Immune Phenomena Research Articles

Efficacy of rituximab in an aggressive form of multicentric Castleman disease associated with immune phenomena

Multicentric Castleman disease (MCD) is an uncommon lymphoproliferative disorder for which the best therapeutic option is not yet well established. Immune-related disorders are rare complications of MCD. We report on an MCD case in a 23-year-old patient with extensive abdominal involvement and associated immune hemolytic anemia and Raynaud phenomenon. He was negative for human immunodeficiency virus (HIV) and human herpesvirus-8 (HHV-8). After 8 courses of the anti-CD20 monoclonal antibody (rituximab), the patient achieved complete remission. Interestingly, Raynaud phenomenon disappeared under treatment and no new hemolytic events occurred. Anti-CD20 antibody treatment could be an attractive therapeutic approach for MCD, mainly when immune-related disorders are associated.

Integrins in Pulmonary Inflammatory Diseases

Integrins are a family of heterodimeric transmembrane glycoproteins that mediate cell-cell and cell-matrix interactions. They participate in inflammatory reactions mainly by regulation of leukocyte migration, activation and survival. Elevated expression of the cell adhesion molecules, such as VCAM, ICAM and MAdCAM on the lumenal surface of vascular endothelial cells is a critical early event in organ inflammatory processes - including the lung. Adhesive interactions with their counter-receptors on leukocytes, selectins and integrins, result in migration of the leukocytes to the inflammed tissues. Integrins also participate in physiological and pathological reorganization of the lung structure during e.g. pneumonia healing, airway remodeling, angiogenesis, emphysema and pulmonary fibrosis. Agents that could inhibit the function of one or more of these integrins could provide a novel therapeutic strategy targeted to inhibit inflammatory and immune phenomena in the lung.

Skin Carcinoma Arising From Donor Cells in a Kidney Transplant Recipient

The incidence of skin cancer is increased in transplant recipients. UV radiation, papillomaviruses, and immunosuppression participate in the pathogenesis of these tumors. In addition, donor cells may leave the grafted organ, reach peripheral tissues and either induce immune phenomena or possibly take part in tissue remodeling. Herein, we investigated the possible involvement of donor cells in the development of skin tumors in kidney allograft recipients. We analyzed a series of 48 malignant and benign cutaneous tumors developing in 14 females who had been grafted with a male kidney. The number of male cells was measured on microdissected material by quantitative PCR for Y chromosome. In the samples with high levels of male cells, fluorescent in situ hybridization (FISH) with X and Y probes and/or immuno-FISH with anticytokeratin antibodies were carried out. Male cells were detected in 5/15 squamous cell carcinomas and Bowen disease (range 4-180 copies), 3/5 basal cell carcinomas (91-645), 6/11 actinic keratosis (7-102), 2/4 keratoacanthoma (22-41), and 2/5 benign cutaneous lesions (14-55). In a basal cell carcinoma specimen with a high number of male cells, FISH showed that most cells within the tumoral buds were XY. In this lesion, immuno-FISH showed the presence of XY cytokeratin-positive cells indicating that the tumor nests contained male keratinocytes. In contrast, in other female transplants, male cells present in the tumors were not epithelial. In conclusion, stem cells originating from a grafted kidney may migrate to the skin, differentiate, or fuse as keratinocytes that could, rarely, undergo cancer transformation.

HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (HIV-1) AND MYCOBACTERIUM LEPRAE CO-INFECTION: HIV-1 SUBTYPES AND CLINICAL, IMMUNOLOGIC, AND HISTOPATHOLOGIC PROFILES IN A BRAZILIAN COHORT

