Autoimmune Disease

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Autoimmune Disease

The term "autoimmune disease" refers to a varied group of more than 80 serious, chronic illnesses that involve almost every human organ system. It includes diseases of the nervous, gastrointestinal, and endocrine systems as well as skin and other connective tissues, eyes blood, and blood vessel. In all of these diseases, the underlying problem is similar--the body's immune system becomes misdirected, attacking the very organs it was designed to protect.

Table I
Female:Male Ratios
in Autoimmune Diseases
Hashimoto's disease/hypothyroiditis  50:1
Systemic lupus erythematosus  9:1 
Sjogren's syndrome  9:1 
Antiphospholipid syndrome  9:1 
Primary biliary cirrhosis  9:1 
Mixed connective tissue disease  8:1
Chronic active hepatitis  8:1
Graves' disease/hyperthyroiditis  7:1
Rheumatoid arthritis  4:1
Scleroderma  3:1
Myasthenia gravis  2:1
Multiple sclerosis  2:1
Chronic idiopathic thrombo-
cytopenic purpura 2:1

A WOMEN'S ISSUE

For reasons we do not understand, about 75 percent of autoimmune diseases occur in women, most frequently during the childbearing years. Table I(list above) lists the female-to-male ratios in autoimmune diseases. Hormones are thought to play a role, because some autoimmune illnesses occur more frequently after menopause, others suddenly improve during pregnancy, with flare-ups occurring after delivery, while still others will get worse during pregnancy.

Autoimmune diseases also seem to have a genetic component, but, mysteriously, they can cluster in families as different illnesses. For example, a mother may have lupus erythematosus; her daughter, diabetes; her grandmother, rheumatoid arthritis. Research is shedding light on genetic as well as hormonal and environmental risk factors that contribute to the causes of these diseases.

Individually, autoimmune diseases are not very common, with the exception of thyroid disease, diabetes, and systemic lupus erythematosus (SLE). However, taken as a whole, they represent the fourth-largest cause of disability among women in the United States.

A NEED FOR KNOWLEDGE

Autoimmune diseases remain among the most poorly understood and poorly recognized of any category of illnesses. Individual diseases range from the benign to the severe. Symptoms vary widely, notably from one illness to another, but even within the same disease. And because the diseases affect multiple body systems, their symptoms are often misleading, which hinders accurate diagnosis. To help women live longer, healthier lives, a better understanding of these diseases is needed, as well as providing early diagnosis and treatment.


MAJOR AUTOIMMUNE DISEASES
CONNECTIVE TISSUE DISEASES
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SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
An inflammation of the connective tissues, SLE can afflict every organ system. It is up to nine times more common in women than men and strikes black women three times as often as white women. The condition is aggravated by sunlight.

Symptoms: Fever, weight loss, hair loss, moth and nose sores, malaise, fatigue, seizures and symptoms of mental illness. Ninety percent of patients experience joint inflammation similar to rheumatoid arthritis. Fifty percent develop a classic "butterfly" rash on the nose and cheeks. Raynaud's phenomenon (extreme sensitivity to cold in the hands and feet) appears in about 20 percent of people with SLE.

Treatment: Anti-inflammatory drugs can help control arthritis symptoms; skin lesions may respond to topical treatment such as corticosteroid creams. Oral steroids, such as prednisone, are used for the systemic symptoms. Wearing protective clothing and sunscreen when outdoors is recommended.


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RHEUMATOID ARTHRITIS
Rheumatoid arthritis is a systemic disorder in which immune cells attack and inflame the membrane around joints. It also can affect the heart, lungs, and eyes. Of the estimated 2.1 million Americans with rheumatoid arthritis, approximately 1.5 million (71 percent) are women.

Symptoms: Inflamed and/or deformed joints, loss of strength, swelling, pain.

Treatment: Rest and exercise; anti-inflammatory drugs when necessary.


