Multiple sclerosis

The most common cause of neurological disability in Western countries Symptoms may include numbness in the limbs, paralysis or loss of vision Most people with MS are between the ages of 20 and 40 diagnosed

Autoreactive T cells form inflammatory lesions along the myelin sheath of nerve fibers Cerebrospinal fluid of patients also contains activated T lymphocytes which destroy the myelin sheath Breakdown in the myelin sheath leads to numerous neurological dysfunctions

Epidemiology
MS is the most common in the Northern hemisphere Populations who live north of the 37th parallel have a prevalence of 110140 cases per 100,000 South of the 37th parallel show a prevalence of 5778 per 100,000 Individuals from south of the 37th parallel who move north assume a new risk if the move occurs before 15 years of age This suggest the involvement of environmental component Other factors are also implicated

Genetic factors
Average person in the United States has about one chance in 1000 Close relatives of people with MS, such as children or siblings, have 1 chance in 50 to 100 Identical twin of a person with MS has a 1 in 3 chance of developing the disease MS affects women two to three times more frequently than men

Infections as triggering factors

Cause of MS, like most autoimmune diseases, is not well understood Infection by certain viruses may predispose a person to MS Some viruses can cause demyelination of the neurons There is no definitive data implicating a particular virus

Experimental autoimmune encephalomyelitis (EAE)

The best studied models of autoimmune diseases EAE is mediated solely by T cells Induced in a variety of species by immunization with myelin basic protein (MBP) or proteolipid protein (PLP) in complete Freunds adjuvant Within 2-3 weeks the animals develop cellular infiltration of the myelin sheaths

Experimental autoimmune encephalomyelitis (EAE) can be induced in rats by injecting them with myelin basic protein (MBP) in complete Freuds adjuvant (CFA).

 Result in demyelination and paralysis Most of the animals die, but others have milder symptoms, and some animals develop a chronic form of the disease Some animals recover and are resistant to the development of disease from a subsequent injection of MBP and adjuvant EAE model provides a system for testing treatments for human MS

 MBP- or PLP-specific T-cell clones are found in the periphery These clones must have escaped negative selection in the thymus Orally administered MBP may make these antigen specific peripheral T cell clones self tolerant

Role of CD4+ cells

Lymph node cells from EAE rats are cultured in vitro with myelin basic protein (MBP) T cells are activated When MBP specific T cell clones are injected intravenously into normal syngenic animals, the cells cross the blood brain barrier and induce demyelination Examination of these T cells has revealed that they are CD4+ cells Weekly injections of anti-CD4 monoclonal antibody abolished the symptoms in mice with EAE

Role of TH1/TH2 ratio

TH1 cells have been implicated in the development of autoimmunity TH2 cells not only protect against the induction of disease but also against progression of the disease Immunohistologic studies revealed the presence of TH1 cytokines (IL-2, TNF-, and IFN-) in the central nervous system tissues at the height of the disease Experiments have shown that only the TH1 clones transfer EAE to normal healthy mice

Role of cytokines
When mice were injected with IL-4 at the time of immunization with MBP plus adjuvant, the development of EAE was inhibited Administration of IL-12 had the opposite effect, promoting the development of EAE IL-4 promotes development of TH2 cells IFN- , in addition to other cytokines such as IL12, promotes development of TH1 cells

Role of MHC complex

HLA-DR2 is implicated in MS Relationship between MHC alleles and development of autoimmune disease is very complex Existence of such an association should not be interpreted to imply that the expression of a particular MHC allele has caused the disease

Role of TCR
T cell receptors containing particular V and V domains also has been linked to a number of autoimmune diseases, including experimental EAE and multiple sclerosis