Co-infections with human immunodeficiency virus (HIV) and Mycobacterium leprae represent unique opportunities to investigate the interaction of both pathogens. We determined the immunologic, virologic, and histopathologic characteristics of 22 co-infected Brazilian patients (median age = 38 years, 81.8% males, 72.2% with paucibacillary leprosy, and 95.4% with acquired immunodeficiency syndrome). The HIV-1 subtypes B and BF predominated in envelope and gag heteroduplex mobility analysis. Borderline tuberculoid (BT), tuberculoid, lepromatous, and indeterminate morphology with CD3+, CD8+, and CD68+ cell distributions compatible with leprosy patients not infected with HIV were observed. Histologic evidence of nerve damage was observed in BT lesions. IgM antibody to M. leprae-specific phenolic glycolipid I was not detected. Two of six co-infected patients monitored during highly active antiretroviral therapy (HAART) developed a leprosy type 1 reaction after an increase in CD4+ cells, suggesting an immune restoration phenomenon. Clinical, immunologic, histopathologic, and virologic features among these HIV-leprosy co-infected patients indicate that each disease progressed as in single infection. However, HAART immune reconstitution may trigger potential adverse effects, such as leprosy acute inflammatory episodes.

Signal regulators in FcR-mediated activation of leukocytes?

Leukocyte membrane receptors for the Fc portion of Igs (FcRs) link antigen recognition by antibodies to effector functions involved in immune phenomena, from pathogen elimination to autoimmunity. Moreover, they also signal for the synthesis and secretion of cytokines and chemokines, thus having a role in immune homeostasis. Even though the structural and functional similarities between FcRs and the clonotypic antigen receptors of lymphocytes (the T-cell receptor and B-cell receptor) are well established, participation of regulatory membrane molecules in leukocyte activation by FcRs has rarely been considered. Here, we summarize evidence demonstrating that FcR-mediated signaling could be modulated by other membrane molecules (signal regulators), and propose that comprehension of this phenomenon is essential for understanding the functions of FcRs, knowledge of which could then be used for therapeutic interventions.

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Ulcerative colitis (UC) is a condition characterized by chronic inflammation targeted at the epithelial layer. In addition to being involved in immune phenomena, UC epithelial cells exhibit decreased oxidation of butyrate, downregulation of oxidative pathway regulatory genes, and overexpression of mitochondrial (mt) genes. We investigated whether these events, which translate an altered energy metabolism, are associated with an abnormal pattern of mtDNA deletions. Highly purified colonocytes were isolated from surgically resected control, involved and uninvolved inflammatory bowel disease mucosa. The frequency, type, and number of mtDNA deletions were assessed by PCR amplification, Southern blot analysis, and cloning and sequencing of amplified DNA fragments. The 4977 mtDNA deletion was less frequent in UC than control and Crohn's disease (CD) epithelium, regardless of patient age. Several other deletions were detected, but all were less common in UC than control and CD cells. The frequency, variety, and number of mtDNA deletions were invariably lower in colonocytes isolated from inflamed mucosa than in autologous cells from noninflamed mucosa. In conclusion, in the absence of inflammation, UC colonocytes exhibit an mtDNA deletion pattern similar to that of control cells, indicating a normal response to physiological levels of oxidative stress. In active inflammation, when oxidative stress increases, the frequency, variety, and number of mtDNA deletions decrease. Because comparable abnormalities are absent in active CD, the mtDNA deletion pattern of active UC suggests that colonocytes respond uniquely to inflammation-associated stress in this condition.

Painful neuropathy vasculitis in HIV infection

The clinical picture of painful neuropathy is generally related to direct HIV involvement in the peripheral nervous system (PNS) or to neurotoxic effect of drugs contained in high activity antiretroviral therapy (HAART). We describe 2 patients with long‐standing HIV infection treated with HAART. Both patients developed a subacute distal painful symmetric neuropathy not influenced by analgesics and anti‐inflammatory drugs. Sural nerve biopsy revealed focal axonal loss, degeneration of myelinated fibers and epineurial necrotizing vasculitis with T‐cell infiltration of vessel wall. In both cases steroid therapy led to improvement of symptoms. Vasculitic neuropathy with a clinical picture of painful neuropathy is most unusual, the common clinical expression of vasculitis being mononeuritis multiplex. Our cases indicate that isolated vasculitis of peripheral nerve can occur in long‐standing HIV‐1 infection and the clinical presentation with distal symmetric polyneuropathy does not rule out such a diagnosis. High activity antiretroviral therapy is unable to prevent vasculitis in peripheral nerves; similar to a previous reported case of Guillain‐Barré syndrome, an immune reconstitution phenomenon plays a role in the induction of a vasculitic autoimmune process. In conclusion, in cases of DSPN with intense and persistent symptoms, a nerve biopsy is necessary for a differential diagnosis to be made and an appropriate and effective therapy given.