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SYSTEMIC SCLEROSIS (SCLERODERMA)
Scleroderma is an activations of immune cells which produces scar tissue in the skin, internal organs, and small blood vessels. It affects women three times more often than men overall, but increases to a rate 15 times greater for women during childbearing years, and appears to be more common among black women.

Symptoms: In most patients, the first symptoms are Raynaud's phenomenon and swelling and puffiness of the fingers or hands. Skin thickening follows a few months later. Other symptoms include skin ulcers on the fingers, joint stiffness in the hands, pain , sore throat, and diarrhea.

Treatment: The drug D-penicillamine has been shown to decrease skin thickening. Symptoms involving other organs such as the kidneys, esophagus, intestines, and blood vessels are treated individually.


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SJÖGREN'S SYNDROME
Sjögren's syndrome (also called Sjögren's disease) is a chronic, slowly progressing inability to secrete saliva and tears. It can occur alone or with rheumatoid arthritis, scleroderma, or systemic lupus erythematosus. Nine out of 10 cases occur in women, most often at or around mid-life.

Symptoms: Dryness of the eyes and mouth, swollen neck glands, difficulty swallowing or talking, unusual tastes or smells, thirst, tongue ulcers, and severe dental caries.

Treatment: Interventions to keep the mouth and eyes moist include drinking a lot of fluids and using eye drops, as well as good oral hygiene and eye care.


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NEUROMUSCULAR DISEASES


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MULTIPLE SCLEROSIS (MS)
A disease of the central nervous system that usually first appears between the ages of 20 and 40, and affects women twice as often as men. MS is the leading cause of disability among young adults.

Symptoms: Numbness, weakness, tingling or paralysis in one or more limbs, impaired vision and eye pain, tremor, lack of coordination or unsteady gait and rapid involuntary eye movement. A history of at least two episodes of a cluster of symptoms is necessary for a diagnosis of MS. Because MS affects the central nervous system, symptoms may be misdiagnosed as mental illness.

Treatment: The drug baclofen is used to suppress muscle spasticity, and corticosteroids help reduce inflammation. Interferons also are being used to treat this disease.


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MYASTHENIA GRAVIS
This is a chronic autoimmune disorder characterized by gradual muscle weakness, often appearing first in the face.

Symptoms: Drooping eyelids, double vision, and difficulty breathing, talking, chewing, and swallowing.

Treatment: The drug edrophonium along with daily rest periods can improve muscle strength.


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GUILLAIN-BARRÉ SYNDROME
Guillain-Barré syndrome is an acute illness that causes severe nerve damage. Two-thirds of all cases occur after a viral infection.

Symptoms: Tingling in the fingers and toes, general muscle weakness, difficulty breathing, and, in severe cases, paralysis.

Treatment: Supportive care until the condition is stabilized, then rehabilitation therapy combined with whirlpool baths to relieve pain and facilitate retraining of movements. A process called plasmapheresis, which removes plasma and nerve-damaging antibodies from the blood, is used during the first few weeks after a severe attack and may improve the chance of a full recovery.


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ENDOCRINE DISEASES


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HASHIMOTO'S THYROIDITIS
Hashimoto's Thyroiditis is a type of autoimmune disease in which the immune system destroys the thyroid, the gland that helps set the rate of metabolism. It attacks women 50 times more often than men.

Symptoms: Low levels of thyroid hormone cause mental and physical slowing, greater sensitivity to cold, weight gain, coarsening of the skin, and goiter (a swelling of the neck due to an enlarged thyroid gland).

Treatment: Thyroid hormone replacement therapy.


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GRAVES' DISEASE
Graves' disease is one of the most common autoimmune diseases, affecting 13 million people and targeting women seven times as often as men.. Patients with Graves' disease produce an excessive amount of thyroid hormone.

Symptoms: Weight loss due to increased energy expenditure; increased appetite, heart rate, and blood pressure; tremors, nervousness and sweating; frequent bowel movements.

