Pathogenesis Of Chronic Disease Research Articles

Human fetal adipokine levels in correlation to birth weight and maternal body mass index

Aims: Recent studies suggest that the perinatal period is a sensitive part in human development in respect to the pathogenesis of chronic diseases in adulthood. For example, newborns, that are small for gestational age, have a greater risk to develop Diabetes mellitus in later live. The terms „perinatal priming“ or „fetal programming“ are used to describe this phenomenon. Beside that it is known from epidemiological studies that offspring of obese patients have an increased risk to develop obesity by themselves. Therefore, the aim of the present study was to investigate, if fetal adipokine levels show a correlation with the birth weight or the maternal BMI.

Hepatic structural alteration in adult programmed offspring (severe maternal protein restriction) is aggravated by post-weaning high-fat diet

The present study aimed to evaluate the effects of a post-weaning high-fat (HF) diet upon hepatic morphology in rats subjected to perinatal protein restriction. Pregnant Wistar rats were assigned to a normal-protein diet (NP; with 19 % of protein) or a low-protein (LP) diet (with 5 % of protein). At weaning, the following groups were formed: NP and NP-HF, males and females, which were fed standard chow and an HF diet, respectively. Likewise, LP rat dams originated LP and LP-HF offspring, both sexes. Euthanasia was performed at 6 months of age. Three-way ANOVA disclosed a three-factor interaction among sex, perinatal diet and HF diet in relation to body mass, retroperitoneal fat pad, liver mass:tibia length ratio, binucleation rate and hepatocyte area at 6 months old (P < 0.05). The high-fat diet intensified the effects of perinatal protein restriction concerning systolic blood pressure, genital fat pad and hepatocyte number (P < 0.05; two-way ANOVA). Furthermore, higher steatosis rates and insulin and leptin concentrations were found in males fed on the HF diet, indicating a sex-post-weaning diet interaction (P < 0.05; two-way ANOVA). Fetal programming and HF diet as a single stimulus caused mild hypertension at 3 months, an important reduction in hepatocyte number as well as stage 1 steatosis at 6 months. However, hypertension and hepatocyte number deficit were worsened and grade 2 steatosis occurred after exposure to the HF diet. All of these serve to highlight the paramount importance of intra-uterine conditions and postnatal diet quality when it comes to the pathogenesis of chronic diseases.

Oxidative stress, chronic disease, and muscle wasting

Underlying the pathogenesis of chronic disease is the state of oxidative stress. Oxidative stress is an imbalance in oxidant and antioxidant levels. If an overproduction of oxidants overwhelms the antioxidant defenses, oxidative damage of cells, tissues, and organs ensues. In some cases, oxidative stress is assigned a causal role in disease pathogenesis, whereas in others the link is less certain. Along with underlying oxidative stress, chronic disease is often accompanied by muscle wasting. It has been hypothesized that catabolic programs leading to muscle wasting are mediated by oxidative stress. In cases where disease is localized to the muscle, this concept is easy to appreciate. Transmission of oxidative stress from diseased remote organs to skeletal muscle is thought to be mediated by humoral factors such as inflammatory cytokines. This review examines the relationship between oxidative stress, chronic disease, and muscle wasting, and the mechanisms by which oxidative stress acts as a catabolic signal.

Molecular Basis of Epithelial Barrier Regulation: From Basic Mechanisms to Clinical Application

The intestinal epithelium is faced with the complex task of providing a barrier while also allowing nutrient and water absorption. The frequency with which these processes are disrupted in disease can be taken as evidence of their importance. It is therefore of interest to define the mechanisms of altered intestinal barrier and transport function and develop means to correct disease-associated defects. Over the past 10 years, some of the molecular events underlying physiological epithelial barrier regulation have been described. Remarkably, recent advances have shown that activation of the same mechanisms is central to barrier dysfunction in both in vitro and in vivo models of disease. Although the contribution of barrier dysfunction to pathogenesis of chronic disease remains incompletely understood, it is now clear that cytoskeletal regulation of barrier function is both an important pathogenic process and that targeted inhibition of myosin light chain kinase, which affects this cytoskeleton-dependent tight junction dysfunction, is an attractive candidate for therapeutic intervention.

Healthy endothelium: The scientific basis for cardiovascular health promotion and chronic disease prevention

The vascular endothelium plays a critical role both in health and in the pathogenesis of chronic diseases, including cardiovascular disease. This review explores the underlying role of normal endothelial function in core public health interventions for health promotion and in the prevention and control of cardiovascular disease and its risk factors, as well as the application of endothelial science toward innovative public health programs and further research. Increased collaboration among basic scientists, clinician-investigators, prevention research centers, and all public health practitioners is needed to facilitate the translation of the endothelial science into practice.

