The pathogenesis of arthritis in Lyme disease: humoral immune responses and the role of intra-articular immune complexes

We studied 78 patients with Lyme disease to determine how immune complexes and autoantibodies are related to the development of chronic Lyme arthritis. Circulating C1q binding material was found in nearly all patients at onset of erythema chronicum migrans, the skin lesion that marks the onset of infection with the causative spirochete. In patients with only subsequent arthritis this material tended to localize to joints where it gradually increased in concentrations with greater duration of joint inflammation. In joints, its concentration correlated positively with the number of synovial fluid polymorphonuclear leukocytes. Despite the prolonged presence of putative immune complexes, rheumatoid factors could not be demonstrated. These observations suggest that phlogistic immune complexes based on spirochete antigens form locally within joints during chronic Lyme arthritis.     

Bacteria-derived human leukocyte interferons alter in vitro humoral and cellular immune responses

Cultures of gradient-purified human peripheral blood mononuclear cells (PBMC) have been employed to examine the effects of three bacteria-derived human leukocyte interferon subtypes on certain aspects of in vitro immune responses. The addition of highly purified IFN-alpha 1, -alpha 2, -alpha 2/alpha 1 to PMBC cultures stimulated with phytohemagglutinin (PHA) or pokeweed mitogen resulted in a significant suppression of the mitogenic response. This suppression required the presence of interferon in the cultures because pretreatment of cells and removal of interferon had no effect on their response to PHA. The presence of these interferons at 200 U/ml also caused a substantial reduction of human mixed-lymphocyte reactions (MLR) as measured by [3H]thymidine incorporation by responder cells. Interestingly, pretreatment of stimulator cells was sufficient for this reduction to occur whereas pretreatment of responder cells had no effect on their ability to respond to allogenic stimulation. In contrast to these suppressive effects, the three interferons enhanced human in vitro primary immune response to sheep red blood cells (SRBC). These data demonstrate that both purified interferon subtypes and genetic hybrids of human interferons produced by recombinant DNA technology have effects on in vitro immune responses.     

Tuberculosis: pathogenesis, immune responses and genetics of the host

Tuberculosis is a chronic infectious disease predominantly affecting the lung. The hallmark of tuberculosis infection is the formation of granulomata in the vicinity of infectious foci. The tuberculous granuloma is a complex, cellulary and biochemically well-orchestrated structure, which development plays a dual role. Restricting dissemination of infection and forming a battlefield for protective immunity, granulomatous process may compromise lung function, threatinig the host health. Both the susceptibility to infection per se and the degree of lung failure and disease severity are under genetic control. Tuberculosis genetics is complex and far from being resolved, but the information available clearly indicates that the control of intracellular infections depends upon biochemical networks, which have not been appreciated with this regard until recently.     

Coordinate regulation of lymphocyte-endothelial interactions by pregnancy-associated hormones

Precursors of uterine NK cells home to the uterus during early pregnancy from multiple lymphohemopoietic sources. In mouse uterine tissue, pregnancy markedly up-regulates both L-selectin- and alpha(4) integrin-dependent adhesion pathways for circulating human CD56(bright) cells, the phenotype of human uterine NK cells. Based on roles for these adhesion molecules in lymphocyte homing, we examined effects of pregnancy or the steroid hormones 17beta-estradiol or progesterone on lymphocyte-endothelial interactions in secondary lymphoid tissues and in uterus. From preimplantation gestation day 3, specialized high endothelial venules in peripheral lymph nodes and Peyer's patches supported elevated L-selectin and alpha(4)beta(7) integrin-dependent lymphocyte adhesion under shear throughout pregnancy, as compared with high endothelial venules of virgin or postpartum donors. Squamous endothelium from nonlymphoid tissue was not affected. Pregnancy-equivalent endothelial responses were observed in lymph nodes and Peyer's patches from ovariectomized mice receiving 17beta-estradiol and/or progesterone replacement therapy. Adhesion of human CD56(bright) cells to uteri from pregnant or hormone-treated ovariectomized mice was enhanced through L-selectin- and alpha(4) integrin-dependent mechanisms and involved multiple vascular adhesion molecules including mucosal addressin cell adhesion molecule-1, VCAM-1, and peripheral lymph node addressin. Analysis of Tie2-green fluorescence protein transgenic mice demonstrated that CD56(bright) cells adhered primarily to vascular endothelium within the decidua basalis. Microdomain localization of adhesion involving large clusters of lymphocytes was induced on uteri from natural matings, but not pseudopregnancy. Steroid hormones also had independent effects on L-selectin function in splenic lymphocytes that mimicked physiological stimulation induced by pregnancy or fever-range temperatures. These results provide the first evidence for coordinated, organ-specific, steroid hormone-induced changes in lymphocyte homing mechanisms that could contribute to local and systemic immune responses during pregnancy.     

