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1.
J Exp Med ; 186(8): 1233-40, 1997 Oct 20.
Article in English | MEDLINE | ID: mdl-9334362

ABSTRACT

The lymphotoxin (LT)/tumor necrosis factor (TNF) family has been implicated in the neurologic inflammatory diseases multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). To determine the role of individual family members in EAE, C57BL/6 mice, LT-alpha-deficient (LT-alpha-/- mice), or LT-beta-deficient (LT-beta-/- mice), and their wild-type (WT) littermates were immunized with rat myelin oligodendrocyte glycoprotein (MOG) peptide 35-55. C57BL/6 and WT mice developed chronic, sustained paralytic disease with average maximum clinical scores of 3.5 and disease indices (a measure of day of onset and sustained disease scores) ranging from 367 to 663 with central nervous system (CNS) inflammation and demyelination. LT-alpha-/- mice were primed so that their splenic lymphocytes proliferated in response to MOG 35-55 and the mice produced anti-MOG antibody. However, LT-alpha-/- mice were quite resistant to EAE with low average clinical scores (<1), an average disease index of 61, and the negligible CNS inflammation and demyelination. WT T cells transferred EAE to LT-alpha-/- recipients. LT-beta-/- mice were susceptible to EAE, though less than WT, with an average maximum clinical score of 1.9 and disease index of 312. These data implicate T cell production of LT-alpha in MOG EAE and support a major role for LT-alpha3, a minor role for the LT-alpha/beta complex, and by inference, no role for TNF-alpha.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/immunology , Lymphotoxin-alpha/physiology , Amino Acid Sequence , Animals , Brain/pathology , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/prevention & control , Lymphotoxin-alpha/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Sequence Data , Myelin Proteins , Myelin-Associated Glycoprotein/immunology , Myelin-Oligodendrocyte Glycoprotein , Oligodendroglia/immunology , Spinal Cord/pathology , Vaccination
2.
Clin Exp Immunol ; 154(1): 22-9, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18727631

ABSTRACT

As a tumour necrosis factor receptor superfamily member, 4-1BB (CD137) is preferentially expressed in CD4+CD25+ regulatory T cells (Tregs) and has been suggested to play an important role in regulating the generation or function of Tregs. Recent studies of human Tregs have shown that blood CD4+CD25(high) T cells were much closer to Tregs in terms of their functionality. Furthermore, CD4+CD25(high) Tregs have been found to have a decreased effector function in patients with multiple sclerosis (MS). In this study, we examined the expression of 4-1BB and soluble 4-1BB (s4-1BB) protein levels in the peripheral blood of MS patients. Compared with healthy controls, MS patients had decreased 4-1BB expression in their CD4+C25(high) Tregs and increased plasma s4-1BB protein levels. Moreover, the plasma s4-1BB levels of MS patients were shown to be inversely correlated with the 4-1BB surface expression of CD4+CD25(high) Tregs. The down-regulated 4-1BB expression on CD4+CD25(high) Tregs of MS patients may be involved in the impaired immunoactivity of these Tregs. The elevated s4-1BB levels may, at least in part, function as a self-regulatory attempt to inhibit antigen-driven proliferation of Tregs or their immunosuppressive activity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Interleukin-2 Receptor alpha Subunit/immunology , Multiple Sclerosis/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 9/analysis , Adult , Analysis of Variance , Case-Control Studies , Female , Flow Cytometry , Humans , Immunomagnetic Separation , Male , Middle Aged , Multiple Sclerosis/blood , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction/methods , Self Tolerance , Tumor Necrosis Factor Receptor Superfamily, Member 9/blood , Tumor Necrosis Factor Receptor Superfamily, Member 9/genetics
3.
Acta Neurol Scand ; 118(4): 256-9, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18384455

