AUTOIMMUNE DISEASE

                   Diptapratim Saha
        Bengal school of technology
             (A college of pharmacy)

 introduction:

Autoimmune disease is a condition which is triggered by the immune system,   attacks   on   self   molecules   due   to   the   degradation   of immunological tolerance of auto reactive immune cells. The immune system specifically recognizes and eliminates foreign agents thereby protecting the host against infection. Autoimmune disease like rheumatoid arthritis (RA) and type I diabetics are known as clinical syndromes, where T cell and B cell or both are inappropriately activated, resulting in damage to one or more organ systems.

Autoimmune disorders are a group of conditions where structural or functional damage to cells are produced by the correlation of immunologically competent cells or antibodies against the normal component of the body. This occurs as a result of interaction between genetic,  environmental  and  endocrine  factors  on  immune  system  by following mechanisms: -

I. Discharge of tissue specific auto antibodies via the initiation of complements lead to cytolysis of the target cells.

II. Auto antibody binding to soluble mediators resulting in immune complex deposition.

III. Auto antibody mediated attack on the natural immune system  resulting  in  phagocytosis,  cytotoxicity  &  antibody mediated cellular immunity.

 IV. Auto immunity directed against foreign antigen resulting in damage of the tissue.

V. Action of auto antibodies on cell surface structures resulting in either stimulation or obstruction of the tissue structure.

A combination of genetic predisposition and environmental factors contribute to the development of autoimmune disease. Many autoimmune diseases are start at a relatively young age and continue throughout life, they have a disproportionate effect on public health. Therefore, most autoimmune diseases are chronic in nature requiring a lifetime of care.

Autoimmune diseases

Autoimmune diseases are a broad spectrum of disease that can affect any part of the body. More than 80% of the individuals have been identified, a considerable number with similar symptoms. Inflammation is the classic sign of autoimmunity. It occurs frequently in the human population. It is defined as diseases in which immune responses to self antigens contribute to the ongoing tissue damage. It may be sometimes tissue  specific  (thyroid,  beta  cells  of  pancreas),  where  only  tissue specific antigens are targeted or it sometimes systemic, where multiple tissues are affected. The etiology of autoimmune diseases are difficult to describe. Several factors are thought to contribute to the development of immune response to self, including genetics and environment.

It defines a variety of diseases which can be described by the irregular

functioning of the immune system that causes an individual’s immune system to generate antibodies which attack their own body tissues.

Several common autoimmune diseases, are such as rheumatoid arthritis,  systemic  lupus  erythematosus  and  multiple  sclerosis,  are geneticallty linked with human major histocompatibility complex (MHC)class 2 molecules and other immune modulators.

Autoimmune diseases are the pathological conditions identified by abnormal autoimmune responses and characterized by auto-antibodies and T- cell responses to self-molecules by immune system reactivity. Autoimmune diseases occur when there is interruption of the usual control process, thereby allowing the system to attack healthy cells and tissues.

A common example of autoimmune disease is Type I Diabetes, which affects nearly a million people in the United States. It is a condition in which the pancreas does not produce enough insulin to control sugar blood levels due to the autoimmune destruction of the insulin-producing pancreatic cells. Some other common autoimmune disorders  include  rheumatoid  arthritis,  systemic  lupus  erythematosus (lupus) and vasculitis.

Classification of Autoimmune Diseases:

For clinicals, autoimmune diseases are classified into two types mainly.

a) Systemic (eg - systemic lupus erythematosus) and

b) Organ specific (eg – type I diabetes mellitus)

A more useful division distinguishes between diseases in which there is a general alteration on the selection, regulation of death of T cells or B cells and those in which produces a response to a particular antigen,  self  or  foreign  causes  autoimmunity.  This  classification  is useful in deciding on therapy, which may differ according to the pathogenic mechanism.

Genetic risk factors:

The development of autoimmune diseases depends on a combination of genetic and environmental factors. Most autoimmune diseases are thought to be polygenic, involving more than one gene. The clustering is familiar and the rate of concordance for autoimmune disease is higher.

A few autoimmune diseases such as autoimmune lymph proliferative syndrome and the syndrome of autoimmune polyglandular endocrinopathy and ectodermal dysplasia (APECED) are due to mutations in single gene.

Most autoimmune diseases are multigenic with multiple susceptibility genes working in concert to produce the abnormal phenotype. In general the polymorphisms also occur in normal people and are compatible with normal immune function.

Some of these genes confer a much higher level of risk than others,   for   e.g.   the   major   histocompatibility   complex   makes   an important contribution to disease susceptibility. Most autoimmune diseases are linked to a particular class I or II HLA molecule, but this association may require linkage with another gene such as that encoding tumor necrosis factor α (TNF-α) or complement. Human lymphocyte antigen or HLA haplotype is the best available predictor of developing an autoimmune disease.