Transient corticosteroid treatment permanently amplifies the Th2 response in a murine model of asthma.

Corticosteroids (CS) remain the most efficacious pharmacotherapeutic option for the management of asthma. Although the acute anti-inflammatory effects of CS treatment have been amply documented both clinically and experimentally, recent human data intimate that exposure to CS may be associated with retrograde immune phenomena, including enhanced synthesis of IgE in vivo and elevated Th2 cytokine production in vitro. We have investigated the long-term immunologic effects of CS treatment in a murine model of allergic airway inflammation. CS treatment during initial exposure to OVA or upon long-term Ag rechallenge remarkably attenuated eosinophilic airway inflammation and airway hyperresponsiveness. Interestingly, however, Th2 cytokine production by cultured splenocytes from CS-treated mice was significantly elevated, while IFN-gamma synthesis was depressed. Moreover, mice rechallenged with OVA several weeks after CS intervention during allergic sensitization not only developed airway inflammation, but also exhibited enhanced Th2 cytokine production in lymphoid tissues and OVA-specific IgE in serum. This amplification of the systemic immune response was associated with an intact APC compartment during CS-conditioned sensitization to OVA. These data indicate that immune processes underlying the allergic phenotype remain impervious to CS treatment and raise the possibility that treatment with CS during sensitization may amplify elements of the allergen-specific immune response.

Participation of maternal and fetal CRH in early phases of human implantation: the role of antalarmin.

The hypothalamic neuropeptide corticotropin-releasing hormone (CRH) is produced by several tissues of the female reproductive system. It is also secreted at inflammatory sites and possesses potent pro-inflammatory properties influencing both innate and acquired immune processes. Uterine CRH participates in local immune early pregnancy phenomena, such as decidualization of endometrial strom a and protection of the fetus from maternal immune system. This is maintained through induction of the expression of apoptotic FasL on invasive extravillous trophoblast and maternal decidual cells at the fetal-maternal interface. Furthermore, CRH increases apoptosis of activated T lymphocytes through FasL induction participating in the process of implantation and early pregnancy. Female rats treated with the non-peptidic CRH receptor 1 (CRHR1) specific antagonist antalarmin, in the first 6 days of gestation, have undergone a decrease of endometrial implantation sites and live embryos and markedly diminished endometrial FasL expression.

Significant enhancement by anti-ICOS antibody of suboptimal tacrolimus immunosuppression in rat liver transplantation.

A member of the costimulatory molecule family, inducible costimulator (ICOS), is expressed on activated T cells and plays a critical role in their primary activation and cytokine production. ICOS is involved in different immune phenomena, such as Th1-mediated autoimmune disease and graft rejection. Although blockade of ICOS costimulation theoretically may protect grafts from rejection, a single dose of anti-ICOS antibody did not result in the prolongation of rat liver allograft survival. However, in this article, we report that anti-rat ICOS antibody markedly enhanced the immunosuppressive activity of a suboptimal dose of tacrolimus (FK506). After fully allogenic DA to LEW liver transplantation, recipients received a single injection of tacrolimus (1 mg/kg, intramuscularly) with or without anti-ICOS antibody (1 mg/kg, intravenously). Recipient survival was significantly prolonged in rats treated with both the antibody and suboptimal tacrolimus (median survival time 44 days vs. 28 days with tacrolimus alone, P <.01). The extent of cell infiltration into the graft was closely associated with prolongation of recipient survival. Our findings thus demonstrate that anti-ICOS antibody immunotherapy combined with suboptimal tacrolimus has a synergistic effect in preventing hepatic allograft rejection and that it may induce long-term graft acceptance intimately associated with a marked reduction of intragraft T lymphocyte infiltration.

Nutraceuticals--a pharmaceutical viewpoint: part II.

