Health and Heparan Sulfate Circulation — Connective Tissue is Alive

--- The other 200 posts are here ---

Arthritis, Alzheimer’s, diabetes, cardiovascular disease, osteoporosis, cancer, etc. are all diseases of cellular metabolism and secretion.  What goes on inside cells and on their surfaces explains a lot about health and why we get sick.  Cells feed off of what’s around them, use some of those materials to replicate and package up cell-made materials for export.  Eat, replicate and secrete.  Symptoms of disease result if those processes are compromised.

Cell that make Cartilage, Eat Cartilage

The connective tissue that makes up the cartilage of tendons and the non-mineral parts of bones, as well as a layers of skin, is made up of proteins (collagen) and polysaccharides (glycosaminoglycans, GAGs), e.g. heparan sulfate, hyaluronan and chondroitin sulfate, produced by  chondrocytes or fibroblasts.  These proteins and polysaccharides are synthesized and then secreted by cells.  This process goes on continuously, since the connective tissue is alive and literally crawling with cells that make the cartilage.  To keep the connective tissue healthy, the old tissue has to be digested, so that new material can replace it.  Thus, the cells that live in cartilage also eat cartilage.  These cells get all of their nutrients, e.g. protein and carbs, from eating cartilage.  They don’t get glucose and amino acids, or even oxygen (they ferment), from the blood, because there are no blood vessels in cartilage.  The photomicrograph at left shows the red chondrocytes surrounded by a light capsule of heparan sulfate as they burrow through the purple cartilage.  The next micrograph shows the cytoskeleton of actin filaments (stained with a red fluorescent dye, that lies under the cytoplasm of a chondrocyte.  Motor proteins move other proteins, such as syndecans, the proteins to which the heparan sulfate chains are attached, through the  cell membrane (see the animations below.)  The last micrograph shows the green stained microtubule network on which vesicles move to carry heparan sulfate products from one end of the cell to the other (under the actin and past the orange-dyed nucleus) during synthesis and digestion.

Chondrocytes Burrow Through Cartilage

Chondrocytes are the cells that eat and make cartilage, but all of this eating and making goes on at the same time that the cartilage is also holding everything together, i.e. it is still strong.  If cartilage is cut and the cut ends are held tightly together, the chondrocytes will knit the cartilage together and it will become as strong as it was. 

Heparan Sulfate Circulates over the Surface of Cells

Chondrocytes are not actually rigidly embedded in the cartilage, but rather maintain a capsule of heparan sulfate around themselves.  Thus, they continue to secrete a mixture of heparan sulfate, chondroitin sulfate and collagen, but the heparan sulfate is recycled through the capsule and the other molecules merge into the existing cartilage.  Thus, the heparan sulfate is a kind of carrier that keeps the cartilage from “setting up” while it is being made and transported.  Other cells of the body, such as neurons, don’t make cartilage, but they still have heparan sulfate (HS) circulation that is intimately involved in many other processes, such as the action of hormones.  Disruption of HS circulation causes the symptoms of Alzheimer’s or type 1 diabetes, for example, since amyloids assemble as filaments on threads of HS, and the amyloid filaments jam essential HS circulation.  Plaque in atherosclerotic vessels is high in HS content.  HS is also a major component surrounding vessels to form the blood brain barrier and the barrier to protein loss from kidneys into urine or loss into the gut lumin.  Heparin (fragments of HS) is continually released from mast cells in the lining of the gut to prevent pathogens from binding to cell HSPGs. 

HS Sweep the Cell Surface

There is a constant flow of heparan sulfate proteoglycans (HSPGs) through the cell membrane from the rear of the chondrocyte to the front where the HS is digested again and the protein that was embedded in the membrane, syndecan, is recycled to the Golgi for another trip.  HSPGs (animation to left with blue protein and yellow HS) are attached to motor proteins that propel them through the membrane along microfilaments of actin that form the cyctoskeleton just under the membrane in the cortical region of the cell.  Thus, the heparan sulfate of the HSPGs stick out like hair from the cell surface and sweep continuously from the back to the front of the cell.  At the front of the cell, the HS sweeps through the intact cartilage and reverses the process of cartilage assembly.  The chondroitin sulfate, collagen and HSPGs are dragged into the cell and digested.  The protein parts of the HSPGs are transported to the Golgi  and the HS is synthesized along with other cartilage components and moved in vesicles along microtubules before it is secreted.

