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Immunoglobulin

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Also listed as: WAS
Related terms
Background
Author information
Bibliography
Types of allergic reactions
Functions
Isotypes (types of immunoglobulin)
Development
Structure

Related Terms
  • Antibodies, auto recessive, B-cells, bone marrow, bone marrow transplant, CBC, genetic disorder, immune system, immunodeficiency, inherited disorder, inherited immunodeficiency, leukocytes, leukemia, lymphoma, lymphocytes, malignancy, platelets, pneumonia, red blood cells, T-cells, thrombocytes, thrombocytopenia, tumor, WASP, white blood cells, Wiskott Aldrich syndrome, Wiskott-Aldrich syndrome protein, X-linked.

Background
  • Wiskott-Aldrich syndrome (WAS) is an inherited, immunodeficiency disorder that occurs almost exclusively in males. The recessive genetic disorder is caused by a mutation in the WAS (Wiskott-Aldrich syndrome) gene, which is an X-linked trait. The gene mutation leads to abnormalities in B- and T-lymphocytes (white blood cells), as well as blood platelet cells. In a healthy individual, the T-cells provide protection against viral and fungal infection, the B cells produce antibodies, and platelets are responsible for blood clotting to prevent blood loss after a blood vessel injury.
  • Individuals diagnosed with WAS suffer from recurrent infections, eczema and thrombocytopenia (low levels of platelets).
  • Before 1935, patients only lived an average of eight months. Today, patients usually live an average of eight years, according to a recent case study. The cause of death is usually attributed to extensive blood loss. However, cancer (especially leukemia) is common and often fatal among WAS patients.
  • The only possible cure for WAS is a bone marrow transplant. However, if a patient's family member is not a possible match for a bone marrow donation, patients may have to wait years for a potential donor. Other aggressive treatments may also increase a patient's life expectancy. For instance, one study found that patients who underwent splenectomy (removal of the spleen) lived to be more than 25 years old. The spleen may harbor too many platelets, and cause a decrease in the number of platelets in circulation. Antibiotics, antivirals, antifungals, chemotherapeutic agents, immunoglobulins and corticosteroids have also been used to relieve symptoms and treat infections and cancer associated with WAS.
  • Researchers estimate that about four people per one million live male births develop the disease in the United States.
  • The syndrome is named after Dr. Robert Anderson Aldrich, an American pediatrician who described the disease in a family of Dutch-Americans in 1954, and Dr Alfred Wiskott, a German pediatrician who discovered the syndrome in 1937. Wiskott described three brothers with a similar disease, whose sisters were unaffected.

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography
  1. Binder V, Albert MH, Kabus M, et al. The genotype of the original Wiskott phenotype. N Engl J Med. 2006 Oct 26;355(17):1790-3.
  2. Jin Y, Mazza C, Christie JR, et al. Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood. 2004 Dec 15;104(13):4010-9. Epub 2004 Jul 29.
  3. Natural Standard: The Authority on Integrative Medicine. .
  4. St. Jude Children's Research Hospital. Inherited Immunodeficiencies: Wiskott-Aldrich Syndrome (WAS). .
  5. U.S. Immune Deficiency Foundation. The Wiskott Aldrich Syndrome. .

Types of allergic reactions
  • Allergic reactions can be classified into four immunopathologic categories using various classification systems. These classifications are based on the immune system's response to the allergen, not on the severity of the reaction.
  • Type I: Type I allergic reactions involve immunoglobulin E (IgE), which is specific for a particular drug, antigen or other allergen that triggers the allergic reaction. The allergen binds to the immunoglobulin on specific immune cells known as basophils and mast cells. This binding results in the release of chemicals that cause inflammation in the body (like histamine, serotonin, proteases, bradykinin generating factor, chemotactic factors from various immune cells, leukotrienes, prostaglandins and thromboxanes) within 30 minutes of exposure. These chemical mediators cause allergy symptoms, such as urticaria (hives), runny nose, watery eyes, sneezing, wheezing and itching.
  • Type II: This classification is known as a cytotoxic reaction, involving destruction of the host cells. An antigen associated with a specific cell initiates cytolysis of the cell by an antigen-specific antibody, such as IgG or IgM. This reaction often involves blood elements such as red blood cells, white blood cells, and platelets. It often occurs within five to twelve hours after exposure to the allergen, which may include penicillin, quinidine, phenylbutazone, thiouracils, sulfonamides or methyldopa.
  • Type III: This category involves the formation of an antigen-antibody immune complex, which deposits on blood vessel walls and activates cell components known as complements. This causes a serum sickness-like syndrome, involving fever, swelling, skin rash and enlargement of the lymph nodes in about three to eight hours. It may be caused by a variety of allergens, including penicillins, sulfonamides, intravenous (IV) contrast media and hydantoins.
  • Type IV: This classification involves delayed cell-mediated reactions. Antigens on the allergen release inflammatory mediators in 24 to 48 hours. This type of reaction is seen with graft rejection, latex contact dermatitis and tuberculin reaction.

