) How the complement cascade participates in neural disease and precipitates injury.
The complement system helps antibodies and other immune cells to destroy pathogens from an organism. It forms part of the immune system that does not change and an individual is born with it. The system and part of the innate immunity can also act together with the adaptive immunity. The complement system is made up of a number of proteins found in the circulatory system, synthesized by the liver, and circulates as inactive precursors also called pro-proteins. When the system is stimulated by one of several triggers, proteases cleave certain proteins to release cytokines and start an amplifying cascade of more cleavages (Boglio 89). The result of the activation cascade is a large amplification of the response and activation of the membrane attack complex. Many proteins and fragments make up the system, including receptors in the cell membrane and proteins in serum all of which make up about 5%of globulin in serum.
Three pathways initialize the system: the mannose binding lectin pathway, classical pathway, alternative pathway (Rother 68). The main features of the system are lysis which involves rupturing membranes of foreign cells, Opsonization which is enhancing phagocytosis of antigens, clumping of antigen-bearing agents, Chemotaxis where there is an attraction of macrophages and neutrophils.
Complement opsonins for example, Clq and C3b interact with surface complement receptors to promote phagocytosis while complement anaphylatoxins C3a and C5a initiate local pro-inflammatory responses that contribute to the protection of the host. Activation of the system to a higher extent has been thought to promote injury to tissues. There is evidence showing that the system is implicated in the pathogenesis of several neurological disorders including the human demyelinating disease multiple sclerosis and experimental allergic encephalomyelitis. Deposition of complement proteins correlates with areas of demyelination and axonal loss observed in EAE and complement inhibition ameliorates disease. However, the precise mechanisms underlying complement-mediated damage are still largely unknown (Alt 98). The recent use of transgenic animals is beginning to make it clear on the significant additions of the different complement activation pathways in the pathogenesis of experimental demyelination.
Although the liver is the major source of complement, glial cells and neurons in the CNS can produce most of the 30 different proteins that make up the complex complement cascade. C1q, mannose binding lectin, and C3 stimulate the activation and chemotaxis of inflammatory cells, promote phagocytosis, and facilitate lysis by the membrane attack complex and Levels of complement components are increased in Huntington's disease (HD) Complement activation products, including the membrane attack complex, colocalize with amyloid plaques and tangle-bearing neurons in Down's syndrome. Using differential mRNA display, C1q B-chain mRNA was found to be strongly increased in an experimental model of prion disease (Rother 23).
Complement activation can lead to the formation of C3 convertases, multiprotein enzyme complexes that cleave the secreted complement factor C3 into C3a and C3b. The C3a can promote chemotaxis of phagocytic cells. C3b binds covalently to acceptor molecules, initiating formation of the MAC and cell destruction. C3b deposition starts the phagocytosis process of the complement system through receptors that are found on macrophages. Host cells are normally covered from complement activation and self to self attacks by complement proteins bound on the membranes that regulate the system. Whether complement activation in neurodegenerative disorders represents an appropriate injury response or results from an impairment of these regulatory systems remains to be determined (Sherwood 61).
2) The role of the complement cascade in neural disease and injury precipitation.
Inflammation is recognized in science as a protective response by a host to injury that has occurred due to physical trauma or infections by pathogenic organisms. It is characterized by features of swelling, redness, pain and heat. But despite its protective role, it also has diverse side effects on the host due to mediators released during this process (Blass 98). In the central nervous system, inflammation is implicated in a wide array of disease pathogenesis including diseases like schizophrenia, Alzheimer’s, Parkinson’s disease and Amyotrophic Lateral Sclerosis.
The inflammatory mediators implicated in the pathogenesis include adhesion molecules, complement system, cyclooxygenase system (both the enzymes and products) and cytokines. All the above mentioned components of the inflammatory pathway play a critical role not only in the defensive aspect of the process but also the injurious and albeit unwanted consequence therein. In the central nervous system, they are implicated in the neuronal injury that is a distinct characteristic of all the above mentioned diseases.
This is due to the fact that years of research have shown that they are increased in levels in patients with the mentioned conditions. This fact cannot be debated since the use of therapeutic inflammatory modulators has shown success in neurodegenerative conditions such as multiple sclerosis (Blass 89).
