       Document 0015
 DOCN  M9580015
 TI    Interferon-gamma, interleukin-4 and transforming growth factor-beta mRNA
       expression in multiple sclerosis and myasthenia gravis.
 DT    9506
 AU    Link J; Department of Clinical Neuroscience and Family Medicine,;
       Karolinska Institute, Stockholm, Sweden.
 SO    Acta Neurol Scand Suppl. 1994;158:1-58. Unique Identifier : AIDSLINE
       MED/95250431
 AB    BACKGROUND. Multiple sclerosis (MS) is characterized by perivascular
       inflammation and high levels of circulating T and B lymphocytes that
       respond to the myelin antigens myelin basic protein (MBP) and
       proteolipid protein (PLP), thereby suggesting a role for
       immunoregulatory cytokines. MATERIALS AND METHOD. Blood mononuclear
       cells (MNC) were prepared from patients with MS, optic neuritis (ON),
       myasthenia gravis (MG), other inflammatory (OIND) and non-inflammatory
       neurological diseases (OND), and from patients with HIV infection and
       healthy controls. MNC expressing cytokine mRNA were detected by in situ
       hybridization with radiolabelled cDNA oligonucleotide probes. Numbers of
       cytokine mRNA expressing cells were presented per standard numbers of
       MNC. RESULTS. MS patients had elevated numbers of MNC in blood
       expressing T helper type 1 (Th1) cell related interferon-gamma
       (IFN-gamma), Th2 cell associated interleukin-4 (IL-4) and the
       endogenously produced immunosuppressant transforming growth factor-beta
       (TGF-beta). IFN-gamma and TGF-beta correlated with MS disability: EDSS
       score < 3 was associated with high numbers of TGF-beta mRNA positive
       cells while IFN-gamma mRNA positive cells tended to be low. The reverse
       was seen in patients with EDSS > or = 3. Cultures of MNC in presence and
       absence of antigen revealed that MBP and PLP induced strong responses in
       MS reflected by high levels of IFN-gamma, IL-4 and TGF-beta mRNA
       expressing cells. Recombinant (r) TGF-beta 1 dose-dependently suppressed
       MBP-induced upregulation of the proinflammatory cytokines IFN-gamma,
       IL-4, IL-6, tumor necrosis factor-alpha, (TNF-alpha), TNF-beta and
       perforin, but not of the immunosuppressive and probably advantageous
       IL-10. Cytokine mRNA expressing cells were enriched in the MS patients'
       cerebrospinal fluid, as were the cytokine mRNA positive cells detected
       after culture in presence of MBP and PLP, reflecting an autonomy of the
       immune response in this compartment. ON, in many instances representing
       early MS, did not differ from clinically definite MS regarding profiles
       of IFN-gamma, IL-4 and TGF-beta. Also patients with MG had elevated
       numbers of IFN-gamma, IL-4 and TGF-beta mRNA expressing blood MNC. They
       were further augmented upon culture of the MG patients' MNC in presence
       of acetylcholine receptor (AChR). An upregulation of AChR-induced
       TGF-beta was observed in thymectomized patients. rTGF-beta suppressed
       AChR-induced upregulation of proinflammatory cytokines but not IL-10.
       Elevated numbers of IFN-gamma, IL-4 and TGF-beta mRNA expressing blood
       MNC were also found in patients with OIND (aseptic meningo-encephalitis,
       chronic inflammatory demyelinating polyneuropathy, polymyositis,
       Eaton-Lambert syndrome) and in HIV-infected patients. In HIV infection,
       numbers of IL-4 mRNA positive cells correlated inversely with CD4+ cell
       counts, reflecting the involvement of IL-4 in later stages of the
       disease. Patients with non-inflammatory neurological diseases and
       healthy subjects had either no or low numbers of IFN-gamma, IL-4 and
       TGF-beta mRNA expressing cells when blood MNC were examined without
       previous culture, and after culture in presence and absence of MBP, PLP
       and AChR as antigens. An exception was a healthy pregnant lady who
       showed high levels especially of IL-4 and IL-10 mRNA expressing cells,
       probably reflecting pregnancy-associated upregulation of Th2 cell
       related cytokines. Numbers of myelin antigen- and AChR-reactive
       IFN-gamma and IL-4 mRNA expressing cells were also elevated, implicating
       upregulation of natural T cell autoimmunity in normal pregnancy.
       CONCLUSION. High numbers of in vivo activated and of organ-specific
       antigen-responsive Th1 and Th2 like cells expressing IFN-gamma and IL-4
       mRNA are characteristic for MS and MG. Upregulation of TGF-beta in MS
       patients with little disability and in MG after thymectomy implicates
       that TGF-beta has desirable effects in human diseases with autoimmune
       background.
 DE    Adolescence  Adult  Aged  Aged, 80 and over  DNA, Complementary/GENETICS
       Female  Gene Expression Regulation/PHYSIOLOGY  Human  HIV
       Infections/GENETICS/IMMUNOLOGY  Interferon Type II/*GENETICS
       Interleukin-4/*GENETICS  Lambert-Eaton Myasthenic
       Syndrome/GENETICS/IMMUNOLOGY  Male  Middle Age  Monocytes/IMMUNOLOGY
       Multiple Sclerosis/*GENETICS/IMMUNOLOGY  Myasthenia
       Gravis/*GENETICS/IMMUNOLOGY  Oligonucleotide Probes/DIAGNOSTIC USE
       Optic Neuritis/GENETICS/IMMUNOLOGY  Polymyositis/GENETICS/IMMUNOLOGY
       Polyradiculoneuritis/GENETICS/IMMUNOLOGY  RNA, Messenger/*GENETICS
       Support, Non-U.S. Gov't  Transforming Growth Factor beta/*GENETICS
       JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

