Immunological Influences Research Articles

Mycotoxin mechanisms of action and health impact: ‘in vitro’ or ‘in vivo’ tests, that is the question

The aim of this paper is to present examples ofin vitro andin vivo tests for mycotoxin mechanisms of action and evaluation of health effects, with a focus on the gut environment and toxicity testing.In vivo investigations may provide information on the net effects of mycotoxins in whole animals, whereasin vitro models represent effective tools to perform simplified experiments under uniform and well-controlled conditions and a suitable alternative toin vivo animal testing providing insights not achievable with animal studies. The main limits ofin vitro models are the lack of interactions with other cells and extracellular factors, lack of hormonal or immunological influences, and lack or different levels ofin vitro expression of genes involved in the overall response to mycotoxins. The translation ofin vitro data into meaningfulin vivo effects remains an unsolved problem. The main issues to be considered are the mycotoxin concentration range in accordance with levels encountered in realistic situations, the identification of reliable biomarkers of mycotoxin toxicity, the measurement of the chronic toxicity, the evaluation of single- or multi-toxin challenge. The gastrointestinal wall is the first barrier preventing the entry of undesirable substances. The intestinal epithelium can be exposed to high concentrations of mycotoxins upon ingestion of contaminated food and the amount of mycotoxin consumed via food does not always reflect the amount available to exert toxic actions in a target organ.In vitro digestion models in combination with intestinal epithelial cells are powerful tools to screen and predict thein vivo bioavailability and digestibility of mycotoxins in contaminated food and correctly estimate health effects. In conclusion,in vitro andin vivo tests are complementary approaches for providing a more accurate picture of the health impact of mycotoxins and improved understanding and evaluation of relevant dietary exposure and risk scenarios.

The Canadian Healthy Infant Longitudinal Development (CHILD) Study: examining developmental origins of allergy and asthma

The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study recruited 3624 pregnant women, most partners and 3542 eligible offspring. We hypothesise that early life physical and psychosocial environments, immunological,...

Vitamin D and Pain: Vitamin D and Its Role in the Aetiology and Maintenance of Chronic Pain States and Associated Comorbidities.

The emergence of new data suggests that the benefits of Vitamin D extend beyond healthy bones. This paper looks at Vitamin D and its role in the aetiology and maintenance of chronic pain states and associated comorbidities. The interfaces between pain and Vitamin D and the mechanisms of action of Vitamin D on pain processes are explored. Finally the association between Vitamin D and pain comorbidities such as sleep and depression is investigated. The paper shows that Vitamin D exerts anatomic, hormonal, neurological, and immunological influences on pain manifestation, thereby playing a role in the aetiology and maintenance of chronic pain states and associated comorbidities. More research is necessary to determine whether Vitamin D is useful in the treatment of various pain conditions and whether or not the effect is limited to patients who are deficient in Vitamin D.

Population dynamics of islet-infiltrating cells in autoimmune diabetes

Type-1 diabetes in the nonobese diabetic (NOD) mouse starts with an insulitis stage, wherein a mixed population of leukocytes invades the pancreas, followed by overt diabetes once enough insulin-producing β-cells are destroyed by invading immunocytes. Little is known of the dynamics of lymphocyte movement into the pancreas during disease progression. We used the Kaede transgenic mouse, whose photoconvertible fluorescent reporter permits noninvasive labeling and subsequent tracking of immunocytes, to investigate pancreatic infiltrate dynamics and the requirement for antigen specificity during progression of autoimmune diabetes in the unmanipulated NOD mouse. Our results indicate that the insulitic lesion is very open with constant cell influx and active turnover, predominantly of B and T lymphocytes, but also CD11b(+)c(+) myeloid cells. Both naïve- and memory-phenotype lymphocytes trafficked to the insulitis, but Foxp3(+) regulatory T cells circulated less than their conventional CD4(+) counterparts. Receptor specificity for pancreatic antigens seemed irrelevant for this homing, because similar kinetics were observed in polyclonal and antigen-specific transgenic contexts. This "open" configuration was also observed after reversal of overt diabetes by anti-CD3 treatment. These results portray insulitis as a dynamic lesion at all stages of disease, continuously fed by a mixed influx of immunocytes, and thus susceptible to evolve over time in response to immunologic or environmental influences.

