immuniglobulin Chemical Pathology Part 2.pptx

Chemical Pathology

1. Immunoglobulin, structure and function Otokunefor , Ochuko

2. Lecture objectives To be able to draw and label a basic immunoglobulin molecule To be able to differentiate the classes of immunoglobulins

3. Immunoglobulins are heterodimeric proteins composed of two heavy (H) and two light (L) chains. ( four polypeptides) They are glycoproteins. They can be separated functionally into variable (V) and constant domains The variable (V) domains that bind antigen and constant (C) domains that specify effector functions such as activation of complement or binding to Fc receptors

4. Heavy and light chains are held together by non-covalent interactions and covalent interchain disulphide bonds, forming a bilaterally symmetric structure.. The V part is the antigen-binding sites of the immunoglobulin (Ig) molecule. The variable region affects both the heavy and light chains Each (Ig) monomer contains two antigen-binding sites and is said to be bivalent.

5. Classes of immunoglobulin There are 5 classes ( or isotypes). These are more or less derived from the principal types of heavy chains IgG- gamma (y) heavy chain IgM – mu (u) heavy chain IgA- Alpha ( ) heavy chain IgD - Delta (d) heavy chain IgE – Epsilon ( ) heavy chain IgG and Ig A have subclasses

6. Pictures

7. Immunoglobulin molecule

8. Immunoglobulin G About 75% of immunoglobulins in a normal healthy adult serum Predominant antibody in lymph fluid, peritoneal fluid, CSF and other body fluids. It is also found in tissues. Present in relatively high amounts in the new born as it crosses the placenta from the mother. It provides passive immunity for the new born within the first few months of life It fixes serum complement It has four sub classes 1-4. with 1 being the most predominant and 4 being the least.

9. Immunoglobulin A About 15% of immunoglobulin Main antibody in external secretions ( eg GIT secretions, tears. Saliva, mucous and sweat. Major antibody in milk and colostrum and provides the newborn with intestinal protection against pathogens It can be monomeric or dimeric The dimeric or secretory IgA consists of 2 unit which are linked by the same joining or J chain found in the Ig M molecule and it has a secretory protein in addition.

10. Immunoglobulin M This is a pentamer. The J is the joining chain or protein and there is a single J chain in each Ig M pentameric molecule. Its molecular weight is about 900KD, It is the best agglutinating of the antibodies and a strong complement activating antibody. It is the first to be synthesized in response to an antigen or infection so it is the first line of defence against blood borne infection. It is involved in primary responses. IgM is the only class of antibody that can be synthesized in the developing foetus. Its synthesis begins at about 5 months of gestation. Elevated levels are indicative of congenital or perinatal infections

11. IgM Its agglutinates bacteria, activates complement by the classical pathway. IgM cannot cross the placenta. It has a short half life of 5 days

12. Immunoglobulin D It is a monomer. Its molecular weight is about 180KD. It’s concentration in serum is in traces. It is liable to degradation by heat or proteolytic enzymes and is seen on the surface of B lymphocytes at certain stages of the cell development.

13. Immunoglobulin E It is also called the reaginic antibody. It is very important in hypersensitivity reactions. Ig E has a MW of 190KD. It is also very important in protection against parasitic infections. It assists in antibody dependent cell cytolysis. It triggers secretions from mast cells and is responsible for the characteristic wheal and flare skin reactions seen on the skin of allergic people when their skins are exposed to allergens. It also plays a role in anaphylactic shock, hay fever and asthma. Its half life is 2 days. It does not activate complement

14. General functions of antibodies Prevention of toxins and viruses from entering cells Coating of bacteria and target cells to make them more vulnerable to attack by other immune cells Activation of complement by antigen- antibody complexes. Crossing the placenta and providing protection to the foetus.

15. IgG is the most abundant of the classes of immunoglobulins. It is the antibody for viruses, bacteria, and anti toxins, it is found in most tissues and plasma. IgM is the first antibody present in an immune response. IgA is an early antibody for bacteria and viruses. It is found in saliva, tears and all other mucous secretions IgD activity is not well understood IgE is present in the respiratory secretions. It is an antibody for parasitic diseases, hay fever, atopic dermatitis and allergic asthma.