Sex steroids, pregnancy-associated hormones and immunity to parasitic infection

A wealth of evidence has accumulated that illustrates the ability of sex-associated hormones to influence directly a variety of diverse immunological functions. Thus, it is not surprising that differences have also been noted between the sexes in their relative susceptibility to parasitic infections. Furthermore, during pregnancy, much of the observed maternal immunomodulation, essential for fetal survival, has been attributed to changes in the levels of steroid hormones. These pregnancy-induced alterations in immune function can also have profound effects on the course of parasitic infection. In this article, Craig Roberts, Abhay Satoskar and James Alexander review the immunological basis for differences in the relative susceptibilities of males, non-pregnant females and pregnant females to parasitic infection, particularly leislumaniasis and toxoplasmosis. They also discuss the role of the major sex- and pregnancy-associated hormones in mediating these effects.     

IFN-gamma and IL-10 mediate parasite-specific immune responses of cord blood cells induced by pregnancy-associated Plasmodium falciparum malaria

Available evidence suggests that immune cells from neonates born to mothers with placental Plasmodium falciparum (Pf) infection are sensitized to parasite Ag in utero but have reduced ability to generate protective Th1 responses. In this study, we detected Pf Ag-specific IFN-gamma(+) T cells in cord blood from human neonates whose mothers had received treatment for malaria or who had active placental Pf infection at delivery, with responses being significantly reduced in the latter group. Active placental malaria at delivery was also associated with reduced expression of monocyte MHC class I and II in vivo and following short term in vitro coculture with Pf Ag compared with levels seen in neonates whose mothers had received treatment during pregnancy. Given that APC activation and Th1 responses are driven in part by IFN-gamma and down-regulated by IL-10, we examined the role of these cytokines in modulating the Pf Ag-specific immune responses in cord blood samples. Exogenous recombinant human IFN-gamma and neutralizing anti-human IL-10 enhanced T cell IFN-gamma production, whereas recombinant human IFN-gamma also restored MHC class I and II expression on monocytes from cord blood mononuclear cells cocultured with Pf Ag. Accordingly, active placental malaria at delivery was associated with increased frequencies of Pf Ag-specific IL-10(+)CD4(+) T cells in cord blood mononuclear cell cultures from these neonates. Generation and maintenance of IL-10(+) T cells in utero may thus contribute to suppression of APC function and Pf Ag-induced Th1 responses in newborns born to mothers with placental malaria at delivery, which may increase susceptibility to infection later in life.     

Stress hormones and immune function

Over the past 20 years we have demonstrated both in animal models and in human studies that stress increases neuroendocrine hormones, particularly glucocorticoids and catecholamines but to some extent also prolactin, growth hormone and nerve growth factor. We have also shown that stress, through the action of these stress hormones, has detrimental effects on immune function, including reduced NK cell activity, lymphocyte populations, lymphocyte proliferation, antibody production and reactivation of latent viral infections. Such effects on the immune system have severe consequences on health which include, but are not limited to, delayed wound healing, impaired responses to vaccination and development and progression of cancer. These data provide scientific evidence of the effects of stress on immune function and implications for health.     

