Multiple sclerosis (MS) is a central nervous system disease in which activated autoreactive T-cells invade the blood brain barrier and initiate an inflammatory response that leads to myelin destruction and axonal loss. The etiology of MS, as well as the mechanisms associated with its unexpected onset, the unpredictable clinical course spanning decades, and the different rates of progression leading to disability over time, remains an enigma. We have applied gene expression microarrays technology in peripheral blood mononuclear cells (PBMC) to better understand MS pathogenesis and better target treatment approaches. A signature of 535 genes were found to distinguish immunomodulatory treatment effects between 13 treated and 13 untreated MS patients. In addition, the expression pattern of 1109 gene transcripts that were previously reported to significantly differentiate between MS patients and healthy subjects were further analyzed to study the effect of cytokine-related pathways on disease pathogenesis. When relative gene expression for 26 MS patients was compared to 18 healthy controls, 30 genes related to various cytokine-associated pathways were identified. These genes belong to a variety of families such as interleukins, small inducible cytokine subfamily and tumor necrosis factor ligand and receptor. Further analysis disclosed seven cytokine-associated genes within the immunomodulatory treatment signature, and two cytokine-associated genes SCYA4 (small inducible cytokine A4) and FCAR (Fc fragment of IgA, CD89) that were common to both the MS gene expression signature and the immunomodulatory treatment gene expression signature. Our results indicate that cytokine-associated genes are involved in various pathogenic pathways in MS and also related to immunomodulatory treatment effects.

A. Achiron

M. Gurevich

D. Magalashvili

I. Kishner

M. Dolev

M. Mandel

Understanding Autoimmune Mechanisms in Multiple Sclerosis Using Gene Expression Microarrays: Treatment Effect and Cytokine-related Pathways

The best therapeutic strategy in virus-induced vasculitides should take            into account the etiology of the disease and be adapted to the pathogenesis. The            combination of antiviral treatments and plasma exchanges has been proven            effective in polyarteritis nodosa (PAN). In human immunodeficiency virus            (HIV)-related vasculitis this strategy is also effective and does not jeopardize, like            cytotoxic agents, the outcome of AIDS. In vasculitis related to HCV-associated            cryoglobulinemia, plasma exchanges improve the outcome but the poor            effectiveness of antiviral drugs is not able to favor,            usually, a definite recovery of the patients and relapses are frequent.

Lo&#239;c  Guillevin

Virus-induced Systemic Vasculitides: New Therapeutic Approaches

Purpose: Elucidating the potential contribution of specific autoantibodies (Ab&#39;s) to the etiology and/or pathology of some human epilepsies. Methods: Six epilepsy patients with Rasmussen&#39;s encephalitis (RE) and 71 patients with other epilepsies were tested for Ab&#39;s to the &#8211;B&#8212; peptide (amino acids 372-395) of the glutamate/AMPA subtype 3 receptor (GluR3B peptide), double-stranded DNA (dsDNA), and additional autoimmune disease-associated autoantigens, and for the ability of their serum and cerebrospinal-fluid (CSF) to kill neurons. Results: Elevated anti-GluR3B Ab&#39;s were found in serum and CSF of most RE patients, and in serum of 17/71 (24%) patients with other epilepsies. In two RE patients, anti-GluR3B Ab&#39;s decreased drastically in CSF following functional-hemispherotomy, in association with seizure cessation and neurological improvement. Serum and CSF of two RE patients, and serum of 12/71 (17%) patients with other epilepsies, contained elevated anti-dsDNA Ab&#39;s, the hallmark of systemic-lupus-erythematosus. The sera (but not the CSF) of some RE patients contained also clinically elevated levels of &#8211;classical&#8212; autoimmune Ab&#39;s to glutamic-acid-decarboxylase, cardiolipin, &#946;2-glycoprotein-I and nuclear-antigens SS-A and RNP-70. Sera and CSF of some RE patients caused substantial death of hippocampal neurons. Conclusions: Some epilepsy patients harbor Ab&#39;s to GluR3 and dsDNA on both sides of the blood-brain barrier, and additional autoimmune Ab&#39;s only in serum. Since all these Ab&#39;s may be detrimental to the nervous system and/or peripheral organs, we recommend testing for their presence in epilepsy, and silencing their activity in Ab-positive patients.

