányú noi emlorák esetében 39%, a 0,22%-os részarányú férfiráknál 60%. Ezzel szemben a halálozási adatok jelentos mértéku csökkenéseket mutatnak mind az összes daganat, mind a noi emlorák vonatkozásában, míg a férfiemlorák esetében a csökkenés nagyobb mértéku. A rosszindulatú daganatok incidenciája és a 2-es típusú diabetes mellitus (2DM) prevalenciája egyaránt magasan szignifikáns korrelációt mutatott az egy fore jutó bruttó nemzeti össztermék (GDP) értékének növekedésével. Új megfigyelés, hogy a 2DM-növekedés idoben megelozte a daganatok incidenciájának növekedését. Következtetés: A vizsgált idoszakban a noi és a férfiemlorákok magyarországi gyakorisági és halálozási adatai a nemzetköziekhez hasonló tendenciákat mutatnak. A férfiemlorákok sokkal ritkábbak, de kezelésük kevésbé hatékony. Új szempont, hogy a rosszindulatú daganatok gyakoribb megjelenésében a klinikailag kedvezotlenebb 2DM százalékos arányának (prevalenciájának) emelkedése is jelentos tényezo lehet az elhízáshoz kapcsolódva. A GDP növekedése kedvezoen hathatott a halálozások csökkenésében a kedvezobb gyógyítási és megelozési feltételek megteremtésével. Ugyanakkor ennek a növekedésnek szerepe lehet az elhízással összefüggo 2DM prevalenciájának emelkedésében is. Orv Hetil. 2022; 163(5): 181-186. INTRODUCTION: The incidence of malignant cancers is continuously growing. In breast cancers, the incidence and clinical course are greatly different in the two genders. OBJECTIVE: We aimed to investigate the incidence and mortality of breast cancers in females and males in Hungary between 2000 and 2016. METHODS: The data derived from the Hungarian Central Statistical Office and the National Cancer Registry were evaluated and standardized for 100 000 inhabitants. RESULTS: In Hungary, the elevation of breast cancer incidence (39%) showed a similar extent as that of total tumours (34%). In female breast cancers representing a much greater percent (8.7% in 2016) than that in males (0.22%), the increase was significant (39%) as in males (60 %). On the other hand, mortality was significantly lower for both of them regarding total malignant and female breast tumours, whereas the decrease was greater in the male breast cancers. The increase of GDP per capita showed highly significant correlation with the incidence of malignant tumours and prevalence of diabetes mellitus type 2 (2DM). It was a new finding that the increase in the prevalence of 2DM precedes the elevation of the incidence of cancer. CONCLUSION: In Hungary, the data of incidence and mortality of female and male breast cancers showed similar tendencies as the international ones. The breast cancers of males were rarer but their treatment was less effective. However, it was a new aspect that in the increased incidence of malignant tumours also the greater prevalence of 2DM could be an important factor related to obesity. Orv Hetil. 2022; 163(5): 181-186.

The majority of severe COVID-19 patients develop anti-cardiac autoantibodies.

