The Great Diet Debate

Cardiovascular disease is one of the major killers in today’s society. There are many risk factors that contribute to cardiovascular disease, some that are modifiable and others that are not. One of the major factors that are modifiable is obesity and hypercholesterolemia. Prevention and treatment for heart disease are very important and sometimes go hand in hand. The South Beach Heart Program is a diet that claims to ‘detect, prevent and even reverse heart disease.’ Studies of this program however did show that LDL levels did not go down and with that in mind high LDL levels is a major factor for cardiovascular disease. So what do the people on this diet do if the diet is not lowering there LDL levels, they take statins, cholesterol lowering drugs. Here is were I believe the problem lies, and that is with the idea that we as a society want a drug or pill to take to help us when there is a cheaper and just as effective way to obtain our optimal health and that is diet and exercise. Diet and exercise can help an individual so much to achieve a healthy life but they need to be done together and be a part of a lifestyle. People who have made intensive changes to their lifestyle with diet and exercise for a year have dropped their LDL levels 40 percent and that is equal to the statin Lipitor. I have no problem with statins and I know that the results that statins get are desired ones, yet I think this falls in line with us as a society being lazy and wanting pill to help us and us not wanting to do physical labor as exercise. Diet and exercise can do so much more than just a pill can do and just help with LDL levels; it can help with the other risk factors for cardiovascular disease as obesity, which can lead to many other problems like diabetes and hypertension. The underlying factor that I believe is and should be is that diet and exercise are vital for us to live and maintain a healthy life as individuals.

How does codeine release histamine?

Simple answer: not known. There are 2 commonly used histamine releasers, codeine and compound 48/80, a synthetic polyamine. Codeine apparently is idiosyncratic: histamine release induced by codeine is not blocked by the opiate antagonist naloxone, and other opiates like fentanyl do not release histamine. Both codeine and 48/80 probably engage the downstream signaling pathway of the IgE receptor, mimicking crosslinking. This can be a side effect of codeine-related medications, as the other Dr. Cohen can attest, after being covered in hives when given some oxycodone.

Type 1 Diabetes and Viral Infections

Type 1 Diabetes has a long standing history as a largely genetic autoimmune disease passed through families. This is of course supported by looking at the genes of an individual and specifically looking at his or her HLA region to give a percent of risk of diabetes. This was only a potential risk and even with continuing markers for diabetes, antibodies being one, we have yet to be able say for sure whether or not a child will get diabetes until they do. A new component has emerged to identify both a genetic and environmental component to disease progression or, as far as immunology is concerned, a link between adaptive and innate immunity in type 1 Diabetes.

The role of the innate immune system in the development of type 1 diabetes in at risk individuals is currently under investigation and while the complete mechanism is still unclear what is clear is that enterovirus infections are involved. A 2005 paper by Merja Roivainen outlines the potential pathways that EV may take in the destruction of insulin producing β-cells and potential clinical applications. At approximately 80% loss of pancreatic insulin producing β-cells diabetes becomes symptomatic and treatment is required. In previous studies by the same author they were able isolate enterovirus RNA via PCR from the postmortem islet cells of T1D (1). Other studies have also demonstrated a link between enterovirus infection and type 1 diabetes, atherosclerosis disease, myocardial infarction, bronchiolitis and asthma (1). While this may be well established it is unclear as to a mechanism for the virus to ultimately induce or influence disease.

There are three major theories on possible mechanisms for the virus to damage β-cells. First, upon reaching β-cells the virus destroys islet cells and exposes the immune system to “previously hidden self-components” (1). This is similar the case we discussed in class where a researcher accidentally exposed his immune system to brain tissue and his immune attacked his brain, which it otherwise never saw, causing encephalitis. Second, there may be a bystander component to the viral infection where the pancreatic islet cells are damaged by being too close to the viral infection. Lastly there also may be a molecular mimicry component in which the immune system reacts to the virus and, because of similarity between autoantigens such as GAD-65 and HSP-60 and viral proteins 2c and VP0, to the islet cells. An interesting genetic component that is also related is an new SNP that has been associated with diabetes on a protein that is involved in the innate immune response. A single nucleotide polymorphism on the IFIH1 (Inerferon-Induced Helicase 1), a protein that dices incoming viral dsRNA and also is involved in intracellular signaling for the release of cytokines and chemokines in, has been associated with diabetes (2). A viral trigger to diabetes does however provide new hope to potential for clinical applications for prevention.