Functions
  • Toll-like receptors are an important part of the body's innate immune system, also called the natural immune system. These receptors are part of the body's first line of defense against harmful substances that enter the body.
  • The receptors, located on the outside of immune system cells, are constantly surveying surrounding cells and tissues for pathogens. Each type of TLR is able to recognize a wide range of pathogens. This is because TLRs recognize pathogens based on their pathogen-associated molecular pattern (PAMP). Since large groups of microbes share the same PAMPs, a single TLR is able to recognize many different invaders.
  • Toll-like receptors (TLRs) become activated once they identify and bind to a foreign substances that enter the body. Once stimulated, the TLRs activate signaling pathways that trigger an immune response. This immune response eventually leads to the expression of many antimicrobial genes that are necessary for immune cells to destroy the invading substances. TLRs also trigger the release of inflammatory chemicals called cytokines.
  • In 1997, researchers discovered that a specific TLR, called TLR4, can activate certain genes needed to initiate an adaptive immune response. Adaptive immunity is a type of protection that develops over the course of an individual's life. Adaptive immunity involves the development of immunoglobulin antibodies that respond to specific foreign substances that enter the body. When individuals are exposed to certain foreign invaders, they develop antibodies against the pathogens. Then, if the same substance enters the body in the future, the body is then prepared to respond quickly because the antibodies are already developed. The antibodies detect and bind to foreign substances that enter the body signaling other immune cells to destroy it. However, it remains unclear exactly how TLR4 is involved in adaptive immunity.

Isotypes (types of immunoglobulin)
  • IgA: Immunoglobulin A (IgA) antibodies are primarily found in the nose, airway passages, digestive tract, ears, eyes, saliva, tears and vagina. These antibodies protect body surfaces that are frequently exposed to foreign organisms and substances from outside of the body. The IgA antibodies make up about 10-15% of the antibodies found in the body.
  • IgG: Immunoglobulin G (IgG) antibodies are the smallest, but most abundant antibodies in the body, making up for 75-80% of all the antibodies in the body. They are present in all body fluids. In addition, they are the only antibodies that can cross the placenta during pregnancy. Therefore, the IgG antibodies of a pregnant woman help protect her fetus. IgG antibodies are considered to be the most important antibodies for fighting against bacterial and viral infections.
  • IgG isotypes are associated with complement fixation (binding of active serum complement to an antigen-antibody pair), opsonization (process by which antigens are altered so that they are more efficiently engulfed and destroyed by immune cells), fixation to macrophages and membrane transport.
  • There are four subclasses of the IgG class of antibodies - IgG1, IgG2, IgG3 and IgG4. As the antibody-producing B-cell matures, it can switch from one subclass to another. In healthy individuals, 60-70% of IgG antibodies in the bloodstream are IgG1, 20-30% are IgG2, 5-8% are IgG3 and 1-3% are IgG4. The levels of IgG subclasses in the bloodstream vary with age. IgG1 and IgG3 reach normal levels by five to seven years of age, while IgG2 and IgG4 levels rise more slowly, reaching normal levels at about 10 years of age. In young children, the ability to make antibodies to bacteria (commonly antibodies of the IgG2 subclass) develops more slowly than the ability to make antibodies to proteins.
  • IgM: Immunoglobulin M (IgM) antibodies are the largest type of antibody. They are found in the bloodstream and lymph fluid. The IgM antibodies are the first antibodies that are produced in response to an infection. They also stimulate other immune system cells, including macrophages, to produce compounds that can destroy invading cells. IgM antibodies normally make up about 5-10% of all the antibodies in the body.
  • IgD: Immunoglobulin D (IgD) antibodies are found in small quantities in the tissues that line the abdominal and chest cavity of the body. The function of IgD antibodies is not well understood. Researchers believe they play a role in allergic reactions to some substances, such as milk, medications and poisons. IgD and IgE are present in very small amounts in normal human serum.
  • IgE: Immunoglobulin E (IgE) antibodies reside in the lungs, skin and mucous membranes. They induce allergic reactions against foreign substances like pollen, fungus spores, parasites and animal dander. IgE antibody levels are often high in people who have allergies. When IgE is active, the antibody triggers an allergic reaction called a hypersensitive reaction.
  • The allergen binds to the immunoglobulin on specific immune cells called basophils and mast cells. This binding results in the release of chemicals that cause inflammation in the body (like histamine, serotonin, proteases, bradykinin generating factor, chemotactic factors from various immune cells, leukotrienes, prostaglandins and thromboxanes) within 30 minutes of exposure. These chemical mediators cause allergy symptoms, such as urticaria (hives), runny nose, watery eyes, sneezing, wheezing and itching.

