MS Pysiology

Summary: In the progression of MS, T-Cells that react with the ProteoLipid Protein (PLP) may be extremely important. The authors examined 23 different T-Cell lines that react against a man made part of the PLP in 3 Japanese MS patients with a particular Genetic make-up (DR2, w15 haplotype). The majority of T-Cells examined were found to have a similar make-up and appear to be unique to the T-Cells found in the brains of these patients. These results indicate that T-Cells that react against the PLP may be involved in the disease progression of MS.

Summary: The authors used mice infected with Theiler's murine encephalomyelitis virus (TMEV) as a model for MS. This well-characterized infection results in a chronic, progressive DeMyelination of the Central Nervous System (CNS). The authors used this model to investigate the potential beneficial relationship between natural autoimmunity and ReMyelination (repair of damaged nerves).

In previous reports, the authors have developed an AntiBody that promotes the repair of the DeMyelinated nerves in mice infected with TMEV.

Treatment of mice chronically infected with TMEV with these AntiBodies lowers the number of T-Cells entering the CNS by 2 to 3 times without lowering the overall number of T-Cells in the mice.

These results are consistent with the proposed method of Immune System regulation of natural autoAntiBodies (AntiBodies against ones self). One way these AntiBodies (named SCH94.03) may promote CNS ReMyelination in infected mice is through the inhibition of a damaging immune response.

Summary: The Serum and CerebroSpinal Fluid (CSF) of rats were measured for Tumor Necrosis Factor alpha (TNF alpha) activity during the course of Experimental Allergic EncephaloMyelitis (EAE).

This is a disease which is similar to MS in rodents. As the clinical symptoms of the disease increased so did the levels of TNF alpha. The authors further investigated the Central Nervous System (CNS) cells involved in TNF alpha production.

They found that the spinal cord, White Matter and optic nerve all showed the presence of TNF alpha during the progression of the disease. These results show that TNF alpha plays an important role in the progression of EAE.

Summary: In MS there is an increased production of AntiBodies within the CerebroSpinal Fluid (CSF).

This observation suggests that there are B cell (AntiBody producing cells) factors present in the CSF. The cytokine interleukin-6 (IL-6) can cause B cells to produce more AntiBodies.

The authors measured the number of IL-6 producing cells in blood and CSF from MS patients, patients with aseptic meningo-encephalitis (AM), blood from patients with other neurological diseases (OND), and healthy control subjects.

The number of IL-6 producing cells were elevated in blood and the CSF of MS patients, and to a similar degree in AM patients' blood.

These experiments suggest that IL-6 is one of several cytokines which are produced in higher amounts in MS particularly in the CSF. However, the role of IL-6 in MS and whether it is involved in causing the disease or preventing it remains unclear.

Summary: Experimental Allergic EncephaloMyelitis (EAE) is an animal model used to study Multiple Sclerosis.

In this study rats with EAE were examined for the levels of nerve growth factor (NGF) in the Central Nervous System (CNS) as well as the amount of NGF that the cells were producing and the amount of receptor sites found on cells of the CNS.

Their studies revealed that NGF and its receptor on the cell surface is higher in several regions of the CNS in EAE rats when compared to normal rats. These results suggest a link between the increased production of NGF and EAE in rats.

Summary: The onset of autoimmune disease usually coincides with the development of new AntiBodies that recognize normal proteins in your body that are not usually recognized by AntiBodies in healthy individuals.

This process is called determinant spreading. The authors looked at this process in the MS disease model Experimental AutoImmune EncephaloMyelitis (EAE) in mice.

They determined where the AntiBodies bound to the Myelin proteolipid protein (PLP) at various times after the EAE disease was induced in mice.

Their findings showed that new sites on the PLP are targeted by AntiBodies over the course of the disease. These findings also demonstrated that the process of determinant spreading results in damage and the progression of the disease.

Knowing this process occurs could help in determining specific therapeutic actions after the onset of the disease.

Summary: This article describes the role of tumor necrosis factor (TNF) in the development of various diseases. TNF is a protein with an important role in the way the Immune System operates.

In the diseases rheumatoid arthritis, systemic inflammatory response syndrome, diabetes, Multiple Sclerosis, and many other immune-mediated disorders there is strong evidence that abnormal TNF levels play a predominant role in the disease process.

Mice have been Genetically engineered by scientists to make larger amounts of TNF. These mice have been used as models for human Rheumatoid Arthritis, systemic inflammation, and Multiple Sclerosis.

These animals will serve as important tools in the future for defining how many of these diseases progress and for determining possible targets for therapeutic drugs.

They will also be used for evaluating potential Genetic and environmental factors involved in the disease state.

Summary: Human HerpesViruses may cause a number of Central Nervous System (CNS) diseases. After infection, these Viruses remain dormant in the normal individual for a lifetime.

Human HerpesVirus 6 (HHV-6) can cause neurological disorders in children while adult cases of Encephalitis causing death have only been reported in AIDS-patients or Immunocomprimised individuals such as transplant patients.

In this report the authors describe an individual with MS who was diagnosed with Encephalitis. Cerebral spinal fluid (CSF) collected from the individual before the Encephalitis was negative for HHV-6 whereas CSF was positive for HHV-6 during the Encephalitis.