Local regulation of immune responses: corneal endothelial cells alter t cell activation and cytokine production

Corneal endothelial cells (CE cells) inhibit antigen- and mitogen-activated lymphocyte proliferation assays, although interleukin 2 receptor (IL-2R) expression and responsiveness to exogenous IL-2 are unaffected. To examine this activity further, co-cultures of CE cells and T cell clones were studied. CE cells inhibited IL-2 and IL-4 production by T cells stimulated with Ag and APC, but not IL-5 or IL-6 production. CE cells also inhibited NFAT-driven lacZ reporter gene production following Ag stimulation of transfected KZO T hybridoma cells. Conversely, stimulation of IL-2 production by ionomycin, with or without PMA, was unaffected by the CE cells. Preincubation of KZO hybridoma or Jurkat cells with CE cells, or CE cell-conditioned culture supernatant, inhibited the intracellular calcium ([Ca(2+)](i)) increase induced by TCR ligation, but not the [Ca(2+)](i)increase induced by ionomycin or thapsigargin. The inhibitory effect was independent of APC and did not act by blocking costimulation, since IL-2 production stimulated by immobilized anti-CD3 alone was also inhibited by CE cells. The supernatant factor was heat labile. This novel activity is unlike other immunoregulatory molecules, including transforming growth factor beta (TGF-beta) and may contribute to local immune privilege.     

Brain heterogeneity leads to differential innate immune responses and modulates pathogenesis of viral infections

The central nervous system (CNS) is a highly complex organ with highly specialized cell subtypes. Viral infections often target specific structures of the brain and replicate in certain regions. Studies in mice deficient in type I Interferon (IFN) receptor or IFN-β have highlighted the importance of the type I IFN system against viral infections and non-viral autoimmune disorders in the CNS. Direct antiviral effects of type I IFNs appear to be crucial in limiting early spread of a number of viruses in CNS tissues. Increased efforts have been made to characterize IFN expression and responses in the brain. In this context, it is important to identify cells that produce IFN, decipher pathways leading to type I IFN expression and to characterize responding cells. In this review we give an overview about region specific aspects that influence local innate immune responses. The route of entry is critical, but also the susceptibility of different cell types, heterogeneity in subpopulations and micro-environmental cues play an important role in antiviral responses.Recent work has outlined the tremendous importance of type I IFNs, particularly in the limitation of viral spread within the CNS. This review will address recent advances in understanding the mechanisms of local type I IFN production and response, in the particular context of the CNS.     

Platelet immune complex interaction in pathogenesis of Kawasaki disease and childhood polyarteritis.

The role of platelets in the pathogenesis of vasculitis and the formation of coronary artery aneurysms was studied in 19 children with Kawasaki disease and five with polyarteritis. All patients with Kawasaki disease developed thrombocytosis in the third week of illness. The peak platelet count was significantly correlated (p less than 0.005) with the subsequent development of coronary artery aneurysms. The rise in platelet count was associated with the appearance in the circulation of a factor that induced aggregation and serotonin release in normal platelets. This factor was shown to be of high molecular weight, and its activity was lost at low pH--features suggestive of an immune complex. Immune complexes, detected by precipitation with polyethylene glycol, also appeared in the circulation as the platelet count increased. These complexes induced platelet aggregation, and there was a significant correlation (p less than 0.001) between the concentrations of IgG and IgA in the polyethylene glycol precipitated material and the platelet aggregating activity. Similar platelet aggregating activity was also detected in patients with polyarteritis but followed a different time course, persisting in the circulation for several months in association with continued disease activity. These findings imply that different mechanisms have a role in distinct phases of Kawasaki disease. The initial feverish phase (probably infective) is probably followed by an immune complex vasculitis that occurs when antibodies to the initiating agent appear in the circulation. The immune complexes aggregate platelets and induce release of serotonin. Platelet derived vasoactive mediators may increase vascular permeability and facilitate further deposition of complexes in the tissues.     