Use of an in Vitro Assay for Determination of Biofilm-Forming Capacity of Bacteria in Chronic Rhinosinusitis

Bacterial biofilms are increasingly implicated in the pathogenesis of chronic disease and have been established in several chronic ear, nose, and throat conditions, including chronic sinusitis (CRS). However, this relies on specialized imaging methods not widely available. We wished to assess the capacity of an easily performed, inexpensive in vitro test to assess biofilm production by bacteria recovered from individuals with CRS with or without nasal polyposis. Bacterial isolates were recovered from patients consulting an academic tertiary rhinology practice. Biofilm formation was determined with an in vitro staining method using crystal violet. Ten isolates of Pseudomonas aeruginosa, Staphylococcus aureus, and 11 of coagulase-negative staphylococcus from patients with CRS having previously undergone endoscopic sinus surgery for >1 year were assessed. Samples were cultured 24 hours at 37 degrees C on 96-well plates in tryptic soy broth 0.5% glucose medium. After staining with crystal violet, optical density at 570 nm was measured to quantify biofilm production. Biofilm-forming capacity was compared with positive and negative controls for each species obtained from commercial sources. Positive controls all grew biofilms, with a tendency of lesser biofilm formation at higher dilutions. Twenty-two of 31 clinical samples produced a biofilm greater or equal to the positive control. Biofilm was recovered consistently for all three species studied. This in vitro assessment method is capable of detecting biofilm-forming capacity in bacteria recovered from individuals with CRS. This simple assay may be a useful complement to existing techniques for clinical research.

Palmitate induced lipoapoptosis of exocrine pancreas AR42J cells

Chronic surplus of dietary consumption, typical to obesity, results in overflow of fat to non-adipose tissues. Intracellular accumulation of fat in non-adipose tissues is associated with cellular dysfunction and cell death and ultimately contributes to the pathogenesis of chronic diseases. The influence of fat overflow on the exocrine pancreas is not known. The purpose of this research was to study the lipotoxic and lipoapoptotic effect of prolonged (72 h) long chain saturated palmitic fatty acid (0.1 mM) on the survival of exocrine pancreas AR42J cells. We demonstrate that chronic exposure of AR42J cells to palmitic acid results in significant increase in triglycerides accumulation (up to 25% of cells area), compared to untreated cultures. Lipid accumulation prompted a typical apoptotic process, demonstrated by both DNA fragmentation and condensed chromatin appearance (DAPI staining). Quantitative real-time PCR studies demonstrated that prolonged palmitic acid supplementation induced down-regulation of the anti-apoptotic Bcl2 mRNA levels (22%) and up-regulation of the pro-apoptotic Bax mRNA levels (300%), leading to disruption of the pro/anti apoptotic balance (Bax/Bcl2=3). No major change was detected in iNOS mRNA expression. In conclusion, prolonged exposure to saturated palmitic acid induces lipoapoptosis in exocrine pancreatic AR42J cells, through disturbance of the Bax/Bcl-2 balance.

Obese state leads to elevated levels of TGF-β and COX isoforms in platelets of Zucker rats

Platelets are rich sources of growth factors and enzymes that are implicated in a number of diseases including obesity, atherosclerosis, heart disease, syndrome X, liver and kidney diseases and certain types of cancers. In this research we investigated, if platelets in Zucker obese rats differ from their lean counterparts with respect to the levels of TGF-beta and COX isoforms, implicated in the pathogenesis of chronic diseases. In addition, we investigated if energy intake of the animals affects the platelet physiology. Platelets were isolated from obese and lean rats bearing preneoplastic lesions in their colon. Prior to platelet isolation these rats were fed either ad libitum (Ob or Ln) or energy restricted (Ob-ER or Ln-ER) diets for 8 weeks (n = 8/group). The levels of TGF-beta1/-beta2 and COX-1/-2 proteins in platelets were analyzed by Western blot. The platelets of the Ob rats had significantly higher levels of TGF-beta1, COX-1/-2 (p < 0.001) than did the platelets of the Ln rats and were not affected by moderate energy restriction. There were no significant differences in the protein expression of platelet TGF-beta2 among any of the groups. These results demonstrate that cytokines and candidates playing a role in the pathogenesis of chronic diseases, such as TGF-beta1 and COX-1/-2, are over-expressed in platelets of Zucker obese rats by comparison to their lean counterparts. These findings also demonstrate that the genotype of the animals exerts a significant effect on the biochemical composition of the platelets and could contribute to the pathogenesis of colon cancer and other metabolic abnormalities associated with obesity.