Environmental factors:

Environmental factor processes various roles in promoting, causing or modifying autoimmune diseases. When specific environmental factors contribute to autoimmune diseases, they may well determine the onset of illness, the nature of clinical manifestations. Environmental factors are one of the most important initiators to determine the time and type of autoimmune disease.

1. Hormones: - Most autoimmune diseases are introduced in women and men. Nearly 80% of individuals with autoimmune diseases  are  woman.  Exceptions  include  Diabetes  mellitus,Alkylosing spondylitis and inflammatory heart disease. Hormones are obtained from external sources like diet (soy), drugs (birth control pills) or skin product of steroids by the body.

Sex hormones are directly inter-act with cells of the immune system via receptors on the surface and steroid hormones are influenced antibody production and immune cell proliferation. Thus hormones can inhibit the immune response.

2. Toxic metal exposure: - Near about 25% of individuals have some form of heavy metal poisoning. In this case exposure to toxic metal such as mercury, cadmium, lead, arsenic, aluminium and nickel can be linked to autoimmune diseases.

3. Toxic  chemical  exposure:  -  Toxins  like  pesticides,  industrial chemicals,  some  household  cleaners  and  hair  dyes  can  be linked to autoimmune diseases.

4. Diet: - Inflammation can be triggered by an inadequate diet. In many  conditions  like  alzheimer’s,  epilepsy,  migraine,  chronic fatigue,    deficiency    of    magnesium,    which    can    trigger autoimmune disease.

5. Vaccinations: - Scientists have found a co-relation between some autoimmune disease and certain vaccinations. Eg- the contentious anthrax vaccine has been causally linked to the development of certain autoimmune diseases.

6. Infections: - Several mechanisms have been introduced for how infection can lead to autoimmune disease including direct viral damage,  antigenic  spread,  molecular  mimicry  and  adjuvant effect. Molecular mimicry is the concept of microorganism that antigens closely resembles self antigens and when an infection occurs, autoimmunity is introduced a number of autoimmune diseases can be induced experimentally by administrating self antigen with adjuvant like rheumatoid arthritis is with collagen.

7. Smoking and autoimmune diseases: - Tobacco smoking is one of the most powerful factors that can prompt autoimmune diseases. Smoking is associated with systemic lupus erythematosus (SLE). Smoking can contribute to autoimmunity by  various  mechanisms.  It  cause  tissue  damage,  increase apoptosis,    release    of    metalloproteinase    and    induces leucocytosis.

Antibody mediated damage:

Antibodies or immunoglobulins are a family of glycoproteins present in the serum and tissue fluids of all mammals. Antibodies can be carried on the surface of B-cells and acting as receptors or free in the blood and lymph. Specific binding of antigens causes B-cells to produce large amounts of antigen-specific antibody. These antibodies provide critical protection against infectious microorganisms immediately following infection and are the key protective immune response induced by vaccination. Similarly, self-reactive or auto-antibodies are important in clearing cellular debris induced by inflammation or physical damage to the body.

A common feature of all autoimmune diseases is the presence of

auto-antibodies which are an important factor in the diagnosis or classification of autoimmune Disease. Due to the chronic nature of most autoimmune   disease,   auto-antibodies   appear   long   before   clinical symptoms. In fact, the risk of developing an autoimmune disease rises from about 10% if one autoantibody is present to around 60-80% if three auto-antibodies are present for a particular autoimmune disease. Auto- antibodies can induce damage to the body by binding to self-tissues by activating the complement cascade and inducing lysis. This occurs in certain forms of haemolytic anemia when auto-antibodies bind to red blood cell surface antigens inducing lysis of red blood cells.

Cell mediated damage:

Cell mediated damage induced by cells of the immune system play a major pathogenic role in many autoimmune diseases. The predominant infiltrating  cells  include  phagocytic  macrophages,  neutrophils,  self- reactive CD4+ T helper cells and self-reactive CD8+ cytolytic cells with smaller  number  of  natural  killer  cells,  mast  cells  and  dendritic  cells. Immune cells damage tissues directly by killing cells or indirectly by releasing   cytotoxic   cytokines,   prostaglandins,   reactive   nitrogen   or oxygen intermediates.

Tissue macrophages and monocytes can act as antigen- presenting cells to initiate an autoimmune response or as effector cells once an immune response has been initiated. Macrophages and neutrophils damage tissues by releasing highly cytotoxic proteins like nitric oxide and hydrogen peroxide. Cytokines and other mediators released by macrophages recruit other inflammatory cells like neutrophils and T-cells to the site of inflammation.