To review pharmaceutical and pharmacological issues relating to the benefits and risks associated with the use of naturally sourced nutraceuticals when administered singly or in combinations. The application of vegetable extracts or dietary supplementation with selenium or antioxidant vitamins results in positive benefits on immunity and other phenomena associated with chronic diseases, ageing and cancer. However, there appear to be no cardiovascular benefits from vitamin mixtures, which may in fact cause harm. Therefore, although recent publications have increased our understanding of the metabolic actions of nutraceuticals, learning to use them to the best advantage is going to require products with uniform and consistent quality. Unfortunately, a single purified substance will not always have the same antioxidant activity, nor provide the same clinical benefits as nutraceutical mixtures and combinations occurring in natural extracts. In order to perform first-class clinical studies to determine safety and efficacy, the stability, compatibility and other pharmaceutical variables inherent in many of these combination products will have to be better controlled. Nutraceuticals have potent biological actions. Their use is increasing dramatically, and there is growing evidence of clinical benefits. No medicinal products are completely safe so their risks need to be characterized and controlled. Imposing pharmaceutical levels of control and regulation would increase costs and reduce patient access to new products, but the evidence is compelling that closer monitoring of raw materials, processing and formulation will be required to maximize the benefits and minimize the risks.

Influence of the mouse Bcg, Tbc-1 and xid genes on resistance and immune responses to tuberculosis infection and efficacy of bacille Calmette-Guérin (BCG) vaccination.

We have studied the role of three mouse distinct non-H-2 genes (Bcg, Tbc-1, xid) in several phenomena of antituberculosis immunity and resistance. On the basis of median survival time (MST) of mice following infection with virulent Mycobacterium tuberculosis H37Rv, Bcg gene did not control resistance to the lethal dose of H37Rv infection in non-vaccinated and Myco. bovis (BCG)-vaccinated mice. However, Bcgr allele, in comparison with Bcgs allele, determined more effective suppression of an early multiplication in spleens of H37Rv mycobacteria after a low dose (5x10(4) colony-forming units (CFU)) injection. CBA/N mice, which are not protected efficiently against tuberculous challenge by BCG vaccination, were characterized by a decreased in vitro proliferation of immune lymph node cells, both spontaneous and stimulated with mycobacterial antigens. The decreased proliferation was due to immunosuppression caused by interactions between responding T cells and CBA/N antigen-presenting cells (APC). We have confirmed that the defective response to BCG-vaccination in CBA/N mice is linked with the X-chromosome and thus is presumably determined by the xid gene itself. I/St mice (Tbc-1s), supersusceptible to H37Rv infection, were not able to restrict the growth of H37Rv mycobacteria in spleens, even following infection with a low dose (5x10(4)), but restricted the growth of Myco.bovis BCG more effectively than Bcgs mice.

Peripheral anergy and local immune hyperactivation in sarcoidosis: a paradox or birds of a feather

