On this page: Immune System Research, RNase L Research and Relevant Books - page 3 of 5

Chronic fatigue Syndrome: evaluation of a 30 criteria-score and correlation with immune activation. Hilgers A, Frank J. Journal of Chronic Fatigue Syndrome 1996; 2(4): 35-47.

Abstract: OBJECTIVE. The development of a score for severity of Chronic Fatigue Syndrome (CFS), the correlation of CFS with parameters of immune activation and the association with pathogens. METHODS. Five hundred five patients with suspicion of Chronic Fatigue Syndrome and no other definitive diagnosis were checked by a 45-criteria-score, basic laboratory programs and immunological profiles. In most of the patients further tests concerning complement system, immune activation markers, hormones and serology of herpesviruses, Chlamydia and Borrelia could be evaluated. Comparison of the symptoms of CFS patients with healthy controls lead to a 30-criteria-score and this score was correlated with laboratory parameters (Spearman rank-correlation-coefficient r(s), ties corrected). RESULTS. Three hundred eighty-five patients fulfilling stronger criteria according to the Centers for Disease Control (CDC) definition showed significant differences to 53 healthy controls in 40 of the 45 criteria (p< 0.001, twitches and food allergies p< 0.05). Thirteen symptoms corresponding to CDC criteria were all significant (p < 0.001), 17 further significant criteria of descending precision were added: respiratory infectins, palpitations, dizziness, dyspepsia, dryness of mouth/eyes, allergies, nausea, paresthesia, loss of hair, skin alterations, dyscoordination, chest pain, personality changes, eczema, general infections, twitches, urogenital infections. A correlation between the 30-criteria-score and immunological parameters could be evaluated in 472 of the 505 patients. Significant postive correlation with the 30-criteria-score was found in numbers of CD8+ T-lymphocytes, HLA-DR+ T-lymphocytes, gamma globulins, IgM, IgG, and for the number of types of autoantibodies (mainly ANA, ACA, antithyroid and antiparietal cell antibodies). Significant negative correlation was found in albumin-globulin-ratio, eosinophils and IgE. Most of these parameters also correlated with one another. On the other hand, in subgroups of the 505 patients the frequency of positivity in serological tests for HHV-6 (49.9%), EBV (35.4%), HSV (29.2%), CMV (12.5%) and Chlamydia (35.0%) was striking. Borrelia Western blots showed 3 or more specific IgG-bands in 54 of 131 patients (41.2%). In some cases infection with EBV, HHV-6 and CMV, respectively, was confirmed by DNA-PCR-test and antigen detection. SUMMARY. In increasingly larger groups of patients with CFS and related constellations we often see clinical signs and longer anamnesis of other symptoms besides the classical criteria of CFS, especially a high prevalence of local and general susceptibility to infections and hints to prolonged inflammation processes. Together with other results, the data confirm the hypothesis that a reduced or unstable immune control or delayed immune reaction to persisting viruses or bacterial intracellular pathogens, possibly triggered by common infections or other environmental factors, can lead to a chronic neuroimmune activation state and auto-immune disorders. Hypersensitivity symptoms of the patients might not be mediated by classical allergies alone but also result from a type-IV-hypersensitivity.

Antibodies to Epstein-Barr virus-specific DNase and DNA polymerase in the chronic fatigue syndrome. Jones JF, Williams M, Schooley RT, Robinson C, Glaser R. Archives of Internal Medicine 1988; 148: 1957-60.

