Meningitis Disease Research Articles

Coccidioidomycosis in a 38‑year‑old man: a case report

The present article describes a case of acute pulmonary coccidioidomycosis in a 38-year-old man, a research worker. The disease started during the patient stay in Arizona, USA, and clinical symptoms persisted after his return to Poland. Acute coccidioidomycosis is one the clinical manifestations of Coccidioides immitis strain endemic infections occurring in the south-western regions of USA including California (mainly San Joaquin Valley), Western Texas, New Mexico and the desert areas of Arizona, and Central and South America. The native environment of Coccidioides immitis is soil penetrated by rodents. People, domestic and wild animals suffer from coccidioidomycosis. The infection rate in endemic areas is about 2-4% a year in the healthy population. Coccidioidomycosis can be observed in non-endemic areas due to population mobility and in immunocompromised patients. The Coccidioides immitis infection is caused by inhaled airborne fungal spores and it may occur as primary pulmonary (acute or chronic) asymptomatic form, meningitis, or disseminated disease. The clinical symptoms of coccidioidomycotis like acute pulmonary manifestations may resemble typical, resistant to empiric antibiotic treatment of bacterial pneumonia. In healthy subjects, pulmonary coccidioidomycosis may occur as asymptomatic infection, which resolves spontaneously without medication. Sometimes, slight shadows like local fibrosis and cavities may be visible on the chest X-ray. The Coccidioides immitis infection in people with immunological deficiency syndromes, e.g. HIV/AIDS, manifests itself as disseminated disease and may lead to severe complications including death.

Hiccups as a myocardial ischemia symptom

A hiccup is involuntary, paroxysmal inspiratory movements of the chest wall associated with diaphragm and accessory respiratory muscle contractions, with the synchronized closure of glottis. The mechanism underlying this common primitive reflex plays an important role in protecting airways against esophageal aspiration. The hiccup reflex mechanism is based on the afferent pathway (vagus and phrenic nerve and sympathetic fibers innervating chest organs, the abdomen, the ear, the nose and the throat stimulation, and the stimulation of hiccup center in the central nervous system, mainly reflecting psychogenic or metabolic disorders) and the efferent pathway (phrenic nerves). An incidental hiccup is a common problem, usually resolves spontaneously and does not present a clinical issue. The clinical issue arises in the case of pathologic persistent hiccups or symptomatic secondary hiccups which may lead to significant fatigue, insomnia or depression. Generally, pathologic hiccups are associated with considerable discomfort concerning both the "stigmatized" person and his or her personal surroundings in which it evokes different emotions, from amusement through impatience to uneasiness and the suggestion of a medical visit as an expression of concern for a given person. The most common causes of pathologic symptomatic hiccups are nervous system diseases, either the central nervous system (proliferative, angiogenic, inflammatory disorders), or the peripheral nervous system: the irritation of the phrenic nerve (proliferative disorders, goitre) and the vagus nerve (otolaryngologic diseases, meningitis, esophageal, stomach and duodenal diseases, hepatitis, pancreatitis, enteritis). The vagus nerve irritation with subsequent hiccups may be caused by chest disorders (injury, surgery) and heart diseases (myocardial infarction). In the present paper we describe the case of a 62-year-old male with recurrent hiccups associated with exertion as a secondary symptom of myocardial ischemia.