Scar-free wound healing and regeneration in amphibians: Immunological influences on regenerative success

Salamanders and frogs are distinct orders of Amphibians with very different immune systems during adult life, exhibiting varying potential for scar free repair and regeneration. While salamanders can regenerate a range of body parts throughout all stages of life, regeneration is restricted to early stages of frog development. Comparison of these two closely related amphibian orders provides insights into the immunological influences on wound repair, and the different strategies that have evolved either to limit infection or to facilitate efficient regeneration. After injury, cells of the immune system are responsible for the removal of damaged cells and providing a cohort of important growth factors and signaling molecules. Immune cells not only regulate new vessel growth important for supplying essential nutrients to damaged tissue but, modulate the extracellular matrix environment by regulating fibroblasts and the scarring response. The profile of immune cell infiltration and their interaction with local tissue immune cells directly influences many aspects of the wound healing outcomes and can facilitate or prevent regeneration. Evidence is emerging that the transition from wound healing to regeneration is reliant on immune cell engagement and that the success of regeneration in amphibians may depend on complex interactions between stem cell progenitors and immune cell subsets. The potential immunological barriers to mammalian regeneration are discussed with implications for the successful delivery of stem cell therapeutic strategies in patients.

Phenotypic Characterisation of Inflammatory Bowel Disease in South Asians in the United Kingdom: Insights into a Shifting Landscape

Purpose: The aetiology of inflammatory bowel disease (IBD) remains elusive; a complex interplay of genetic, environmental and immunological influences. The increasing incidence of IBD in developing countries and immigrant populations appears to outpace what genetic influences alone could instigate and may provide valuable insights into aetiology. There is a relative dearth of literature on the phenotypic characteristics of South Asian immigrant populations. The aim of our study was to define the clinical phenotype of IBD in South Asians living in North-West England. Methods: We conducted a retrospective study of 102 patients of South Asian origin attending IBD clinics at our hospital. Clinical data including demographics, disease characteristics (Montreal classification), treatment and blood results were obtained using electronic case records. Results: Of 102 patients reviewed, 54 were male. The median age was 38 years (range 16-80) and mean disease duration was 9.4 years. Seventy-three patients had ulcerative colitis (UC) and 29 had Crohn's disease (CD). Five patients were current or ex smokers (4.9%). Seventeen patients had extra-intestinal manifestations of IBD (16.7%). Of UC patients 35 had pancolitis, 33 left sided disease and 5 had proctitis. Of patients with CD, 3 had ileal disease, 10 colonic disease and 16 had ileocolonic disease. Five CD patients had stricturing disease, 10 had penetrating disease (6 also stricturing) and 14 had non-penetrating, non-stricturing disease. Perianal disease was noted in 3 at diagnosis and 5 subsequently developed it. Eighty patients received steroids, topical steroids (29), 5-ASA (96), topical 5-ASA (30), azathioprine (55), 6-mercaptopurine (4), cyclosporine (2), methotrexate (9), infliximab (20) and adalimumab (9). Fifty-seven patients received at least one immunomodulatory therapy with the median time to use being 12 months (range 0-276 mo). Thirteen patients (7 CD, 3 UC) required surgery (3 total colectomy, 10 subtotal). Mean time to surgery was 4 years (range 0-13 years). Seventeen patients had disease progression leading to Montreal reclassification (median time 60 months; range 1-216 mo). Conclusion: We noted a higher prevalence of UC with a predominance of pancolonic disease and a significant proportion of CD with penetrating or stricturing disease. The majority of patients required immunomodulatory therapy with the median time to use being only 12 months, suggesting a relatively more aggressive disease course. Epidemiologic insights from such populations may provide further clues in defining an aetiological paradigm for IBD and should form an important area of further research. A case control study exploring differences is underway at our institution.