This finding is consistent with the Encephalitis being caused by the reactivation of a dormant HHV-6 in the MS patient which may be the result of an altered Immune System.

Summary: In MS patients there is an increase in the amount of Major Histocompatibility Complex (MHC) Class I produced in the Central Nervous System (CNS).

The authors designed experiments to determine if MHC Class I production by nerve cells (called Oligodendrocytes) causes destruction of the White Matter in the brain.

To determine this, the authors used Genetically engineered mice that expressed MHC Class I that is under the control of the Myelin Basic Protein (MBP) regulatory DNA elements (ie. whatever circumstances alters the expression of MBP will have the same effect on the expression of MHC Class I).

The authors found that MHC Class I expression by the Oligodendrocytes slows down the normal Myelination but does not cause inflammatory DeMyelination commonly seen in MS patients. These animals may be used in the future for studies into the interactions between molecules which affect the Immune System and disorders which affect Myelin.

Summary: One of the prominent features of the pathology of MS (as well as the animal model of MS, EAE) is a condition called reactive astrogliosis.

It is characterized by hypertrophy (shrinkage) of a type of nerve cell called Astrocytes and an increase in these cells of a protein called Glial Fibrillary Acidic Protein (or GFAP).

Previous studies that looked at the changes in the amount of GFAP in affected Astrocytes in animals with EAE used a detection method that relied on staining for GFAP with a specific AntiBody.

It has been realized that these studies suffered from technical problems, and the amount of GFAP staining by the AntiBody method did not really coincide with the actual amount of GFAP content in the cells.

In order to get around this technical problem, the authors used a different method of detecting the amount of GFAP in Astrocytes.

Rather than looking for the protein itself with an AntiBody, they used a technique called in situ hybridization, which looks for the messenger RNA (the blueprint for the protein) that codes for the synthesis of GFAP.

Using this sensitive method, they found that GFAP content in Astrocytes increases at two different times during an EAE episode: an early phase at the onset of Central Nervous System inflammation and clinical disease, and a later phase during the resolution of inflammation and clinical improvement.

The Astrocytes undergoing increases in GFAP content were located in different areas during the early and late stages, and appeared to represent different subtypes of Astrocytes that had different functions.

The authors conclude that the location and function of Astrocytes involved in reactive astrogliosis may vary during the course of immune-mediated DeMyelination in EAE and MS.

Summary: This report is about seizures called PLEDs in a young man who has had MS for many years. After 2 different MS episodes, 3 years apart, the man had a seizure.

The authors believe that the seizures were caused by the MS relapses. This is an unusual cause for this type of seizure.

Summary: Multiple Sclerosis is an AutoImmune Disease in which a certain type of effector cell of the Immune System called a T-Cell is specifically directed against and attacks the components of the Myelin sheath of nerves, including Myelin Basic Protein (MBP).

T-Cells recognize their specific targets using a cell surface protein called the T-Cell receptor (TCR).

T-Cell receptors are made by randomly combining the products of a number of different TCR Genes together, and each T-Cell has a distinct T-Cell receptor capable of recognize only one type of target molecule.

In many autoimmune diseases, such as MS, there is a tendency to over-use one particular product of a TCR Gene to form the TCR that recognize the autoantigen (which in the case of MS would be MBP).

This over-representation of a particular piece of the T-Cell receptor can itself cause an autoimmune response to be mounted against it, so the T-Cells attacking the Myelin can themselves become the targets of other T-Cells and AntiBodies that attack them.

In this way, the autoimmune attack on the nerve cells can be reduced and recovery can take place. This natural regulatory network can be manipulated (at least in animal models of MS) by injecting the over-used components of the anti-Myelin T-Cell receptors and causing a sustained immune response against these components.

This acts to continually suppress the anti-Myelin T-Cells. Thus, this type of manipulation of the inherent regulatory network of an autoimmune response might be able to be exploited in the treatment of MS and other autoimmune diseases.

Summary: The authors set out to examine the expression of basic fibroblast growth factor (FGF-2) and one of its receptor sites (FGFR-1/flg) found on the surface of cells.

To do this they produced rats with the disease experimental autoimmune encephalopathy (EAE) a rodent disease similar to MS.

Control animals were found to have low levels of FGF-2 in T-Cells and these cells were found primarily in blood vessels with a few found in the spinal cord.

In rats with EAE there was an increase in cells producing FGF-2 in the spinal cord. There were two types of cells in the spinal cord producing FGF-2, macrophage and microglia.

Once the rats had recovered from the disease the level of FGF-2 dropped down to normal levels. The FGF-2 receptor (FGFR-1/flg) also increased in rats with EAE compared to normal rats.

The receptor was also located on astrocytes (a type of nerve cell found in White Matter in the brain) bordering the regions of inflammation.

From these experiments the authors conclude that increased production of FGF-2 could serve two main functions in EAE.

First, it might affect the function of neurological cells (macroglia) and second, it might help to direct the protein called insulin-like growth factor-I to injured nerve cells in the DeMyelination process.