Treatment: Antithyroid drug therapy or removal of the thyroid gland surgically or by radioiodine.


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INSULIN-DEPENDENT (TYPE 1) DIABETES
Type 1 diabetes is caused by too little insulin production in the pancreas, and usually occurs in children and young adults, but it can occur at any age.

Symptoms: Increased thirst, increased urination, weight loss, fatigue, nausea, vomiting, frequent infections.

Treatment: Monitoring of diet and insulin.


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GASTROINTESTINAL DISEASES


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INFLAMMATORY BOWEL DISEASE
Inflammatory bowel disease describes two autoimmune disorder of the small intestine--Crohn's disease and ulcerative colitis.

Symptoms of Crohn's disease: Persistent diarrhea, abdominal pain, fever, and general fatigue.

Symptoms of ulcerative colitis: Bloody diarrhea, pain, urgent bowel movements, joint pains, and skin lesions.

In both diseases, there is a risk of significant weight loss and malnutrition.

Treatment: Antidiarrheal pills or bulk formers for mild cases. For more serious cases, anti-inflammatory drugs are effective. Corticosteroids are reserved for acute flare-ups of these diseases. In some cases, surgery may be required to remove obstructions or repair perforation of the colon.



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OTHER AUTOIMMUNE DISEASES VASCULITIS SYNDROMES
This is a broad and heterogeneous group of diseases characterized by inflammation and damage to the blood vessels, thought to be brought on by an autoimmune response. Any type, size, and location of blood vessel may be involved. Vasculitis may occur alone or in combination with other diseases, and may be confined to one organ or involve several organ systems.


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HEMATOLOGIC AUTOIMMUNE DISEASES
Blood also can be affected by autoimmune disorder. In autoimmune hemolytic anemia, red blood cells are prematurely destroyed by antibodies. Other autoimmune diseases of the blood include autoimmune thrombocytopenic purpura and autoimmune neutropenia.


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AUTOIMMUNE SKIN DISEASES
The skin frequently gives the first sign that an autoimmune diseases is present. In many of the diseases mentioned, the skin is only peripherally involved, but in others, the skin is the primary site of the disease. One of the foremost is psoriasis, a common skin disease that results from a malfunction in the life cycle of skin cells. The process of skin cell production that normally takes about a month is speeded up to several days, resulting in a build-up of thick scales.


SUMMARY

Autoimmune diseases run the gamut from mild to disabling and potentially life threatening. Nearly all affect women at far greater rates than men. The question before the scientific community is "why?" We have come a long way in the diagnosis and treatment of autoimmune disease. But more work is needed, especially in the areas of discovering the causes and developing more effective treatments and prevention strategies.

The U.S. Public Health Service's (PHS) Office on Women's Health in the Department of Health and Human Services, was established to redress the inequities in research, health services, and education that have placed the health of American women at risk. Its mission is to direct, stimulate, and coordinate women's health research, health care services, and public and health care professional education and training across the Public Health Service agencies and to collaborate with other government organizations, foundations, private industry, consumer and health care professional groups to advance women's health. The focal point for women's health activities in the Department of Health and Human Services, the PHS Office on Women's Health is working to improve the health of American women in this decade and beyond into the 21st century.

The programs and activities in autoimmune diseases of the PHS Office on Women's Health, joined with initiatives and programs across the agencies and office of the Department of Health and Human Services, are providing a solid foundation from which to increase knowledge about autoimmune disorders in women.

For more information on autoimmune diseases, contact:
American Autoimmune Related Diseases Association
15475 Gratiot Avenue
Detroit, MI 48205
Phone: (313) 371-8600
Definitions of Autoimmune disorders on the Web:

Autoimmune disorders are conditions in which the body’s immune system attacks its own cells, causing tissue destruction.


