Hungarian Immunology

[The role of nerve growth (NGF) factor in the immune and inflammatory events and in autoimmune thyroid diseases]

MOLNÁR Ildikó

MARCH 20, 2006

Hungarian Immunology - 2006;5(02)

[Nerve growth factor (NGF) is a neurotroph cytokine, and beside its effect on the central and peripheral nervous systems NGF plays an important role in the inflammatory and autoimmune processes. There are two types of NGF receptors, the high-affinity (TrkA) and the low-affinity (p75), which activations via signal transduction could lead to the inhibition or induction of apoptosis. Suppression of apoptosis could be induced by cytokines, hormones, antioxidans and increased intracellular Ca2+-levels. In the pathogenesis of many autoimmune diseases (systemic lupus erythematosus, 1-type diabetes mellitus, multiple sclerosis) could detect elevated serum levels of NGF associated with the disease activity. Our study demonstrated increased levels of NGF in autoimmune thyroid diseases (Graves’ disease, Hashimoto’s thyroiditis) in comparison with the controls. Decreased serum levels of NGF were found in Graves’ ophthalmopathy suggesting the role of apoptosis in the development of the eye symptoms. Orbital tissues are characterized with the high expression of TrkA receptors. NGF plays an important role in the pathomechanisms of neuro-immuno-hormonal diseases and its knowledge may be helpful in the diagnosis and therapy.]

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Hungarian Immunology

[Paraneoplastic diseases of the locomotor system]

ANDRÁS Csilla, SZÁNTÓ János, SZEKANECZ Zoltán, CSIKI Zoltán, ILLÉS Árpád, SZEKANECZ Éva, DANKÓ Katalin

[Paraneoplasias in rheumatology can be present in different forms of arthropathies, myopathies. In addition, we often see atypical forms of systemic autoimmune diseases. Vasculitis is mainly associated with lymphoproliferative diseases. The direct invasion of bones and joints is not present in paraneoplasia, as this entity is a collection of symptoms generated by the tumour itself by producing biologic mediators, hormones, peptides, antibodies, cytotoxic lymphocytes, autocrine and paracrine mediators. Recognition of paraneoplasia is of outmost importance because it attires attention to the presence of tumour in the organism and thus enables us for early treatment of the malignancy. Monitoring of the severity of paraneoplastic symptoms serves as a marker for determination of efficacy of the targeted oncological therapy. On the other side, because these severe symptoms affect the patient's quality of life and can lead even to death their in time recognition and treatment is extremely important.]

Hungarian Immunology

[Familial autoinflammatory syndromes]

ORBÁN Ilonka, BALOGH Zsolt

[A group of rare inherited disorders, the familial autoinflammatory syndromes are characterised by attacks of seemingly unprovoked inflammation without significantly elevated autoantibody and autoreactive T cell levels. The rare diseases are present from infancy to lifelong, with periodic fever attacks and usually are accompanied by recurrent systemic inflammatory symptoms such as abdominal pain, diarrhoea, rash, arthralgia, polyarthritis, polyserositis, ocular disorders are separated by symptom-free intervals. Referred to as hereditary periodic fever syndromes appear by spontaneous crisis attacks and reveal a severe acute-phase response during the fever. In their pathogenesis there are no evidence neither of infection nor the common characteristics for autoimmune diseases: the production of high-titer auto-antibodies and antigenspecific T cell activation. The basic disease mechanism consists of the recently identified mutations in genes enconding important proteins: pyrin, cryopyrin, tumour necrosis factor (TNF) receptor and other mediators of apoptosis, inflammation and morbid citokine processing. The differential diagnosis of the diseases is not easy, their treatment is not resolved, although in same cases the biological treatment may be efficacious.]

Hungarian Immunology

[Molecular mechanisms and clinical importance of the RANK - RANK ligand - osteoprotegerin system]

SZENTPÉTERY Ágnes, BALOGH Ádám, VARJÚ Tibor, SZEKANECZ Zoltán

[The receptor activator of nuclear factor κB ligand (RANKL) is an essential cytokine for the formation and activation of osteoclasts. RANK, expressed on osteoclasts, interacts with RANKL, produced by osteoblasts and stromal cells. RANK-RANKL interaction is involved in osteoclastogenesis and bone resorption underlying metabolic bone diseases, arthritis, malignant bone disorders and some vascular diseases. Osteoprotegerin (OPG) physiologically counterbalance the action of RANKL. Several factors including estrogens, citokines and others regulate the RANKL-OPG ratio and thus bone resorption. RANKL blockade using recombinant OPG or anti-RANKL antibody may prevent bone loss in osteoporosis, chronic inflammatory and vascular disorders, as well as tumors. Active vaccination and gene therapy are further future perspectives in therapy. All these treatment modalities may be included in the future management of bone and vascular diseases.]