Although inflammation is essentially a protective event, it may lead to damage of host tissue around the site of the inflammation. For one to understand how the injury occurs, it is vital that one knows the events in inflammation. During tissue injury, either due to trauma or the offending toxins released by pathogens that have infected the host, the body releases an array of chemicals meant to carry out certain protective roles.
The roles include; to recruit a large number white blood cells to the site of the event thus stopping the infection or preventing its further progression, to increase the blood flow to the affected region thus bringing more nutrition (oxygen and glucose) to the affected tissues and aid in removal of accumulated toxins, and to cause an increase in the size of the tissues (swelling) thus creating a ‘walled off’ area from the rest of the surrounding tissue that is not affected. The chemicals/mediators that carry out this functions include; cytokines, Prostranoids, Kinins, substance P, Histamine, Serotonin and Nitrous Oxide ( Cutler 15).
Cytokines are a family of chemicals that are key in the mediation of the inflammatory process. They are divided into interleukins and interferon. Further divided into those that enhance cellular immune responses, type 1 (IFN-γ, TGF-β, etc.), and type 2 (IL-4, IL-10, IL-13) for antibody (Neal.R. 102).
The brain has very distinct and unique features when it comes to inflammation and its response to inflammatory insults. The brain is described as an immunologically privileged site and the tight junctions of the cerebral vasculature prevent large molecules and cells from entering. The brain is also tightly confined in the cranium thus according very limited space for brain tissue swelling.
Inflammation in the central nervous system has been implicated in both acute and chronic diseases. Most neurodegenerative central nervous system diseases are due to chronic inflammation. Multiple sclerosis, for example, is one of the most common of these diseases. The exact etiopathogenesis of this disease has not been fully unraveled (Wiley-Blackwell 45). But years of research have shown that inflammation has a key role to play, that of the autoimmune type.
Evidence points to autoimmune condition that leads to T-cell activation and deactivation of suppressor T-cells leading to invasion of the central nervous system by the T-cells and macrophages (Prat et al. 2002). This leads to axonal demyelination, consequent degeneration and plaque formation. Both clinical studies and experimental studies (in mice immunized against myelin basic protein) have shown increased levels of TNF-alpha and INF-gamma, which are directly toxic to oligodendrocytes. These, effect on neurons, have been shown clinically. The autoimmune condition that causes release of these harmful cytokines has a snowball effect. The above cytokines lead to stimulation and production of more cytokine, therefore, leading to further disease progression and neurodegeneration.
3) The advantages and disadvantages of pharmacotherapeutics that target adhesion molecules and leukocytic infiltration into the CNS, such as in MS-spectrum disorders.
The goal of pharmacotherauptic drugs acting in the CNS is to diminish or breakdown certain immune responses that are triggering by Multiple Sclerosis, while also causing minor side-effects, and not having to weaken the immunity of the body.
Multiple sclerosis an autoimmune disease dealing with immune action targeted against central nervous system antigens (Sherwood 67). It is the most common inflammatory-demyelinating diseases targeting the CNS. With the support of the immune system participation in the progress of MS has grown, trials of many different new therapies to suppress the immune response and even alter the system are being conducted.
Most therapies are still experimental. Data of recent randomized clinical trials are showing that immunosuppressive drugs that target adhesion molecules and leukocyte infiltration and methods can encouragingly affect the progress of Multiple Sclerosis. Toxic side effects often prevent their overall use. Immunosuppression of the host leaves the patient prone to a number of opportunistic infections.
Amongst the many demyelinating conditions that have an effect on the CNS, those induced by an inflammatory process come out because of their relevance. The well described inflammatory-induced demyelinating condition is multiple sclerosis, but the immunity system response is a frequent pathogenic mechanism in less common diseases for example acute disseminated encephalomyelitis. Hence, changing of the immune system response is likely to be a best therapeutic choice.
The introduction of these pharmacotherauputic agents has dramatically changed how neuro-degenerative diseases can be treated. These agents are immune-modulators, which in essence means, they can change the functioning of your immune system by suppressing or increasing in built immune responses. The more specific the specific target to be blocked is, the less the effect is to the other bodily functions, making the agent more effective.
With the use of these agents in neuro-degenerative treatment, serious side-effects from treatment with the agents have been documented; even deaths have been noted with their usage. If there was a preexisting disease, such as tuberculosis or other serious diseases, the risk for severe side-effects from their therapy with these agents increases. Some research has shown their capabilities for increasing cancer through their actions on the body's immunity. Research into these drugs is still continuous and ongoing on the many disadvantages as their long time use has not yet been documented (Alt 56).