Development
  • T-cells are continually produced in the bone marrow. T-cells in the bone marrow are considered immature because they are not fully developed. During this stage, the T-cells do not have receptors on their surfaces yet because they do not express CD4 or CD8 glycoproteins (carbohydrate and protein molecules located on the surface of T-cells). Therefore, they are considered double-negative cells (Cd4- Cd8-).
  • The cells then enter the bloodstream and travel to the thymus gland, where they develop into mature T-cells.
  • The T-cells develop receptors on their outer surfaces. This means they express both CD4 and CD8 glycoproteins on their surfaces. Because they express both glycoproteins, these cells are called double-positive T-cells (CD4+ Cd8+).
  • These cells then move to the outer layer of the thymus gland. Here, the T-cells are presented with self-antigens (antigens that are derived from the host), which are combined with what is called either a class I or class II major histocompatibility complex (MHC) molecule from the surfaces of cells that line the internal and external surfaces of the body. The MHC molecules help T-cells detect host cells that have been invaded by infectious organisms. These molecules present parts of the foreign invader's proteins on the surface of the host cell for the T-cell to identify. This is called the MHC peptide. Once a T-cell recognizes the MHC peptide, it binds to it.
  • Only the T-cells that are able to successfully bind to the MHC peptide will survive and continue to mature. The other 98% that are unable to bind to the MHC peptide die in a process called apoptosis (programmed cell death). Other immune cells called macrophages engulf the dead T-cells. This process is called positive selection.
  • The T-cells that survived will mature into single-positive cells. This means that they either have CD4 or CD8 on their cell surfaces. Whether the cell has CD4 or CD8 depends on the molecule for which it was positively selected. T-cells that were positively selected on MHC class I molecules will become CD8 cells, while T-cells that were positively selected on MHC class II cells will become CD4 cells.
  • Then, the mature T-cells move towards the central portion of the thymus gland, called the thymic medulla. Here, the T-cells are presented with another self-antigen that is combined with MHC molecules on antigen-presenting cells (APCs) like B-cells, dendritic cells, and macrophages.
  • The thymocytes that interact too strongly with the antigen receive an apoptosis signal from the APC, which stimulates their death. A minority of the surviving cells become regulatory T-cells, while the remaining are released into the bloodstream as mature native T-cells. This process, which is called negative selection, is important because it ensures that the T-cells are able to recognize body cells. This prevents the development of autoimmune disorders. Autoimmunity occurs when the body's immune cells mistakenly destroy body cells because they are perceived as foreign invaders.
  • Once the T-cells have been successfully activated, they become helper T-cells, also called CD4 T-cells or effector cells. These cells divide rapidly and secrete proteins called cytokines, which trigger immune cells to engulf the antigen. It also stimulates cellular division (multiplication) of both T-cells and antibody-producing B-cells.

Structure
  • Neutrophils are continually produced in the bone marrow.
  • A mature neutrophil has a segmented nucleus, while an immature neutrophil has a band-shaped nucleus. On average, neutrophils typically live about three days.
  • The neutrophil plasma membrane contains several membrane channels, adhesive proteins, receptors for various ligands (molecules that bind to specific proteins), ion pumps and ectoenzymes (enzymes located on the outer surface of the cell).
  • Neutrophils have a complex cytoskeleton, which is responsible for chemotaxis (movement), phagocytosis (engulfing organisms) and exocytosis (secretions released outside of the cell). Proteins that make up the cytoskeleton include, actin, actin-binding protein, alpha-actinin, myosin, tubulin gelsolin, profilin and tropomyosin. About 45% of the neutrophil cytosolic protein is made of migration inhibitory factor-related proteins (MRPs), MRP-8 and MRP-14.
  • Neutrophils contain a large amount of glycogen (a stored form of glucose) in the cytoplasm. The glycogen provides neutrophils with energy.
  • Once fully developed, neutrophils are no longer able to grow or divide. Mature neutrophils contain at least four types of granules, which are specialized lysosomes (particles that contain enzymes necessary for digestion). Granules are classified as, (1) primary or azurophil granules, (2) secondary or specific granules, (3) tertiary or gelatinase granules and (4) secretory vesicles.

Copyright © 2011 Natural Standard (www.naturalstandard.com)


The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.

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