Schizophrenia and the immune system: Pathophysiology, prevention, and treatment

Published evidence on established and theoretical connections between immune system dysfunction and schizophrenia is reviewed, with a discussion of developments in the search for immunologically-targeted treatments. A growing body of evidence indicates that immunologic influences may play an important role in the etiology and course of schizophrenia. A literature search identified more than 100 articles pertaining to suspected immunologic influences on schizophrenia published over the past 15 years. Schizophrenia researchers have explored a wide range of potential immune system-related causal or contributory factors, including neurobiological and neuroanatomical disorders, genetic abnormalities, and environmental influences such as maternal perinatal infection. Efforts to establish an immunologic basis for schizophrenia and identify reliable immune markers continue to be hindered by sampling challenges and methodological problems. In aggregate, the available evidence indicates that at least some cases of schizophrenia have an immunologic component, suggesting that immune-focused prevention strategies (e.g., counseling of pregnant women to avoid immune stressors) and close monitoring of at-risk children are appropriate. While antipsychotics remain the standard treatments for schizophrenia, a variety of drugs with immunologic effects have been investigated as adjunctive therapies, with variable and sometimes conflicting results; these include the cyclooxygenase-2 inhibitor celecoxib, immune-modulating agents (e.g., azathioprine and various anticytokine agents such as atlizumab, anakinra, and tumor necrosis factor-α blockers), and an investigational anti-interferon-γ agent. The published evidence indicates that immune system dysfunction related to genetic, environmental, and neurobiological influences may play a role in the etiology of schizophrenia in a subset of patients.

Gender Disparities in Patients With Melanoma: Breaking the Glass Ceiling

The past decade has seen increased attention to gender and racial disparities in outcome for a wide variety of malignancies, and melanoma is no exception. Although cutaneous melanoma is predominantly a disease of whites, when it does occur in darker-skinned peoples, outcomes are clearly inferior stage for stage. There are also gender disparities in melanoma incidence and outcome. In the United States in 2011, there were an estimated 70,230 cases of invasive cutaneous melanoma, of which 43% (30,220 cases) occurred in women. However, of the 8,790 melanoma-related deaths, only 35% (3,040 deaths) occurred in women. In Journal of Clinical Oncology, Joosse et al add prospective clinical trial data to the large amount of retrospective information suggesting women with melanoma fare better, stage for stage, than men. In a pooled analysis of 2,672 patients with clinically localized (stage I/II) melanoma enrolled onto four European Organisation for Research and Treatment of Cancer prospective trials, women had observed advantages in overall survival, melanomaspecific survival, and time to lymph node and distant metastases. These advantages were consistently in the 30% range, even when adjusted for other prognostic factors, and were consistent across various subgroups and in younger (presumably premenopausal) and older (postmenopausal) age groups. As is so often the case in melanoma, these observations generate at least as many questions as they answer. A few of the most cogent questions are addressed herein. 1. Is this gender-based disparity real or artifactual? As previously alluded to, a great deal of prior retrospective single-institution and pooled data support improved outcomes for women with melanoma. Population-based data from most countries demonstrate similar trends, such as a recent study from Germany, which showed that women with melanoma were 38% more likely to survive than men and 32% less likely to have melanoma progression (with reduced risk for both nodal and visceral metastases). These results closely mirror those of Joosse et al and seem to strongly support that the gender-based disparity is real rather than artifactual. 2. If real, what is the cause of the disparity? Is the benefit confined to only a subset of women? Available data have addressed the potential cause(s) of a gender-based outcome disparity in melanoma by evaluating estrogen and estrogen-related factors—the contribution of which has been suspected for many years. Whereas previously the only known estrogen receptor (ER) was ER, now ERexpression has been shown to be significantly associated with mortality in melanoma. Furthermore, methylation of ERseems to be associated strongly with progression in melanoma. Additionally,otherdifferencesinhost-tumorinteractions, including potentialprotectivefactorsinwomenormelanoma-stimulatingfactorsin men, have been hypothesized. If the difference was purely based on hormonal influences, the age of onset should affect outcomes in women, in contrast to the findings of Joosse et al. Etiologic and site-specific differences could play a role, given different patterns of occupational and recreational ultraviolet light exposure between men and women. But perhaps most importantly, men consistently demonstrate lower awareness, resistance to screening, and less knowledgeseeking behavior when it comes to skin malignancies. Possibly as a direct consequence of these behavioral traits, men—especially older men—present with thicker tumors and an attendant increased mortality risk. Available data are limited and somewhat conflicting on whether there are subsets of women who fare better or worse. Pregnancy status at diagnosis or afterward was inversely associated with melanoma survival in Sweden. Inverse associations with parity were observed for melanoma and nonmelanoma skin cancer outcomes in a prospective Norwegian case-control study and for choroidal melanoma outcome in a single-institution study in Massachusetts. The possible influence of parity bears further scrutiny, because it could implicate either hormonal or immunologic influences on melanoma outcomes. 3. What if any therapeutic implications are there for this observation? Should men be treated differently than women (eg, more aggressively)? Should we revisit hormone receptor analysis and/or hormonal therapies such as tamoxifen? At present, the lack of definitive data implicating hormonal or other specific factors in melanoma outcome disparities makes any consideration of different therapeutic interventions for men and women with cutaneous melanoma premature. At one point, tamoxifen was frequently used along with systemic cytotoxic chemotherapy for stage IV melanoma, but prospective clinical trials have not supported its use. An intriguing area that should be further explored is whether the indications for sentinel lymph node biopsy should be different for men and women, given the observed greater propensity for lymphatic metastases in men. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 18 JUNE 2