Hungarian Immunology

[Clinical and immunoserological characteristics of mixed connective tissue disease (MCTD) associated with pulmonary arterial hypertension (PAH)]

VÉGH Judit, CSÍPŐ István, UDVARDY Miklós, KAPPELMAYER János, LAKOS Gabriella, ALEKSZA Magdolna, ZEHER Margit, SZEGEDI Gyula, BODOLAY Edit

[INTRODUCTION - The authors investigated the clinical characteristics, survival, accumulated damage index and immunoserological abnormalities in patients with mixed connective tissue disease (MCTD) associated with pulmonary arterial hypertension (PAH). PATIENTS AND METHODS - Anti-U1RNP autoantibodies, anti-endothelial cell antibodies, anti-cardiolipin antibodies and serum trombomodulin as well as von Willebrand factor antigen concentrations were measured in 25 patients with MCTD associated with PAH (11 right heart catheterization and 14 Doppler echocardiography) and in 154 MCTD patients without PAH. Changes in arterial pulmonary pressure were followed up by echocardiography. RESULTS - In the 25 patients PAH followed MCTD diagnosis in the average 11.6±4.5 years of the diseases. The probability of survival was lower in MCTD patients with PAH than in the 154 non-PAH MCTD patients (five years survival rate in MCTD with PAH: 73.39%, vs. 96.43% in non PAH MCTD; p<0.01; 10 years survival rate 86.74% vs. 93.25%; p<0.01). Anti-endothelial cell antibodies were more frequently present in MCTD patients sera with PAH than in non PAH MCTD (p<0.001). Serum trombomodulin and vWFAg levels were higher in MCTDPAH patients than in non PAH MCTD patients (trombomodulin:34.2±15.3 ng/ml vs. 11.8±6.5 ng/ml; p<0.001; vWFAg: 311.1±147% vs. 172.5± 141%. Significant correlations were noticed between the quantity of anti-endothelial cell antibodies and serum trombomodulin level (r=0.466) as well as the quantity of anti-endothelial cell antibodies and vWFAg serum level (r=0.550). CONCLUSION - Survival probability was worse for MCTD patients with PAH than for non PAH MCTD patients. Our results suggest that in MCTD the presence of anti-endothelial cell antibodies and endothelial cell activation may play a role in the development of pulmonary arterial hypertension and in the maintenance of obliterative vascular processes.]

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[Several types of diseases, among others autoimmune illnesses, could be coupled with the general processes of aging. The two-edged sword of the immune defense is directed once against environmental attacks and on the other side against the self. However, one has to make a difference between normal (physiological) clearance and autoimmune diseases, although both sides of autoimmunity are influenced by the general processes of senescence. Aging of the thymus seems to be one of the key elements of the etiology of autoimmunity, although other cell types and their aging also play a substantial role in this process. The spontaneous genetic instability, the acquired genetic mutations due to aging and the age-related alterations of the information level of the body together may be important elements of the patomechanism of both the physiological autoimmunity and the autoimmune diseases. Nevertheless, physiological autoimmunity seems to be directed mostly by natural factors (such as aging and apoptosis) but primary autoimmune diseases may be caused by genetic instability that is enhanced by aging as well.]

Hungarian Immunology

[Therapeutic treatment of rheumatoid arthritis by gene therapy-induced apoptosis]

WOODS M. James, VOLIN V. Michael

[Gene therapy was initially conceptualized as a treatment for individuals with genetic disorders, where defective genes would be replaced with functional ones. This concept was eventually broadened to include the use of gene therapy as a delivery mechanism for gene products effective in the treatment of diseases. The latter use of gene therapy, essentially as a drug delivery mechanism, was recognized to be particularly useful in the treatment of rheumatoid arthritis because it may have many advantages over traditional therapies. Two groups of target genes that are potentially useful for gene transfer include soluble inflammatory mediators that in theory could suppress the inflammatory process, and apoptotic mediators that may induce cell death, thereby suppressing the accumulation of inflammatory cells in the joint. To date the former group of target genes has received most of the attention, but it is the latter group of apoptosis-inducing targets that will be discussed in this review. We will focus our discussion on target genes that have shown success at inducing apoptosis in animal models of arthritis and will also include discussion of the apoptotic pathways that are altered in the attempts to reduce inflamed synovial tissue.]