HS is Secreted at One End and Eaten at the Other

The animation left shows 1) the initial digestion of the cartilage proteins and polysaccharides on the left.  These cartilage components of amino acids and sugars, are used by the chondrocytes as their sole nutrients 2), and to produce new proteoglycans 3) HS and chondroitin sulfate proteoglycans, in the Golgi, are 4) packaged into secretory vesicles and are 5) secreted on the right.  The HS chains, attached to proteins, are 6) swept through the membrane (see the first animation above) toward the front of the cell, leaving the collagen and chondroitin sulfate for form cartilage behind.  In the process, the heparan sulfate proteoglycans 7) disrupt and solublilize old cartilage ahead as the chondrocytes 8) move through the connective tissue like moles digging through soil.

Other Cell Processes Involving Heparan Sulfate:

• Amyloids of Alzheimer’s and type I diabetes assemble bound to HS.
• Hormones bind to receptors wrapped around HS.
• Blood clotting is controlled by HS.
• Complement is controlled by HS.
• Blood brain barrier is composed of HS.
• Kidney protein barrier is composed of HS.
• Inflammation blocks HS synthesis and promotes heparanase synthesis.
• GAGs are animal soluble fiber when eaten and feed gut flora.
• Pathogens bind to HS.
• HIV-TAT is transported between cells by HS circulation.
• Heparin is made by heparanase fragmentation of HSPG in mast cells and is secreted along with histamine. 
• NFkB activation inhibits HSPG production and stimulates heparanase production.
• Heparan sulfate proteoglycans organize nerve synapses and acetylcholine esterase binds to HS. 
• Gastric proteases cleave around heparin binding domains of proteins, e.g. milk, consist of clusters of basic amino acids.  Peptides with heparin binding domain are antimicrobial; all of the heparin binding peptides are subsequently degraded by pancreatic proteases.
• Heparanase is initially secreted inactive and bound to HSPGs, but it remains bound and is internalized again along with the recycling HSPGs, and is activated before being secreted again.
• Allergens and autoantigens are unusual proteins with sequences of three adjacent basic amino acids (arginine or lysine) that require HSPG circulation for presentation of the immune system.  Nuclear proteins that interact with nucleic acids have sequences of four basic amino acids, the nuclear translocation signal, and are therefore common antinuclear auto antigens.

Health Diagrams

Health Diagrams II — Curing Autoimmunity and Allergies

---All 200 posts here---

In this second in a series of posts explaining the concepts that I think are central, but misunderstood, about health, I am focusing on how diet and gut flora impact the immune system and cause autoimmunity and allergies.  This cause also suggests a simple cure.

Health in Diagrams I -- Gut Flora and Diet
Health in Diagrams III -- Inflammation from Cell to Tissue

Gut Flora to Tregs to Suppression of Autoimmunity

It is important to understand at the outset that autoimmunity and allergies are caused by a damaged immune system, and repairing the damage cures the diseases.  Damage to the immune system typically represents a break in the continual development of immune cells in the lining of the intestines.  Immune cell development in the gut is dependent on bacteria, the gut flora.  Damage to the gut flora, e.g. by antibiotics, processed foods that lack flora feeding fiber or extreme diets, disrupts development of immune cells.  Typically, loss of the immune cells that keep the aggressiveness of the immune system in check, regulatory T cells or Tregs, results in autoimmunity.  Fix the gut flora and autoimmunity recedes.  