A Nurse Contracts Tuberculosis on the Job, 1944 – 45

In our post-HIV/AIDS era, health care professionals know well the risks of infection and the need to practice universal precautions with all patients. Awareness of the dangers of infection grew in the late nineteenth century, although it had long been clear that caring for the sick entailed the risk of becoming ill. Moreover, prior to the development of antibiotics, nurses and others ministering to the sick contracted fatal and/or debilitating illnesses that had few or no effective treatments. Historians know little of these experiences. Constance Mally (pseudonym), a nurse working in the Sydenham Hospital, Baltimore, Maryland, in the 1940s was one such professional: she contracted tuberculosis when caring for patients. Letters about one part of Mally's experiences in the History of Medicine Division of the National Library of Medicine allow historians to explore a small part of the risks facing nurses working with patients suffering from contagious illnesses. They can also provide an important teaching tool to help students explore the complicated and complex historical dimensions of one particular experience. Health Department ran Sydenham Hospital for the isolation and treatment of communicable diseases. From 1909 until it closed in 1949-in large part because of the widespread use of antibiotics-the hospital had an average daily population of sixty patients, many of them children, with scarlet fever, smallpox, poliomyelitis, diphtheria, pneumonia, whooping cough, meningitis, syphilis, measles, chickenpox, and other contagious diseases. Patients stayed for weeks and sometimes months, nursed back to health with rest, a careful diet, and any available medical treatments. Hospital policy called for chest X-rays of new employees, and when Mally arrived at the hospital in September 1942 her lungs were clear. As the following letters reveal, within a few months she likely contracted tuberculosis from caring for a patient with fulminating infection and a tracheotomy tube. The patient died. A few years later, X-rays revealed a cavity in Mally's lung. Sent to a sanatorium in 1944, she underwent several operations and seemed to improve. Parts of Mally's experience are revealed in a set of letters exchanged between the hospital's medical director, the director of the city's Bureau of Tuberculosis, and the superintendent of the Maryland Tuberculosis Sanatoria. The letters do not make clear whether Mally fully recovered, left the sanatorium, and resumed her nursing career, although they suggest that such stren uous work after discharge would have been hazardous. They do reveal, however, how the hospital negotiated Mally's sick pay. Then, as now, hospitals kept a careful watch over their expenditures, balancing their need to support the workers who put their lives on the line with the interests of those paying the bills, in this case the taxpayers of Baltimore, who, through their elected officials, kept a tight rein over the budget. These letters also offer a window into other themes and issues in health care when analyzed within a broader context. Readers of these letters as well as those teaching history might want to use them to consider what has changed in hospitals, patient care, and medicine since the 1940s-and what has stayed the same. Here we would need more about the institution, about the work of nurses caring for contagious patients, and about the medical treatment of specific illnesses. Materials are available. The records of the Sydenham Hospital itself, including the correspondence regarding Mally, are located in the History of Medicine Division of the National Library of Medicine (for an online finding aid, see http://www.nlm.nih.gov/hmd/manuscripts/ead/sydenham.html). A brief history of the Sydenham hospital can be found in Baltimore's Sydenham Service for Hospital Care of Communicable Diseases 1909-1924-1949, Baltimore Health News, July 1949, 147-57; and an analysis of tuberculosis nursing can be found in Barbara Bates, Bargaining for Life: A Social History of Tuberculosis, 1876-1938 (Philadelphia: University of Pennsylvania Press, 1992). …

Recent Developments in Synthetic Oligosaccharide-Based Bacterial Vaccines

Synthetic advances made possible chemical assembly of complex oligosaccharide fragments of polysaccharide domains on the surface of human pathogenic bacteria. These oligosaccharides may be recognized by antibodies raised against high molecular weight, native, polysaccharides. In addition to their antigenicity, synthetic oligosaccharides can also function as haptens in their protein conjugates that can elicit not only oligo- but also polysaccharide-specific IgG antibodies in animal models and in humans. A major milestone in the development of new generation vaccines was the demonstration that protein conjugates of synthetic fragments of the capsular polysaccharide of Haemophilus influenzae type b are as efficacious in preventing childhood meningitis and other diseases as is the corresponding licensed commercial vaccine containing the bacterial polysaccharide. The lessons learnt in this and other endeavors described herein are manifold. For example, they teach us about the significance of the oligosaccharide epitope size, the number of their copies per protein in the conjugate, the possible effect of the spacer on anti-saccharide immune response, and the proper choice of the carrier protein combined with the selection of the animal model. The H. influenzae b story also teaches us that that the synthetic approach can be commercially viable.