Co-infection with the friend retrovirus and mouse scrapie does not alter prion disease pathogenesis in susceptible mice

Prion diseases are fatal, transmissible neurodegenerative diseases of the central nervous system. An abnormally protease-resistant and insoluble form (PrP(Sc)) of the normally soluble protease-sensitive host prion protein (PrP(C)) is the major component of the infectious prion. During the course of prion disease, PrP(Sc) accumulates primarily in the lymphoreticular and central nervous systems. Recent studies have shown that co-infection of prion-infected fibroblast cells with the Moloney murine leukemia virus (Mo-MuLV) strongly enhanced the release and spread of scrapie infectivity in cell culture, suggesting that retroviral coinfection might significantly influence prion spread and disease incubation times in vivo. We now show that another retrovirus, the murine leukemia virus Friend (F-MuLV), also enhanced the release and spread of scrapie infectivity in cell culture. However, peripheral co-infection of mice with both Friend virus and the mouse scrapie strain 22L did not alter scrapie disease incubation times, the levels of PrP(Sc) in the brain or spleen, or the distribution of pathological lesions in the brain. Thus, retroviral co-infection does not necessarily alter prion disease pathogenesis in vivo, most likely because of different cell-specific sites of replication for scrapie and F-MuLV.     

Endogenous hormones subtly alter women's response to heat stress

The thermoregulatory responses of menstruant women to exercise in dry heat (dry-bulb temperature/wet-bulb temperature = 48/25 degrees C) were evaluated at three times during the menstrual cycle: menstrual flow (MF), 3-5 days during midcycle including ovulation (OV), and in the middle of the luteal phase (LU). Serum concentrations of estradiol-17 beta (E2), progesterone (Pg), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured by radioimmunoassay, and these values were used to determine the dates of OV (peak LH and FSH) and LU (peak postovulatory Pg). After heat acclimation, subjects received heat stress tests (HST) consisting of a 2-h cycle-ergometer exercise at 30% of maximal O2 consumption in the heat. Rectal (Tre) and mean skin (Tsk) temperatures, heart rate (HR), and sweat rate on the chest and thigh were recorded continuously. Total sweat loss (Msw), as indicated by weight loss, was recorded every 20 min, and equivalent water replacement was given. Steady-state exercise metabolic rate (M) was measured at 45 and 110 min. Seven of eight subjects had ovulatory cycles during experimental months. At rest, Tre was lowest at OV and significantly higher at LU. During steady-state exercise both Tre and Tsk were lowest at OV and significantly higher at LU. There were no differences between phases in Msw, sweat rate on the chest and thigh or M. Despite higher Tre and Tsk at LU, all subjects were able to complete the 2-h of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low-frequency electromagnetic fields do not alter responses of inflammatory genes and proteins in human monocytes and immune cell lines

The effects of low frequency electromagnetic fields (LF EMF) on human health are the subject of on-going research and serious public concern. These fields potentially elicit small effects that have been proposed to have consequences, either positive or negative, for biological systems. To reveal potentially weak but biologically relevant effects, we chose to extensively examine exposure of immune cells to two different signals, namely a complex multiple waveform field, and a 50 Hz sine wave. These immune cells are highly responsive and, in vivo, modulation of cytokine expression responses can result in systemic health effects. Using time course experiments, we determined kinetics of cytokine and other inflammation-related genes in a human monocytic leukemia cell line, THP-1, and primary monocytes and macrophages. Moreover, cytokine protein levels in THP-1 monocytes were determined. Exposure to either of the two signals did not result in a significant effect on gene and protein expression in the studied immune cells. Also, additional experiments using non-immune cells showed no effects of the signals on cytokine gene expression. We therefore conclude that these LF EMF exposure conditions are not expected to significantly modulate innate immune signaling.     

The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease

SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) is a T- and natural killer (NK)-cell-specific protein containing a single SH2 domain encoded by a gene that is defective or absent in patients with X-linked lymphoproliferative syndrome (XLP). The SH2 domain of SAP binds with high affinity to the cytoplasmic tail of the haematopoietic cell-surface glycoprotein SLAM and five related receptors. SAP regulates signal transduction of the SLAM-family receptors by recruiting SRC kinases. Similarly, the SAP-related proteins EAT2A and EAT2B are thought to control signal transduction that is initiated by SLAM-related receptors in professional antigen-presenting cells. In this review, we discuss recent findings on the structure and function of proteins of the SAP and SLAM families.     