Health Requires Suppression of the Aggressive Immune System

For simplicity, I am focusing on the T cells of the immune system that develop in the intestines and either kill other human cells that are dangerous, e.g. virus-infected or cancer cells, or provide protection by regulating the aggression, Tregs.  Normal functioning of the immune cells permits elimination of damaged or dangerous human cells, while at the same time avoiding rampages of lethally armed T killers.  Examples of untamed T killers in action are degenerative autoimmune diseases, such as arthritis, asthma, prostatitis, celiac, Hashimoto’s thyroiditis, type I diabetes, inflammatory bowel diseases and atherosclerosis. 

Milk Births Baby Immune System

It should not be surprising that the focus of immune system development is the gut.  We start as babies with explicit links between nourishment and immunological protection.  Milk connects the immune systems of mother to baby.  Immune cells from the mother are transferred in milk and colonize the respiratory and digestive system of the baby — the mother’s immune system coats and buffers the baby’s exposure to the world.  Milk hormones close the baby’s gut and milk bacteria are the first probiotics that exploit the milk prebiotics (bifidus factor, human milk oligosaccharides) to produce a gut flora.  [Also note that most commercial probiotics are adapted to grow on cow’s milk and hence these dairy probiotics do not survive in adults.]  The lymphatic system of the breast terminates at the nipple and samples antigens/pathogens from the baby’s mouth, resulting in baby-specific secretory antibodies that return in the milk.  Milk supports a starter set of gut flora, essentially dairy probiotics, that stimulates development of the baby immune system, but inhibits adult gut flora that would digest the protective components of milk.  Formula, on the other hand, is inflammatory to the baby gut, because it supports adult gut flora before the immune system is ready.  Inflammation and stimulation of innate immunity is sufficient, if supported with high levels of sanitation, to permit survival of babies fed formula.  Milk of any type is incompatible with adult gut flora, so breast milk will attack adult gut flora and adult gut flora will digest and inactivate the otherwise beneficial components of the milk.

Milk, Kefir and Gut Flora

Aggressive and Suppressive Cells of Immune System Develop in Intestines

Gut bacteria are required for the development of immune T cells in the lining of the intestines.  Mice grown without gut flora do not have functional immune systems.  In humans, extensive antibiotic treatment produces defective immune systems that are either overly aggressive, i.e. autoimmune, or susceptible to infection and cancer.  They can’t be both.  Aggressive T killers are stimulated to develop by filamentous bacteria and Tregs develop in response to members of the Clostridium family.  In a healthy body, there is a balance between aggression and suppression; there are functional defenses against infection and cancer, while also avoiding autoimmune disease and allergies.

Suppressive Tregs are Deficient in Autoimmunity

Immune cells result from replicative divisions of stem cells.  Antibody producing B cells are produced through a million random rearrangements of antibody genes and those B cells producing antibodies against common self proteins are killed (clonal deletion).  Similarly, T cells are produced by rearrangements of receptors and those that would recognize self are eliminated.  The T cells then migrate to the intestines where they can develop into killer T cells or Tregs, in response to gut flora.  The Tregs act to suppress killer T cells that mistakenly recognize healthy self cells.  Thus, the initial elimination of self-attacking T cells or for B cells that produce antibodies that bind to normal cells, is not perfect and the Tregs are needed to avoid the mistakes.  Tregs are necessary to avoid the immune attack on healthy cells that is the basis of autoimmunity.

Autoimmunity Starts with Inflammation, but Requires Deficient Tregs

Bacterial or viral infections, or physical damage causing inflammation is the first step in autoimmunity.  It is the inflammation that initiates the interactions between proteins, autoantigens, of normal cells and cells of the immune system that bind, internalize, fragment and present the antigen fragments/peptides to activate B or T cells with corresponding receptors.  The activated B cells make antibodies specific for the antigen and the T cells will kill cells displaying the antigen.  It is interesting that most proteins are not autoantigens and are never involved immune reactions.  Only proteins with an unusual triplet of basic amino acids, similar to the quartet of basic amino acids used to transport proteins into the cell nucleus, are candidates to be autoantigens or allergens.  In fact, since nuclear proteins already have a quartet, i.e. the nuclear localization signal, they are common autoantigens.  The last requirement for autoimmunity is a deficiency in Tregs, because if the Tregs are functioning, they will block attack on healthy cells.  Treg deficiency usually results from loss of the type of gut bacteria that stimulate Treg production in the lining of the intestines, i.e. species of Clostridium.