Comparative evaluation of virulence and pathology of Streptococcus suis serotypes 2 and 9 in experimentally infected growers

Streptococcus ( S.) suis is an invasive porcine pathogen causing meningitis, septicemia, arthritis and other diseases. Studies on pathogenesis as well as vaccine trials have focused on serotype 2 strains, which are worldwide the most prevalent among invasive isolates. However, in Europe serotype 9 strains also contribute substantially to S. suis-associated invasive diseases of piglets. The objective of this study was to determine the virulence of an MRP* SLY+ serotype 9 S. suis strain in comparison to an MRP+ EF+ SLY+ serotype 2 strain. Experimental intranasal and intravenous infections of 7–8 weeks old SPF piglets were investigated with regard to clinic and pathology. In contrast to the virulent serotype 2 strain, the serotype 9 strain did not cause disease with clinical manifestations after intranasal administration. However, histological screenings of these animals revealed pathological lesions, such as mild focal suppurative meningitis. Clinical manifestations related to meningitis, arthritis and serositis could be induced by intravenous application of this serotype 9 strain. Bacteriological culture and immunohistochemistry of the brain confirmed association with the S. suis challenge strains in all cases with clinical manifestations. Interestingly, expression of MRP within meningitis lesions was demonstrated for both pathotypes via immunohistochemistry. In conclusion, this study demonstrates that MRP* SLY+ serotype 9 strains are less virulent for growers than MRP+ EF+ SLY+ serotype 2 strains. Thus, intravenous application of this serotype 9 strain is required to evaluate heterologous protection in the course of vaccine development based on serotype 2 strains in the future.

Childhood tuberculosis: old and new vaccines

The world is witnessing an escalation of the tuberculosis (TB) epidemic, particularly in sub-Saharan Africa and South-East Asia. The problem has been compounded by the evolution of the human immunodeficiency virus pandemic, the increase in multidrug-resistant TB and the emergence of extensively drug-resistant TB. This has led to renewed interest in vaccines aimed at preventing tuberculosis. The current Bacille Calmette-Guérin (BCG) vaccine prevents the invasive complications of childhood tuberculosis, such as meningitis and miliary disease, but provides variable protection against adult pulmonary disease. This review discusses the history of the BCG vaccine, the reasons for its variable efficacy, protective immunity and TB, and the evolution of and obstacles to development of new candidate vaccines. Several new TB vaccines have demonstrated promising results in animal models; a number have gone into phase I clinical trials in humans, and it is anticipated that phase III trials will commence by 2009. Licensing of an effective new TB vaccine by 2015 is thus a possibility.

Live attenuated Streptococcus pneumoniae strains induce serotype-independent mucosal and systemic protection in mice.

Streptococcus pneumoniae is an important human pathogen causing both mucosal (otitis media and pneumonia) and systemic (sepsis and meningitis) diseases. Due to increasing rates of antibiotic resistance, there is an urgent need to improve prevention of pneumococcal disease. Two currently licensed vaccines have been successful in reducing pneumococcal disease, but there are limitations with their use and effectiveness. Another approach for prevention is the use of live attenuated vaccines. Here we investigate the safety and protection induced by live attenuated strains of S. pneumoniae containing combinations of deletions in genes encoding three of its major virulence determinants: capsular polysaccharide (cps), pneumolysin (ply), and pneumococcal surface protein A (pspA). Both the cps and ply/pspA mutants of a virulent type 6A isolate were significantly attenuated in a mouse model of sepsis. These attenuated strains retained the ability to colonize the upper respiratory tract. A single intranasal administration of live attenuated vaccine without adjuvant was sufficient to induce both systemic and mucosal protection from challenge with a high dose of the parent strain. Immunization with cps mutants demonstrated cross-protective immunity following challenge with a distantly related isolate. Serum and mucosal antibody titers were significantly increased in mice immunized with the vaccine strains, and this antibody is required for full protection, as microMT mice, which do not make functional, specific antibody, were not protected by immunization with vaccine strains. Thus, colonization by live attenuated S. pneumoniae is a potentially safe and less complex vaccine strategy that may offer broad protection.