Autoimmunity is a result of a misdirected immune system that causes one’s own immune system to attack itself. Rheumatic heart disease, multiple sclerosis, Graves disease, Sjogren syndrome, autoimmune thyroiditis, psoriasis, Kawasaki disease and insulin-dependent diabetes mellitus are all autoimmune disorders that have been linked to several foodborne bacteria including, Staphylococcus, Streptococcus, Yersinia and Clostridium.


A disease whereby an individual's immune system mounts an attack on a portion of its own tissues. Tissues undergoing such an attack can be destroyed in the process. Rheumatoid arthritis is an example of an autoimmune disease.


Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. Today there are more than 40 human diseases classified as either definite or probable autoimmune diseases and they affect 5-7% of the population. Almost all autoimmune diseases appear without warning or apparent cause and most patients suffer from fatigue.

Adminஐﻬ:
Drug-induced lupus erythematosus

Definition: 
Drug-induced lupus erythematosus is an inflammatory autoimmune disorder that may affect many organ systems. It is caused from an adverse reaction to a medication. 
Causes, incidence, and risk factors: 
Several medications are known to cause a syndrome that resembles systemic lupus erythematosus (SLE) -- a chronic inflammatory autoimmune disorder that may affect many organ systems.

Drug-induced lupus erythematosus occurs as a result of a hypersensitivity reaction to a medication. The drug may react with cell materials, causing the body to react to itself and form antinuclear antibodies.

Drugs that are known to cause this type of reaction in some people include: procainamide, isoniazid, chlorpromazine, penicillamine, sulfasalazine, hydralazine, methyldopa, and quinidine. Symptoms tend to occur after taking the drug for a reasonable period of time, usually at least 3 to 6 months.

In drug-induced lupus erythematosus, the features of arthritis, systemic symptoms, and cardiac and pulmonary (lung) symptoms may be present. Other symptoms associated with SLE, such as lupus nephritis and neurological disease, are rare.

Drug-induced lupus erythematosus also differs from SLE in that the course of the disease is usually not as severe as SLE. Usually, the symptoms resolve within a few days to weeks after stopping the medication. The sex distribution of drug-induced lupus erythematosus is equal, whereas in SLE, women are affected more often than men
 

Adminஐﻬ:
What is mixed connective tissue disease (MCTD)? 

An autoimmune disease first described in 1972
Combines symptoms of lupus, scleroderma and polymyositis


Mixed connective tissue disease (MCTD) is an autoimmune disease first described in 1972 and is considered an "overlap" of three diseases, systemic lupus erythematosus (lupus), scleroderma and polymyositis. People with MCTD experience symptoms of each of these three diseases.  In many cases, this mixed set of symptoms is eventually dominated by symptoms characteristic of one of the three illnesses, especially scleroderma or lupus.


How common is MCTD? 

MCTD is rare.
It mostly affects women.


Mixed connective tissue disease is relatively rare, and the vast majority of people with the disease (80 percent) are women. MCTD occurs among people of all ages.


What are the warning signs of MCTD? 

Can start with subtle symptoms and is often misdiagnosed
Initial symptoms can include swollen fingers, joint pain, Raynaud’s phenomenon, a purplish rash on the face, fatigue and more
Blood tests can help to confirm a diagnosis of MCTD


Most people with MCTD experience subtle signs of the disease many years before having it diagnosed.  These symptoms can include swollen fingers, joint or muscule pain, acid reflux or difficulty swallowing, Raynaud's phenomenon (fingers become pale and numb in response to cold or emotional stress), muscle weakness, shortness of breath on activity, dry cough, a general malaise and fatigue. .
 Symptoms of MCTD vary widely and each person's illness can be quite different.
 
Often a person with MCTD will visit many doctors before they receive a confirmed diagnosis. Although the diagnosis is often made based on the overlapping symptoms of lupus, scleroderma and polymyositis, a blood test for the ANA (anti-nuclear antibodies) – a general test of autoimmune disease – is taken.

 Abnormally high test results for ANA are an indicator for MCTD. Further testing of the blood will detect a more specific antibody, anti-ribonucleoprotein (RNP), which is present in almost all people who have MCTD.
 