Hospitals are Notorious for Clostridium difficile Infections

Fecal transplants are now recommended as a safe and efficacious treatment for C. diff hospital infections.  That makes sense, because hospitals are where antibiotics are routinely used and C. diff can only infect people missing their healthy species of Clostridium.  Thus, the hospitals wipe out the gut flora with antibiotics and then recolonize them with their own antibiotic resistant C. diff.  More antibiotics can’t fix it, but providing healthy gut flora (transplant) can.

Autoimmune Diseases are Treated/Exacerbated with Antibiotics

Both the aggressive and the suppressive immune cells require gut flora, so after initial antibiotic treatment wipes out bacteria required for suppression and results in autoimmunity, the remaining aggressive half of the immune system can be eliminated by blasting the remaining gut flora with more antibiotics.  Of course this will leave a highly compromised, incompetent immune system that will ultimately yield more extreme symptoms.  This is the typical medical progression for Crohn’s disease, for example.  The alternative is just fixing the gut flora to begin with and curing autoimmunity.

Cure Autoimmunity by Feeding Clostridium Resistant Starch

Autoimmune diseases, by their symptoms, show that sufficient gut flora to stimulate the aggressive half of the immune system is still present.  What is missing are the Clostridium species that convert soluble fiber, such as resistant starch, into short chain fatty acids, e.g. butyrate.  Patients treated with antibiotics usually walk away from the hospital with a suggestion to eat some yogurt to repopulate their missing gut flora.  Unfortunately, dairy probiotics don’t survive in the gut and cannot repair the gut flora and immune system.  The result, after the gut fails to repair and the immune system crashes, is autoimmunity.  There is a more appropriate possibility to avoid or fix autoimmunity.  Some people suffering from autoimmunity (and with remnants of their gut flora intact) have simply fed their gut flora on resistant starch and achieved complete recoveries.  Others fail to respond, because their gut flora is too severely damaged and necessary bacterial species are gone.  Those individuals need to eat the missing species of bacteria and some probiotics (more common in Asia) contain Clostridium species.  Consistent with this use of soluble fiber to feed gut bacteria that produce butyrate and stimulate the suppressive immune system are reports of healing by combining potato starch (RS) and probiotics with Clostridium butyricum (Probiotic-3).  Repair of the suppressive immune system by repair of gut flora (including fecal transplants) and feeding gut flora with appropriate soluble fiber, may be a general approach to the cure of most autoimmune diseases and allergies.

Paleo Gut Flora Repair

The Cause of Allegies and Autoimmune Diseases

Keyhole Limpet Hemocyanin (KLH): Internalized Antigen

Scanning the literature for a common protein that can be used as an experimental antigen, it becomes quickly obvious that a favorite is KLH. This would seem to be an odd choice -- why a keyhole limpet protein? But that is the wrong question.

Why is KLH such a good antigen, i.e. why is it readily presented to the host immune system? If you have been reading my posts, you might be thinking about triplets of basic amino acids and that is the answer.

As soon as I remembered the prominent use of KLH as an antigen, I checked the NCBI protein database and immediately found an unusual KKK (triple lysine) near the amino terminus of hemocyanin II ( it comes in two pieces). This triplet explains why KLH is such a good experimental antigen, because it is internalized into antigen presenting cells by its strong heparin-binding domain. Other components, adjuvants, are typically added to the KLH for injection to make sure that a strong local inflammation occurs.