Abstract: In an attempt to examine further the association between active Epstein-Barr virus (EBV) infection and the chronic fatigue syndrome (chronic EBV syndrome, or chronic or atypical mononucleosis), antibodies acting against EBV-specific DNase and DNA polymerase, which are expressed only during virus replication, were assayed. Serum samples from 25 healthy EBV-seropositive individuals neutralized 3.5 ± 5.1 U (mean ± SD) of DNase activity and 14.7 ± 8.5 U of DNA polymerase activity. From these values were selected upper limits of anti-EBV enzyme activity of 17.9 and 31.3 U neutralized in normal individuals, respectively (representing the 95% confidence limit). Serum samples from six groups of subjects representing a variety of EBV-related illnesses were then studied. Only patients with notably elevated anti-EBV antibody titers to viral capsid antigen (VCA) (greater than 10,000) had elevated levels of anti-EBV DNase (38 to 56 U neutralized) and anti-EBV DNA polymerase (72 to 106 U neutralized). Three additional patients and two geriatric controls with average anti-EBV early antigen/VCA titers had slightly elevated levels of antibody to EBV DNA polymerase. IgA anti-VCA, anti-early antigen antibodies, or both, were also detected in the same patients who had high EBV DNase and polymerase antibody levels. These antibody profiles are similar to those in patients with nasopharyngeal carcinoma. Since three of the six patients with elevated anti-EBV enzyme antibody levels developed fatal lymphomas, patients with chronic EBV and this antibody profile might be in another illness category at risk for malignant disease.

Immunologic abnormalities in chronic fatigue syndrome. Klimas NG, Salvato FR, Morgan R, Fletcher MA. Journal of Clinical Microbiology 1990; 28: 1403-10.

Abstract: The chronic fatigue syndrome (CFS), formerly known as chronic Epstein-Barr virus syndrome, is a clinical state of some complexity and uncertain etiology. In order to characterize in a comprehensive manner the status of laboratory markers associated with cellular immune function in patients with this syndrome, 30 patients with clinically defined CFS were studied. All of the subjects were found to have multiple abnormalities in these markers. The most consistent immunological abnormality detected among these patients, when compared with normal controls, was low natural killer (NK) cell cytotoxicity. The number of NK cells, as defined by reactivity with monoclonal antibody NKH.1 (CD56), was elevated, but the killing of K562 tumor cells per CD56 cell was significantly diminished. Lymphoproliferative responses after stimulation with phytohemagglutinin and pokeweed mitogen were decreased in most patients when compared with those in normal controls, as was the production of gamma interferon following mitogen stimulation. Lymphocyte phenotypic marker analysis of peripheral blood lymphocytes showed that there were significant differences between patients with CFS and controls. There was an increase in the percentage of suppressor-cytotoxic T lymphocytes, CD8, and a proportionally larger increase in the number of CD8 cells expressing the class II activation marker. Most patients had an elevated number of CD2 cells which expressed the activation marker CDw26. The numbers of CD4 cells and the helper subset of CD4+CD29+ cells in patients with CFS were not different from those in controls. There was, however, a significant decrease in the suppressor inducer subset of CD4+ CD45RA+ cells.

Autoantibodies to nuclear envelope antigens in chronic fatigue sydrome. Konstantinov K, von Mikecz A, Buchwald D, Jones J, Gerace L, Tan EM. Journal of Clinical Investigation 1996; 98(8): 1888-96.

Abstract: We have identified and partially characterized the autoantibodies in sera of 60 patients with chronic fatigue syndrome. Approximately 52% of the sera were found to react with nuclear envelope antigens. The combination of nuclear rim staining observed in immunofluorescence microscopy and immunoblot analysis of highly purified nuclear envelope proteins provided initial characterization of these autoantibodies. Further characterization showed that some sera immunoprecipitated the in vitro transcription and translation product of a human cDNA clone encoding the nuclear envelope protein lamin B1. The autoantibodies were of the IgG isotype. The occurrence of autoantibodies to a conserved intracellular protein like lamin B1 provides new laboratory evidence for an autoimmune component in chronic fatigue syndrome.

Chronic fatigue syndrome - clinical condition associated with immune activation. Landay AL, Jessop C, Lennette ET, Levy JA. Lancet 1991; 338: 707-12.