Sarcoidosis is a multisystem non-caseating granulomatous disorder, which is frequently self-limiting. Not only does its aetiology remain an enigma, but equally curious is its immunological background, which appears to be pathognomonic for this disease. Studies have shown aberrant cell-mediated active, if not overactive, immune responses at sites of inflammation [1] in the presence of hypergammaglobulinaemia [2] and cutaneous anergy to particular antigens, including tuberculoprotein but not Kveim antigen [3]. This apparent paradox in peripheral and local cellular immune responses, with preferential activation at the organ level, has provoked a great deal of interest over the years, and begged the question of whether the proposed depression in peripheral cellmediated immunity in sarcoidosis is in fact real or apparent. The accumulation of activated oligoclonal CD4 T lymphocytes [4] and specific subpopulations of macrophages [5,6], together with a release of various proinflammatory cytokines [7], determine the immune phenomena as well as the development and fate of granulomata at the sites of sarcoid inflammation. The recruitment of CD4 T lymphocytes around granulomata is more prominent within fresh active lesions, and tends to diminish as the granulomata mature [8]. Indeed, as lesions become less active, these cell types decrease, and T cells expressing CD8 surface antigens predominate [8]. A similar switch in immunoregulatory T cells has also been observed in animal models of granulomatous lung disease [9,10]. In patients with active sarcoidosis, the increase in activated T cell numbers at sites of granulomatous inflammation is simultaneously accompanied by an absolute decrease in the number of circulating T cells in autologous peripheral blood. One of the earliest immunological abnormalities to be observed in active sarcoidosis is a partial to complete anergy to tuberculin purified protein derivative (PPD). Such skin anergy also extends to certain antigens, e.g. Trichophyton, mumps virus, streptokinase/ streptodornase, Candida, as well as dinitrochlorobenzene. The incidence of anergy to tuberculoprotein and other antigens in sarcoid patients varies from 30% to 70%, depending on the number of antigens used [3,11,12]. This anergy appears to parallel disease severity, being especially marked when the sarcoidosis is clinically active, and disappearing months to years after resolution of the disease. Usually such cutaneous anergy is associated with depressed cellular immunity. The partial cutaneous anergy observed in sarcoidosis is frequently attributed to a reduction in the number and function of circulating T lymphocytes [13]. It has been suggested that the reduction of delayed-type skin test reactivity could reflect a depletion of the population of immunoreactive cells being sampled from the skin. It is recognized that in granulomatous disease there is an altered circulating pattern for T lymphocytes with the onset of inflammation. In particular, CD4 T cells become sequestrated in central lymphoid organs and sites of inflammation, leaving proportionately increased numbers of CD8 T cells in the peripheral blood [14]. In sarcoid patients, the ratio of CD4 to CD8 T cells in the blood may be normal or slightly decreased, with corresponding T cell ratio in the lung being 4–10 times greater than normal [15]. At the height of inflammation, the compartmentalized CD4 T cells have been shown to express IL-2R, very late activation Ag1, and DR class II MHC molecules: the hallmarks of antigenstimulated T cells [16,17]. In addition, it appears that these CD4 T lymphocytes are oligoclonal, consistent with a conventional antigen-driven process [18,19] (albeit the nature of the antigenic stimulus in sarcoidosis remains unclear). However, whilst T cells obtained from inflamed sites appear to be activated both morphologically and functionally, with augmented responses to external stimuli such as lectins and antigens, the functional response of autologous peripheral blood lymphocytes to mitogen and recall antigen is impaired, with consequent depression of B cell function in vitro. In addition, inhibitory factors, partly derived from monocytes, have been isolated from the blood of active sarcoid patients, and shown to inhibit the in vitro response of normal lymphocytes to mitogens and antigens [13,20,21]. Such findings in the peripheral blood have been related to the observed depression in certain cutaneous delayed hypersensitivity responses [13,22]. Despite this apparent cutaneous anergy, patients with sarcoidosis are uniquely capable of mounting a positive cutaneous reaction to a Kveim antigen. The mechanisms of this Kveim response are not entirely clear. Although Kveim test lesions exhibit histopathologic similarities to sarcoid granulomata, there are marked differences between the Kveim reaction and the classic DTH skin response. The most obvious difference is in the kinetics of the two reactions. DTH reaction begins at 8 h, peaks at 24–48 h, and resolves by 96–120 h. By contrast, the Kveim reaction takes 4–6 weeks to develop. Furthermore, no specific antigen in the Kveim preparation has been identified as the inducing agent in this response, and no convincing data have been generated to show reproducibly that sarcoid lymphocytes are actively sensitized to the Clin Exp Immunol 1997; 110:1–3

Autoimmune pancreatitis: pathological, clinical, and immunological features.

In recent years a type of chronic pancreatitis has been described that is clearly distinct from alcoholic chronic pancreatitis. It is characterized by its special pathology, immunologic features, clinical presentation, and steroid responsiveness. Because of its histologic hallmarks, i.e., ductal and periductal infiltration by lymphocytes, plasma cells, and granulocytes, it has been called duct-destructive chronic pancreatitis. The frequent association of this type of pancreatitis with other autoimmune diseases such as Sjögren's disease and a number of other immune phenomena has led to the concept that it is an autoimmune disease. Hence, the term autoimmune pancreatitis has been introduced and will be used in this review. This review focuses on the pathology and related clinical and immunologic features of this new type of pancreatitis. As the ability to diagnose autoimmune pancreatitis on the basis of clinical, imaging, and laboratory findings improves, it seems likely that fewer patients with this diagnosis will undergo resection. Thus, there is a need to accumulate and study additional retrospective series of patients undergoing resection because of mass-forming chronic pancreatitis.