Autoantigens Have Strong Heparin-Binding Triplet

I also learned that Hashimoto’s thyroiditis is an autoimmune disease mediated by the autoantigen thyroid peroxidase. A quick search reveals that thyroid peroxidase is an autoantigen, because it also has a triplet of basic amino acids that can enhance presentation under inflammatory conditions. Grave’s disease of hyperthyroidism is an autoimmune disease in which the thyroid receptor (with a basic triplet) is an autoantigen. The same kind of triplet of basic amino acids was found when I searched today for fire ant antigens and mosquito antigens.

I have also looked for the triplets in protein databases. The triplets are rare in cytoplasmic and extracellular proteins. The proteins that have triplets are usually identified as autoantigens in some disease. The triplets are common in nuclear proteins, since heparin-binding and nucleic acid-binding share the same basic amino acid domains. The nuclear internalization signal also results in rapid cellular internalization, e.g. HIV-TAT, heparanase, IGF-binding proteins. Nuclear proteins are common autoantigens in lupus.

Inflammation Plus Heparin-Binding Internalization: Allergy, Autoimmunity

Chronic inflammation can produce antibodies against proteins (foreign or self) with strong heparin-binding domains (triplets or sometimes neighboring pairs of basic amino acids, lysine or arginine). The generalization explains why particular proteins in pollens, foods, insects, pets, mites, asthma, MS, lupus, celiac, etc. produce antibody responses.

Suffering from Inflammation?

How do you know if your symptoms result from inflammation?

My interest is the molecular basis of inflammation, how inflammation is triggered and how inflammation contributes to numerous diseases. I try to expose the inflammatory underpinnings of various diseases by initially linking a disease to inflammation and then unraveling the molecular events that lead to and make up the disease.

How Do I Link a Disease to Inflammation?

My first task is to check the biomedical literature to see if there are research articles that support anti-inflammatory interventions that prevent or limit the disease. I just do a PubMed search the disease name plus anti-inflammatory treatments, e.g. omega-3 fish oils, vitamin D, NSAIDs, etc. It is also possible to see if a disease, such as diabetes, that produces chronic inflammation is a risk factor for the new disease being examined. It is shocking to me that omega-3 fish oils (EPA/DHA) or even flax seed oil, have been found to be effective treatments for numerous diseases that range from allergies, arthritis, inflammatory bowel diseases, depression and even septic shock and multiple organ failure. Aspirin has been used to treat infertility and post partum depression, and at high levels to treat cancer.

Dietary Suppression as Prima Fascia Evidence of Inflammatory Cause

If I find that omega-3 oils have been used successfully to treat a disease, then I attempt to link inflammation to the molecular events that initiate the disease. The biomedical literature is of minimal help here. [Biomedical research is usually limited to assessing the impact of drugs on the symptoms of diseases, so the biomedical literature typically does not provide information on the cause of diseases or ways to cure diseases. Causes and cures do not receive research funding.] I have to learn the basic workings of the organs involved and the alterations of function associated with the disease. I have also found by long experience, that major molecular components are systematically missing from typical explanations of function.

Heparan sulfate/heparin Is Missing in Action

Heparan sulfate proteoglycans (HSPGs) dominate the extracellular environment and yet they are systematically excluded from biomedical research. On this blog, I have provided dozens of examples of the essential role played by HSPGs and disruption of these roles by heparin. The majority of cytokines, growth factors, clotting events, complement cascades and even lipid transport (LDL) act via HSPGs. Leaking of proteins into the urine, across the intestines or the blood brain barrier is controlled by HSPGs, is reduced by inflammation and can be partially repaired by heparin. Autoimmune and allergic diseases are initiated by disruptions in HSPG metabolism. Viral and bacterial pathogens bind to human cells via HSPGs. Cancer cells reduce their HSPGs and start to secrete heparanase in order to metastasize. Mast cells secrete heparin! HSPGs and heparin are major players in tissue function and yet the major cell biology text book does not even discuss them. HSPGs are not mentioned in medical school training even though heparin is the most commonly administered drug.

One of the insights that I bring to my conceptualization of diseases is the role of heparan/heparin in cellular physiology. It explains a lot.