Almost everyone with MCTD will have aching joints. The disease also damages the muscle fibres causing weakness and soreness, especially in the muscles around the shoulders and hips.
 
Frequently, MCTD causes swollen hands and fingers. A purplish butterfly-shaped rash on the cheeks and the bridge of the nose, red patches on the knuckles, a violet discolouration of the eyelids and spidery veins on the face and hands may also occur.



What causes MCTD? 

The cause of MCTD is not known.

The cause of MCTD is not known. There may be a genetic predisposition and it is known that autoimmune diseases like MCTD run in families. It also appears that hormones may play a role in increasing susceptibility to developing the disease.


What can you do about MCTD? 

Treatment is similar to treatment for lupus and other autoimmune diseases
Mild cases can be treated with NSAIDs
Severe cases may require immunosuppressive drugs
As the disease progresses it can become less responsive to treatment



Medicine
Treatment of MCTD is directed at suppressing immune-related inflammation of tissues and is similar to treatment for lupus. Corticosteroids (for example, prednisone) are usually effective, especially when the disease is diagnosed early. Mild cases can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine or similar drugs, and low doses of corticosteroids.
 
The more severe the disease, the higher the dose of corticosteroid needed. Prednisone is the most common corticosteroid used and is taken in pill form. Prednisone is usually considered when the symptoms of MCTD are not being controlled by other treatments.
 
Prednisone use needs to be carefully monitored because of its many side effects, and the drug must never be stopped abruptly. Some of the side effects from long-term use include cataracts, high blood pressure, sleep problems, muscle loss, bruising, thinning of the bones (osteoporosis), weight gain and increased risk of infections.  The goal with this and most drugs is to find the lowest effective dose to avoid as many of the side effects as possible.

In severe cases of MCTD, immunosuppressive drugs (e.g. cytotoxic drugs) may also be needed. These drugs are powerful medications that suppress inflammation and the immune system. You may be prescribed these if your MCTD symptoms are difficult to control with prednisone alone or if you are experiencing side effects from prednisone.
 
Cyclophosphamide (Procytox) and Imuran (azathioprine) are commonly prescribed immunosuppressant drugs. Serious side effects from these drugs include decreased blood cell counts, increased risk of infection, and a risk of developing certain types of cancer. People taking these medications must have regular blood tests and be monitored very closely by their doctor.
 
In general, the more advanced the disease and the greater the organ damage, the less effective the treatment will be. Scleroderma-like damage to the skin and esophagus (pronounced e-sof-a-gus) is least likely to respond to treatment. Symptom-free periods can sometimes last for many years through minimal or no ongoing treatment.
However, MCTD will progress in spite of treatment in about 13 percent of cases.

A Word about Medication Safety
The need to effectively monitor new drugs once they have been approved and introduced into the market has been a key advocacy issue for The Arthritis Society for several years. This advocacy helps to ensure that unfavorable side effects are reported, documented, and addressed.

All medications have potential side effects whether they are taken by themselves or in combination with other herbal, over-the-counter and prescription medications. It is therefore important for patients to discuss the benefits and potential side effects of all their medications with their doctor.


Additional tips for living well with MCTD 

The Arthritis Society offers a variety of programs and services that can be helpful
You can also reach them throughr their website at www.arthritis.ca
 

Along with the physical symptoms of MCTD, many people experience feelings of helplessness and depression. Learning daily living strategies to manage your arthritis gives you a greater feeling of control and a more positive outlook.