Abstract: There is much conflicting immunological and viral data about the causes of chronic fatigue syndrome (CFS); some findings support the notion that CFS may be due to one or more immune disorders that have resulted from exposure to an infectious agent. In the present study, flow cytometry and several different monoclonal antibodies recognising T, B, and natural killer (NK) cell populations as well as activation and cell adhesion antigens were used to study 147 individuals with CFS. Compared with healthy controls, a reduced CD8 suppressor cell population and increased activation markers (CD38, HLA-DR) on CD8 cells were found. The differences were significant (p = 0.01) in patient with major symptoms of the disease. These immunological indices were not observed in 80 healthy individuals, in 22 contacts of CFS patients, or in 43 patients with other diseases. No correlation of these findings in CFS patients with any known human viruses could be detected by serology. The findings suggest that immune activation is associated with many cases of CFS.

Immunological abnormalities in the chronic fatigue syndrome. Lloyd AR, Wakefield D, Boughton CR, Dwyer JM. Medical Journal of Australia 1989; 151: 122-4.

Abstract: The chronic fatigue syndrome is a disorder of unknown aetiology which is characterized by debilitating fatigue. Recent evidence has suggested that viruses may persist in the tissues of patients with chronic fatigue syndrome. A concurrent immunological disturbance is likely to be associated with the persistence of viral antigens. Therefore, the humoral and cellular immunity of 100 patients who were suffering from chronic fatigue syndrome and that of 100 healthy, age- and sex-matched control subjects were compared. This study documents the frequent occurrence of abnormalities within the cellular and humoral immune systems of patients with well-defined chronic fatigue syndrome. Disordered immunity may be central to the pathogenesis of chronic fatigue syndrome. In patients with chronic fatigue syndrome, a significant (P less than 0.01) reduction was found in the absolute number of peripheral blood lymphocytes in the total T-cell (CD2), the helper/inducer T-cell (CD4) and the suppressor/cytotoxic T-cell (CD8) subsets. A significant (P less than 0.001) reduction also was found in T-cell function, which was measured: in vivo by delayed-type hypersensitivity skin-testing (reduced responses were recorded in 50 [88%] of 57 patients); and in vitro by phytohaemagglutinin stimulation. Reduced immunoglobulin (Ig) levels were common (56% of patients), with the levels of serum IgG3- and IgG1-subclasses particularly (P less than 0.05) affected.

Immunity and the pathophysiology of chronic fatigue syndrome. Lloyd AR, Wakefield D, Hickie I. Ciba Foundation Symposium 1993; 173: 176-87.

Abstract: The pathophysiology of chronic fatigue syndrome (CFS) remains unknown. The syndrome often follows a recognized or presumed infection and the disorder may therefore result from a disordered immune response to a precipitating infection or antigenic challenge. Abnormalities of both humoral and cellular immunity have been demonstrated in a substantial proportion of patients with CFS. The most consistent findings are of impaired lymphocyte responses to mitogen and reduced natural killer cell cytotoxicity. Cutaneous anergy and immunoglobulin G subclass deficiencies have also been found. Further studies are needed examining cytokine levels in serum and cerebrospinal fluid, and cytokine production in vitro in patients with CFS. Interpretation of the findings of published studies of immunity is limited by probable heterogeneity in the patient groups studied, and by the lack of standardization and reproducibility in the assays used. The pattern of abnormalities reported in immunological testing in patients with CFS is consistent with the changes seen during the resolving phases of acute viral infection. These data provide circumstantial support for the hypothesis that CFS results from a disordered immune response to an infection. Longitudinal studies of immunity in patients developing CFS after defined infectious illnesses will provide the best means of further examining this hypothesis.

Relationships of cognitive difficulties to immune measures, depression and illness burden in CFS. Lutgendorf S, Klimas NG, Antoni M, Brickman A, Fletcher MA. Journal of Chronic Fatigue Syndrome 1995; 1(2): 23-41.