ABSTRACT

OBJECTIVES: As a member of the tumor necrosis factor superfamily (TNFSF), LIGHT (TNFSF14) was recently found to be associated with platelets and released upon activation. Increased plasma levels of LIGHT have been reported in patients with myocardial infarction and unstable angina. The aim of the study was to analyze plasma levels of LIGHT in acute ischemic atherosclerotic stroke. MATERIALS AND METHODS: The soluble LIGHT protein was analyzed by an enzyme-linked immunosorbent assay in peripheral blood of patients with acute ischemic atherosclerotic stroke (n = 20), asymptomatic carotid stenosis (n = 19) and normal controls (n = 23). RESULTS: During the initial 24 h after onset, the stroke patients had an increased plasma LIGHT levels as compared with normal controls. Moreover, the plasma LIGHT levels of the stroke patients were correlated with blood platelet count (r = 0.6341, P = 0.0027). CONCLUSION: The elevated LIGHT levels may reflect a persistent chronic inflammatory response that may have been induced during early stages of the disease. We speculate that this derangement of LIGHT may be important for atherogenetic process of ischemic stroke.


Subject(s)
Biomarkers/blood , Stroke/blood , Tumor Necrosis Factor Ligand Superfamily Member 14/blood , Aged , Enzyme-Linked Immunosorbent Assay , Female , Humans , Intracranial Arteriosclerosis/complications , Intracranial Thrombosis/complications , Male , Middle Aged , Platelet Count , Risk Factors , Stroke/etiology
4.
J Leukoc Biol ; 69(3): 331-9, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11261778

ABSTRACT

Chronic inflammation is a complex pathophysiological process with accumulation of mononuclear cells seen in response to invading pathogens, neoplastic transformation, or autoimmune recognition of self-antigens. The inflammatory process has evolved to facilitate effective elimination of pathogens and tumors and it is normally transient and turned off when the causative stimulus has been eliminated. Occasionally, however, the process is sustained for a long time and can lead to severe tissue damage. This is seen in organ-specific autoimmune diseases such as rheumatoid arthritis, Sjögren's syndrome, and Hashimoto's thyroiditis, but also in infectious diseases such as Helicobacter pylori-induced gastritis. Disturbingly, many of these chronic inflammatory diseases are associated with an increased risk for neoplastic transformation and development of lymphomas. This review summarizes experimental evidence suggesting that chronic inflammation involves ectopic de novo formation of organized lymphoid tissue and that this lymphoid neogenesis is regulated by expression of homing chemokines.


Subject(s)
Cell Transformation, Neoplastic/pathology , Chemokines/biosynthesis , Inflammation/pathology , Lymphoid Tissue/pathology , Animals , Cell Transformation, Neoplastic/immunology , Cell Transformation, Neoplastic/metabolism , Humans , Inflammation/immunology , Inflammation/metabolism , Lymphoid Tissue/immunology , Lymphoid Tissue/metabolism , Lymphoma/etiology
5.
Cancer Epidemiol Biomarkers Prev ; 9(10): 1067-70, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11045789

ABSTRACT

HLA genes have been shown to be associated with cervical intraepithelial neoplasia (CIN), a precursor of cervical cancer. The human papillomaviruses (HPV) types 16 and 18 are the major environmental cause of this disease. Because the immune system plays an important role in the control of HPV infection, the association of polymorphic HLA could lead to a different immune response to control the development of cervical cancer. The aim of this study was to analyze the association between CIN and a microsatellite polymorphism of tumor necrosis factor (TNFa) taking HPV exposure and CIN-associated HLA haplotypes into account. In a nested case-control study in northern Sweden, 64 patients and 147 controls matched for age and sex and derived from the same population-based cohort were typed for TNFA, HLA-DR, and DQ and assayed for antibodies to HPV types 16 and 18. TNFa polymorphism was not associated with CIN per se. However, there was a significant increase in the frequency of TNFa-11 among HPV16-positive and HLA DR15-DQ6 (B*0602) patients compared with HPV16- and HLA-DQ6-negative patients (odds ratios, 5.4 and 9.3, respectively). The relative risk for CIN conferred by the combination of TNFa-11, HLA-DQ6, and HPV 16 positivity was 15. Our study suggests that the TNFa-11 allele is associated with HPV16 infection and associated with CIN in combination with HLA-DQ6 but not by itself.