From another website:


Mixed connective tissue disease (MCTD) is a rare autoimmune disorder. People with this disorder have signs and symptoms of three diseases — lupus, scleroderma and polymyositis. They also have antibodies to U1-RNP protein in their blood. This disorder occurs most often in females between the ages of 15 and 25. Signs and symptoms may include:

Raynaud's phenomenon — blood vessel spasms that interrupt blood flow to the finger, toes, ears and nose
Arthritis with painful, swollen joints
Swelling in the hands (edema)
Muscle weakness (myositis)
Shortness of breath
Skin changes, such as thickening or rash, typically on the face or hands
A doctor may make a diagnosis of MCTD based on:

Physical examination
Signs and symptoms
Blood tests that detect the presence of antibodies to U1-RNP protein
Your doctor may recommend further testing to help determine the severity of the disease and the appropriate treatment. There's no cure for MCTD. Treatment is usually directed at managing the signs and symptoms and may include:

Nonsteroidal anti-inflammatory drugs
Corticosteroids
Vasodilators, which improve blood flow
Immunosuppressant medications
 

Lupus & Connective Tissue Disorder Website Information
www.LupusMCTD.com


This website is provided for educational and informational purposes only. Lupus and Mixed Connective Tissue Disorder is not engaged in rendering medical advice or professional services and this information should not be used for diagnosing or treating a health problem. The site author and the content providers make no representation or warranties, expressed or implied. Providing links to other websites does not imply that Lupus and Connective Tissue Disorder endorses the information or services provided on those websites. The organizations operating those websites are solely responsible for the content found on their websites. All material on this web site is copyright © 2005 by Lupus and Mixed Connective Tissue Disorder.

Adminஐﻬ:
MEDICAL GENOMICS GROUP
COMPARATIVE GENOMICS CENTRE
Mail Address: Comparative Genomics Centre,
Molecular Sciences Bldg 21, James Cook University,
Townsville, 4811, Queensland, Australia
Telephone: 61-7-4781 6265 Fax:  61-7-4781 6078


RESEARCH OVERVIEW:
    The Medical Genomics Group is working to determine the causes of autoimmune diseases using both cellular and genetic techniques. Current projects study: the genetics of autoimmune diabetes, gastritis and lupus in mice; the effects of mycobacteria on autoimmune diseases; and the role of immunoregulatory NKT cells in childhood diabetes.

     A major focus for the group is the study of interactions between genetic and environmental factors in causing autoimmune disease. Our understanding of these genetic and environmental factors has been greatly aided by the inbred NOD mouse model (pictured) which spontaneously develops autoimmune diabetes, but is protected by treatment with Mycobacterium bovis, the BCG vaccine.

   NOD mice are a well established model of both type 1 diabetes and systemic lupus erythematosus. They spontaneously develop lymphocytic infiltrates of their islets of Langerhans in the pancreas, and in the majority of females, this pathology progresses to complete destruction of the insulin-producing beta cells, resulting in diabetes. Many genes encoding susceptibility to diabetes in this model have been mapped by us and other groups.
 
    If NOD mice are exposed to mycobacteria between three and ten weeks of age, they are protected from the onset of diabetes, but tend to develop another autoimmune disease, systemic lupus erythematosus. Our group was responsible for all of the original characterisation of this model. Lupus in both patients and NOD mice is characterised by the production of antibodies specific for multiple cellular constituents. This results in antibody clumping and deposition in fine vascular beds (such as those in the kidneys and skin) resulting in the activation of inflammatory processes and tissue damage. About 50% of women with lupus develop kidney failure.

    We postulated that the autoimmune diseases diabetes and lupus represented two different expressions of the same basic tendency to autoimmune disease in these mice, and that exposure to the environmental factor mycobacteria was responsible for switching between the two expressions (phenotypes) of this underlying susceptibility.

    This hypothesis was disproved in two ways. Firstly, mycobacteria were sonnicated and then subfractionated, and the individual subfractions tested for their abilities to prevent diabetes and precipitate lupus. We have identified a single subcomponent, MAPG, which can prevent diabetes without inducing lupus. This product is in the final stages of preparation for clinical trials in children who are known to be at a high risk of developing type 1 diabetes.