Graft-Versus-Host Disease (GVHD) Induced Graft-Versus-Leukemia (GVL) Effect: More Impact on Later Relapse and Disease-Free Survival Following Reduced Intensity Conditioning

Abstract 1014GVHD can induce non-relapse transplant-related mortality (TRM) and can augment the GVL effect after hematopoietic cell transplantation (HCT). The net impact on survival represents a balance of these parallel immunologic influences. We examined the effect of acute and/or chronic GVHD on risks of late (beyond 1 year) relapse, TRM and disease-free survival (DFS) after allogeneic HCT for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS); and probed any differential influences using either myeloablative (MA) or reduced intensity conditioning (RIC). Landmark analysis was performed at 1-year as all acute GVHD and over 95% of chronic GVHD had occurred within 1 year after HCT. Eligible patients had to be disease-free and alive at 1-year. Between 1997–2006, 5741 patients with AML/MDS received HCT; of these, 2369 patients survive disease-free at 1-year. Approximately 70% had AML and 30% MDS. Disease status at HCT for the study cohort (alive disease-free at 1-year), were 40% in first complete remission (CR), 17% in 2nd or later CR and 43% in relapse. MA conditioning recipients (70% of the cohort) had a median age of 42 years; RIC (30% of the cohort) median 56 years. For analysis we compared: 1) patients without acute or chronic GVHD [baseline control group; No], 2) acute GVHD only [Ac], 3) chronic GVHD only [Chr] and 4) both acute and chronic GVHD [Ac/Chr]. Following MA conditioning late relapse risks were not significantly different in the 4 groups: No GVHD (RR 1.0), Ac GVHD only (RR 0.96, p=0.87), Chr GVHD only (RR 1.01, p=0.94) and Ac/Chr GVHD (RR 0.96, p=0.81) (Figure 1). In contrast, TRM risks were higher with any GVHD; Ac GVHD only (RR 2.31, p=0.004), Chr GVHD only (RR 3.43, p<0.0001) and Ac/Chr GVHD (RR 4.50, p<0.0001). Consequently, after MA HCT, treatment failure (TRM or relapse) was similar with Ac GVHD only (RR 1.32, p=0.13) compared to those with No GVHD, but was significantly higher with either Chr GVHD only (RR 1.62, p=0.0002) or Ac/Chr GVHD (RR 1.85, p<0.0001). Following RIC regimens, relapse risks were similar with no GVHD (RR 1.0), Ac GVHD only (RR 0.70, p=0.37) and Chr GVHD only (RR 0.72, p=0.22), but relapse was significantly lower in patients Ac/Chr GVHD (RR 0.49, p=0.02) (Figure 2). TRM was similar with No GVHD, Ac GVHD only (RR 1.25, p=0.63) and Chr GVHD only (RR 1.36, p=0.36), but TRM was higher in patients with Ac/Chr GVHD (RR 2.69, p=0.002). Consequently, treatment failure was similar in all groups: No GVHD (RR 1.0), Ac GVHD only (RR 0.88, p=0.67), Chr GVHD only (RR 0.93, p=0.73) and Ac/Chr GVHD (RR 1.22, p=0.32) (Figure 3). These data suggest that when using MA conditioning either Ac and/or Chr GVHD has an adverse effect on TRM without compensatory augmentation of GVHD-associated GVL, thus leading to worse DFS. MA HCT must use better strategies to prevent any GVHD. However, using RIC regimens, Ac plus Chr GVHD limits risks of relapse, but without adverse effect on survival and disease-free survival. Therefore, following RIC HCT, GVHD-associated GVL may be more important in limiting late leukemia recurrence. Overly suppressive approaches to eliminate any GVHD might increase relapse risks after RIC HCT for AML and MDS. [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Molecular mechanisms underlying neurovascular protection in stroke