P2102 Pre-admission penicillin in patients with meningitis or meningococcal disease

P2102 Pre-admission penicillin in patients with meningitis or meningococcal disease

Is Mumps Making a Comeback?

Mumps is a viral disease caused by a paramyxovirus that exhibits glandular and nervous system tropism. It is a disease that has affected humankind for centuries. The classical clinical form of mumps was first described by Hippocrates in the fifth century BC as a disease associated with unilateral or bilateral swelling of the parotid glands and, in certain cases, unilateral or bilateral swelling of the testicles (1). Before the introduction of mumps vaccination, it was mainly a disease affecting children and young adults (2). Although mumps is a relatively benign disease in childhood, meningitis and orchitis are not uncommon complications in adults (1,2).

Prognostic Factors for Cryptococcosis

Cryptococcosis is usually an opportunistic infection in immunocompromised hosts. The causative agent, Cryptococcus neoformans , enters the body through the lungs. Infection ranges from asymptomatic colonization of the airways to meningitis or disseminated disease. In a prospective study involving 77 centers in France, researchers investigated prognostic parameters in patients with cryptococcosis. From 1997 through 2001, 230 patients were enrolled (57% of the cases …

CSF protein profiling using Multiplex Immuno-assay

The diagnosis of leptomeningeal metastases (LM) is based on clinical symptoms, magnetic resonance imaging (MRI) of brain and spine and cytological analysis of cerebrospinal fluid (CSF). The clinical picture of LM is highly variable and both cytological CSF analysis and contrast-enhanced MRI are limited in sensitivity. More sensitive tools are needed to diagnose LM. We measured a profile of proteins involved in adhesion and inflammation in the CSF of LM and control patients and determined their potential diagnostic value for LM. Using Multiplex Immuno-Assay (MIA), the CSF concentrations of nine soluble adhesion molecules, cyto- and chemokines were measured in patients with cytologically proven LM (n = 57) and control patients with a systemic malignancy (n = 20), aseptic/viral meningitis (n = 11) or other (non-)neurological diseases (n = 19). We found high CSF levels of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), soluble Intercellular Adhesion Molecule-1 (sICAM-1), Interleukin-8 (IL-8), Pulmonary and Activation Regulated Chemokine (PARC), Interleukin-18 (IL-18) and Interferon-gamma inducible protein (IP-10) in patients with LM. The CSF protein profile in LM patients differed significantly from the profile found in control patients. Multivariate logistic regression and ROC analysis showed that the MIA-measured CSF protein profile has an additive discriminating value for LM above standard CSF parameters. A combination of total protein, glucose, IL-8, PARC and IP-10 CSF levels proved to be most discriminative between LM and non-LM patients. Our results warrant a prospective study to determine whether a CSF protein profile, including IL-8, PARC and IP-10 has diagnostic value compared with CSF cytology, the golden standard for LM.

Parapharyngealabszess und Osteomyelitis im Bereich des Dens axis

We report the case of a 55 year old man with osteomyelitic destruction of the odontoid process and a parapharyngeal abscess. The patient was admitted with diagnosis of meningitis and degenerative cervical spine disease without compression of spinal cord or nerve roots but progressive impairment of cervical spine mobility. Inflammatory parameters in serum and cerebrospinal fluid were detected and antibiotic therapy was initiated resulting in subjective improvement of symptoms. When impairment of cervical spine motility persisted and gait disturbance developed, a parapharyngeal abscess and an osteomyelitic destruction of the odontoid process caused by infection with staphylococcus aureus was diagnosed. After cleavage of the abscess and four months of antibiotic therapy the gait disturbance disappeared and mild impairment of cervical spine motility persisted.