Physiologic studies on nitric oxide in rat small bowel isografts.

The enteric nervous system (ENS), especially the nonadrenergic noncholinergic (NANC) inhibitory nerves, is an important factor in intestinal peristalsis. Recently, it was established that nitric oxide (NO) is released after stimulation of NANC inhibitory nerves. Inhibitory nerves such as NANC inhibitory nerves in the ENS are more easily damaged than excitatory nerves by reperfusion or ischemic injuries during small bowel transplantation (SBT). To evaluate the effects of reperfusion and ischemic injuries to the ENS in the transplanted small bowel, we examined the ENS responses, including the effects of NO in the isografted rat jejunum, using the nontransplanted jejunum as a control. To avoid potentially confounding immune phenomena, we used syngeneic Lewis (LEW) rats. Orthotopic entire SBT with portocaval drainage was performed from LEW rats to LEW rats. Isografted muscle strips were obtained from 8 LEW rats 130 days after SBT (n = 24). As controls, normal muscle strips of the jejunum were obtained from 20 nontransplanted LEW rats (n = 60). A mechanograph was used to evaluate in vitro jejunal responses to electrical field stimulation of the adrenergic and cholinergic nerves before and after treatment with various autonomic nerve blockers, N(G)-nitro-Ll-arginine ( L-NNA), and L-arginine. The results indicated that excitatory nerves, especially NANC excitatory nerves, were more dominant in the isografted jejunum than in the normal jejunum (p < 0.01). NANC inhibitory nerves were found to act on the normal jejunum and to a lesser extent on the isografted jejunum (p < 0.05). NO mediates the relaxation reaction of NANC inhibitory nerves in the normal jejunum and to a lesser extent in the isografted jejunum. These results indicated that the intrinsic intestinal innervation contains excitatory and inhibitory nerves and that the former, especially NANC excitatory nerves, are more dominant in the isografted jejunum than in the normal jejunum. In addition, reduction of the action of NANC inhibitory nerves such as that by NO may be largely related to impaired motility in the isografted jejunum. Thus over a long period of time (more than 130 days after SBT) transplanted small bowel dysmotility may be influenced by reperfusion or ischemic injury to the ENS (especially NANC inhibitory nerves) via NO in the transplanted jejunum after syngeneic SBT.

Corticotropin-releasing hormone (CRH) and immunotolerance of the fetus

The hypothalamic neuropeptide corticotropin-releasing hormone (CRH) is produced by several tissues of the female reproductive system, including the endometrial glands and decidualized stroma, as well as the trophoblast, syncytiotrophoblast, and placental decidua. CRH is also secreted at inflammatory sites and possesses potent pro-inflammatory properties influencing both innate and acquired immune processes. Recent experimental findings show that uterine CRH participates in local immune phenomena associated with early pregnancy, such as differentiation of endometrial stroma to decidua and protection of the fetus from the maternal immune system. CRH induces the expression of apoptotic Fas ligand (FasL) on invasive extravillous trophoblast and maternal decidual cells at the fetal–maternal interface. Furthermore, CRH increases the apoptosis of activated T lymphocytes through FasL induction, participating in the processes of both implantation and early pregnancy tolerance.