Subject(s)
HLA-DQ Antigens/genetics , HLA-DR Antigens/genetics , Papillomaviridae/pathogenicity , Papillomavirus Infections/complications , Polymorphism, Genetic , Tumor Necrosis Factor-alpha/genetics , Tumor Virus Infections/complications , Uterine Cervical Dysplasia/genetics , Uterine Cervical Dysplasia/virology , Uterine Cervical Neoplasms/genetics , Adult , Alleles , Case-Control Studies , Female , Humans , Microsatellite Repeats/genetics , Risk Assessment , Sweden/epidemiology , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/virology , Uterine Cervical Dysplasia/epidemiology
6.
J Neuroimmunol ; 81(1-2): 76-81, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9521608

ABSTRACT

Interleukin 1 (IL-1)beta, TaqI restriction fragment length polymorphism (RFLP) in exon 5 and IL-1 receptor antagonist (IL-1Ra) polymorphism, variable numbers of an 86-bp tandem repeat (VNTR), were analysed in 107 patients with myasthenia gravis (MG) and 82 ethnically matched healthy control (HC) individuals. Positive association was found with IL-1beta TaqI RFLP allele 2 carriage in MG (OR = 2.007), while allele 1 was negatively associated with MG (OR = 0.498). When homozygous individuals for allele 2 were considered, the association was stronger (OR = 4.630), indicating a dose effect of allele 2. Analysis of IL-1beta TaqI RFLP in relation to HLA-B8 demonstrated that the allelic association was more pronounced in patients without HLA-B8 (OR = 2.813). There was no difference in IL-1Ra VNTR allelic distribution in MG patients compared with HC. However, MG patients who were noncarriers of IL-Ra allele 2 had a significantly higher percentage of IL-1beta TaqI RFLP allele 2 carriage (OR = 3.085), while there was no such difference in IL-1Ra allele 2 carriers. Our results demonstrate a new genetic marker in MG, which exerts its maximum effect in patients with the lowest MHC-associated susceptibility. We propose a possible pathogenetic role of IL-1beta and a possible intrinsic dyregulation of IL-1 in MG.


Subject(s)
Autoimmune Diseases/genetics , Myasthenia Gravis/genetics , Polymorphism, Restriction Fragment Length , Sialoglycoproteins/genetics , Adult , Alleles , Case-Control Studies , Deoxyribonucleases, Type II Site-Specific , Disease Susceptibility , Female , Genetic Markers , Genotype , HLA-B8 Antigen/genetics , Humans , Interleukin 1 Receptor Antagonist Protein , Male , Middle Aged , Minisatellite Repeats
7.
J Neuroimmunol ; 85(1): 102-5, 1998 May 01.
Article in English | MEDLINE | ID: mdl-9627003

ABSTRACT

Myasthenia gravis (MG) is characterized by muscle weakness due to autoimmunity against the nicotinic acetylcholine receptor (nAChR). MG is associated with polymorphisms in HLA-DQ genes and the aim of the present study was to characterize structural differences in the peptide binding groove of HLA-DQ molecules positively and negatively associated with MG. Three dimensional models of the positively associated DQ2 (DQB1*02) and negatively associated DQ6 (DQB1*0603) molecules were constructed by homology modeling techniques. The differences in peptide binding properties were primarily localized to peptide-anchor pockets P7 and P9, which might be of importance for the binding of disease-associated peptides from the nAChR.


Subject(s)
HLA-DQ Antigens/analysis , HLA-DQ Antigens/genetics , Models, Molecular , Myasthenia Gravis/immunology , Humans
8.
J Neuroimmunol ; 113(1): 109-18, 2001 Feb 01.
Article in English | MEDLINE | ID: mdl-11137582

ABSTRACT

A complete prevention of clinical experimental autoimmune myasthenia gravis (EAMG) was observed in lymphotoxin (LT)-alpha deficient (LT-alpha(-/-)) mice compared to LT-alpha(+/+) mice when immunized with acetylcholine receptor. However, only a partial prevention of clinical EAMG incidence was observed in LT-beta(-/-) mice compared to LT-beta(+/+) mice. LT-alpha(-/-)and LT-beta(-/-) mice had lower mean titers of total IgG, IgG(1), IgG(2a) and IgG(2b) and higher or equal mean titers of IgM anti-AChR antibodies compared to controls. Therefore, LT-alpha(-/-)and LT-beta(-/-) AChR immunized mice are capable of mounting a primary (IgM) humoral immune response to AChR, but are less capable of switching to the pathogenic anti-AChR IgG isotypes. LT could play a significant role in the pathogenesis of myasthenia gravis.


