Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions.

Abstract

SummaryResting autoreactive T cells are present in the circulation ofnormal individuals without pathologic consequences . In autoimmune animal models, stimulation of these self-reactive T cells in the presence of costimulatory molecules B7-1 results in T cell-mediated autoimmune disease, whereas B7-2 stimulation generates regulatory autoreactive T cells that abrogate disease severity . Thus, reactivation in the brain of myelin-autoreactive T cells by antigen with costimulatory molecules may be a critical event in the pathophysiology of multiple sclerosis (MS), a putative autoimmune disease of central nervous system (CNS) myelin. We investigated the expression of cytokines and costimulatory molecules in a panel of 41 histologically characterized CNS specimens from 15 MS and 10 control cases using semiquantitative reverse transcriptase-polymerase chain reaction and immunocytochemistry . In four cases, vascular CNS infarcts with inflammation were compared with MS plaques from the same brain. We observed increased expression ofB7-1 and interleukin (IL) 12p40 in acute MS plaques, particularly from early disease cases but not in inflammatory infarcts. B7-1 staining was localized predominantly to the lymphocytes in perivenular inflammatory cuffs but not the parenchyma. In contrast, B7-2 was expressed predominantly on macrophages both in MS lesions ofvaried time duration and in inflammatory infarcts. These findings indicate that an early event in the initiation ofMS involves upregulation o£ B7-1 and IL-12, resulting in conditions that maximally stimulate T cell activation and induction of T helper 1-type immune responses .A utoimmune disease is presumably mediated by activated, autoantigen-reactive T cells (1-8) . Two distinct signals are required to induce differentiation of naive to activated, effector T cells : an antigen-specific signal mediated through the T cell receptor, and a second non-antigenspecific "costimulatory" signal (9, 10) . Interactions between CD28 and its counterreceptors, B7-1 (CD80) and B7-2 (CD86), are important T cell-costimulatory signals (11, 12) . Essentially all CD4 + and most CD8+ T cells express CD28 constitutively, and CD28-deficient T cells show a markedly reduced response to antigen stimulation (13) . A second ligand for B7 is CTLA-4, which is expressed on T cells after activation (14) and also may regulate T cell function (15) . The B7 molecules regulate IL-2 secretion and costimulate T cell proliferation (16)(17)(18) . Blocking of the B7-CD28 pathway in vitro results in T cell anergy (19-21) whereas in vivo blocking of the B7-CD28 pathway results in immunosuppression (22)(23)(24) .Aberrant expression of B7-costimulatory molecules is important in experimental autoimmune diabetes . Doubletransgenic mice with T cell receptors recognizing a viral antigen expressed on pancreatic islet cells do not develop diabetes . Triple-transgenic mice that additionally expressed B7-1 on pancreatic islet cells, however, developed massive tissue destruction and diabetes (25) . Moreover, double transgeni...

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

“…diseases, such as MSrEAE. Windhagen et al 1995 have evaluated expression of B7-1 and B7-2 in relation to IL-12 production in human MS brain. These authors found increased expression of B7-1 and IL-12p40 in acute MSplaques, particularly from early disease cases.…”

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

“…In this capacity, IL-12 plays a key role in the defense against intracellular microorganisms. In addition, excessive IL-12 production has been found in several organ-specific autoimmune diseases, including rheumatoid arthritis, 5 type I diabetes mellitus, 6 multiple sclerosis (MS) 7 and Crohn's disease (CD). 8 The latter are associated with a strong genetic component in disease susceptibility, which renders the possibility that genetic alterations in the genes affecting the height of the IL-12 response are involved in the susceptibility to autoimmune as well as infectious diseases.…”

Astrocyte-Targeted Expression of IL-12 Induces Active Cellular Immune Responses in the Central Nervous System and Modulates Experimental Allergic Encephalomyelitis

“…Expression of IL-12 in the CNS is found in a number of immunoinflammatory states including multiple sclerosis (MS) 5 (4), experimental allergic encephalomyelitis (EAE) in rats (5) and in mice (6), and in murine endotoxemia (7,8). Besides being produced by CNS-infiltrating immune cells, IL-12 can be produced by neural cells including microglia (7)(8)(9)(10) and astrocytes (8,11).…”