Pharmacotherapeutic therapy is very expensive and most times not a probable treatment choice. Their use is limited to those who can afford. Those agents that are approved for use in treating patients with neuro-degenerative diseases can be divided into three types: tumor necrosis factor-alpha inhibitors which block the chemical messengers, T cell modulators that get the T cells and cytokine inhibitors that block specific intercellular connections and all this block leukocyte infiltration and cell adhesions (Lezonni 56).
Any increase in strength of multiple sclerosis drugs could affect with the protective immunosurveillance of the central nervous system. One probable impact is an increased prevalence of opportunistic diseases. An increased surveillance for central nervous system infections in the prospect of immunosuppression is important to avoid major side-effects (lezonni 78).
Many of these drugs are very helpful in controlling some of these neuro-degenerative diseases, but due to the many side-effects their use is still debatable.
4) Promising targets of therapeutics to be used in treatment of neuroimmunological disorders and the possible impact of such therapeutics on disease progression.
Research has been ongoing into the possible development of neurodegenerative disorders treatments. But the main hurdle most researchers face lies in the thin line between the helpful and detrimental effects of inflammation. Delineating these two has proved to be a major headache to researchers. Another major setback is the inability of scientists to be able to identify which specific inflammatory mediators are involved, and the role they play in the different types of acute or chronic inflammatory diseases.
In acute central nervous system injury, for example stroke or brain injury, there is a lot of literature available on the specific types of mediators involved and their role. Most of this data was obtained from experimental rodent studies (Sluis 44). In acute injury, research has shown that general anti-inflammatory therapy is helpful in the prevention of serious brain injury. Drugs like aspirin and Statins have been shown to help in management of the above mentioned injuries. Although Statins are known to exert their effects on cholesterol and aspirin on coagulation, most schools of thought do not dispute their anti-inflammatory effect as contributory (John P 42).
Apart from these well established drugs in use, research is ongoing to develop drugs that are more specific and target certain mediators. For example, a drug targeting interleukin-1(IL-1) is already in early safety trials and so far no adverse drug reactions have been reported. This drug, interleukin-1 receptor antagonist (IL-1RA), is being used to reduce levels of IL-1 during inflammation.
Interleaukin-1 has been shown to be in increased levels in acute neurodegenaration. It has also been shown to play a role in fever development following brain injury (fever is very common and is detrimental sequelae of brain damage). By decreasing the levels of interleaukin-1, the drug is aimed at reducing the intensity of the inflammatory response and reducing the development of fever. Though this drug has shown so much promise, the main setback is that it is a large molecule and its bioavailability in the brain is reduced since the brain blood barrier keeps most of it out. Researchers are trying to circumvent this short coming by employing cleavage enzymes, soluble receptors and inhibition of expression (Robin Thorpe 67).
Apart from targeting interleukin-1, other cytokines can also be targeted and modulated using pharmacological agents. Research on this front is still poorly advanced, but it is still a very promising one. Cytokines like tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), which are widely known to be involved in central nervous system inflammation, can also be targeted. They can either be targeted by employing receptor antagonists or enzyme inhibitors. This would consequently lead to a diminished inflammatory response.
Apart from pro-inflammatory cytokines, another target site can be anti-inflammatory cytokines like interleukin-10, interferon-beta (IFN-beta) and transforming growth factor-beta amongst others. The data on just how much neuroprotection they accord are very limited, but facts point to their ability to reduce inflammation in the brain (Robin Thorpe 106). Pharmacological agents can be developed either as analogs of these chemicals or by increasing their production through enzyme activities.
The inflammatory process can also be targeted by preventing activation of microglia cells. Microglias are types of glial cells that are macrophages in the spinal cord and the brain. They are thus the primary form of active immunological defense in the central nervous system. When activated, they take an amoeboid shape and release cytokines and other inflammatory mediators that lead to neuron degeneration (Blass 100). This modulation can be achieved be achieved by Inhibition of activation, Regulation of chemokine receptor, Inhibition of amyloid deposition and Inhibition of cytokine synthesis.
These are just but a few of the targets than can be isolated in the neuroimmflammatory pathway and appropriately modulated to reduce neuronal destruction in neurodegenerative process. By modulating the inflammatory process with the right drugs, the disease process can be halted, and even reversed in the long run.