Subject(s)
Lymphotoxin-alpha/genetics , Lymphotoxin-alpha/immunology , Myasthenia Gravis, Autoimmune, Experimental/immunology , Receptors, Cholinergic/immunology , Animals , Antigens, CD/genetics , Antigens, CD/immunology , Autoantibodies/blood , B7-2 Antigen , Gene Expression/immunology , Immunodominant Epitopes/immunology , Immunoglobulin G/blood , Immunoglobulin M/blood , Membrane Glycoproteins/genetics , Membrane Glycoproteins/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Tumor Necrosis Factor/immunology , Spleen/cytology , Spleen/immunology
9.
J Neuroimmunol ; 65(2): 125-31, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8964894

ABSTRACT

The association between myasthenia gravis (MG) and polymorphic amino acid domains in the HLA-DQ molecule was studied in 79 Swedish patients and 155 unrelated, population-based controls. A domain unique for DQB1*0201 was positively associated in MG patients with thymic hyperplasia or an early disease onset, and two domains with residues common to DQA1*01 alleles or DQB1*05 and DQB1*06 alleles were negatively associated in patients with thymic hyperplasia or an early disease onset. Our results suggest that MG associated with thymic hyperplasia and thymoma differ in their HLA-DQ association and thus are likely to have different pathogenic mechanisms.


Subject(s)
HLA-DQ Antigens/genetics , Myasthenia Gravis/genetics , Myasthenia Gravis/immunology , Polymorphism, Genetic , Adolescent , Adult , Aged , Amino Acid Sequence , Child , Exons , Female , HLA-DQ alpha-Chains , HLA-DQ beta-Chains , Humans , Male , Middle Aged , Molecular Sequence Data , Myasthenia Gravis/physiopathology
10.
J Neuroimmunol ; 88(1-2): 137-43, 1998 Aug 01.
Article in English | MEDLINE | ID: mdl-9688335

ABSTRACT

The aim of this study was to analyze associations between myasthenia gravis (MG) and polymorphisms in the tumor necrosis factor (TNF) region in 79 Swedish patients and 155 unrelated controls. The frequency of the TNFa2 allele of a microsatellite located 3.5 kb upstream of the lymphotoxin alpha (LT-alpha) gene in the TNF region was found to be increased in overall MG patients compared to controls. The frequency of the short 5.5 kb fragment (TNFB * 1) of a bi-allelic NcoI RFLP polymorphism located at the first intron of the LT-alpha gene was increased in patients with an early onset of disease compared to patients with a later onset.


Subject(s)
Myasthenia Gravis/genetics , Polymorphism, Genetic/genetics , Tumor Necrosis Factor-alpha/genetics , Age of Onset , Alleles , Humans , Introns/genetics , Lymphotoxin-alpha/genetics , Microsatellite Repeats/genetics , Myasthenia Gravis/epidemiology , Peptide Fragments/genetics , Polymorphism, Restriction Fragment Length , Reference Values
11.
Hum Immunol ; 60(10): 970-3, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10566597

ABSTRACT

Cervical intraepithelial neoplasia (CIN) is associated with human papillomaviruses (HPV) and the HLA genes. The MICA (MHC class I chain-related gene A) is expressed by keratinocytes and epithelial cells and interacts with gamma delta T cells. It is therefore possible that MICA might influence the pathogenesis of CIN and cervical cancer through presentation of viral or tumor antigens. To investigate this, we determined the MICA transmembrane allele frequencies in a prospective population-based cohort study from the Västerbotten County in northern Sweden. 74 women developed CIN. 153 control women who remained healthy during follow up were matched for age. Five polymorphic microsatellite alleles of MICA were identified by a polymerase chain reaction-based (PCR) technique using fluorescent-labeled primers. MICA A5 and A5.1 were the most common alleles in this population. None of the alleles of MICA were associated with disease. The frequency of MICA allele A5 was higher among HPV 18 seropositive than HPV 18 seronegative patients but this difference was not significant after the correction of p value. In conclusion, microsatellite allele polymorphism of MICA transmembrane part is not associated with cervical intraepithelial neoplasia.