Molecular mechanisms underlying neurovascular protection in stroke

Identification of Cells with Colony-Forming Activity, Self-Renewal Capacity, and Multipotency in Ovarian Endometriosis

Endometriosis, the growth of endometrial tissue outside the uterine cavity, is a common gynecological disorder affecting 10% to 15% of women in their reproductive years. Retrograde menstrual shedding containing endometrial stem/progenitor cells has been postulated to be involved in its pathogenesis. In this study, we identified putative endometriotic stem/progenitor cells by their colony-forming potential, self-renewal capacity, and multipotency. Purified epithelial and stromal cells isolated from ovarian endometriotic cysts formed large and small colony-forming units (CFUs) in clonogenic assay. The colony-forming activity of epithelial and stromal cells was found to differ greatly between autologous endometrium and ovarian endometrioma samples. The large CFUs could propagate more than the small CFUs. The endometriotic epithelial small CFUs expressed epithelial markers (epithelial cell adhesion molecule, cytokeratin, and α6 integrin); only occasional large CFUs expressed α6 integrin. Aside from the expression of fibroblast markers, stromal CFUs also expressed three somatic stem cell markers: sal-like 4, CD133, and Musashi-1. Endometriotic stromal cells derived from large CFUs could differentiate into four mesenchymal lineages when cultured in the respective inducing-media, as determined by histochemical staining and RT-PCR of lineage specific markers. These findings demonstrate that ovarian endometrioma contains a subset of cells displaying somatic stem cell properties.

Immunological Influences and Trophoblastic Proliferation

The unique biological behaviour of the mammalian placenta has wide implications in transplantation, and tumour, immunology. Immunological influences in trophoblastic proliferation have been sought, in experimental animals, by the investigation of normal and ectopic trophoblast development, and, in man, by studies of normal placental development, and of the clinical and epidemiological behaviour of trophoblastic tumours.

Age‐dependent histoarchitectural changes in human lymph nodes: an underestimated process with clinical relevance?

Experimental evidence indicates that lymph nodes in humans undergo alterations during ageing. This is clinically important because of the crucial role of these organs in the immune system and their lymph reabsorption and drainage function. Although some age-related changes in lymph node histoarchitecture have been described, they are seldom taken into account in traditional depictions of lymph nodes. Recently introduced clinical procedures, such as intranodal vaccination or lymph node transplantation, have demonstrated the need for an accurate knowledge of these degenerative processes. In this study, superficial inguinal lymph nodes were obtained from 41 deceased patients between 17 and 98 years old. To minimize immunological influences, such as chronic diseases, specimens were only obtained from forensic pathology autopsies. An immunohistochemical analysis was carried out, on the basis of which lymph node degeneration was scored according to the numbers of lymphocytes and high endothelial venules, and degree of fibrosis and lipomatosis. We observed an age-dependent tendency towards the replacement of areas populated with diverse immune cells by connective tissue. Paradoxically, these changes were also detected in some of the nodes from younger age groups. In conclusion, lymph nodes can display degenerative changes that are mainly age-related and often diverge from the common description found in textbooks. These alterations should be taken into account when dealing with lymph nodes diagnostically and therapeutically in clinical practice.