Abstract: OBJECTIVE. We related the subjective assessment of cognitive difficulties with lymphocyte phenotypes, cell-mediated immunity (CMI), cytokine and neopterin levels in patients with chronic fatigue syndrome (CFS), in order to determine if CFS patients complaining of greater cognitive difficulties would show greater impairments in cell-mediated immunity and a greater degree of immune system dysregulation, and to determine if these cognitive difficulties would correlate with the other non-affective measures of CFS-associated illness burden. We also assessed whether these relationships would hold independent of depression in two ways, by statistically covarying depression severity scores and by comparing subsets of CFS patients with and without a concurrent diagnosis of major depressive disorder. DESIGN. A case series of CFS patients. SETTING. Outpatient tertiary referral clinic at the Unversity of Miami School of Medicine, Miami, FL. PATIENTS. Consecutive sample of 65 patients who were referred as CFS to the University of Miami Diagnostic Immunology Clinic, who met the Centers for Disease Control and Prevention (CDC) criteria for diagnosis of CFS and consented to participate. MAIN MEASURES. Self-assessment of cognitive difficulties, depression and illness burden, clinician-assessed depression and CFS symptoms, lymphocyte phenotype, proliferative response to mitogens, serum levels of cytokines and neopterin. RESULTS. Among CFS patients, high Cognitive Difficulty Scale (CDS) scores were significantly related to lower lymphocyte proliferative responses to mitogens, higher neopterin levels, and higher CD4 and lower CD8 lymphocyte counts. These relationships, with the exception of T cell subset percentages, were maintained when depression severity was used as a co-variate. High CDS scores were also significantly related to lower Karnofsky scores, and greater illness burden as measured by the Sickness Impact Profile. Evidence is presented that CFS patients with higher cognitive difficulty scores have more immune and clinical dysfunction than those with less cognitive difficulty, and that these relationships are independent of depression. These observations provide support for the concept that although both cognitive difficulties and immunologic abnormalities, such as immune activation and impaired cell-mediated immunity, may represent secondary sequelae to the same event(s), they are not likey to be secondary sequelae to depression.

Cell-mediated immunity in patients with myalgic encephalomyelitis syndrome. N Murdoch JC. ew Zealand Medical Journal 1988; 101: 511-2.

Abstract: Cell-mediated immunity was measured in 33 patients with myalgic encephalomyelitis syndrome and 33 age and sex matched controls, using the multitest CMI device. The multitest scores in myalgic encephalomyelitis syndrome were significantly less than the controls suggesting a T-cell abnormality in these patients.

Dysregulated expression of tumor necrosis factor in chronic fatigue syndrome - interrelations with cellular sources and patterns of soluble immune mediator expression. Patarca R, Klimas NG, Lutgendorf S, Antoni M, Fletcher MA. Clinical Infectious Diseases 1994; 18(Supp 1): S147-53.

Abstract: Among a group of 70 individuals who met the criteria established by the Centers for Disease Control and Prevention (Atlanta) for chronic fatigue syndrome (CFS), 12%-28% had serum levels exceeding 95% of control values for tumor necrosis factor (TNF) alpha, TNF-beta, interleukin (IL) 1 alpha, IL-2, soluble IL-2 receptor (sIL-2R), or neopterin; overall, 60% of patients had elevated levels of one or more of the nine soluble immune mediators tested. Nevertheless, only the distributions for circulating levels of TNF-alpha and TNF-beta differed significantly in the two populations. In patients with CFS-but not in controls-serum levels of TNF-alpha, IL-1 alpha, IL-4, and sIL-2R correlated significantly with one another and (in the 10 cases analyzed) with relative amounts (as compared to beta-globin or beta-actin) of the only mRNAs detectable by reverse transcriptase-coupled polymerase chain reaction in peripheral-blood mononuclear cells: TNF-beta, unspliced and spliced; IL-1 beta, lymphocyte fraction; and IL-6 (in order of appearance). These findings point to polycellular activation and may be relevant to the etiology and nosology of CFS.

Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. Peterson PK, Sirr SA, Grammith FC, Schenck CH, Pheley AM, Hu S, Chao CC. Clinical and Diagnostic Laboratory Immunology 1994; 1(2): 222-6.