Clinical immunizations may be the future of diabetes prevention but there are some hurdles to overcome. We know little about what specific strains are causing the progression of diabetes and given that there are currently one hundred known enteroviruses that can infect humans. Also there could be only single amino acid differences between one virus that causes diabetes and one that doesn’t so given that viral RNA replication in a host is error-prone it is likely that an immunization wouldn’t be able to keep-up with the continually mutating virus. While these may be true continued research in viruses my one day both wipe them of the face of the earth and cure disease.

1. Roivainen, Merja. Enertoviruses: New findings on the role of enteroviruses in type 1 diabetes. The Int. J. of Biochem and Cell Bio., 2006. 38:721-725.

2. Smyth, Deborah, Jason Cooper, Rebecca Bailey, Sarah Field, Oliver Burren, Luc Smink, Cristina Guja, Constantin Ionescu-Tirgoviste, Barry Widmer, David Dunger, David Savage, Neil Walker, David Clayton and John A Todd. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nature Genetics, 2006. 38:6, 617-619.

"Spicing Up" of the Immune System by Curcumin

It is quite possible that scarfing down some Indian food could actually strengthen your immune system! Turmeric is a Indian curry spice in which its orange-yellow coloring comes from curcumin. As it is most often known to be an antiinflammatory agent, curcumin has recently proven to be an agent that varies activation of T cells, B cells, macrophages, neutrophils, natural killer cells, and dendritic cells. Curcumin downregulates the expression of several proinflammatory cytokines such as TNF, IL-1, IL-2, IL-6, IL-8, IL-12, along with chemokines, through the inactivation of the transcription factor NF-kB. In low doses curcumin can also increase antibody responses. Reportedly curcumin has been beneficial in treating patients with arthritis, allergies, asthma, atherosclerosis, heart disease, Alzheimer's disease, diabetes, and cancer maybe from its regulatory effect on the immune system.
Turmeric is actually the rhizome powder from a certain herb in the ginger family. For those of you who do not know, rhizome is the stem of a plant found underground. Turmeric is a major cash crop in Asia, India, and China and is largely used as a spice in curries, food additive, and pigment. It also has medicinal purposes as it has been used to treat rheumatism, body aches, skin diseases, diarrhea, inflammations and several other conditions. Ladies forget the Midol, cause Turmeric is here! It is considered to be an emmenagogue which stimulates blood flow to the pelvis/uterus but also is considered to be a carminative or drug used against cramps!
Several studies have shown that curcumin regulates both the activation and the proliferation of T cells. In one particular study curcumin inhibited the proliferation of lymphocytes induced by concanavalin A, phytohemagglutinin, and phorbol-12-myristate-13-acetate of lymphocytes in human spleen. Curcumin, in the same study, inhibited IL-2 synthesis and IL-2 induced proliferation of lymphocytes. From these results curcumin appears to be immunosuppressive by way of regulating IL-2.
Curcumin also has the ability to affect autoimmune diseases due to its ability to modulate immune cells and immune cell cytokines. Alzheimer's disease is known for amyloid plaques forming on the brain due to inflammation. Curcumin downregulates cytokines, such as TNF-alpha, IL-1beta, activities in blood monocytes as well as reducing the amyloid-beta plaque formation. In asthma, curcumin reduces lymphocyte production of IL-2, IL-5, GM-CSF, and IL-4. For all you inflammatory bowel diseases lovers out there, cucumin has got something for you too! In this disease it reduces inflammatory cytokine levels, impeding NO and O2 production along with suppressing NF-kB activation in colon epithelium.


Ganesh Chandra Jagetia, Bharat B. Aggarwal
Journal of Clinical Immunology, Vol 27, No. 1 January 2007

Celiac Disease

Celiac Disease is an autoimmune disorder that is becoming more recognized among the medical profession and is a disease that is being diagnosed on a more frequent basis based on the growing knowledge of the disease. Celiac disease is linked to interactions between gluten and immune, genetic, and environmental factors (1). One known cause of celiac disease is the ingestion of gluten in genetically predisposed people (1). Gluten is the protein storage for wheat, barley, and rye, a major food component ingested by most individuals. Celiac disease was once known as celiac sprue, a rare malabsorption syndrome of childhood and is now known as a common condition affecting many organ systems (1).