    The second way in which we were able to demonstrate that diabetes and lupus were independent in the NOD mouse model, was by performing a whole genome screen of loci encoding susceptibility to lupus induced by mycobacteria. We then compared the genetic locations of the lupus genes with those of the diabetes genes. With the exception of the MHC region on chromosome 17, which is involved in almost all autoimmune diseases, the genes did not co-localise.

    NKT cells are a small population of white blood cells that play a critical role in controlling the size and character of immune responses against bacteria, viruses, parasites, tumours and the body's own tissues. Indeed, both diabetes and lupus are associated with numerical deficiencies in these cells; we were responsible for demonstrating this deficiency in NOD mice. When we mapped the genes controlling numbers of NKT cells in mice, only two genetic regions were identified: one was on distal chromosome 1 and mapped to the same location as our previously mapped major lupus gene, and the other was on chromosome 2, and mapped to the same region as an important diabetes susceptibility gene. It seems likely that these two regions play important roles in both autoimmune disease susceptibility and control of NKT cells, and it is possible that disease susceptibility is a consequence of these genes' effects on NKT cell numbers.

    Our current work is focussed on identifying the coding sequences responsible for these phenotypes. We have produced congenic mice for each segment in order to narrow down the region under consideration, and are now applying the candidate approach to positional cloning by examining the protein coding regions within these areas that could conceivably play a role in controlling NKT cell numbers. These protein coding regions are being characterised by sequencing the cDNA from both parental strains and characterising the levels of expression of the gene in each strain and the congenic lines by reverse transcriptase PCR.

    The Medical Genomics Research Group is very grateful for the generous support of Diabetes Australia and the National Health and Medical Research Council of Australia.


Autoimmune Diseases

    Autoimmune diseases are conditions in which the body's defence (immune) system attacks part of the body itself. The targeting of this attack is directed either by specialised proteins called antibodies, or else by a subset of white blood cells called T cells. It is not known why some individuals develop these diseases while most do not, but they are relatively common and can cause serious health problems and even death. The most common autoimmune diseases are:
  DISEASE FREQUENCY (%)
Autoimmune thyroid disease (Hashimoto's Disease, Graves Disease) 2
Rheumatoid arthritis 1
Vitiligo 0.5
Childhood Diabetes 0.25


One way of discovering the cause of these diseases is to examine the genes associated with them.



Childhood Diabetes

    Childhood diabetes (type 1, or Insulin dependent diabetes mellitus) is known to be caused by autoimmune mediated destruction of the insulin producing cells in the pancreas. The NOD mouse is a type of mouse which develops a disease equivalent to human type 1 diabetes and has been used as a model for testing new therapies for prevention and treatment of potential value in the human disease.  The genes responsible for diabetes in these mice have been well studied, but one hurdle facing future work is our ignorance of the mechanisms whereby they actually affect the immune system.

     In many immune responses, one or other pattern of reactivity dominates. In some reactions, a predominantly cellular response occurs and white blood cells (especially T lymphocytes) mediate tissue destruction. This is a common response to viral infections. In other reactions, antibody production predominates, often in response to bacterial infection. These two types of response are counter-regulated so that the cell hormones (lymphokines) which mediate cellular responses tend to ameliorate antibody responses. There are many lines of evidence to suggest that type 1 diabetes is mediated by an inappropriate cellular response to the insulin-producing beta cells (pictured) and may be  prevented by an ongoing antibody response.

Although NKT cells make up only a tiny proportion of the lymphocytes in the immune system, they have a powerful action and produce large amounts of the lymphokine (IL4) which enhances antibody responses and inhibits cellular responses. Two recent experiments suggest that they are responsible for determining whether a cellular or antibody response is made. NOD mice spontaneously develop type 1 diabetes and we have shown that they have very few NKT cells.

Other workers have shown that NOD mice make less IL4 than other strains, which is consistent with their relative lack of NKT cells. We think this defect may result in these mice being more likely to make cellular responses and may partly explain the nature of the autoimmune response to the islets in diabetes. In support of this hypothesis, we have shown that we can prevent diabetes in NOD mice by injecting them with extra NKT cells.