Modification of lymphocyte DNA damage by carotenoid supplementation in postmenopausal women

Oxidative stress has been implicated in the pathogenesis of chronic diseases related to aging such as cancer and cardiovascular disease. Carotenoids could be a part of a protective strategy to minimize oxidative damage in vulnerable populations, such as the elderly. Our aim was to determine the protective effect of carotenoids against DNA damage. A randomized, double-blind, placebo-controlled intervention study was conducted. Thirty-seven healthy, nonsmoking postmenopausal women aged 50-70 y were randomly assigned to 1 of 5 groups and were instructed to consume a daily dose of mixed carotenoids (beta-carotene, lutein, and lycopene; 4 mg each), 12 mg of a single carotenoid (beta-carotene, lutein, or lycopene), or placebo for 56 d. Plasma carotenoid concentrations were analyzed by using HPLC, and lymphocyte DNA damage was measured by using a single-cell gel electrophoresis (comet) assay. At day 57, all carotenoid-supplemented groups showed significantly lower endogenous DNA damage than at baseline (P < 0.01), whereas the placebo group did not show any significant change. Significantly less (P < 0.05) endogenous DNA damage was found as early as day 15 in the mixed carotenoid (P < 0.01) and beta-carotene (P < 0.05) groups. The results indicate that carotenoid supplementation decreases DNA damage and that a combination of carotenoids (4 mg each of lutein, beta-carotene, and lycopene), an intake that can be achieved by diet, or a larger dose (12 mg) of individual carotenoids exerts protection against DNA damage.

Increasing prevalence of obesity: implications for the health and functioning of older people

The prevalence of obesity is increasing, both in developed and developing, countries. Since obesity is a major factor in the pathogenesis of chronic diseases including type 2 diabetes and cardiovascular disorders, the dramatic increase in obesity prevalence in recent years has major implications for the health of individuals and for the health economy. The number of aged individuals and their longevity is also increasing. Age is a major factor in the pathogenesis of chronic diseases.

Au(III), Pd(II), Ni(II), and Hg(II) alter NFκB signaling in THP1 monocytic cells

The transcription factor NFkappaB plays a key role in the tissue inflammatory response. Metal ions released into tissues from biomaterials (e.g., Au, Pd, Ni, Hg) are known to alter the binding of NFkappaB proteins to DNA, thereby modulating the effect of NFkappaB on gene activation and, ultimately, the tissue response to biomaterials. Little is known about the effect of these metals on key signaling steps prior to NFkappaB-DNA binding such as transcription factor activation or nuclear translocation, yet these steps are equally important to modulation of the pathway. Oxidative stress is known to alter NFkappaB proteins and is suspected to play a role in metal-induced NFkappaB signaling modulation. Our aim in the current study was to assess the effects of sublethal levels of Ni, Hg, Pd, and Au ions on NFkappaB activation and nuclear translocation in the monocyte, which is acknowledged as an important orchestrator of the biological response to materials and the pathogenesis of chronic disease. Sublethal concentrations of Au(III), Ni(II), Hg(II), and Pd(II) were added to cultures of human THP1 monocytic cells for 72 h. In parallel cultures, lipopolysaccharide (LPS) was added for the last 30 min to activate the monocytic cells. Then cellular cytoplasmic and nuclear proteins were isolated, separated by electrophoresis, and probed for IkappaBalpha degradation (activation) and NFkappaB p65 translocation. Protein levels were digitally quantified and statistically compared. The levels of reactive oxygen species (ROS) in the monocytic cells were measured as a possible mechanism of metal-induced NFkappaB modulation. Only Au(III) activated IkappaBalpha degradation by itself. Au(III) and Pd(II) enhanced LPS-induced IkappaBalpha degradation, but Hg(II) and Ni(II) suppressed it. Au(III), Ni(II), and Pd(II) activated p65 nuclear translocation without LPS, and all but Ni(II) enhanced LPS-induced translocation. Collectively, the results suggest that these metal ions alter activation and translocation of NFkappaB, each in a unique way at unique concentrations. Furthermore, even when these metals had no overt effects on signaling by themselves, all altered activation of signaling by LPS, suggesting that the biological effects of these metals on monocytic function may only be manifest upon activation. None of the metal ions elevated levels of ROS at 72 h, indicating that ROS were probably not direct modulators of the NFkappaB activation or translocation at this late time point.