Characteristics of hearing-impairment among patients in Ghana

The causes, and characteristics of hearing-impairment were determined prospectively among six thousand, four hundred and twenty-eight (6,428) patients who reported at the Komfo Anokye Teaching Hospital (KATH) with hearing problems. The purpose of the study was to determine the characteristics and some causes of hearing loss of patients who report for management at Komfo Anokye Teaching Hospital. The procedure adopted included a detailed case history, Otoscopy and Pure-tone Audiometry. Of the 6,428 patients, 5,734 (89.9 %) were diagnosed as having significant hearing loss. There were more hearing impaired women than men at all ages. Majority of the patients had mild hearing loss. The overall prevalence of Sensorineural Hearing Loss was more in worse ear than better ear. Again, the occurrence of Sensorineural Hearing Loss was more than other types of hearing loss. Noise, Fever, Presbycusis, Sickness, Meningitis and Meniere's diseases were the major causes of Sensorineural Hearing Loss. Conductive Hearing Loss was attributed in the main to Wax, Foreign Bodies, Otitis Media, and Traumas. These findings have important implications on the need of resources for rehabilitation.

Meningitis recurrente aséptica secundaria a toma de ibuprofeno y ketorolaco

Aseptic meningitis is a process that is characterised by an inflammatory reaction of the meninges that is not due to any infectious agent. Its aetiology is varied and is most frequently caused by rheumatologic and/or autoimmune processes, chemical or medication-induced meningitis, the most notable drugs involved being antibiotics and non-steroidal anti-inflammatory drugs (NSAI). We report the case of a 70-year-old male, with no relevant history, who was admitted to hospital five times over a period of 16 months because of acute meningitis with polymorphonuclear pleocytosis, high protein levels in cerebrospinal fluid and normal glucose in cerebrospinal fluid. No evidence of an infectious causation, chemical meningitis, carcinomatosis or autoimmune disease was found and the patient was diagnosed with recurrent aseptic meningitis. It was found that the patient had taken ibuprofen or ketorolac on several occasions, a few hours before the appearance of symptoms. These episodes were quickly resolved after withdrawal of this medication. A number of NSAI have been reported as inducers of aseptic meningitis, one of the most notable being ibuprofen. We report the case of a patient who, as a consequence of taking ibuprofen and ketorolac, presented episodes of recurrent aseptic meningitis. To our knowledge this side effect of ketorolac has not been reported before. Its clinical features are impossible to differentiate from those of infectious meningitis. Diagnosis is reached by exclusion and a careful pharmacological study, including over-the-counter drugs like some of the NSAI, must be performed in patients with this condition, since it is a problem that can easily be solved by withdrawing the drug that causes it.

The Streptococcal Lipoprotein Rotamase A (SlrA) Is a Functional Peptidyl-prolyl Isomerase Involved in Pneumococcal Colonization

Streptococcus pneumoniae expresses two surface-exposed lipoproteins, PpmA and SlrA, which share homology with distinct families of peptidyl-prolyl isomerases (PPIases). In this study, we demonstrated for the first time that the lipoprotein cyclophilin, SlrA, can catalyze the cis-trans isomerization of proline containing tetrapeptides and that SlrA contributes to pneumococcal colonization. The substrate specificity of SlrA is typical for prokaryotic and eukaryotic cyclophilins, with Suc-Ala-Ala-Pro-Phe-p-nitroanilide (pNA) being the most rapidly catalyzed substrate. In a mouse pneumonia model the slrA knock-out D39DeltaslrA did not cause significant differences in the survival times of mice compared with the isogenic wild-type strain. In contrast, a detailed analysis of bacterial outgrowth over time in the nasopharynx, airways, lungs, blood, and spleen showed a rapid elimination of slrA mutants from the upper airways but did not reveal significant differences in the lungs, blood, and spleen. These results suggested that SlrA is involved in colonization but does not contribute significantly to invasive pneumococcal disease. In cell culture infection experiments, the absence of SlrA impaired adherence to pneumococcal disease-specific epithelial and endothelial non-professional cell lines. Adherence of the slrA mutant could not be restored by exogenously added SlrA. Strikingly, deficiency in SlrA did not reduce binding activity to host target proteins, but resulted in enhanced uptake by professional phagocytes. In conclusion, SlrA is a functional, cyclophilin-type PPIase and contributes to pneumococcal virulence in the first stage of infection, namely, colonization of the upper airways, most likely by modulating the biological function of important virulence proteins.