Abstract: Chronic fatigue syndrome (CFS) is an idiopathic disorder characterized by fatigue that is markedly exacerbated by physical exertion. In the present study, we tested the hypothesis that mild exercise (walking 1 mph [1 mile = 1.609 km] for 30 min) would provoke serum cytokine and cerebral blood flow abnormalities of potential pathogenic importance in CFS. Interleukin-1 beta, interleukin-6, and tumor necrosis factor alpha were nondetectable in sera of CFS patients (n = 10) and healthy control subjects (n = 10) pre- and postexercise. At rest, serum transforming growth factor beta (TGF-beta) levels were elevated in the CFS group compared with the control group (287 ± 18 versus 115 ± 5 pg/ml, respectively; P < 0.01). Serum TGF-beta and cerebral blood flow abnormalities, detected by single-photon emission-computed tomographic scanning, were accentuated postexercise in the CFS group. Although these findings were not significantly different from those in the control group, the effect of exercise on serum TGF-beta and cerebral blood flow appeared magnified in the CFS patients. Results of this study encourage future research on the interaction of physical exertion, serum cytokines, and cerebral blood flow in CFS that will adopt a more rigorous exercise program than the one used in this study.

Naloxone-reversible monocyte dysfunction in patients with chronic fatigue syndrome. Prieto J, Subira ML, Castilla A, Serrano M. Scandinavian Journal of Immunology 1989; 30: 13-20.

Abstract: We studied monocyte function in 35 consecutive patients with chronic fatigue syndrome (CFS) and 25 healthy controls. Eighty-five per cent of the patients showed monocyte dysfunction characterized by marked reduction in the number of monocytes displaying immunoreactive cytoskeletal vimentin filaments, a low phagocytosis index, and a reduced expression of HLA-DR antigens. These values increased dramatically after incubation of the patients' monocytes with the opioid antagonist naloxone. Other immunological abnormalities also noted in the patients were low lymphocyte blastogenesis and diminished numbers of monocytes displaying receptors for Fc of IgG (FcR) and C3b (CR1). These findings suggest that an increased opioid activity acting through a classical receptor mechanism is active on monocytes from a high proportion of patients with CFS and that this represents a novel example of immunomodulation by opioid peptides in human disease. We suggest that endogenous opioids are involved in the pathogenesis of the chronic fatigue syndrome.

Long term improvements in patients with chronic fatigue syndrome treated with Ampligen. Strayer DR, Carter W, Strauss KI, Brodsky I, Suhadolnik RJ, Ablashi D, Henry B, Mitchell WM, Bastein S, Peterson D. Journal of Chronic Fatigue Syndrome 1995; 1(1): 35-53.

Abstract: Fifteen patients who fit the CDC definition of chronic fatgiue syndrome (CFS) and had evidence of severe reduction in performance levels by low Karnofsky performance scores (KPS) of 20 - 60 were treated with Ampligen. At baseline most patients showed evidence of cerebral dysfunction by neuropsychological testing, were antigen positive by cell culture assay for human herpesvirus-6 (HHV-6), and displayed reduced performance during exercise tolerance testing, as measured by oxygen consumption. These patients represented a subset of CFS patients with especially severe and sustained symptomatology. Following 12 - 48 weeks of Ampligen therapy, sustained improvements were noted in KPS (p< .01) Cognitive function improved including IQ and memory. Oxygen uptake and treadmill duration during exercise tolerance testing was also improved after 24 weeks of treatment (p< 0.01). Reduction in HHV-6 expression as measured by the giant cell assay was significant (p< 0.001). Patients continued to show significant improvement late in therapy, taking 8 to 12 weeks as baseline. It was concluded that while receiving Ampligen, the severely afflicted patients studied here derived long-lasting clinical benefit from the Ampligen therapy. .

Page 5: RNase L Research and Relevant Books

Page 1: Immune System Research

Page 2: Immune System Research (continued)

Page 3: Immune System Research (continued)