Clinical Neuroscience

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[Blockade of retrograde transport of nerve growth factor (NGF) in a peripheral sensory nerve is known to induce transganglionic degenerative atrophy (TDA) of central sensory terminals in the upper dorsal horn of the related, ipsilateral segments(s) of the spinal cord. The ensuing temporary blockade of transmission of nociceptive impulses has been utilized in the therapy of intractable pain, using transcutaneous iontophoresis of the microtubule inhibitors vincristin and vinblastin, drugs which inhibit retrograde transport of NGF. Since microtubule inhibition might inhibit (at least theoretically) mitotic processes in general, we sought to find a drug which inhibits retrograde transport of NGF without microtubule inhibition. Vinpocetine, a derivate of vincamine, which does not interfere with microtubular function, was found to inhibit retrograde axoplasmic transport of NGF in peripheral sensory nerves, similarly to vincristin and vinblastin. Blockade of NGF transport is followed by transganglionic degenerative atrophy in the segmentally related, ipsilateral superficial spinal dorsal horn, characterized by depletion of the marker enzymes of nociception, fluoride resistant acid phosphatase (FRAP) and thiamine monophosphatase (TMP) from the Rolando substance and by decrease of the pain-related neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) from lamina I-II-III. Based upon these findings, it has been suggested that vinpocetine may result in a locally restricted decrease of nociception. Herewith, the structural and behavioral effects of perineurally administered vinpocetine are discussed. Nociception, induced by intraplantar injection of formalin, was mitigated by perineural application of vinpocetine; also formalin-induced expression of c-fos in the ipsilateral, segmentally related superficial dorsal horn, was prevented by this treatment. Since vinpocetine is not a microtubule inhibitor, its mode of action is enigmatic. It is assumed that the effect of vinpocetine might be related to interaction with membrane-trafficking proteins, such as signalling endosomes and the endocytosis-mediating „pincher” protein, involved in retrograde axoplasmic transport of NGF, or to interaction with glial elements, recently reported to be involved in the modulation of pain in the spinal cord. Based on animal experiments it is assumed that the temporary, locally restricted decrease of nociception, induced by vinpocetine applied via transcutaneous iontophoresis, might open up new avenues in the clinical treatment of intractable pain.]

Clinical Neuroscience

[EXPERIMENTAL DEMYELINATION CAUSED BY PRIMARY OLIGODENDROCYTE DYSTROPHY Regional distribution of the lesions in the nervous system of mice brain]

KOMOLY Sámuel

[Background and purpose - Heterogeneity of multiple sclerosis lesions has been recently indicated: In addition to T-cell-mediated or T-cell plus antibody-mediated autoimmune mechanisms (patterns I-II) two other patterns (III-IV) were described. Patterns III-IV are characterized by primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. It was described more than 30 years ago that dietary application of a copper-chelating agent called cuprizone results in primary oligodendrocyte degeneration which is followed by demyelination. The aim of the present study was to examine the regional distribution of cuprizone induced oligodendrocyte dystrophy and demyelination in the nervous system of mice. Material a methods - Demyelination was induced in male weanling Swis-Webster mice by feeding them on a diet containing 0.6% (W/W) cuprizone bis(cyclohexanone)-oxalyldihydrazone (G. F. Smith Chemical, Columbus OH) for 8 weeks. Animals were sacrificed after 3, 7, 14, 27, 35, 56 days of cuprizone administration. Samples were taken from corpus callosum, anterior commissure, optic nerve, cervical spinal cord and sciatic nerve. Samples were examined by immunohistochemistry, in situ hybridization for myelin proteins and myelin protein mRNA-s, respectively. Conventional neuropathological stainings and electron microscopy was also performed. Results - Oligodendrocyte degeneration and demyelination followed a particular standard pattern in the central nervous system. Profound myelin loss developed in the superior cerebellar peduncle, anterior comissure and corpus callosum, whereas the optic nerves, velum medullare anterior and spinal cord showed little or no demyelination. Sciatic nerves were unaffected. No infiltration by lymphocytes or blood-brain barrier damage was observed during cuprizone treatment. Conclusion - Cuprizone induced oligodendrocyte damage and demyelination follows a particular standard pattern in the central nervous system of mice. Cuprizone induced demyelination might be considered as a model for human demyelinating disorders with primary oligodendrocyte dystrophy and apoptosis.]