Severe cases of COVID-19 are characterized by an inflammatory burst, which is accompanied by multiorgan failure. The elderly population has higher risk for severe or fatal outcome for COVID-19. Inflammatory mediators facilitate the immune system to combat viral infection by producing antibodies against viral antigens. Several studies reported that the pro-inflammatory state and tissue damage in COVID-19 also promotes autoimmunity by autoantibody generation. We hypothesized that a subset of these autoantibodies targets cardiac antigens. Here we aimed to detect anti-cardiac autoantibodies in severe COVID-19 patients during hospitalization. For this purpose, 104 COVID-19 patients were recruited, while 40 heart failure patients with dilated cardiomyopathy and 20 patients with severe aortic stenosis served as controls. Patients were tested for anti-cardiac autoantibodies, using human heart homogenate as a bait. Follow-up samples were available in 29 COVID-19 patients. Anti-cardiac autoantibodies were detected in 68% (71 out of 104) of severe COVID-19 patients. Overall, 39% of COVID-19 patients had anti-cardiac IgG autoantibodies, while 51% had anti-cardiac autoantibodies of IgM isotype. Both IgG and IgM anti-cardiac autoantibodies were observed in 22% of cases, and multiple cardiac antigens were targeted in 38% of COVID-19 patients. These anti-cardiac autoantibodies targeted a diverse set of myocardial proteins, without apparent selectivity. As controls, heart failure patients (with dilated cardiomyopathy) had similar occurrence of IgG (45%, p = 0.57) autoantibodies, while significantly lower occurrence of IgM autoantibodies (30%, p = 0.03). Patients with advanced aortic stenosis had significantly lower number of both IgG (11%, p = 0.03) and IgM (10%, p < 0.01) type anti-cardiac autoantibodies than that in COVID-19 patients. Furthermore, we detected changes in the anti-cardiac autoantibody profile in 7 COVID-19 patients during hospital treatment. Surprisingly, the presence of these anti-cardiac autoantibodies did not affect the clinical outcome and the prevalence of the autoantibodies did not differ between the elderly (over 65 years) and the patients younger than 65 years of age. Our results demonstrate that the majority of hospitalized COVID-19 patients produce novel anti-cardiac IgM autoantibodies. COVID-19 also reactivates resident IgG autoantibodies. These autoantibodies may promote autoimmune reactions, which can complicate post-COVID recuperation, contributing to post-acute sequelae of COVID-19 (long COVID).

Altered peripheral invariant natural killer T cells in atopic dermatitis.

BACKGROUND: Conflicting data exist on the number of invariant NKT (iNKT) cells in atopic dermatitis (AD); furthermore, no data have been published on their functional capacity. METHODS: The frequency and number of circulating CD3+6B11+ iNKT cells and their CD4+ and CD4- subpopulations were evaluated in peripheral blood obtained from 41 patients with AD by four-color flow cytometry. Likewise, functional properties of iNKT cells were measured by five-color intracellular cytokine staining. RESULTS: The number and percentage of total iNKT cells and their CD4/CD8 subpopulations were significantly lower than the controls. Of further importance, the CD4-CD8- (double negative, DN) iNKT subgroup showed the strongest positive correlation with total iNKT cells. In addition, the DN subgroup exhibited the most pronounced functional alteration with significantly decreased levels of intracellular IFNγ and significantly increased levels of intracellular IL-4 in AD patients compared with the controls. CONCLUSION: The significantly altered number and cytokine production of iNKT cells from AD patients suggests that these cells may play an important role in the pathogenesis of AD.

Association between serum IL-16 levels and the degree of sensitization in patients with atopic dermatitis.

BACKGROUND: Interleukin (IL)-16 has been characterized as an immunomodulatory cytokine. Besides its chemotactic properties, IL-16 amplifies inflammatory processes and possesses immunoregulatory functions. Our aim was to investigate the association between serum IL-16 levels and the degree of allergic sensitization in patients with atopic dermatitis (AD). METHODS: The serum level of IL-16 was measured by immunoenzymatic assays. Eosinophil cell count, serum total and specific IgE levels were assessed; prick tests were also carried out. Based on specific IgE levels and prick tests, AD patients were divided into sensitized and nonsensitized subgroups, and correlations among serum IL-16, total IgE levels and eosinophil cell counts were measured in the total patient group and in subgroups. RESULTS: In the total patient group, significantly higher levels of IL-16 were found in the sera of patients with AD, compared to healthy individuals and patients with psoriasis. A significant correlation was detected between serum levels of IL-16 and total IgE, total IgE and eosinophil counts, but not between IL-16 and eosinophils. When sensitized and nonsensitized subgroups were compared, IL-16 levels showed a significant difference in subgroups that were divided based on specific IgE measurements, but not in those subgroups which were divided based on prick tests. On the other hand, serum total IgE levels showed a significant difference between sensitized and nonsensitized subgroups, assessed by the specific IgE method and also by prick test. CONCLUSION: Serum IL-16 levels of AD patients correlate to some extent with sensitization. This correlation is not as strong as the correlation between total IgE levels and allergic sensitization.