Autoantibodies characteristic for autoimmune hepatitis found in chronic hepatitis C

In the patients with chronic hepatitis C (HHC) there have been found different autoantibodies, some typical for autoimmune hepatitis (AIH) type 1, like: antinuclear antibodies (ANA) in 15-60%, anti-smooth muscle antibodies (ASMA) in 34-60%, or AIH type 2: anti liver/kidney microsomes 1 autoantibodies (LKM 1) in 0-6%. Also, antimitochondrial autoantibodies (AMA), which defines PBC, is discovered in 0.7-1.5% patients with HHC. The purpose of the research was to determine the titr of the serum autoantibodies, which characterise AIH in the patients with HHC and to compare demographical, clinical, biochemical, histological and immunological parameters in the groups of patients: with or without autoantibodies. In 50 patients with HHC are defined clinical (demographical, troubles) facts, laboratorical (the values of complete bilirubin, ALT), histological diagnosis of the liver tissue (PH), and virusological diagnosis (antibodies and antigens of the hepatitis C virus), immunological (autoantibodies, immunoglobulins). The analysis of the results show us that ANA and AMA haven't been present in the patients with HHC in considerable titr (> 1:80), while in 10% of the patients there have been titr of ASMA. In 2 patients were both titrs, ANA (1:40) and ASMA (1:40), as well, which considered important, so there is entirely 7 patients (14%) with detected ANA and ASMA in considerable titr. Autoantibodies, which are characteristic for AIH 2, have not been found in the patients with HHC. Considered the sex, between the group of patients with HHC and autoantibodies, and the group of patients with HHC without autoantibodies, there is no important difference, although the percent of male is a little bit bigger in the second group. Considering the growth, there were no important difference between the patients groups. The fact that appearance of autoantibodies has no correlation with the growth, we can explain with the fact that she most of patients with HHC are persons from 21 to 30 years old, and that the older are no so present. The troubles are present in about the half patients with HHC, and it isn't proved that the appearance of autoantibodies have the influence on this particular clinical parameter. The comparison of activities of the disease, the analysis of the ALT values and the bilirubin, we also didn't get considerable difference between these two groups of patients. Three patients who haven't autoantibodies, but they have the ALT values expended between 5 and 10 times, which we consider the high grade of the necrosis. This high values we can't notice in the patients with autoantibodies. The parameters of grade inflammatory reactions of the extent values of Ig, so as IgG category, also doesn't show we the important difference between the groups. The most patients have normal values both: Ig and IgG. Despite that in both categories of the patients, there is no considerable difference in PH, as well as, in the stage of fibrosis, two patients without autoantibodies have more visible degree of necrosis, manifested like reasonable necrosis, while all the others patients have gently visible necrosis. It is important to say that the patients with autoantibodies have no histological indications for AIH, in the PH sense, and the presence of more important plasmatic infiltrate. All the patients with HHC and autoantibodies have higher values CIC, but the frequency of appearance is not different between the both groups, which show us the variety of becaming autoimmune and immune phenomena in HHC. Based on produced results, we can conclude that: 1. autoantibodies which are characteristic for AIH 1 are visible in 14% of the HHC patients, 2. there are more ASMA in HHC, then ANA; 3. there is no autoantibodies, which caracterize AIH 2, in HHC; 4. the growth and the sex of the patients with HHC have no influence on showing autoantibodies characteristic for AIH; 5. the presence of autoantibodies, characteristic for AIH 1, have no importance of showing the burdens in the patients, degree of PH and the stadium of the diseases, and also on the value of Ig and IgG; 6. discovering the autoantibodies in HHC, no matter there Is no considerable presence on it's symptomatology and the prognosis, oblige us on further following and analysis for starting antivirus therapy, In order to present eventual beginning of AIH.

Current Concepts of the Irritable Bowel Syndrome

The irritable bowel syndrome is one of the most common clinical problems encountered by the generalist and gastroenterologist. The goal of this review is to critically evaluate, based on available peer-reviewed literature, the current status of our understanding of the pathophysiology of the irritable bowel syndrome. The epidemiology of this disorder, including the characteristics of its presentation, natural history and associated phenomena, have been clarified. Differences between those who seek specialist care (`the consulters') and those in the community are now recognized. While, in both, symptoms may be similar in nature and severity; `the consulters' are differentiated by how they react to their complaints. In terms of pathophysiology, the focus has moved to visceral sensation and central perception and has led to the identification of visceral hypersensitivity, visceral hyperalgesia and abnormal central perception of visceral events. This is not to dismiss dysmotility; subtle abnormalities in gas transit may be closely associated with the induction of certain symptoms. On the psychological front, attention now focuses on such complex issues as somatosization, abuse and response to major life events. Interactions between enteric flora, mucosal inflammation, immune phenomena and the enteric neuro-muscular apparatus also attract interest; the entity of post-infectious irritable bowel is now clearly recognized and there is experimental evidence to suggest a role for inflammation. While the precise aetiology of irritable bowel syndrome remains uncertain, considerable progress has been made, with recent advances in pathophysiology offering hope for the development of new therapeutic approaches.