Check for Inflammatory Symptoms by Trying the Anti-Inflammatory Diet

If your symptoms are due to inflammation, there is an easy way to find out. Since diet is the biggest source of inflammation and most of the cells of the immune system congregate in your intestines, it makes sense to check to see your health problems are rooted in inflammation by making simple changes in your diet. Since this is just a test, don’t worry about whether or not this is diet for the rest of your life. Just stick to it for a week and see if it changes your life.

The Basic Anti-Inflammatory Diet and Lifestyle Guidelines are here.

(Vitamin D and omega-3 fish oil amounts are minimal levels. More severe examples of inflammation will require higher levels. Vitamin D up to 10,000 IU per day has been found safe. Some individuals require up to 12 fish oil capsule per day to experience relief from symptoms. Increases should be gradual over weeks of time.)

Try it for a week and let me know if your symptoms disappear. The prevalence of diet-based inflammation, makes me confident that you will be glad that you tried these simple, healthy changes. For immediate relief of pain, see my articles on capsaicin, castor oil and menthol/Vicks.

This is not medical advice and is used only in appropriate support of primary medical care.

Cure Acne, Back Pain, Tendonitis, Depression

Remedies Include Vicks Vaporub, Castor Oil and Anti-Inflammatory Diet

Simple anti-inflammatory treatments cure some of the most common health complaints. The big question is why people tolerate the problems rather than applying the readily available remedies.

It seems to me that one reason people don’t simply live anti-inflammatory lives and avoid health problems is that attacking the underlying inflammation by approaches that would have prevented the health problem in the first place, is inadequate for fixing the problem after it becomes established.

Health problems based on inflammation may have many different sources of inflammation. Many dietary deficiencies, for example, contribute to inflammation, so what we eat or don’t eat is a major health risk. Other common contributors to inflammation are dental cavities/infections and inadequate exercise.

Common Symptoms of Chronic Inflammation: Acne, Back Pain, Tendonitis, Depression

I have started to ask casual acquaintances if they have any aches or pains, because eliminating dietary sources of inflammation will be evident in relief of these problems. Common complaints are sore joints and tendons related to repeated use. An example is my barber who complained of pain in all of the tendons used to raise his arms to cut hair. Another friend just had her second child and suffered from shooting pains in the tendons of the arm she used to cradle the youngest when she used the other arm on some task.

Simple Anti-Inflammatory Diet Adjustments Get Quick Results

In many cases, a simple change in diet can lower chronic inflammation enough to provide relief from symptoms. Vitamin D deficiency is probably an underlying source of inflammation of most people in the US. So a simple supplement of 2000-5000 IU per day will have noticeable, anti-inflammatory impact on most people.

I recommended vitamin D and fish oil supplements to a friend suffering from chronic back pain. The back pain persisted, but his acne resolved. He stopped taking the supplements, but after physical therapy relieved the back pain, he returned to the supplements as an acne treatment. Now he has long term relief from all of his pains.

Elimination of Dietary Inflammation May Not Resolve Inflammation Based Health Problems

Health problems that start from aggrevated inflammation, may not be eliminated with resolution of the initial cause. My friend’s back ache, for example, didn’t respond to just elimination of deficiencies in his diet. It seemed that the back problems were self-sustaining. After he did exercises to remove the physical aggravation of his back, lack of dietary inflammation prevented the return of the back ache.

Complex Inflammatory Webs

A student of mine suffers from celiac. This is a complex autoimmune disorder of the intestines that is triggered by wheat gluten and is self-perpetuating. Of interest in this context is that celiacs frequently also have back problems. This indicates that the inflammation of the disease is systemic and impacts other tissues. Clearly, reducing dietary inflammation can go only so far in relieving this complex web of reinforcing sources of inflammation.