Tolerance:

 Mechanisms of Autoimmune Disease

Mechanisms of self-tolerance defined as a state of non-responsiveness to self can be divided into central and peripheral tolerance. In central tolerance, immature lymphocytes in the bone marrow (B-cells) and thymus (T-cells) that recognize self-antigens with high affinity die by apoptosis or programmed cell-death. In peripheral tolerance, mature self reactive lymphocytes are inactivated and killed by regulatory mechanisms including functional energy, ignorance and suppression by regulatory T-cells. Defects in tolerance leading to autoimmune disease may occur in one or multiple tolerance mechanisms. For e.g - changes in the apoptotic cell death or survival or disturbances in clearing apoptotic cells are thought to be involved in the pathogenesis of a number of autoimmune diseases such as rheumatoid arthritis and lupus.

Types of autoimmune disease and their symptoms:There are more than eighty indentified autoimmune diseases. Some of these are the followings...

1. Alopecia areata: - The immune system attacks hair follicles. It usually threatens health, but it can greatly affect the way a person looks.

Symptoms: - Patchy hair loss on the scalp, face or other areas of the body.

2. Autoimmune hepatitis: - The immune system attacks and destroys the liver cells. This can lead to scarring of the liver and possibly liver failure. Symptoms: - Fatigue, Enlarged liver, Yellowing of the skin, Whites of eyes, Itchy skin, Joint pain and Stomach pain.

3. Antiphospholipid antibody syndrome: - A disease that causes problems in the inner lining of blood vessels resulting in blood clots in arteries or veins.

Symptoms: - Blood clots in veins or arteries, multiple miscarriages. 4.Celiac disease: - A disease in which people can’t tolerate gluten, a substance found in wheat, rye and barley. When people with celiac disease eat foods or use products that have gluten.

Symptoms: - Abdominal bloating and pain, Diarrhea, Weight loss, Fatigue, Itchy skin rash, Constipation.

5. Diabetes type 1: - A disease in which immune system attacks the cells that make insulin, a hormone needed to control blood sugar levels. Too high blood sugar can hurt the eyes, kidneys, nerves, gums and teeth. The most serious problem caused by this disease is heart disease.

Symptoms: - Being very thirsty, urinating often, Weight loss, Itchy skin, Feeling very hungry or tired, having blurry eyesight.

6. Grave’s disease: - A disease that causes the thyroid to make too much thyroid hormone.

Symptoms: - Insomnia, Weight loss, Heat sensitivity, Sweating, Muscle weakness.

7.Guillain-Barre syndrome: - The immune system attacks the nerves that connects with the brain and spinal cord with the rest of the body.

Damage to the nerves makes it harder to transmit signals.

Symptoms: - Weakness or tingling feeling in the legs that might spread to the upper body, sometimes it causes paralysis.

8. Hashimoto’s disease: - A disease that causes the thyroid to not make enough thyroid hormone.

Symptoms: - Fatigue, Weakness, Weight gain, Sensitivity to cold, Muscle aches and stiff joints, Constipation.

9. Hemolytic anemia: - The immune system destroys the red blood cells. Yet the body can’t make new red blood cells fast enough to meet the body’s needs. As a result body does not get the oxygen.

Symptoms: - Fatigue, Shortness of breath, Dizziness, Headache, Cold hands or feet, Paleness, Yellowish skin or whites of eyes, Heart problems including heart failure.

10. Idiopathic thrombocytopenic purpura: - A disease in which the immune system destroys blood platelets, which are needed for blood to clot.

Symptoms : - Very heavy menstrual period, Tiny purple or red dots on the skin, sometimes bleeding in the mouth occurs.

11. Inflammatory bowel disease (IBD): - A disease that causes chronic inflammation of the digestive tract. Crohn’s disease and ulcerative colitis are the most common forms of inflammatory bowel syndrome.

Symptoms: - Abdominal pain, Diarrhea, Rectal bleeding, Fever, Weight loss, Fatigue, Mouth ulcers.

12. Inflammatory myopathies: - A group of disease that involve muscle

 inflammation and muscle weakness. Polymyositis and dermatomyositis are the two types of disease, which are more common in women than men.

Symptoms:   -   Muscle   weakness,   Skin   rash,   Fatigue,   Difficulty   in swallowing and breathing.

13. Multiple sclerosis: - A disease in which immune system attacks the protective coating around the nerves. The damage effects the brain and spinal cord.

Symptoms: - Weakness and trouble with coordination, balance, speaking and walking, Paralysis, Tremors.

14. Myasthenia gravis: - A disease in which the immune system attacks the nerves and muscles throughout the body.

Symptoms: - Double vision, Trouble swallowing, Weakness or paralysis, Trouble talking.

15. Primary biliary cirrhosis: - The immune system slowly destroys the liver’s bile ducts. Bile is a substance made in the liver. It travels through the bile ducts to help the digestion. When the ducts are destroyed, the bile builds up in the liver and hurts it. The damage causes the liver to harden and scar and eventually stop working.