Subject(s)
Genetic Predisposition to Disease , Histocompatibility Antigens Class I/genetics , Polymorphism, Genetic , Uterine Cervical Dysplasia/genetics , Exons , Female , Gene Frequency , HLA-DQ Antigens/isolation & purification , Humans , Microsatellite Repeats , Papillomaviridae/isolation & purification , Prospective Studies , Sweden/epidemiology , Trinucleotide Repeats , Uterine Cervical Dysplasia/epidemiology , Uterine Cervical Dysplasia/etiology
12.
Autoimmunity ; 22(1): 59-65, 1995.
Article in English | MEDLINE | ID: mdl-8882423

ABSTRACT

The aim of this study was to determine the association between HLA-DQ and myasthenia gravis (MG) in 79 Swedish patients and 155 unrelated population based controls. HLA genotyping was done using polymerase chain reaction combined with sequence specific oligonucleotide probes. The DQB allele, DQB1*0201 was positively associated with MG, 39/79 (49%) patients and 43/152 (28%) controls (OR 2.47, Pc = 0.037). DQB1*0201 was observed more frequently in patients with an early onset of disease, below 30 years (Pc = 0.033). A negative association was found for DQA1*0103, 7/78 (9%) patients and 38/154 (25%) controls (OR 0.30, Pc = 0.037). DQA1*0501-DQB1*0201 and DQA1*0201-DQB1*0201 together was significantly increased in patients when compared to controls (OR 2.68; Pc = 0.019). In conclusion, two different DQ2 haplotypes (DQA1*0501-DQB1*0201 and DQA1*0201-DQB1*0201) were positively and the DQA1*0103 allele was negatively associated with MG. Susceptibility and resistance to MG in Swedish patients is mediated by HLA-DQ.


Subject(s)
HLA-DQ Antigens/genetics , Myasthenia Gravis/genetics , Myasthenia Gravis/immunology , Adolescent , Adult , Aged , Child , Female , HLA-DQ alpha-Chains , HLA-DQ beta-Chains , Haplotypes/immunology , Humans , Linkage Disequilibrium/immunology , Male , Middle Aged , Sweden
13.
Neuroreport ; 11(1): 199-202, 2000 Jan 17.
Article in English | MEDLINE | ID: mdl-10683857

ABSTRACT

Tetrodotoxin-resistant sodium currents contribute to the somal and axonal sodium currents of small diameter primary sensory neurons, many of which are nociceptive. NaN is a recently described tetrodotoxin-resistant sodium channel expressed preferentially in IB4-labeled dorsal root ganglion (DRG) neurons. We employed an antibody raised to a NaN specific peptide to show that NaN is preferentially localized along axons of IB4-positive unmyelinated fibers in the sciatic nerve and in axon terminals in the cornea. NaN immunoreactivity was also found at some nodes of Ranvier of thinly myelinated axons of the sciatic nerve, where it was juxtaposed to Kv1.2 potassium channel immunoreactivity. This distribution of NaN is consistent with a role for NaN sodium channels in nociceptive transmission.


Subject(s)
Neuropeptides/drug effects , Nociceptors/drug effects , Sodium Channels/drug effects , Tetrodotoxin/pharmacology , Amino Acid Sequence , Animals , Axons/drug effects , Axons/ultrastructure , Cornea/innervation , Female , Ganglia, Spinal/drug effects , Ganglia, Spinal/ultrastructure , Image Processing, Computer-Assisted , Immunohistochemistry , Molecular Sequence Data , Myelin Sheath/physiology , NAV1.9 Voltage-Gated Sodium Channel , Nerve Fibers/physiology , Nerve Fibers/ultrastructure , Neurons, Afferent/drug effects , Neurons, Afferent/ultrastructure , Presynaptic Terminals/physiology , Presynaptic Terminals/ultrastructure , Ranvier's Nodes/physiology , Ranvier's Nodes/ultrastructure , Rats , Rats, Sprague-Dawley , Sciatic Nerve/physiology , Sciatic Nerve/ultrastructure
14.
Eur Rev Med Pharmacol Sci ; 18(10): 1525-32, 2014.
Article in English | MEDLINE | ID: mdl-24899613