Therapeutic Blockade of TCR Signal Transduction and Co-Stimulation in Autoimmune Disease

Autoimmune diseases are initiated and maintained by presentation of self antigen through complex interactions between different cells of the immune system. In most autoimmune disorders, autoantigen-specific responses are induced by the activation of specific T cells with self peptides displayed on activated antigen presenting cells (APCs). These T cells may then activate and drive B cell responses that either initiate or contribute to chronic disease pathogenesis. In order to activate the T cell, two signals are required: T cell receptor (TCR) engagement by autoantigen presented in the context of self MHC class II and costimulation (CD28-CD80/CD86 interactions). Feedback must also be provided to the APC through MHC class II engagement by the TCR and through costimulatory events controlling T cell differentiation and effector function (CD154-CD40 interactions, among others). With this in mind, numerous strategies have been developed to block the engagement and activation of self-reactive cells. We review and discuss recent progress in understanding the efficacy and underlying molecular mechanisms of three separate immunotherapeutic strategies targeting the TCR and costimulatory molecules: i) blocking TCR signaling (using non-mitogenic anti-CD3 monoclonal antibody); ii) blocking CD28 costimulation (anti-B7 monoclonal antibody blockade); and iii) blocking CD40 engagement on APCs (anti-CD154 monoclonal antibody blockade).

Age alterations in extent and severity of experimental intranasal infection with Chlamydophila pneumoniae in BALB/c mice.

The intracellular bacterium Chlamydophila ("Chlamydia") pneumoniae is a pathogen for several respiratory diseases and may be a factor in the pathogenesis of chronic diseases of aging including atherosclerosis and Alzheimer's disease. We assessed whether aging is coupled with increased burden of infection in BALB/c mice after intranasal infection by C. pneumoniae. Six- and twenty-month-old BALB/c mice were infected intranasally with 5 x 10(4) inclusion forming units (IFU) or 5 x 10(5) IFU of C. pneumoniae. Lung, brain, and heart tissue were analyzed for infectious C. pneumoniae and for Chlamydophila antigen by immunohistochemistry. At both doses, aging was associated with a decreased proportion of animals that cleared infection from the lung and greater burden of infectious organism within the lung. We observed dose-dependent spread to the heart/ascending aorta in animals infected with C. pneumoniae. In mice given 5 x 10(4) IFU, spread to the heart by day 14 was only observed in old mice. By day 28, all animals inoculated with 5 x 10(4) IFU showed evidence of spread to the heart, although higher C. pneumoniae titers were observed in the hearts from old mice. In mice inoculated with 5 x 10(5) IFU, spread of C. pneumoniae to the heart was evident by day 14, with no discernible age effect. C. pneumoniae was also recovered from the central nervous system (brain and olfactory bulb) of all mice by day 28 postinfection, with higher C. pneumoniae titers in old animals than in young animals. Our results suggest that infection with C. pneumoniae may be more severe in old animals.

P53 tumor suppressor gene mutations in fibroblast-like synoviocytes from erosion synovium and non-erosion synovium in rheumatoid arthritis

Abnormalities in the p53 tumor suppressor gene have been detected in rheumatoid arthritis (RA) and could contribute to the pathogenesis of chronic disease. To determine whether synoviocytes from invasive synovium in RA have an increased number of mutations compared with non-erosion synoviocytes, p53 cDNA subclones from fibroblast-like synoviocytes (FLS) derived from erosion and non-erosion sites of the same synovium were examined in patients requiring total joint replacement. Ten erosion FLS lines and nine non-erosion FLS lines were established from nine patients with RA. Exons 5–10 from 209 p53 subclones were sequenced (114 from erosion FLS, 95 from non-erosion FLS). Sixty percent of RA FLS cell lines and 8.6% of the p53 subclones isolated from FLS contained p53 mutations. No significant differences were observed between the erosion and non-erosion FLS with regard to the frequency or type of p53 mutation. The majority of the mutations were missense transition mutations, which are characteristic of oxidative damage. In addition, paired intact RA synovium and cultured FLS from the same joints were evaluated for p53 mutations. Matched synovium and cultured synoviocytes contained p53 mutations, although there was no overlap in the specific mutations identified in the paired samples. Clusters of p53 mutations in subclones were detected in some FLS, including one in codon 249, which is a well-recognized 'hot spot' associated with cancer. Our data are consistent with the hypothesis that p53 mutations are randomly induced by genotoxic exposure in small numbers of RA synoviocytes localized to erosion and non-erosion regions of RA synovium. The determining factor for invasiveness might be proximity to bone or cartilage rather than the presence of a p53 mutation.

