Multiple sclerosis cytokines

Cannella, B. and Raine, C. S. Multiple sclerosis cytokine receptors on oligodendrocytes predict innate regulation. Ann. Neurol. 55 46-57, 2004. 

The class III cytokine receptor family includes two TNE receptors, the low affinity NGE receptor and 7-ceU surface recognition sites that appear to play a role in proliferation, apoptosis, and immunodeficiency. TNE-a (- 17, 000 protein) is produced by astrocytes and microglia and can induce fever, induce slow-wave sleep, reduce feeding, stimulate prostaglandin synthesis, stimulate corticotrophin-releasing factor and prolactin secretion, and reduce thyroid hormone secretion. TNE-a stimulates IL-1 release, is cytotoxic to oligodendrocytes, and reduces myelination this has been impHcated in multiple sclerosis and encephalomyelitis. Astrocyte TNE-a receptors mediate effects on IL-6 expression and augment astrocytic expression of MHC in response to other stimulants such as lEN-y. 

Sorensen TL, Sellebjerg F (2001) Distinct chemokine receptor and cytokine expression profile in secondary progressive MS. Neurology 57 1371-1376 Sorensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, Qin S, Rottman J, Sellebjerg F, Strieter RM, Frederiksen JL, Ransohoff RM (1999) Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 103 807-815... 

S.2.2.9. Markers of immune activation and process. Acting with TNF-a-mRNA, sICAM-1, IL-lO-mRNA, and sTNF-R, these proteins and nucleic acids can be used as markers of the immunologically mediated inflammatory process seen in multiple sclerosis (M4). This disorder is associated with deregulation of cytokine expression, especially in regard to TNF-a. 

H2. Havrdova, E., Racek, P., and JedUcka, R, Relation of intrathecal synthesis of IgG including IgG subclasses to cytokine levels in cerebrospinal fluid in patients with multiple sclerosis. Clin. 

The molecular mechanism by which IFN-/1 induces its therapeutic effect is complex and not fully understood. It is believed that the pathology of multiple sclerosis is linked to the activation and proliferation of T lymphocytes specific for epitopes found on specific myelin antigens. Upon migration to the brain, these lymphocytes trigger an inflammatory response mediated by the production of pro-inflammatory cytokines, most notably IFN-y, IL-1, IL-2 and TNF-a. The inflammatory response, in addition to other elements of immunity (e.g. antibodies and... 

While the specific mechanisms of action of interferon-pia and interferon-pib in MS are not fully understood, each interferon has a number of immune-mediating activities (see Section 7.1). A recent review article on multiple sclerosis observed The interferons reduce the proliferation of T cells and the production of tumor necrosis factor a, decrease antigen presentation, alter cytokine production to favor ones governed by type 2 helper T (Th2) cells, increase the secretion of interleukin-10, and reduce the passage of immune cells across the blood-brain barrier by means of their effects on adhesion molecules, chemokines, and proteases [2]. 

In 106 patients (76 women) with multiple sclerosis who received interferon beta-la or beta-lb for up to 84 (median 42) months, there was baseline thyroid autoimmunity in 8.5% and hypothyroidism in 2.8% (562). Thyroid dysfunction (80% hypothyroidism, 92% subclinical, 56% transient) developed in 24% (68% with autoimmunity) and autoimmunity in 23% (46% with dysfunction), without a significant difference between the two cytokines 68% of the cases of dysfunction occurred within the first year. Thyroid dysfunction was generally subclinical and was transient in over half of cases. Autoimmunity was the only predictive factor for the development of dysfunction (relative risk = 8.9), but sustained disease was also significantly associated with male sex. 

Sun D., Newman T. A., Perry V. H., and Weller R. O. (2004). Cytokine-induced enhancement of autoimmune inflammation in the brain and spinal cord implications for multiple sclerosis. Neuropathol. Appl. Neurobiol. 30 374-384. 