According to Green et. al., gluten is digested by luminal enzymes into amino acids and peptides. The main peptide used in the innate immune system is the gliadin peptides which cause a change in the epithelium. Gliadin peptides cause damage to the epithelial cells causing an over expression of Interleukin-15. When Interleukin 15 is expressed, intraepithelial lymphocytes are activated which causes the activated cells to become cytotoxic and kill the enterocytes marked with MIC-A (major-histocompatibility-complex class I chain-related A) (1). In the adaptive immune system gliadin causes changes in the lamina propria. Gliadin enters the lamina propria during infection, where gliadin is deamidated by tissue transglutaminase. The adaptive immune response is mediated by the glidian-reactive CD4+ T cells which are bound to HLA class II molecules on APCs (1). Interferon-γ cytokines are released by the T cells causing an inflammatory response.

CD8+ T lymphocytes represent one of the diagnostic hallmarks of Celiac disease (3). These CD8+ T lymphocytes recognize peptides in HLA Class I molecules which are found in patients with celiac disease. According to Gianfrani et. al., the peptide A-gliadin is selectively recognized by CD8+ T lymphocytes from HLA-DQ2 or HLA-DQ8 celiac patients. Studies have shown that gliadin-specific CD8+ T cells infiltrating celiac mucosa, along with CD4+ T cells may play an important role in CD pathogensis (3).

Genetic factors of the disease seem to be strongly linked in determining individuals who have a high risk of developing the disease. Because the disease is linked to the adaptive immune response, specific class II HLA genes play a specific role on the development of celiac disease. Persons with alleles that encode for HLA-DQ2 or HLA-DQ8 have a high risk of developing (2). Green et al. say that the presence of these HLA genes is necessary but not sufficient in the development of Celiac disease because there are many people who do not have Celiac Disease but carry these alleles. It is known that HLA-DQ2 is found in 90-95% of patients with celiac disease, while the HLA-DQ8 is identified in the rest of the patients (1). The presence of absence in these HLA genes is important in determining who should be tested for the disease if symptoms appear.

Diagnosing celiac disease has become increasingly easier with HLA assessment, biopsy, and serological testing. Antibody testing is used to diagnose celiac disease. The main antibodies used are the antigliadin antibodies, connective tissue antibodies, and antibodies that are directed against tissue transglutaminase (2). Patients who have celiac disease often have low IgA endomysial antibodies and IgA antitissue antibodies against tissue transglutaminase. If levels from serological testing indicate a possibility of disease, then a biopsy of the small intestine is performed.

It is interesting to note that both the innate and adaptive immune response is involved in Celiac disease. Many studies have shown that the activation of the innate immune response sets the stage for activation of the adaptive immune response, by the activating of dendritic cells (3). There are still many unanswered questions as to the true mechanisms behind this disease, but with the knowledge of the immune response pathways, there is a better understanding of the processes and roles that are actually occurring in Celiac’s Disease.

(1) Peter H.R. Green, M.D., and Christophe Cellier, M.D., Ph.D. Celiac Disease. N Engl. J Med. 2007 Oct 25;357(17):1731-43.

(2) Armin Alaedini, Haruka Okamoto, Chiara Briani, Kurt Wollenberg, Holly A. Shill, Khalafalla O. Bushara, Howard W. Sander, Peter H. R. Green, Mark Hallett, and Norman Latov. Immune Cross-Reactivity in Celiac Disease: Anti-Gliadin Antibodies Bind to Neuronal Synapsin I. Journal of Immunology. May 2007; 178: 6590 - 6595.

(3) Gianfrani C, Auricchio S, Troncone R. Adaptive and innate immune responses in celiac disease. Immunol Lett. 2005 Jul 15;99(2):141-5.

Using Immunity in Cancer Therapy

One in two Americans will be diagnosed with cancer at some point in their lives. Traditional options for treating these patients usually involve surgery, chemotherapy, and/or radiation therapy. The goal of these modalities is to destroy or remove the cancer cells. However, the limitation of these therapies is that they are highly-toxic or invasive and as a result the side effects can be debilitating. A relatively new approach to improve cancer treatment involves engaging the body’s immune system to recognize and destroy the cancer cells; this biological approach is termed immunotherapy.

To date, a common and somewhat successful approach to immunotherapy has involved the use of monoclonal antibodies (mAb). In this type of therapy, donor antibodies are injected into a vein and go on to attach to specific antigens, some attach to cancer cells and others to cells that help tumors grow. However, one limitation of this approach is that tumor specific antigens are often intracellular and therefore out of reach of the humoral immune response. To overcome this issue an alternative or complimentary therapy is required.