ABSTRACT

BACKGROUND: CD137 ligand (CD137L) is expressed by various immune cells and exists in membrane-bound and soluble forms. Recently, CD137L was found to be localized to macrophages in human atherosclerotic lesions and CD137L levels were much higher in atherosclerotic lesions than in normal arteries. However, the role of CD137L with different forms in atherothrombotic stroke remains unclear. PATIENTS AND METHODS: The soluble CD137L (sCD137L) protein and CD137L expression on monocytes were analyzed by an enzyme-linked immunosorbent assay and flow cytometry in peripheral blood of patients with acute ischemic atherosclerotic stroke, atherosclerosis controls and normal controls. RESULTS: During the initial 24h after onset, the stroke patients had elevated plasma sCD137L levels (133.2 pg/ml) and CD137L expression on monocytes [7.9 ± 4.1%, 7.0 ± 4.0 mean fluorescence intensity (MFI)] as compared with normal controls (75 pg/ml, p < 0.05; 4.6 ± 2.4%, 4.1 ± 2.7 MFI, p < 0.05). CONCLUSIONS: The dysregulation of CD137L expression may reflect a persistent chronic inflammatory response that may have been induced during early stages of the disease. Our results strongly suggest that the abnormal expression of CD137L on monocytes may lead to dyregulated CD137L/CD137 signaling and consequently form part of a positive-feedback, inflammation-promoting circuit in stroke, while the elevated sCD137L protein levels may function as a self-regulatory mechanism of CD137/CD137L interaction and costimulation.


Subject(s)
4-1BB Ligand/blood , Atherosclerosis/blood , Stroke/blood , Aged , Female , Humans , Male , Middle Aged , Monocytes/metabolism
16.
Scand J Immunol ; 64(4): 412-9, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16970683

ABSTRACT

4-1BB ligand (4-1BBL; CD137L) is a member of the tumour necrosis factor superfamily expressed primarily on antigen presenting cells such as B cells, macrophages and dendritic cells. Its engagement with the receptor 4-1BB (CD137) has been shown to promote T-cell activation and regulate proliferation and survival of T cells. The role of the costimulatory molecule in multiple sclerosis (MS) remains unclear. In this study, the expression of 4-1BBL and soluble 4-1BBL (s4-1BBL) protein levels were analysed in peripheral blood of MS patients. Compared with healthy controls, MS patients had an increase in both plasma s4-1BBL protein levels and expression of 4-1BBL in CD14(+) monocytes. In contrast, myelin basic protein-reactive T-cell proliferation was not found to be inhibited by the use of an anti-4-1BBL antibody. The elevated s4-1BBL protein levels in the MS patients may function as a self-regulatory mechanism of 4-1BB/4-1BBL interaction and costimulation.


Subject(s)
Antigens, CD/metabolism , Monocytes/metabolism , Multiple Sclerosis/blood , Receptors, Nerve Growth Factor/metabolism , Receptors, Tumor Necrosis Factor/metabolism , Tumor Necrosis Factors/blood , 4-1BB Ligand , Adult , Antigens, CD/physiology , Cells, Cultured , Female , Humans , Ligands , Lipopolysaccharide Receptors/biosynthesis , Lipopolysaccharide Receptors/blood , Male , Monocytes/immunology , Multiple Sclerosis/immunology , RNA, Messenger/biosynthesis , Receptors, Nerve Growth Factor/physiology , Receptors, Tumor Necrosis Factor/physiology , Signal Transduction/immunology , Solubility , Tumor Necrosis Factor Receptor Superfamily, Member 9 , Tumor Necrosis Factors/biosynthesis , Tumor Necrosis Factors/genetics , Tumor Necrosis Factors/physiology
17.
Eur J Immunogenet ; 24(3): 179-189, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9226124