Measles: immune suppression and immune responses

Measles is a highly contagious viral disease that remains the leading vaccine-preventable cause of child mortality worldwide. Deaths from measles are due largely to an increased susceptibility to secondary bacterial and viral infections, attributed to a prolonged state of immune suppression. Several abnormalities of the immune system have been described, including changes in lymphocyte number and function, shifts in cytokine responses, immunomodulatory effects of interleukin-10, down regulation of interleukin-12, impaired antigen presentation, and altered interferon alpha/beta signaling pathways. Although the current vaccine is very effective, knowledge of the molecular basis of the immune responses to measles virus could contribute to the development of a safer, more immunogenic measles vaccine. However, the safety of new measles vaccines must be carefully investigated, as two measles vaccines have resulted in unintended immunologic consequences: atypical measles following administration of the formalin-inactivated measles vaccine and increased mortality in girls following administration of high-titer measles vaccines.     

Cytokine responses during mucosal infections: role in disease pathogenesis and host defence

Mucosal pathogens use diverse and highly specific molecular mechanisms to activate mucosal inflammation. It may even be argued that their virulence depends on the inflammatory response that they induce. Some bacteria target epithelial cells and trigger them to produce inflammatory mediators but others cross the mucosa and activate macrophages or dendritic cells. Although systemic release of inflammatory mediators causes many symptoms and signs of infection, local chemokine production leads to the recruitment of inflammatory cells and lymphocytes that participate directly in the clearance of bacteria from mucosal sites. In this way, mucosal inflammation is a two-edged sword responsible for disease associated tissue destruction and crucial for the antimicrobial defence. Understanding of these pathways should create tools to enhance the defence and interfere with disease.     

Nutrition and immune responses

Clinical and epidemiologic data suggest a causal relationship between nutritional deficiency and infection. Among other factors, impaired immune responses secondary to malnutrition increase susceptibility to infectious illness. Protein-energy undernutrition and deficiencies of iron, zinc, pyridoxine, and other nutrients depress a variety of immunity functions. Cell-mediated immunity, complement system, microbicidal activity of phagocytes, secretory antibody response, and antibody affinity are often decreased. Recent studies have revealed many metabolic and hormone alterations as well as changes in the number and function of lymphocyte subpopulations. Obesity also is associated with impaired cellular immune functions. Dietary factors may play a critical role in host resistance to disease.     

Innate immune responses are increased in chronic obstructive pulmonary disease

Background

Chronic obstructive pulmonary disease (COPD) is characterised by irreversible airflow obstruction, neutrophilic airway inflammation and chronic bacterial colonisation, however the role of the innate immune response in the pathogenesis of COPD remains unclear.

Methods

Induced sputum was obtained from adults with COPD (n = 22), and healthy controls (n = 29) and was processed for differential cell counts. The sputum supernatant was assayed for innate immune mediators using ELISA, whilst sputum gene expression was measured using real-time PCR. Peripheral blood neutrophils were isolated and their response to lipopolysaccaride (LPS) stimulation was assessed in a subgroup of participants with COPD (n = 13) and healthy controls (n = 21).

Results

Participants with COPD had significantly higher protein levels of interleukin (IL)-8, and neutrophil elastase (NE) and detection of oncostatin M (OSM) compared to healthy controls. Gene expression for toll-like receptor (TLR) 2, IL-8 and OSM were also significantly higher in COPD participants. The level of IL-1β, surfactant protein (SP)-A, matrix metalloproteinase (MMP)-9 and TLR4 mRNA was not significantly different between groups. The level of innate immune response markers were highly associated with the presence of sputum neutrophils, each other and the degree of airflow limitation (FEV₁/FVC). Peripheral blood neutrophils from participants with COPD had an increased response to stimulation by LPS; with a greater fold increase in the production of IL-8 and MMP-9 protein, and gene expression of IL-8, TLR2 and TLR4.

Conclusions

The innate immune response is increased in the airways and circulating neutrophils in COPD, and may be an important mechanism involved in disease pathogenesis.