The Impact of Nanomaterials in Immune System

As a nanotechnology has been actively applied to the overall areas of scientific fields, it is necessary to understand the characteristic features, physical behaviors and the potential effects of exposure to nanomaterials and their toxicity. In this article we review the immunological influences induced by several nanomaterials and emphasize establishment of the animal models to estimate the impact of these nanomaterials on development of immunological diseases.

Tumor cell dormancy: implications for the biology and treatment of breast cancer

Despite progress made in the therapy of solid tumors such as breast cancer, the prognosis of patients even with small primary tumors is still limited by metastatic relapse often long after removal of the primary tumor. Therefore, it has been hypothesized that primary tumors shed tumor cells already at an early stage into the blood circulation. A subset of these disseminated tumor cells may persist in a state of so-called "dormancy". Based on cell culture and animal models, dormancy can occur at two different stages. Single dormant cells are defined as cells with a lack of proliferation and apoptosis with the cells undergoing cell cycle arrest. The micrometastasis model defines tumor cell dormancy as a state of balanced apoptosis and proliferation of micrometastasis resulting in no net increase of tumor mass. Mechanisms leading to a growth activation of dormant tumor cells and the outgrowth of manifest metastases are not completely understood. Genetic predisposition of the dormant cells as well as immunological and angiogenetic influences of the surrounding environment may contribute to this phenomenon. In this review, we summarize findings on different factors for tumor cell dormancy and potential therapeutic implications that should help to reduce metastatic relapse in cancer patients.

Neuroendocrine-Immune Mechanisms of Behavioral Comorbidities in Patients With Cancer

Patients with cancer experience a host of behavioral alterations that include depression, fatigue, sleep disturbances, and cognitive dysfunction. These behavioral comorbidities are apparent throughout the process of diagnosis and treatment for cancer and can persist well into the survivorship period. There is a rich literature describing potential consequences of behavioral comorbidities in patients with cancer including impaired quality of life, reduced treatment adherence, and increased disease-related morbidity and mortality. Medical complications of cancer and its treatment such as anemia, thyroid dysfunction, and the neurotoxicity of cancer chemotherapeutic agents account in part for these behavioral changes. Nevertheless, recent advances in the neurosciences and immunology/oncology have revealed novel insights into additional pathophysiologic mechanisms that may significantly contribute to the development of cancer-related behavioral changes. Special attention has been focused on immunologic processes, specifically activation of innate immune inflammatory responses and their regulation by neuroendocrine pathways, which, in turn, influence CNS functions including neurotransmitter metabolism, neuropeptide function, sleep-wake cycles, regional brain activity, and, ultimately, behavior. Further understanding of these immunologic influences on the brain provides a novel conceptual framework for integrating the wide spectrum of behavioral alterations that occur in cancer patients and may reveal a more focused array of translational targets for therapeutic interventions and future research. Such developments warrant complementary advances in identification of cancer patients at risk as well as those currently suffering, including an increased emphasis on the status of behavior as a "sixth vital sign" to be assessed in all cancer patients throughout their disease encounter.