Tryptophan degradation during and after gestation.

In mice, activation of indoleamine-(2,3)-dioxygenase (IDO), an enzyme converting tryptophan to N-formyl-kynurenine, is required to achieve immunotolerance against the fetus and thus uncomplicated pregnancy. On the other hand, postpartum blues and depression appear to be related to reduced availability of tryptophan and serotonin. In healthy pregnant women with singleton pregnancies we consecutively analyzed kynurenine and tryptophan concentrations during pregnancy and postpartum. The kynurenine to tryptophan ratio (kyn/trp) was calculated as an estimate of IDO activity, and data were compared to concentrations of neopterin and 55kD soluble tumor necrosis factor receptor, two indicators of immune activation, and to alanineaminotransferase (ALT) levels. Increasing kynurenine and decreasing tryptophan concentrations were found during pregnancy. The data confirm earlier results and suggest significant degradation of tryptophan. In parallel, increasing concentrations of immune activation markers neopterin and sTNF-R55 were found, correlating significantly to the kyn/trp. The data point to an involvement of cytokine-induced IDO activation in the degradation of tryptophan observed during pregnancy. After pregnancy, sTNF-R55 and also neopterin concentrations declined, whereas tryptophan concentrations increased, indicating that immune activation and activation-induced tryptophan degradation has ceased. By contrast, still increased kynurenine concentrations and also increased kyn/trp suggest continuing turnover of tryptophan. Because also ALT was increased postpartum, abnormal activity of hepatic tryptophan pyrrolase and possibly other enzymes could be involved. We conclude that the decrease of tryptophan during pregnancy might be related to immune activation phenomena. Sustained increase of kynurenine postpartum seems independent from immune activation process, rather it seems related to abnormal activity of liver enzymes.

Longitudinal study of tryptophan degradation during and after pregnancy

In mice, activation of indoleamine-2,3-dioxygenase (IDO), an enzyme converting tryptophan to N-formyl-kynurenine, was found to be necessary requirement to achieve immunotolerance against the fetus and thus uncomplicated pregnancy. In plasma from 20 healthy pregnant women with singleton pregnancies we consecutively analyzed kynurenine and tryptophan concentrations during pregnancy (1 specimen at each trimester of gestation) and postpartum (week 6). None of the women had any signs of infection at the time of plasma sampling, but the study population was otherwise unselected. The kynurenine to tryptophan ratio (kyn/trp) was calculated as an estimate of IDO activity, and data were compared to concentrations of neopterin and 55kD soluble tumor necrosis factor receptor (sTNF-R55), two indicators of immune activation, and to alanineaminotransferase (ALT) levels. Increasing kynurenine and decreasing tryptophan concentrations were found during pregnancy, data suggesting significant degradation of tryptophan. In parallel, increasing concentrations of immune activation markers neopterin and sTNF-R55 were observed, correlating significantly to kyn/trp. The data point to an involvement of cytokine-induced IDO activation in the degradation of tryptophan observed during pregnancy. After pregnancy, sTNF-R55 and also neopterin concentrations declined, whereas tryptophan concentrations increased, indicating that immune activation and activation-induced tryptophan degradation returned to baseline. By contrast, still increased kynurenine concentrations and also increased kyn/trp point to continuing catabolism of tryptophan. Postpartum elevation of liver enzyme ALT may suggest that increased activity of hepatic tryptophan pyrrolase could be involved in increased conversion of tryptophan despite low degree of immune activation. We conclude that IDO is activated in pregnancy and that the decrease of tryptophan might be related to immune activation phenomena. Sustained increase of kynurenine postpartum seems independent from immune activation process.