The intramuscular injection of naked pDNA has also been evaluated for therapy of EAE, a mouse model of multiple sclerosis. The disease is induced in mice by s.c. injection of myelin basic protein (MBP) or proteolipid protein (PLP). In a recent study, mice were injected i.m. with pDNA encoding either IL-4/IgG or TGF / 48 hours prior to each MBP injection (on days zero and seven) (Piccirillo and Prud -homme, 1999). The disease severity was 70% lower in the IL-4/IgG or TGF / -treated mice and the mean clinical scores were significantly reduced in both groups. In addition, the IL-4 and TGF -treated mice had significantly reduced CNS inflammation, reduced T cell proliferative responses to MBP and low levels of the Th 1 cytokines IL-12 and IFN7. Thus, the pDNA therapy appeared to shift the mice to a Th2 response, which was therapeutic and reduced the severity of the disease. 

Cytokines are a potential way to modify the immune system in several situations because of their ability to act as immunoregulatory chemicals. For example, cytokines such as interferon-alpha and interleukin-2 can be administered to treat certain forms of cancer (see Chapter 36). Likewise, certain interferons can help control viral infections, and interferon-beta may be helpful in autoimmune diseases such as multiple sclerosis (see Chapter 34). Researchers continue to investigate how immune function can be manipulated to treat various diseases, and additional immune system modulators will almost certainly be forthcoming. 

A.R. Massaro, D.D. Pascalis, A. Berto-lotto, G. Biasi, and P. Gallo. 2001. Inter-feron-beta (INF-beta) antibodies in inter-feron-betala- and interferon-betalb-treated multiple sclerosis patients. Prevalence, kinetics, cross-reactivity, and factors enhancing interferon-beta immuno-genicity in vivo. Eur. Cytokine Netw. 12 56-61. 

IFN 3 is produced in vivo normally by fibroblasts. In humans, only one IFN 3 is found, which has 166 amino acids and a molar mass larger than 20 kDa. The molecule has a disulfide bond as well as an N-linked carbohydrate chain bound to asparagine 80. Structurally, it is characterized by the presence of five a-helices. Recombinant IFN 3 is marketed under the names of Betaferon , Betaseron , Avonex , and Rebif , being indicated for the treatment of multiple sclerosis, since it blocks the secretion of other cytokines involved in the pathogenesis of this disease. 

In addition to the effect of increased VLCFA on membrane and possibly cellular function, the rapid cerebral form of X-ALD is characterized by an inflammatory response that is believed to contribute to the demyelination that characterizes this phenotype and which is similar to that seen in multiple sclerosis. These cerebral lesions are characterized by breakdown in myelin with sparing of the axons accompanied by the accumulation of cholesterol ester in the neurons. A perivascular inflammatory response with infiltration of T cells, B cells, and macrophages also is present. Therefore, it is believed that the rapid cerebral disease has an im-munologically-mediated component. It has been suggested that the inflammatory response occurs in response to the elevated levels of VLCFA in lipids, which elicits an inflammatory cascade that may be mediated in part by cytokines. Once this cascade begins, it may be more difficult to intervene in the disease process, and in general therapeutic interventions studied to date have been most effective when initiated early. Therefore, prevention of the initiation of the immune response is important for improving outcome. 

Keywords Alzheimer disease Brain Cytokines Glial cells Huntington s disease Ik IkB kinase Ischemic and traumatic brain injury Learning Memory Multiple sclerosis Neuronal Plasticity Neuroprotection NF-kB Nuclear factor Parkinson s disease Rel family Seizures Synaptic transmission Therapeutic target Transcription factor... 

Martino G, Furlan R, BtambiUa E, Betgami A, Rufifini F, Gironi M, Pohani PL, Grimaldi LME, Comi G (2000) Cytokines and immunity in multiple sclerosis the dual signal hypothesis. J Neuroimmunol 109 3-9... 

Keywords Chemokine Cytokine Growth factor HTV-l associated dementia Alzeimer s disease Multiple sclerosis Inflammation Chemotaxis... 

Matusevicius D, Navikas V, Soderstrom M, Xiao BG, Haglund M, Frediikson S, Link H (1996) Multiple sclerosis The proinflammatory cytokines lymphotoxin-alpha and tumour necrosis factor-alpha aie upregulated in cerebrospinal fluid mononuclear cells. J Neuroimmunol 66 115—123. 

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