Regulation of nitric oxide synthesis by dietary factors.

Nitric oxide (NO) is synthesized from L-arginine by NO synthase (NOS). As an endothelium-derived relaxing factor, a mediator of immune responses, a neurotransmitter, a cytotoxic free radical, and a signaling molecule, NO plays crucial roles in virtually every cellular and organ function in the body. The discovery of NO synthesis has unified traditionally diverse research areas in nutrition, physiology, immunology, pathology, and neuroscience. Increasing evidence over the past decade shows that many dietary factors, including protein, amino acids, glucose, fructose, cholesterol, fatty acids, vitamins, minerals, phytoestrogens, ethanol, and polyphenols, are either beneficial to health or contribute to the pathogenesis of chronic diseases partially through modulation of NO production by inducible NOS or constitutive NOS. Although most published studies have focused on only a single nutrient and have generated new and exciting knowledge, future studies are necessary to investigate the interactions of dietary factors on NO synthesis and to define the underlying molecular mechanisms.

Encefalomielitis por infección con el virus de Theiler como modelo experimental de esclerosis múltiple: citocinas y posibles mecanismos patogénicos

Theiler's murine encephalomyelitis virus (TMEV) disease is induced following intracerebral inoculation of TMEV, a member of picornavirus family, in susceptible animals. The pathogenesis of paralytic syndrome is associated with a chronic progressive demyelinating disease characterized by perivascular of immune inflammatory cells. Although TMEV induced demyelinating disease (TMEV IDD) is initiated by virus specific CD4+ T cells targeting CNS persistent virus, CD4+ T cell responses against self myelin epitopes activated via epitope spreading contribute to chronic disease pathogenesis. In the present report we delineated possible pathogenic mechanisms related with inflammatory process, leading to demyelination and axonal loss. The importance of proinflammatory cytokines in sustaining the inflammatory process and cause direct oligodendrotoxicity is emphasized. Different approaches in therapeutic strategies affecting cytokines are also presented.

CD28 costimulatory blockade exacerbates disease severity and accelerates epitope spreading in a virus-induced autoimmune disease.

Theiler's murine encephalomyelitis virus (TMEV) is a natural mouse pathogen which causes a lifelong persistent infection of the central nervous system (CNS) accompanied by T-cell-mediated myelin destruction leading to chronic, progressive hind limb paralysis. TMEV-induced demyelinating disease (TMEV-IDD) is considered to be a highly relevant animal model for the human autoimmune disease multiple sclerosis (MS), which is thought to be initiated as a secondary consequence of a virus infection. Although TMEV-IDD is initiated by virus-specific CD4(+) T cells targeting CNS-persistent virus, CD4(+) T-cell responses against self myelin protein epitopes activated via epitope spreading contribute to chronic disease pathogenesis. We thus examined the ability of antibodies directed against B7 costimulatory molecules to regulate this chronic virus-induced immunopathologic process. Contrary to previous studies showing that blockade of B7-CD28 costimulatory interactions inhibit the initiation of experimental autoimmune encephalomyelitis, treatment of SJL mice at the time of TMEV infection with murine CTLA-4 immunoglobulin or a combination of anti-B7-1 and anti-B7-2 antibodies significantly enhanced clinical disease severity. Costimulatory blockade inhibited early TMEV-specific T-cell and antibody responses critical in clearing peripheral virus infection. The inhibition of virus-specific immune responses led to significantly increased CNS viral titers resulting in increased damage to myelin-producing oligodendrocytes. Following clearance of the costimulatory antagonists, epitope spreading to myelin epitopes was accelerated as a result of the increased availability of myelin epitopes leading to a more severe chronic disease course. Our results raise concern about the potential use of B7-CD28 costimulatory blockade to treat human autoimmune diseases potentially associated with acute or persistent virus infections.