ABSTRACT

To characterize better the functional aspects of the HLA class II associations with myasthenia gravis (MG), T-cell receptor (TCR) V alpha/beta elements were studied in peripheral blood in 29 Swedish MG patients. HLA typing had previously been done using polymerase chain reaction with sequence-specific primers (PCR-SSP) or combined with sequence-specific oligonucleotide probes (PCR-SSO). The TCR V gene expression was determined by fluorescence-activated cell sorter (FACS) analysis using 12 monoclonal antibodies (mAb) that detected 30-40% of CD4+ and CD8+ T cells. No correlation between HLA-DQ genotype and TCR V elements could be found, nor was any restricted V gene usage seen. Fourteen (48%) of the patients had T cells showing signs of abnormal expansion in peripheral blood. There was an increased expression of TCR V gene elements in CD8+ T cells in patients (13/29) compared with CD4+ T cells in patients (5/29) (P < 0.05) and in unthymectomized patients compared with controls (14/56) (P < 0.005). TCR V gene expression was also increased in the CD8+ population in unthymectomized (7/8) compared with thymectomized patients (6/21) (P < 0.01). There was an increased expression in both CD4+ and CD8+ populations in unthymectomized patients (7/8, 88%), compared with thymectomized patients (7/21) (P < 0.05). We conclude that the abnormal T-cell expansion in peripheral blood could be a reflection of non-specific pathogenic processes in the muscle and thymus.


Subject(s)
HLA-DQ Antigens , Myasthenia Gravis/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , Adolescent , Adult , Age of Onset , Aged , Antibodies, Monoclonal , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Child , Female , Gene Frequency , Histocompatibility Testing/methods , Humans , Male , Middle Aged , Statistics, Nonparametric , Sweden , T-Lymphocyte Subsets , White People/genetics
18.
J Immunol ; 164(1): 419-26, 2000 Jan 01.
Article in English | MEDLINE | ID: mdl-10605038

ABSTRACT

Experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 (H-2b) mice is characterized by early (day 12) acute paralysis, followed by a sustained chronic clinical course that gradually stabilizes. Extensive inflammation and demyelination coincide with clinical signs of disease. To identify the mechanisms of these processes, individual proinflammatory and anti-inflammatory cytokines and chemokines were studied. Sensitive single-cell assays were utilized to determine the cellular origin and kinetics of cytokine production in the CNS. Immunization with MOG35-55 peptide resulted in priming of both Th1 (lymphotoxin, IFN-gamma, and TNF-alpha) and Th2 (IL-4) cells in the spleen. However, only Th1 cells were apparent in the CNS. CD4 T cells that produced IFN-gamma or TNF-alpha were present in the CNS by day 7 after immunization with MOG35-55, peaked at day 20, and then waned. TNF-alpha was also produced in the CNS by Mac-1+ cells. On days 7 and 10 after immunization, the TNF-alpha-producing Mac1+ cells were predominantly microglia. By day 14, a switch occurred in that the Mac1+ TNF-alpha-producing cells had the phenotype of infiltrating macrophages. RANTES, IFN-inducible protein 10 (IP-10), and monocyte chemotactic protein 1 chemokine mRNA were detected in the CNS by day 8 after immunization. The early presence of monocyte chemotactic protein 1 (MCP-1) in the CNS provides a mechanism for the recruitment of macrophages. These data implicate TNF-alpha production by a continuum of T cells, microglia, and macrophages at various times during the course of disease. The importance of Th1 cytokines is highlighted, with little evidence for a role of Th2 cytokines.


Subject(s)
Central Nervous System/immunology , Central Nervous System/metabolism , Cytokines/biosynthesis , Encephalomyelitis, Autoimmune, Experimental/immunology , Myelin-Associated Glycoprotein/immunology , Amino Acid Sequence , Animals , Central Nervous System/cytology , Chemokines/biosynthesis , Encephalomyelitis, Autoimmune, Experimental/etiology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Female , Immunophenotyping , Inflammation Mediators/metabolism , Injections, Subcutaneous , Interferon-gamma/biosynthesis , Interferon-gamma/metabolism , Kinetics , Lymphocyte Activation , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Microglia/immunology , Microglia/metabolism , Molecular Sequence Data , Myelin Proteins , Myelin-Associated Glycoprotein/administration & dosage , Myelin-Oligodendrocyte Glycoprotein , Spleen/cytology , Spleen/immunology , Spleen/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Th2 Cells/immunology , Th2 Cells/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/metabolism
19.
Am J Pathol ; 156(4): 1133-8, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10751336