The concept of lymphocyte immunotherapy was assisted by the evolution of organ transplantation. In transplant recipients, graft-versus-host disease (GVHD), where the transplant T-cells attack host tissue, is an undesirable complication. However, some leukemia and lymphoma patients who experience mild GVHD have a demonstrated a decreased risk of recurrent cancer. In these cases it appears that the transplant cells reject the cancer cells of the host. This concept helped to generate the idea of utilizing immuno-competent donor T-cells to treat cancer patients.

The use of monoclonal T-cells or T-cell receptors (mTCRs) is being investigated as viable approach. This is based on the ability of lymphocyte receptors to recognize peptide or major histamine complex (MHC) molecules in tumor cells. As with mAb therapy, a key challenge is to generate a therapeutic response that has high specificity for the tumor cells so that normal tissue is not destroyed. One significant study found effective results when CD4+ T cells, together with CD8+ T cells, and interleukin-2 (IL-2) were transferred to melanoma patients. T-cells proliferated and attacked tumor cells and there was significant regression of the metastatic melanoma in 6 of the 13 patients.

Immunotherapy does not come without side effects. Thankfully, they are often considered mild compared to chemotherapy. Five patients in the aforementioned study exhibited onset of antimelanocyte autoimmunity. Four of these patients developed vitiligo and one developed uveitis. Vitiligo is a condition where the melanocytes are destroyed and skin pigmentation is lost on patches of the skin. Uveitis is inflammation of the interior eye that can result in blindness. Presence of these side effects indicates that although there are benefits, the treatment needs to be refined. Although immunotherapy is still in the early stages of development, great advancements have been made in the last decade. It will be interesting to see what the future holds.

References:
1. Davis ID, Jefford M, Parente P, Cebon J. Rational approaches to human cancer immunotherapy. J Leukoc Biol 2003;73:3-29.
2. Dudley ME, Wunderlick JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002;298:850-4.

New Markers For Airway Inflammation In Asthma?

Biopsies, sputum eosinophil levels and exhaled nitric oxide levels are the tests used currently when monitoring airway inflammation in asthma patients. The 2006 study by Piacentini suggests an easier method for testing inflammation. Piacentini used subjects with mild asthma and control subjects without asthma to test different markers of inflammation. The subjects rested for one hour before the initial test and rested for ten minutes between tests. Room temperature, humidity and axillary body temperature were strictly controlled.
This study found a positive correlation between end-expiratory manoeuvre plateau temperature (PLET), eosinophil percentage in sputum and exhaled nitric oxide. The use of salbutamol, a bronchodilator, caused an increase in PLET for both the asthmatics and the controls. The study also found no correlation between the above numbers and the rate on increase in exhaled breath temperature, which was a previously suggested method for measuring inflammation. This study also found that using a microbial filter during exhalation tests skewed the test curves and should not be used.
The conclusion is that PLET (exhaled air temperature) is a good marker of airway inflammation in asthma patients and could be used in adjusting treatment plans for asthma patients. More studies need to be done to determine a standardized procedure for testing PLET.

Piacentini GL, Peroni D, Crestani E, Zardini F, Bodini A, Costella S, Boner.
Exhaled air temperature in asthma: methods and relationship with markers of disease. Clinical and Experimental Allergy, 37, 415-419

Paredi P, Kharitonov SA, Barnes PJ. Faster rise of exhaled breath temperature in asthma: a novel marker of airway inflammation? Am J Respir Crit Care Med 2002; 165:181–4.

Paredi P, Kharitonov SA, Barnes PJ. Correlation of exhaled breath temperature with bronchial blood flow in asthma. Respir Res 2005; 6:15.

Piacentini GL, Bodini A, Zerman L et al. Relationship between exhaled air temperature and exhaled nitric oxide in childhood asthma. Eur Respir J 2002; 20:108–11.

Tonsils - in or out?

So, this post is a more personal one.

I have my tonsils. I've often wondered why others have theirs removed, since I've always considered them a part of my immune system. I came across this article: "The rise and decline of tonsillectomy in twentieth-century America" by Gerald N. Grob, which as its title describes, explains the history of tonsillectomy in America.

I'm amazed that so many physicians in the early 20th century really believed in the "focal infection theory," or the idea that the tonsils, as diseased organs contributed to systemic disease / infection, such as rheumatism or endocarditis...especially with no evidence! Wow. Fortunately, through numerous epidemiologic studies, and continued scrutiny, tonsillectomy has been on the decline...especially now with the success of antibiotics for various bacterial infections.