Herpesviruses as unrecognised components of the pathogenesis of chronic diseases

Herpesviruses as unrecognised components of the pathogenesis of chronic diseases

Platelet‐activating factor (PAF)‐like oxidized phospholipids: Relevance to atherosclerosis

Lipid peroxidation is involved in the pathogenesis of chronic diseases including atherosclerosis. Oxidized lipoprotein has diverse biological activities and is believed to initiate atheroma formation and maturate fatty plaque. The active components of oxidized lipoproteins still remain to be clarified, but a likely candidate is the phosphatidylcholine (PC) having an sn-2-short-chain acyl group with a methyl, hydroxyl, aldehydic or carboxylic terminal. These unique PCs, formed by oxidative fragmentation of the polyunsaturated acyl group of the parent PC in liposomes, low density lipoproteins and blood plasma, induce platelet aggregation through the activation of the receptor for platelet-activating factor (PAF), due to their resemblance in structure with PAF. We have found that PAF-like lipids regulate DNA synthesis and production of nitric oxide independently of the activation of the PAF receptor in vascular smooth muscle cells. Regulation of vascular cell function through two distinct signaling pathways mediated by PAF-like lipids provides new insight into the mechanism of induction of atherosclerosis.

Pathogenesis of chronic bacterial infections

Chronic infectious disease is frequently perceived in a unitary fashion from the cellular point of view; i.e. all cells in a chronically infected host harbor the infectious agent, and the kinetics and result of infection are essentially the same in each infected cell. An alternative hypothesis is that these diseases involve simultaneous interrelated cycles of chronic and acute infections between a limited number of cell types. Infection of one cell type may be chronic and latent, produce little cytopathology and only rarely lead to the release of infectious units. Infection of other cell type(s) may be more acute, cause rapid and extensive cytopathic effects and the release of large numbers of infectious units. Signs and symptoms of chronic disease in the host are often dominated by damage to the cell type that exhibits the more acute and cytopathic response to infection.Interrelated cycles of chronic and acute patterns of infection in different cell types have been most clearly delineated in HIV infection[1xHo, D.D. J. Clin. Invest. 1997; 99: 2565–2567Crossref | PubMedSee all References][1]. Chronically HIV-infected dendritic cells and other mononuclear phagocytes show little cytopathic effect, whereas the raging acute HIV infection of activated CD4+ T cells leads to their destruction. A somewhat similar, but less completely defined, pattern occurs in herpes simplex infections[2xRaguin, G. and Malkin, J.E. Ann. Med. Interne (Paris). 1997; 148: 530–533PubMedSee all References][2]. In this case, the occasional production of infectious virions by chronically infected neurons is associated with the more acute and cytopathic mucocutaneous infection of epithelial cells. In malaria caused by Plasmodium vivax, a symptomatic, cytolytic, intraerythrocytic infection is superimposed on an essentially asymptomatic chronic hepatic infection[3xKumar, V. et al. Acta Leprol. 1992; 8: 87–94PubMedSee all References][3].Whether a similar pattern of interrelated cycles of infection and response of different cell types is also involved in the pathogenesis of chronic bacterial diseases is unclear. Infection of macrophages by Mycobacterium leprae is apparently not highly cytopathic in lepromatous leprosy, and direct infection of Schwann cells appears to be at least partly responsible for peripheral nerve dysfunction in this disease[3xKumar, V. et al. Acta Leprol. 1992; 8: 87–94PubMedSee all References, 4xBirdi, T.J., D'Souza, S., and Antia, H. Microb. Pathog. 1997; 22: 181–185Crossref | PubMed | Scopus (2)See all References], but evidence for a differential response to infection by these two cell types is limited[5xShetty, V.P., Uplekar, M.W., and Antia, N.H. Acta Neuropathol. 1994; 88: 300–306Crossref | PubMed | Scopus (26)See all References][5]. Tuberculosis presents an even more speculative case for interrelated acute and chronic infections of different cell types, as the types involved have not been fully defined. However, the relative inability of mice to control the growth of Mycobacterium tuberculosis in the lung, as compared with in the liver and spleen[6xMedina, E. and North, R.J. J. Exp. Med. 1996; 183: 1045–1051Crossref | PubMed | Scopus (81)See all References, 7xMedina, E. and North, R.J. Immunology. 1998; 93: 270–274Crossref | PubMed | Scopus (166)See all References], is consistent with an indolent infection in a cell type localized to the lung (e.g. pneumocytes or alveolar macrophages) with the occasional release of viable bacteria leading to active new infections in resident and recruited inflammatory macrophages. In both these diseases, the role of interrelated cycles of infection in pathogenesis is likely to be amplified by, and be in addition to, that played by the hypersensitivity of the host to mycobacterial antigens.Recognition of the role that dual patterns of infection may play in pathogenesis of chronic diseases caused by intracellular bacteria is likely to suggest new approaches to their study and lead to a more refined view of chronic infectious disease at the cellular level.