Summary: E-Selectin and vascular adhesion molecule-1 (VCAM-1) are responsible for controlling the migration of immune cells into areas of inflammatory lesions.

The authors determined the levels of VCAM-1 and E-Selectin in Cerebral spinal fluid (CSF) and Serum of patients with MS, Viral encephalitis and control individuals.

MS patients with active lesions had significantly higher levels of VCAM-1 in Serum than normal control individuals and patients with Viral encephalitis had high levels of VCAM-1 in both CSF and serum. The levels of E-Selectin were similar in all three groups.

The authors conclude that the process responsible for attracting immune cells to a damaged site can be demonstrated in MS patients by measuring VCAM-1 in the serum. VCAM may be useful in monitoring inflammatory activity in the Central Nervous System of MS patients.

Summary: CD40 is a protein found on the surface of certain types of cells of the Immune System.

Another protein called CD40-ligand is present on other types of cells and when it interacts with CD40, it causes the CD40-bearing cell to become activated (turn on).

The authors investigated if activation of immune cells through CD40 was involved in Multple Sclerosis.

Brain tissue from MS patients was found to contain helper T-Cells (a type of immune cell) that had CD40-ligand on their surface, but these were not present in brain tissue from normal controls or from controls that suffered from other types of neurological diseases.

Cells with CD40 and cells with CD40-ligand were both found to be located in active lesions. To evaluate the significance of CD40 interactions with CD40-ligand in MS, mice with EAE, an animal model of MS, were treated with AntiBodies directed against CD40-ligand.

The effect of these AntiBodies is to either block the interaction with CD40 or to cause the destruction of the CD40-ligand bearing cells.

It was found that treatment with the AntiBodies completely prevented the development of EAE in the mice. In addition, if the AntiBodies were administered after the disease had been allowed to progress almost to the point of maximum disability, they still led to a dramatic disease reduction.

These results suggest that blocking interactions between CD40 and CD40-ligand may be a method for treating active MS.

Summary: Tumor necrosis factor-alpha (TNF-) and lymphotoxin (LT) are two related chemicals that the Immune System produces and uses to signal a number of reactions, including inflammation.

Their involvement in Multiple Sclerosis has been previously suggested by other studies that found them in acute and chronic MS brain lesions.

The authors of this study used a method called "in situ hybridization" to detect and count cells from MS patients and control patients that were producing TNF- and LT.

They found that MS patients had many more cells that were producing these two chemicals than healthy patients or patients with other types of neurological diseases.

Also, during times when MS symptoms became worse, increased levels of TNF- was being produced. Patients that had Optic Neuritis (which often represents very early MS) also were found to have increased levels of TNF- and LT, similar to individuals with definite MS.

The results of this study support the idea that TNF- and LT are involved in the development of MS. They also suggest that TNF- could be a useful marker for disease activity in MS.

Summary: In this study, a number of patients with Multiple Sclerosis were treated with an antibody that caused the destruction of many immune cells.

Although the numbers of white blood cells in the blood were quickly reduced, an interesting observation was that there was a significant exacerbation or re-awakening of pre-existing disease symptoms after the first infusion of antibody.

These side effects of the antibody treatment correlated with increased levels of cytokines, which are chemicals produced and used by the Immune System to communicate between cells and signal various responses.

Cytokines that increased their levels in response to antibody treatment included tumour necrosis factor alpha (TNF-), interferon-gamma (IFN-) and interleukin-6 (IL-6).

Summary: Matrix MetalloProteinases (MMPs) are a family of enzymes that are involved in remodelling the structural components of many tissues.

They are also thought to play a role in opening up gaps in tissues, thus allow immune cells to infiltrate them and get to sites of inflammation.

This study looked at which type of cells produced MMPs in the normal human Central Nervous System (CNS) and in MS lesions and other conditions of the CNS. It was found that in MS lesions, the types of cells that express the MMPs are different than they are in normal CNS.

Also, the individual members of the MMP family that are expressed are different, depending upon the condition and the cells expressing them.

The authors suggest that in MS lesions, the MMPs produced by certain cells may allow immune cells to gain access to the CNS and may also contribute towards DeMyelination and other processes involved in MS PathoGenesis.

Summary: Experimental Allergic EncephaloMyelitis (EAE) is an animal model of MS. It is induced in mice by vaccinating them with portions of proteins found in the Myelin sheath of nerves, such as Myelin Oligodendrocyte Glycoprotein or ProteoLipid protein.

This causes the mice to develop an autoimmune response against these proteins, which leads to the destruction of the Myelin sheath. Myelin Basic Protein (MBP) is another major component of the myelin sheath.

In this study, the authors tried to induce EAE in mice by vaccinating them with whole MBP or with defined pieces of it. Although MBP did not cause EAE in the particular strain of mice tested, certain pieces of it did cause mild disease.

When these pieces were investigated more closely, it was found that they were very similar to the defined pieces of Oligodendrocyte Glycoprotein and ProteoLipid Protein that are known to cause EAE.

The similarity between the pieces of the 3 different proteins that cause EAE allowed the authors to identify a pattern that is important for recognition by the mouse's Immune System. These findings may have relevance in the design of future treatment strategies.