I had fun with this article, as it satisfied my curiosity, and wanted to share it with you.


J Hist Med Allied Sci. 2007 Oct;62(4):383-421. Epub 2007 Apr 10.

Tight Skin, Crusty Organs, and Novel Immunoglobulin Function

Tight Skin, Crusty Organs, and Novel Immunoglobulin Function: A Peculiar Tale of Stimulatory IgG Antibodies and Systemic Sclerosis

Considering its fund-hindering prevalence, it is unlikely that few reading this have ever heard of Systemic Sclerosis, or Scleroderma (SSc) so here’s a brief description…I stress “brief”: Scleroderma is a chronic connective tissue autoimmune disease characterized by systemic tissue fibrosis (i.e. too much collagen in places it shouldn’t be) with symptoms that can range from mild to life threatening (1).

“So where do the antibodies come into play, and what’s all this stimulatory jazz,” you might be asking? Rightly so. Stimulatory antibodies, until recently a curiosity associated mainly with Graves’ disease and hyperthyroidism, are immunoglobulins with the unusual ability to bind to a cell’s receptor and stimulate some form of physiological function or process not originally thought to be associated with the immune system. In the case of Graves’ disease, stimulatory antibodies bind (in excess) to thyrotropin receptors on the thyroid and stimulate the release of thyroid hormone (2). Since the body can regulate Thyroid Stimulating Hormone production but not, apparently, autoantibody production the result is chronic thyroid over-stimulation with hyperthyroidism ensuing. It is important to remember that until recently Graves’ disease was the only condition in which this stimulatory autoantibody phenomenon was known to occur. Enter Scleroderma. In a recent study by Baroni et al., 46 SSc patients (all that were in the study) were shown to have elevated serum stimulatory IgG levels (3). These IgG autoantibodies bound to, and stimulated, Platelet-Derived Growth Factor Receptors (PDGFR) resulting in excess collagen production. More importantly, none of the 75 controls, who displayed other autoimmune diseases such as Raynauds’s Phenomenon, Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Idopathic Pulmonary Fibrosis, displayed elevated PDGFR stimulatory IgG levels. With additional experiments Baroni et al. was able to tease out the pathways resulting in increased fibroblast (cells that make collagen) activity: 1) SSc autoantibody IgGs bind to PDGFR, 2) This binding increases Reactive Oxygen Species (ROS) production, 3) Long term accumulation of ROS stimulates collagen-gene expression, 4) Too much collagen equals thick skin and crunchy-stiff blood vessels. …Okay, so step 4 was not in their original paper, but you can see how it is a logical corollary.

Hopefully by now you are thinking, “So what?” Well, Gleicher et al. realized the importance immediately and discusses it in his recent paper published last June (4). Basically, the finding by Baroni et al. (stimulatory IgGs in SSc patients) changes the way we must view the role of autoantibodies in human physiology and autoimmune disease. It has been known for some time that even healthy people occasionally harbor low levels of autoantibodies in their system. It is only when these concentrations rise excessively that they become problematic. That there is a stimulatory (Gleicher uses the term “functional”) role for autoantibodies in Graves’ disease and Scleroderma, and that there might be similar undiscovered autoantibodies with similar functions in other diseases, brings with it a new paradigm in which to view autoimmune function and future research.

1. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA, Jr., Rowell N, Wollheim F. Scleroderma (systemic sclerosis): classification, sub-sets and pathogenesis. J. Rheumatol 1988; 15:202-5.

2. Morgenthaler NG, Hodak K, Seissler J, Steinbrenner H, Pampel I, Gupta M, McGregor AM, Scherbaum WA, Banga JP. Direct binding of thyrotropin receptor autoantibody to in vitro translated thyrotropin receptor: a comparison to radioreceptor assay and thyroid stimulating bioassay. Thyroid 1999 May; 9(5):466-75.

3. Baroni SS, Olivieri A, Campelli N, Luchetti M, Poloni A, Trappolini S, Moroncini G, Bacigalupo A, Leoni P, Avvedimento EV, Gabrielli A. Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease. Blood 2007 Jul 1;110(1):237-41.

4. Gleicher N, Barad D, Weghofer A. Functional autoantibodies, a new paradigm in autoimmunity? Autoimmun Rev 2007 Nov;7(1):42-5.