HIV-1 RNA levels in cerebrospinal fluid and plasma and their correlation with opportunistic neurological diseases in a Brazilian AIDS reference hospital

Plasma HIV RNA levels reflect systemic viral replication but in CNS it may occur relatively independent of systemic infection, yet clinical application of CSF HIV-1 RNA levels is less clear. To compare CSF and plasma HIV-1 RNA levels of patients with different opportunistic neurological diseases to those without neurological disease, as well as to correlate these levels with the outcome of the disease and use of HAART. 97 patients who had lumbar puncture for routine work up of suspected neurological diseases, were divided in 2 groups: without neurological disease (23) and with neurological disease (74). NASBA was used for plasma and CSF HIV RNA. Median CSF viral load was higher in toxoplasmic encephalitis, cryptococcal meningitis, HIV dementia and neurological diseases without a defined etiology when compared to patients without neurological disease. There was no difference between plasma viral load in patients with and without neurological diseases. Median viral load was higher in plasma and CSF among patients who died when compared to those successfully treated. CSF and plasma viral load were lower in patients with opportunistic diseases on HAART than without HAART. CSF viral load was higher in patients with any neurological disease, but this difference was not present in plasma viral load, suggesting that neurological disease influences more the CSF than plasma compartments. Notwithstanding different neurological diseases were not possible to be differentiated by the levels of CSF HIV-1.

Staphylococcal Infections

Staphylococcal Infections

Staphylococcal Infections

Staphylococcal Infections

The Role of Cryptococcal Antigen Assay in Diagnosis and Monitoring of Cryptococcal Meningitis

In a recent paper evaluating the significance of cryptococcal antigen test results for 29 Chinese human immunodeficiency virus (HIV)-negative patients affected by cryptococcal meningitis, Lu and colleagues (8) showed in all patients a decrease of antigen titer from the baseline following antifungal therapy and suggested that a decrease can be used to monitor antifungal therapy efficacy but cannot be used as an index of cure. We have reviewed our experience with 66 HIV-positive patients out of 118 with cryptococcal meningitis for whom at least three serial determinations (at baseline, day 7, and day 14) of cryptococcal antigen tests on cerebrospinal fluid (CSF) were available (1). A total of 440 determinations (range, 3 to 28 antigen determinations; median, 5 antigen determinations) were available, and for 55 patients the last determination was considered (median, 13 weeks; range, 2 to 84 weeks). In Fig. ​Fig.11 is depicted the kinetics of CSF cryptococcal antigen together with the results of CSF culture. Overall, 53 patients (80%) showed a decrease of CSF antigen titer from the baseline (7 of whom had negative results), as follows: 27 cases of 1 to 3 dilutions, 16 cases of 4 to 6 dilutions, and 10 cases of 7 or more dilutions. However, 13 out of 15 of these patients for whom postmortem examination was available, despite evidence of several intravitam negative CSF cultures, still had cryptococcal meningitis or disseminated disease at autopsy (demonstrated by histopathology). Eight patients had an increase in the CSF antigen titer (four of 1 to 3 dilutions and four of 4 to 8 dilutions), and five showed stable (i.e., the same value) results throughout the follow-up. All the patients but two with an increase of CSF antigen titer had persistent positive CSF culture and died; four underwent autopsy showing disseminated cryptococcosis. FIG. 1. Change over time of CSF cryptococcal antigen titers and correlation with CSF cryptococcal cultures in 66 HIV-positive patients. Data of CSF antigen are median values. Data regarding CSF cultures refers to the total number of patients (n = 66), ... Our experience regarding the role of cryptococcal antigen to monitor antifungal therapy in AIDS patients is in keeping with that previously reported by Powderly et al. (11), who showed the lack of any correlation of changes of CSF or serum cryptococcal antigen and the outcome of cryptococcal meningitis. However, a high CSF antigen level has been identified as a sign of poor prognosis in patients with AIDS (1, 7); interestingly, more recently Thay cohorts of HIV-positive patients with cryptococcal meningitis showed a significant positive correlation between CSF cryptococcal colony-forming units (CFU) and CSF cryptococcal antigen titers at baseline (P < 0.0001), but the rapid rate of decline in CSF CFU was not correlated with that in CSF cryptococcal antigen titers (2). As shown in Table ​Table1,1, regardless of the different hosts in whom cryptococcal meningitis is diagnosed, among all methods employed the cryptococcal CSF antigen had the best overall sensitivity (94.1%) followed by the serum antigen (93.6%). However, some differences were observed in the different categories of hosts, with lower sensitivity in AIDS and immunocompetent patients (92%) and higher sensitivity among the other immunocompromised hosts without HIV infection. Persistently elevated CSF cryptococcal antigen in HIV-infected patients carries a poor prognosis and indicates ongoing production of viable Cryptococcus neoformans in tissue. In conclusion, CSF cryptococcal antigen seems to be the best test for diagnosis of cryptococcal meningitis in terms of sensitivity, but it is an unreliable tool, at least among HIV-positive patients, to drive therapeutic monitoring, particularly in assessing the point of discontinuation of antifungal therapy in HIV-infected patients. TABLE 1. Efficiency of different techniques in the diagnosis of cryptococcal meningitis in different hostsa