Beneficial effects of theophylline infusions in surgical patients with intra-abdominal hypertension.

BACKGROUND: Intra-abdominal hypertension (IAH) can cause high mortality. Recently, we found that IAH was associated with increased serum levels of adenosine and interleukin 10. Our present "hypothesis-generated study" was based on the above mentioned results. MATERIALS AND METHODS: In this uncontrolled clinical trial, a total of 78 patients with IAH were enrolled representing a 13-20 mmHg range of intra-abdominal pressure (IAP). Patients requiring surgical abdominal decompression were excluded. Patients were treated with the following protocols: standard supportive therapy (ST, n = 38) or ST plus infusion with the adenosine receptor antagonist theophylline (T, n = 40). Over the 5-day measurement period, IAP was monitored continuously and serum adenosine concentration and other clinical and laboratory measurements were monitored daily. Mortality was followed for the first 30 days following the diagnosis of IAH. RESULTS: Mortality of ST patients was 55%, which is compatible to other studies. Serum adenosine concentration was found to be directly proportional to IAP. Of the 40 patients receiving T treatment, survival was 100%. An increased survival related to theophylline infusion correlated with improving serum concentrations of IL-10, urea, and creatinine, as well as 24-h urine output, fluid balance, mean arterial pressure, and O(2)Sat. CONCLUSIONS: Adenosine receptor antagonism with T following IAH diagnosis resulted in markedly reduced mortality in patients with moderated IAH (<20 mmHg). Theophylline-associated mortality reduction may be related to improved renal perfusion and improved MAP, presumably caused by adenosine receptor blockade. Because this study was not a randomized controlled study, these compelling observations require further multicentric clinical confirmation.

Adenosine inhibits the release of arachidonic acid in activated human peripheral mononuclear cells. A proposed model for physiologic and pathologic regulation in systemic lupus erythematosus.

In the current work, the pathways are presented and reviewed showing how adenosine acts on the production and release of arachidonic acid (AA) in activated human monocytes by the involvement of various phospholipase A2 (PLA2) and protein kinase C (PKC) enzymes in physiological (normal) conditions and in a pathologic state in systemic lupus erythematosus (SLE). Two molecules of activated monocytes mainly determine the actual amounts of AA released: (1) interleukin-1 beta (IL-1 beta) increasing and (2) adenosine (Ado) suppressing this process. The AA production of monocytes mainly depends on two (IV and VI) types of PLA2 enzymes. PKC alpha phosphorylates the cytosolic, Ca2+-dependent and steroid-sensitive PLA2 (type IV), whereas PKC delta phosphorylates the Ca2+-independent PLA2 (type VI). By the suppression of IL-1 beta production in the activated human monocytes, adenosine can decrease the release of AA causing a diminished phosphorylation of both PKC isoenzymes. In SLE monocytes, the disease-specific decreased release of AA that we found earlier could be related to the decreased expression of PKC delta. These pathways are summarized in a proposed model.

Level of the SARS-CoV-2 receptor ACE2 activity is highly elevated in old-aged patients with aortic stenosis: implications for ACE2 as a biomarker for the severity of COVID-19.