Symptoms: - Fatigue, Itchy skin, Dye eyes and mouth, Yellowing of skin and whites of eyes.

16. Psoriasis:- A disease that causes new skin cells that grow deep in skin to rise too fast and pile up on the skin surface.

Symptoms: - Thick red patches, Itching and pain, Back pain, a form of arthritis that often affects the joint and the end of the fingers and toes.

17. Rheumatoid arthritis: - A disease in which immune system attacks the linings of the joints throughout the body.

Symptoms: - Painful, swollen and deformed joints, Fatigue, Fever, Eye

 inflammation, Weight loss, Lung disease, Anemia.

Types of Autoimmune Disease

Autoimmune Disease Pathogenesis:

Multiple strategies of the immune system may be involved in autoimmune pathology. Antigens are taken up by antigen presenting cells (APC) such as dendritic cells (DC) and processed into peptides which are loaded onto MHC molecules for presentation to T cells via clonotypic T cell receptors (TCR). Cytolytic T cells (Tc, activated by MHC class I on APC) can directly lyse a target while T helper cells (Th, activated by MHC class II) release cytokines that can have direct effects or can activate macrophages, monocytes and B cells. B cells themselves have surface receptors that can bind surface antigens. Upon receiving signals from T cells and B cells secrete antibodies specific for the antigens. Antibody may bind its specific target alone or may bind to and activate macrophages simultaneously. Multiple mechanisms have been described to explain how pathogens might induce activation and critical expansion of autoreactive T cells and start autoimmune disease. A microbial antigen can include an epitope that is structurally similar to an autoantigen epitope providing the basic element of the mechanism referred to as molecular mimicry.

Treatments for Autoimmune Diseases:

Since cures are currently unavailable for most autoimmune disorders, patients often face a lifetime of debilitating symptoms, loss of organ and  tissue  function,  and  high  medical  costs.  For  many  autoimmune disorders, the goals of treatments are to reduce chronic symptoms and lower the level of immune system activity while maintaining the immune system’s ability to fight foreign contaminants. Treatments vary widely and depend on the specific disease and the symptoms. For example, those afflicted with Type I Diabetes must replenish their insulin levels, usually through injections. In autoimmune diseases like Type I Diabetes, patients may need supplements to provide a hormone or vitamin that the body is lacking. If the autoimmune disorder either directly or indirectly affects  the  blood  or  the  circulatory  system,  such  as  autoimmune hemolytic   anemia   (AIHA),   lupus,   and   anti-phospholipidal   antibody syndrome   (AAS),   patients   may   require   blood   transfusions.   In autoimmune disorders that affect the bones, joints, or muscle, such as multiple sclerosis (MS) and rheumatoid arthritis, patients often require assistance to maintain mobility or medication to suppress pain and reduce inflammation in affected areas.

There are four general approaches to therapy are being  explored

(Table 1): altering thresholds of immune activation, modulating antigen specific responses, reconstituting the immune system with autologous or allogenic stem cells and sparing of target organs. Interference with costimulation,  signaling,  chemokines  and  other  molecules  critical  to immune activation is designed to restore homeostasis in the immune system and autoimmune response. It is based on the concept that small changes in the availability of proteins that control interactions between cells or participate in intracellular signaling can divert the immune system away from auto reactivity. Antigen-specific therapies aim to induce tolerance to a particular antigen. Exposure of the immune system to auto antigens or appropriate peptides delivered either by ingestion to induce oral tolerance or by ingestion has worked well in animals but not in human. Perhaps this approach can only work during the initial activation of auto reactive cells.

An approach involving stem-cell transplantation has engendered much excitement recently and pilot studies of reconstitution with autologous and allogenic stem cells are proceeding in patients with systemic lupus erythematosus, rheumatoid arthritis, scleroderma and multiple sclerosis with a hope to restore homeostasis with regulatory cells.

Therapeutic Approaches

molecules.

Modulation of antigen-specific cells

• Induction of regulatory cells (intravenous, subcutaneous or oral delivery of antigen).

• Alteration in peptide ligands

• Formation of complexes of peptide and major- histocompatibility complex molecules

• Development of T-cell receptor vaccines

• Induction of B-cell tolerance

• Immune deviation from type I to type II helper T- cells

Reconstitution of the immune system

• Bone marrow ablation with autologous stem cells

• Bone marrow ablation with donor stem cells

• Bone marrow ablation without stem cells.

Conclusion:

The development of autoimmune disorder is a complex process. The complex causes of autoimmune diseases not only present a challenge to the development and testing of new therapies but also offer a framework that allows the identification of subgroups of patients who might benefit from particular approaches. Although we will encounter the successes and setbacks, continued studies of autoimmune diseases in humans and animals are necessary to help identify the most appropriate strategies for each disease.

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