Yonatan  Ganor

Hadassa  Goldberg-Stern

Dina  Amrom

Tally  Lerman-Sagie

Vivian I. Teichberg

Dori  Pelled

Anthony H. Futerman

Bruria  Ben Zeev

Michael  Freilinger

Denis  Verheulpen

Patrick  Van Bogaert

Mia  Levite

Autoimmune Epilepsy: Some Epilepsy Patients Harbor Autoantibodies to Glutamate Receptors and dsDNA on both Sides of the Blood-brain Barrier, which may Kill Neurons and Decrease in Brain Fluids after Hemispherotomy

Several different cytokines trigger the development of determined cell subsets            in BALT of growing Wistar rats. Early appearance (4 days post partum) of &#947;&#948;T cells in            BALT has been shown, as well as its role in up-regulating TNF-&#945; production. In the            present report, we studied in the BALT: (1) the profile of the cytokines, TNF-&#945;, INF-&#947;            and IL-10 and (2) in TCR &#947;&#948;+ cells, the existence of a colocalization with TNF-&#945; as well            as with INF-&#947;. All the cytokines studied were observed at an early stage of BALT            development by immunohistochemistry and in bronchoalveolar cells (BAL cells) by            flow cytometry and western blot. (1) The principal cytokine found at 4 days of age in            BALT cells was TNF-&#945; that increases along BALT development. The same behavior            was found for cells containing IL-10 and INF-&#947;. (2) TCR &#947;&#948;+ cells colocalize mainly with            TNF-&#945; as it has been shown by immunohistochemistry in BALT and by flow cytometry             when we studied BAL.The early appearance of TNF-&#945; concomitant with TCR &#947;&#948;+ cell suggests             an important role for this cytokine along BALT development. Moreover, mutual             regulation between them exists taking             part in the immune surveillance and repair of damaged epithelia.

Dreanina  Delettieres

Cecilia A. Frecha

Maria E. Roux

Early Appearance of TNF-&#945; and Other Cytokines in Bronchus Associated Lymphoid Tissues (BALT) from Growing Wistar Rats. What is the Role of TNF-&#945;?

M. Eric Gershwin

Yehuda Shoenfeld

Introduction: Organ Specific Immunopathology

The pathogenesis of Crohn&#39;s disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), is still unclear, but both autoimmune and immune-mediated phenomena are involved. Autoimmune phenomena include the presence of serum and mucosal autoantibodies against intestinal epithelial cells in either form of IBD, and against human tropomyosin fraction five selectively in UC. In addition, perinuclear antineutrophil cytoplasmic antibodies (pANCA) are common in UC, whereas antibodies against Saccharomyces cerevisiae (ASCA) are frequently found in CD. Immune-mediate phenomena include a variety of abnormalities of humoral and cell-mediated immunity, and a generalized enhanced reactivity against intestinal bacterial antigens in both CD and UC. It is currently believed that loss of tolerance against the indigenous enteric flora is the central event in IBD pathogenesis. Various complementary factors probably contribute to the loss of tolerance to commensal bacteria in IBD. They include defects in regulatory T-cell function, excessive stimulation of mucosal dendritic cells, infections or variants of proteins critically involved in bacterial antigen recognition, such as the products of CD-associated NOD2/CARD15 mutations.

Zhonghui  Wen

Claudio  Fiocchi

Inflammatory Bowel Disease: Autoimmune or Immune-mediated Pathogenesis?

Our understanding of biliary epithelial cells (BEC) in physiobiology and            immunology has steadily expanded. BEC transports IgA as well as IgM into bile,            synthesizes and secretes various chemokines, cytokines, and expresses adhesion            molecules involved in cell interaction and signal transduction. These then suggest            a myriad of potential roles for BEC in defense from invading microorganisms as well            as the pathogenesis of diverse immunologically driven diseases such as primary            biliary cirrhosis (PBC), graft-versus-host disease, and primary sclerosing cholangitis            (PSC). Despite the progress, there still remain many areas of BEC biology that            require further investigation. Most importantly, it remains to be clarified that the            extent to which the immunologic activities observed in BEC represent a BEC            response to tissue injury or whether BEC themselves are the active participants            in the pathogenesis of various cholestatic immunological diseases, including PBC            and PSC.