Omalizumab decreased IgE‐release and induced changes in cellular immunity in patients with allergic asthma

Omalizumab, a recombinant monoclonal anti-immunoglobulin E (IgE) antibody, shows proven efficacy in the treatment of allergic diseases. A little is known about the immunological pathways affected by the decrease of circulating free IgE during omalizumab treatment. To investigate the immunological consequence of IgE withdrawal, we studied the influence of omalizumab on stimulated IgE-release of cultured peripheral blood mononuclear cells (PBMC) and on the relative number of lymphocytes in the peripheral blood (cellular immune status) in patients with allergic asthma. Nineteen patients were enrolled and received omalizumab at a dose of at least 0.016 mg/kg/IgE (IU/ml) every 4 weeks. PBMC were isolated from peripheral blood. Cells were cultured and stimulated with IL-4 (5 ng/ml) and CD40 ligand (1 microg/ml) for 10 days. IgE release was detected in cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). Cellular immune status was investigated by fluorescence-activated cell sorting. Omalizumab treatment induced significant inhibition of stimulated IgE release (median 1.38-0 ng/ml vs. 1.64-2.0 ng/ml in placebo group, P<0.05). B-lymphocyte counts were also significantly lower in the omalizumab group compared with placebo after 12 weeks of treatment (median 18.2-15.6% lymphocytes vs 12.7-13.7% lymphocytes after placebo, P<0.01). There were no significant differences in the other lymphocyte subpopulations between the groups. These findings provide evidence of immunological influences of omalizumab treatment, leading to a downregulation of IgE secretion and decrease of lymphocyte subpopulations (B-cells) indicating their anti-inflammatory potency.

Immunologic influences on emotion regulation

Recent data document meaningful interactions between the immune system and the brain that provide the foundation for considering the potential influence of immunologic processes on emotion regulation. Studies from both laboratory animals and humans demonstrate that cytokine signals can access the brain and in turn lead to profound changes in neurochemistry, neuroendocrinology and behavior. Interestingly, data suggest that the behavioral and physiological consequences of stressful life experiences may also derive in part from the effects of stress on the immune response. The extant literature on brain–immune interactions is reviewed herein with special emphasis on data derived from patients undergoing treatment with the cytokine, interferon alpha. Consideration is also given to the mechanisms by which cytokines induce behavioral change, including an examination of the differential mechanisms that may be involved in cytokine effects on mood and cognition versus cytokine effects on neurovegetative function. Finally, implications of these findings are examined both from an evolutionary perspective and in terms of their relevance for treatment of patients with neuropsychiatric disorders.

Endothelial cell loss after autologous rotational keratoplasty

To investigate whether it may be possible to ascertain the influence of immunological factors on chronic endothelial cell loss by comparing chronic endothelial cell loss after autologous rotational penetrating keratoplasty and after homologous penetrating keratoplasty. For six patients who had undergone autologous rotational penetrating keratoplasty the relative annual loss of endothelial cells was calculated by means of an exponential regression analysis. The findings were compared with those in a homogeneous historical control group (53 patients undergoing homologous penetrating keratoplasty for keratoconus). After autologous rotational keratoplasty relative annual loss of endothelial cells was 1.1%+/-2.6% (mean +/- standard deviation). Relative annual loss of endothelial cells in the control-group was 16.7%+/-20.8%. The results of the study lead to the assumption that immunological influences might be the main cause for chronic endothelial cell loss after homologous penetrating keratoplasty.

Immunologic influences on allergy and the T H1/T H2 balance

T H2 cell–mediated immune responses against “innocuous” antigens play a triggering role in atopic allergy. Several epidemiologic studies have clearly shown that the reduced microbial exposure of children caused by the westernized lifestyle is responsible for the increased prevalence of allergy that has occurred in the last decades in developed countries (“hygiene hypothesis”). The immunologic changes caused by the reduced exposure to pathogenic and nonpathogenic microbes during childhood are still controversial. The initial interpretation has been a lack of shift of allergen-specific responses from the T H2 to the T H1 phenotype. This is because of reduced production of IL-12 and IFNs by cells of the natural immunity stimulated by bacterial products through their Toll-like receptors (missing immune deviation). Another interpretation emphasizes the importance of reduced activity of T-regulatory cells (reduced immune suppression). However, although there are impressive amounts of data in favor of the missing immune deviation, experimental evidence supporting the role of reduced immune suppression in explaining the increased prevalence of allergy is currently weak or even contradictory. The solution to this question is very important not only from a theoretic point of view but also because of its therapeutic implications.