Coronavirus disease 2019 (COVID-19) has a high mortality in elderly patients with pre-existing cardiovascular diseases. The cellular receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the angiotensin-converting enzyme 2 (ACE2), thereby implicating a link between cardiovascular diseases and SARS-CoV-2 susceptibility. Aortic stenosis (AS) represents a chronic inflammatory state with severe cardiovascular complications in the elderly, a prime condition for COVID-19 mortality. The circulating ACE2 levels were measured in 111 patients with severe AS and compared to patients with hypertension and healthy individuals. About 4 times higher circulating ACE2 activity was found in patients with severe AS than in hypertensives or healthy individuals (88.3 ± 61.6., n = 111, 20.6 ± 13.4, n = 540, and 16.1 ± 7.4 mU/L, n = 46, respectively). Patients with severe AS were older than patients with hypertension (80 ± 6 years vs. 60 ± 15 years, P < 0.05). Serum ACE2 activity correlated negatively with the left ventricular ejection fraction, aortic root area, TAPSE, and positively with the right ventricular systolic pressure, cardiac diameters in patients with AS. In contrast, circulating ACE2 activity was independent of the blood pressure, peak flow velocity at the aortic root, kidney function (GFR), and inflammatory state (CRP). We found no effect of RAAS inhibitory drugs on the serum ACE2 activity in this group of patients. Our results illustrate circulating ACE2 as a potential interface between chronic inflammation, cardiovascular disease, and COVID-19 susceptibility. Elderly patients with AS have markedly elevated ACE2 levels together with altered left and right ventricular functions, which may pose higher risks during COVID-19. Our clinical data do not support a role for RAAS inhibitors in regulating circulating ACE2 levels.

T-cell Subset Profile in Kidney Recipients of Extended or Standard Donors.

INTRODUCTION: The usage of extended-criteria donors (ECD) became a routinely accepted manner in the last decade. ECD is a potential risk factor for antibody-mediated rejection. Analysis of lymphocyte subsets might be a complementary diagnostic toolkit because there is limited knowledge about this term. METHOD: Between May 12, 2016, and September 4, 2019, a total of 130 patients who had undergone kidney transplant were investigated. Patients were divided in ECD and standard criteria donor (SCD) groups. Blood samples were collected before the operation, then in the first week and after 30, 60, 180, and 365 days. Besides routine laboratory tests, multicolor flow cytometry was performed for lymphocyte subsets. RESULTS: ECD grafts were transplanted to older recipients. The number of CD4+ cells increased in the SCDs from the first week to until the end of first month, and then decreased. The number of CD4+ cells decreased from the beginning of the study until the end of first year to 66% of its original value in ECDs. At the first month, the number of CD19+ cells was higher in SCD compared with ECD cases; the number then decreased in both groups. T-regulatory cells had a drop at the first week that lasted until the first month. A bigger increase in SCD and a moderate increase in ECD group were then observed. The kinetics of CD19+ and CD19+ naive cells are similar in the ECD and SCD groups. In the SCD group, cell count decreased in both CD19+ (13%) and CD19+ naive (12%) between third and sixth month. The count of CD19+ cells decreased by 9%, but the count of CD19+ naive cells increased by 11% between the sixth month and first year. DISCUSSION: The prolonged postoperative uremic state caused by the poorer initial function, together with an aging immune system, explains the weaker immune response in ECD patients, which may be the cause of the decreased number of memory and regulatory T cells. Older patients with an ECD graft need a tailored, personalized, and less aggressive immunosuppressive treatment.

New classification of the shared epitope in rheumatoid arthritis: impact on the production of various anti-citrullinated protein antibodies.

OBJECTIVE: HLA-DR [shared epitope (SE)] alleles have recently been re-classified into S1, S2, S3P and S3D groups. S2 and S3P have been associated with increased risk for RA. We assessed the impact of S1, S2, S3P and S3D alleles on anti-citrullinated protein antibody (ACPA) production. Instead of comparing allele-carriers to non-carriers, we studied each allele group individually, using the X/X (non-SE) genotype as reference. METHODS: Serum and genomic DNA samples of 91 RA patients and 78 healthy controls were obtained. Various ACPAs and IgM RF were determined by ELISA. HLA-DRB1 genotyping and subtyping was performed by PCR. HLA-DRB1 alleles were re-classified as described above. Correlations between SE and ACPAs were determined. RESULTS: Not only S2 and S3P, but, to a lesser extent, S1 and S3D alleles also predisposed to anti-cyclic citrullinated peptide (CCP) production (P < 0.0001, P = 0.004, P = 0.01 and P = 0.027, respectively), with the following hierarchy of association: S2+S3P > S1+S3D > X/X. Similar associations were observed for anti-citrullinated vimentin. Anti-citrullinated fibrinogen (CF) exerted a different association pattern with the strongest correlation with S1 alleles [odds ratio (OR) 16.00; P = 0.05]. In addition, HLA-DRB1*15 alleles may represent a special predisposing effect for anti-CF antibody production. Finally, in this study, RF production was associated only with the HLA-DRB1*0401 SE allele (P = 0.04). CONCLUSIONS: Our approach of comparing individual S allele carriers with X/X genotype patients allowed us to perform unequivocal analyses and demonstrate new associations. Thus, novel subgroups of RA could be identified with potential relevance for prognosis and therapy.