Chih-Te  Wu

Paul A. Davis

VelImir A. Luketic

A Review of the Physiological and Immunological Functions of Biliary Epithelial Cells: Targets for Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis and Drug-induced Ductopenias

Abstract
Keratinocytes were shown to induce the activation of plasminogen activator resulting in
the formation of plasmin and the initiation of proteolysis in vitro. Activation of surface
bound plasminogen may localize protease activity in the pericellular microenvironment
and play a role in inducing both a conformational change and cell locomotion. Plasmin,
however, can induce non-proteolytic effects on certain cell functions in a variety of cell
lineages. In the present study we examined the effects of plasmin on keratinocytes with
a focus on its role in the process of re-epithelialization, which included studies of cell
migration, phagocytic-killing and cell proliferation. Migration of freshly isolated human
epidermal keratinocytes was analyzed utilizing the agarose gel assay in the presence of
10% human serum. Plasmin at the concentration of 25 U/l induced a 160% increase in
the chemotactic migration of keratinocytes that was completely blocked by the plasmin
inhibitor α2-antiplasmin (Serpin). In the absence of serum, plasmin also induced a reversible
chemotactic migration of HaCaT keratinocytes as determined utilizing the microchemotaxis
assay. Dose-response analysis showed a bi-phasic effect of plasmin with a maximum
increase of 52% in keratinocyte chemotaxis at a concentration of 25 U/l. HaCaT cells on
the other hand, showed no detectable in vitro chemokinesis by
plasmin. Phagocytic-killing
of Candida albicans by freshly isolated epidermal keratinocytes was enhanced in the
presence of 25 U/l plasmin which was also reversible by the addition of Serpin.
Spontaneous proliferation of HaCaT keratinocytes as determined by 3H-Thymidine uptake
on the other hand, was reduced by 47 and 13% in cultures with 25 U/l plasmin for 24 and
48 h respectively, in a Serpin reversible manner. These data suggest that plasmin-induced
chemotactic migration of epidermal keratinocytes is accompanied by enhanced
phagocytic-killing coupled with suppression of proliferation of these cells which may
facilitate re-epithelialization following skin injury.

Imre Szabo

Miklos Simon

Janos Hunyadi

Plasmin Promotes Keratinocyte Migration and Phagocytic-killing Accompanied by Suppression of Cell Proliferation which may Facilitate Re-epithelialization of Wound Beds

C-reactive protein (CRP) is a blood component comprised of five identical subunits with a combined molecular mass of 110 kDa; in the presence of Ca++ it binds phosphocholine (PC) with high affinity. Ligand-bound CRP activates complement and the protein reportedly binds various Fc receptors. Coincident with a now decade-long resurgence in clinical interest in associations of CRP with disease, our laboratory has been investigating the biology of CRP in vivo using human CRP transgenic mice (CRPtg). At that time we confirmed that CRP affects a host defense function mediated at least in part through the elimination of pathogens. Less appreciated and not as well understood as CRP&#39;s ability to bind antigen and aid in the elimination of microbes, is its known ability to bind autoantigens and presumed capacity to promote clearance of apoptotic cells. These latter properties of CRP have long been suspected to contribute to homeostasis and to autoimmune disease. In this article we review and update the evidence generated in CRPtg by our group and in vitro by others&#39; that indicates CRP is more than just an antimicrobial molecule and convenient marker of inflammation - rather, it protects against autoimmunity. A mechanistic hypothesis is presented to account for this cause-and-effect relationship.

Alexander J. Szalai

C-Reactive Protein (CRP) and Autoimmune Disease: Facts and Conjectures

The thymus is considered to play an important role in the pathogenesis of Myasthenia gravis, an autoimmune disease characterized by antibody-mediated skeletal muscle weakness. However, its role is yet to be defined. The studies described herein summarize our efforts to determine how intrathymic expression of the neuromuscular type of acetylcholine (ACh) receptors is involved in the immunopathogenesis of this autoimmune disease. We review the work characterizing the expression of neuromuscular ACh receptors in the thymus and advance a new hypothesis that examines the intrathymic expression of this autoantigen in disease pathogenesis.

Arnold I. Levinson

Decheng Song

Glen Gaulton

Yi Zheng

The Intrathymic Pathogenesis of Myasthenia Gravis

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Journal of Immunology Research provides a platform for scientists and clinicians working in different and diverse areas of immunology and therapy.

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Chief Editor, Professor Holland, has a background focusing on researching the development of conjunctival fibrosis and the characterisation of immune responses to potential C. trachomatis vaccine candidates.

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Journal of Immunology Research

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