ABSTRACT

Secondary lymphoid tissue chemokine (SLC) and B lymphocyte chemoattractant (BLC) are homing chemokines that have been implicated in the trafficking of lymphocytes and dendritic cells in lymphoid organs. Lymphotoxin-alpha (LTalpha), a cytokine crucial for development of lymphoid organs, is important for expression of SLC and BLC in secondary lymphoid organs during development. Here we report that transgenic expression of LTalpha induces inflammation and ectopic expression of SLC and BLC in the adult animal. LTbeta was not necessary for induction of BLC and SLC in inflamed tissues, whereas, in contrast, tumor necrosis factor receptor-1 was found to be important for the LTalpha-mediated induction of these chemokines. The ectopic expression of LTalpha is associated with a chronic inflammation that closely resembles organized lymphoid tissue and this lymphoid neogenesis can also be seen in several chronic inflammatory diseases, including in the pancreas of the prediabetic nonobese diabetic (NOD) mouse. Expression of SLC was also observed in the pancreas of prediabetic NOD mice. This study implicates BLC and SLC in chronic inflammation and presents further evidence that LTalpha orchestrates lymphoid organogenesis both during development and in inflammatory processes.


Subject(s)
Chemokines, CC/metabolism , Chemokines, CXC/metabolism , Inflammation/metabolism , Animals , Antigens, CD/physiology , Chemokine CCL21 , Chemokine CXCL13 , Chemokines, CC/genetics , Chemokines, CXC/genetics , Chronic Disease , Female , Lymphotoxin-alpha/genetics , Lymphotoxin-alpha/physiology , Lymphotoxin-beta , Membrane Proteins/genetics , Membrane Proteins/physiology , Mice , Mice, Inbred NOD/genetics , Mice, Transgenic/genetics , Pancreas/metabolism , Pancreatitis/genetics , Pancreatitis/metabolism , Protein Isoforms/physiology , RNA, Messenger/metabolism , Receptors, Tumor Necrosis Factor/physiology , Receptors, Tumor Necrosis Factor, Type I
20.
J Immunol ; 161(9): 4480-3, 1998 Nov 01.
Article in English | MEDLINE | ID: mdl-9794370

ABSTRACT

Myelin oligodendrocyte glycoprotein (MOG) induced experimental allergic encephalomyelitis (EAE) is an animal model for the central nervous system disease multiple sclerosis (MS). The roles of individual components of the immune system have not been completely defined in the mouse model, and to determine the role of B cells and Abs in the induction of EAE and demyelination, B cell-deficient muMT (H-2b) mice were immunized with MOG peptide 35-55. The muMT mice were susceptible to MOG-induced EAE and developed a chronic sustained disease, with inflammatory lesions and primary demyelination in the spinal cord, brain, and optic nerves, similar to that seen in wild-type C57BL/6 mice. The inflammatory cells in the central nervous system of muMT mice included both activated and memory T cells and macrophages. The data suggest that B cells and Abs are not necessary for primary demyelination in MOG-induced EAE in mice.


Subject(s)
Autoimmune Diseases/immunology , B-Lymphocytes/pathology , Demyelinating Diseases/etiology , Encephalomyelitis, Autoimmune, Experimental/immunology , Immunologic Deficiency Syndromes/complications , Myelin-Associated Glycoprotein/immunology , Oligodendroglia/immunology , Amino Acid Sequence , Animals , Autoimmune Diseases/pathology , B-Lymphocytes/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Immunization , Immunocompromised Host , Immunologic Deficiency Syndromes/immunology , Immunologic Memory , Lymphocyte Activation , Macrophage Activation , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Myelin Proteins , Myelin-Oligodendrocyte Glycoprotein , Peptide Fragments/immunology , T-Lymphocyte Subsets/immunology
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