The immunoregulatory role of vitamins A, D and E in patients with primary Sjogren's syndrome.

OBJECTIVE: The aim of the present study was to investigate the immunomodulating role of fat-soluble vitamins in 25 patients with primary SS (pSS) and 15 healthy individuals. METHODS: Plasma levels of vitamins A, D and E were determined by HPLC. Peripheral NK, NK T cells, T-cell subsets, B cells, IL-10 producing Tr1 cells, CD4(+)CD25(+) Treg cells and Th17 were determined by flow cytometry. Various Th1- and Th2-soluble cytokines were assessed by ELISA, whereas intracytoplasmic cytokines (IFN-gamma, IL-4, -10 and -17) were measured by flow cytometry. Correlation was assessed between vitamin levels and immunological and clinical parameters. RESULTS: Vitamin A levels did not differ between patients and controls, yet in patients with extraglandular manifestations (EGMs) a significant decrease in vitamin A levels was apparent compared with pSS patients without EGMs (P = 0.005). Vitamin E levels were increased in patients compared with controls (P = 0.004), whereas vitamin D levels were similar in pSS and control subjects. In patients, vitamin A showed a positive correlation with both NK cell (P = 0.038) and Th17 cell (P = 0.025), and a negative correlation with Schirmer's test values (P = 0.035). Positive correlation was found between vitamin E and NK cells (P = 0.043), Th1 cells (P = 0.049) and the Th1/Th2 ratio (P = 0.043). In the control group, we found correlation between vitamin E and serum IL-10 levels (P = 0.003). CONCLUSIONS: Our data suggest that fat-soluble vitamins may be important in immunoregulatory processes in patients with pSS.

Increased serum adenosine and interleukin 10 levels as new laboratory markers of increased intra-abdominal pressure.

BACKGROUND: Increased intra-abdominal pressure (IAP), intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are severe complications of surgical interventions with a high rate of mortality. The technique of IAP measurement is accurate, precise, reproducible and cost-effective. However, laboratory measures for monitoring of IAH have not been defined. We investigated the linkage between the serum levels of adenosine and interleukin 10 (IL-10) with IAP. METHODS: The sera of 25 surgical patients with IAP <12 mmHg and of 45 surgical patients with IAP >12 mmHg were tested. Serum adenosine concentration was measured by HPLC. Serum IL-1ß, IL-2, IL-4, IL-10, TNFα, IFNγ and IL-10 were determined by enzyme linked immunosorbent assay (ELISA). CRP was measured by nephelometry. RESULTS: Significant correlations of IAP were found only with serum levels of adenosine and IL-10. In the sera of patients with IAP >12 mmHg, the levels of both adenosine (1.61 versus 0.06 µM, p < 0.01) and IL-10 (63.23 versus 27.27 pg/ml, p < 0.01) were significantly higher than those in patients with IAP <12 mmHg. Moreover, significant correlations were found between individual patient IAP-adenosine values (r = 0.766, p < 0.001), IAP-IL-10 values (r = 0.792, p < 0.001) and adenosine-IL-10 values (r = 0.888, p < 0.001). A direct linear correlation between IAP-adenosine and IAP-10 values was only observed with IAP >15 (Grade II-IV). CONCLUSION: We report associations between IAP and the serum adenosine and IL-10 levels providing new tools for the laboratory monitoring of IAH as well as further understanding of the pathomechanisms contributing to ACS.