Expression of the immune-tolerogenic major histocompatibility molecule HLA-G in multiple sclerosis: implications for CNS immunity

HLA-G is a non-classical major histocompatibility complex (MHC) class I antigen with highly limited tissue distribution under non-pathological conditions. Although capable of acting as a peptide-presenting molecule, its strong immune-inhibitory properties identify HLA-G as a mediator of immune tolerance with specific relevance at immune-privileged sites such as trophoblast or thymus. To assess the role of HLA-G in CNS immunity, we investigated its expression in brain specimens from patients with multiple sclerosis (n = 11), meningitis (n = 2) and Alzheimer's disease (n = 2) and non-pathological CNS controls (n = 6). Furthermore, cultured human microglial cells and CSF of patients with multiple sclerosis and controls were assessed. Furthermore, CSF from MS patients and controls, as well as cultured human microglial cells were assessed. Using several HLA-G specific mAb and immunohistochemistry, HLA-G protein was found strongly expressed in brain specimens from patients with multiple sclerosis while it was rarely detectable in the non-pathological control specimens. In multiple sclerosis brain specimens, HLA-G immunoreactivity was observed in acute plaques, in chronic active plaques, in perilesional areas as well as in normal appearing white matter. In all areas microglial cells, macrophages, and in part endothelial cells were identified as the primary cellular source of expression. HLA-G was also found in other disease entities (meningitis, Alzheimer's specimens) where expression correlated to activation and MHC class II expression on microglial cells. Importantly, ILT2, a receptor for HLA-G, was also found in multiple sclerosis brain specimens thus emphasizing the relevance of this inhibitory pathway in vivo. HLA-G mRNA and protein expression and regulation could also be corroborated on cultured human microglial cells in vitro. Further, expression of HLA-G in the CSF of multiple sclerosis patients and controls was analysed by flow cytometry and ELISA. Monocytes represented the main source of cellular HLA-G expression in the CSF. Corresponding to the observations with the tissue specimens, CSF mean levels of soluble HLA-G were significantly higher in multiple sclerosis than in non-inflammatory controls (171 +/- 31 versus 39 +/- 10 U/ml; P = 0.0001). The demonstration of HLA-G and its receptor ILT2 on CNS cells and in areas of microglia activation implicate HLA-G as a contributor to the fundamental mechanisms regulating immune reactivity in the CNS. This pathway may act as an inhibitory feedback aimed to downregulate the deleterious effects of T-cell infiltration in neuroinflammation.