Simple Anti-inflammatory Interventions

My friend with tendonitis from holding her child got immediate relief from topical application of castor oil and dietary supplements eliminated the problem. Castor oil and capsaicin react with skin heat-sensing neurons to initiate an anti-inflammatory response in adjacent tissue. In a similar way, menthol acts on cold-sensing neurons and relieves pain by reducing inflammation. Vicks Vaporub is a common commercial source of menthol (other sources are blue Listerine mouthwash and Noxema lotion), which give faster relief than longer lasting castor oil for many connective tissue/joint aches. Exercise is another source of relief for inflammation-based aches and pains.

Health: Combinations of Interventions and an Anti-Inflammatory Diet

Anti-inflammatory drugs, such as aspirin, disrupt the molecular signals that produce inflammation and result in relief from inflammation and pain. The common ailments discussed here respond to anti-inflammatory drugs. Depression was mentioned to point out the psychological dimensions of inflammation. Reproduction/birth is controlled at many points by the processes that we call inflammation and the most inflammatory stage is birth. It is not surprising that disruption of the normally rapid resolution of inflammation following birth leads to postpartum depression. It is surprising that postpartum depression can be relieved by anti-inflammatory drugs.

Fighting Inflammation-Based Diseases

Complex diseases such as allergies, asthma, arthritis, vascular/heart diseases, inflammatory bowel diseases, cancers, etc. are all based on chronic inflammation, but they are also self-reinforcing inflammatory diseases. Cures will require elimination of sources of chronic inflammation, e.g. diet, plus disruption of the disease-supporting inflammation, e.g. food/gut flora-stimulation of inflammation of the bowel.

Fundamental to the cure of all diseases is a supporting anti-inflammatory diet and lifestyle.

Arthritis Antibodies

Antibodies can be used to attack the signaling (TNF) molecule that mediates the autoimmune attack on arthritic joint tissues. These anti-TNF antibodies minimize inflammatory signaling, reduce joint inflammation and also reduce bone attrition.

Inflammation is an activated state of a tissue in which inflammatory cytokines, TNF, IL-1, IL-6 are secreted by T-cells and the tissue responds by expressing genes that cause characteristic vascular dilation and accumulation of migrating cells of the immune system. One particular type of blood cell, a macrophage, can also migrate to the site of inflammation and develop, in response to signals from the inflamed tissue and resident bone secreting cells, osteoblasts, into osteoclasts that degrade bone. Thus, inflammation of joints can result in bone destruction and increase in serum calcium.

TNF is particularly pivotal in the development of osteoclasts and bone destruction. Thus, drugs, such as thalidomide, that block TNF production, also block the symptoms of arthritis. Antibodies can also be developed that bind to TNF and some of these antibodies have been chemically and genetically modified to make them useful as drugs. Examples are Infliximab and Andalimumab. These are proteins that bind to and inactivate TNF. In a similar alternative strategy, a portion of the TNF receptor was engineer to serving as a neutralizing molecule to bind TNF in inflamed tissue. All of these TNF inactivators can reduce symptoms and provide effective therapy for arthritic joints.

The unanswered question in the use of TNF inactivators is, “What caused the inflammation of the joint in the first place?” Inactivation of TNF can provide a temporary return to approximately normal tissue function, but the symptoms are expected to return.

Thus, we come to the unifying question of what causes inflammatory disease mediated by the immune system and directed at normal tissue components. Two obvious candidates are diet and infectious agents.

Food ingredients can exacerbate or ameliorate the symptoms of inflammatory disease, and particular diets determine the risk of acquiring these diseases. Diet is a major factor in inflammation of any source. Bacterial or viral infections frequently precede inflammatory conditions.

The association of infection with inflammation remains controversial, but there is growing evidence that bacteria in particular reside in almost all inflamed tissues. Moreover, there is abundant anecdotal evidence of effective use of antibiotics in numerous inflammatory diseases, including arthritis, inflammatory bowel disease, atherosclerosis and cancers of various types.

I expect that elucidation of the link between chronic inflammation, diet and bacterial infection will provide increasingly effective and simple therapies for most diseases in the near future.