    We are currently trying to find out how these cells prevent diabetes, identify the genes which control them and examine their role in human diabetes.



Lupus

    Systemic lupus erythematosus (lupus) is an autoimmune disease in which the production of antibodies against many normal cell components results in the deposition of proteins in the small blood vessels, inflammation, and subsequent damage to many parts of the body, including the skin, joints, kidneys and brain.  About half of lupus patients develop significant kidney disease (termed lupus nephritis) and this is a strong predictor of a poor outcome. In lupus nephritis, immune complexes, consisting of antibody and cell components, are deposited in the filtering units of the kidney. This gives a characteristic "lumpy bumpy" pattern when stained with fluorescent reagents that bind either antibody or the inflammatory mediator complement.

   We have found that injecting BCG (the anti-tuberculosis vaccine, M.bovis) into NOD mice prevents diabetes, but causes the onset of lupus. We have been studying what genes are responsible for causing lupus in NOD mice, and comparing them to the genes already known to cause diabetes. We examined the idea that some genes cause both lupus and diabetes because they control how likely the immune system is to attack the body's own tissues. This project was a major undertaking for the group and has taken five years to complete.

Approximately 900 female mice were clinically monitored for almost a year after vaccination with BCG. Mice which developed haemolytic anaemia, antinuclear antibodies and  lupus nephritis (pictured), as well as a group of unaffected mice were then gene typed at over 150 genetic locations. This linkage analysis localised both genes which are shared with diabetes as well as other genes which are shared with other mouse models of lupus. The identification of these genes will be of great help in understanding what causes lupus and in developing safer ways of treating or preventing diabetes.
    We are now using the genetic information obtained in the gene mapping study to produce mice carrying only one or two disease susceptibility genes on a normal genetic background, in order to study the interactions between them and the environmental disease trigger, BCG.
 


Gastritis

    Gastritis is a disease in humans which destroys the acid-producing cells in the stomach and is associated with the development of pernicious anaemia (vitamin B12 deficiency) and cancer of the stomach. The thymus is the organ that produces T cells, which are the white blood cells that provide the cellular defence from infections and cancer. If the thymus is removed from some kinds of mice while they are still very young, the few T cells that have left the thymus start to damage the host's own tissues.

 Together with collaborators in Dr Ian van Driel's laboratory at the University of Melbourne, we are using this experimental approach to study the BALB/c inbred strain of mice. These mice, after removal of the thymus, develop T cell-mediated damage of the acid-producing cells of the stomach, resulting in a disease that closely resembles autoimmune gastritis in humans. We have identified the locations of four genes which are responsible for causing gastritis amd one of them appears to be especially important, because it has the strongest effect and may also be involved in diabetes and lupus. We currently characterizing this gene in more detail by locating it more exactly and by examining its effect on mice not normally prone to gastritis.

Adminஐﻬ:
Faulty Cells Thought to Start Autoimmune Process
February 2006 Vol. 311. no. 5764, pp. 1160-1164 - Science 
 
Autoimmune diseases such as lupus have been linked to the body’s failure to clean up after an immune response, since there is a need to eliminate inflammatory cells once a virus or bacteria has been fought off.  In order to ensure the clean-up process is efficient, these inflammatory cells normally undergo a process known as apoptosis – or programmed cell death. When this occurs, the cells bring proteins up to their surface that attract the “clean-up” cells which come in and dispose of them.

 

When apoptosis is inefficient, the persistence of the used-up inflammatory cells in the blood stream will lead to more inflammation, and could be one of the key triggers of autoimmune diseases such as lupus.  However, research has found that inhibiting apoptosis in immune cells is not enough, in and of itself, to cause autoimmunity, suggesting the additional involvement of other cell types in causing autoimmune diseases.  The researchers of this study are working to fill in the gaps between what happens when apoptosis is prevented and the start of autoimmune disease.

 

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