16. Clinical significance Since immunoglobulins are involved in humoral immunity, disorders usually predispose the patient to different disease conditions A. Clinical conditions that present with increased immunoglobulins are, Multiple myeloma Waldenstroms’s macroglobulinaemia B. Immunodeficiency diseases There are two types of immunodeficiency diseases; primary and secondary. Secondary disorders occur in normal healthy people that have an underlying disease. The situation reverses once the disease is treated Immunodeficiency syndromes are primary immunodeficiency diseases occurring because of defective B cells antibodies. They are the most prevalent type.

17. Immunodeficiency states X linked agammaglobulinaemia Selective IgA deficiency Transient hypogammaglobulinaemia of infancy Others are Common variable immunodeficiency Ig heavy chain deletions Selective IgG subclass deficiencies IgG deficiency with hyper IgM

18. Those with increased Ig For clinical conditions that arise due to an increase in immunoglobulins, It is important to note that there is usually an abnormal production of Ig’s thus even though the number is increased, the function is subnormal since it is an abnormal clone

19. Multiple myeloma It is also known as myelomatosis or plasma cell myeloma It is caused by a malignant proliferation of plasma cells in the bone marrow and disordered immunoglobulin synthesis The immunoglobulin most frequently increased in IgG, then IgA and IgM, the others are rare. Bence Jones protein is usually found in the urine but can also be found in the plasma (in 20% of cases) Bence Jones proteins are para proteins, they are light chains ( of immunoglobulins) Patients present with bone pain which can be severe and there may be pathologic fractures

20. Multiple myeloma There may be generalized osteoporosis and there is little osteoblastic activity. Therefore alkaline phosphatase activity is normal. (unless there is liver involvement) Hypercalcaemia and renal failure may occur. Renal failure can be precipitated by the Bence jones proteinuria and/ or hypercalcaemia. Amyloidosis may occur

21. Multiple myeloma Laboratory diagnosis is usually done by electrophoresis, this shows a reduced albumin band and an increased monoclonal band in the gamma region

22. Waldenstrom’s macroglobulinaemia It is a disorder caused by malignancy of B cells, with IgM being synthesized in large quantities. There is generalized lymphadenopathy. It has a male predilection unlike MM that occurs equally in both sexes. Hyper viscosity is commoner in Waldenstrom’s macroglobulinaemia . Skeletal symptoms are rare.

23. X linked agammaglobulinaemia It is an inherited disease. The defect is on the X chromosome and consequently this disease is seen more frequently in males than females. The defect results in a failure of B cells to mature Mature B cells are capable of making antibodies and developing memory, a feature in which the B cells will rapidly recognise and respond to an infectious agent the next time it is encountered. All classes of antibodies are decreased in agammaglobulinaemia

24. Selective IgA deficiency It is an inherited disease. Resulting from a failure of B cells to switch from making IgM the early antibody to IgA. B cell numbers are normal and B cell function is otherwise normal, (because they can make all other classes of antibodies) the amount of IgA produced is limited. The end result is more infections of the mucosal surfaces such as the nose, throat, lung and intestines.

25. Transient hypogammaglobulinaemia of infancy This is a temporal disease of unknown cause. It is speculated to be caused by a defect in the development of T helper cells. (cells that recognise foreign antigens and activate T and B cells in an immune response) As the child grows the number and conditions of T helper cells improves and this situation corrects itself. It is characterised by low levels of gammaglobulin in the blood. During the disease period, patients have decreased levels of IgG and IgA antibodies. The antibodies that are present do not react well with infectious bacteria

26. Others Common variable immunodeficiency; it is a defect in both B cells and T lymphocytes. It results in a near complete lack of antibodies in the blood Ig heavy chain deletions it is a genetic disease in which part of the antibody molecule is not produced. It results in the loss of several antibody classes and subclasses, including most IgG antibodies and all IgA and IgE antibodies. The disease occurs because part of the gene for the heavy chain has been lost. Selective IgG subclass deficiencies. It is a group of genetic diseases in which some of the subclasses of IgG are not made. There are four subclasses in the IgG class of antibodies. As the B cell matures, it can switch from one subclass to another. In these diseases there is a defect in the maturation of the B cells that results in a lack of switching.

27. Others IgG deficiency with hyper IgM; is a disease that results when the B cell fails to switch from making IgM to IgG. This produces an increase in the amount of IgM antibodies present and a decrease in the amount of IgG antibodies. This disease is the result of genetic mutation

28. Treatment Immunodeficiency diseases cannot be cured. Patients ate treated with antibodies and immune serum. Immune serum is a source of antibodies. Antibodies are useful for fighting bacteria infections. There are some drugs that are effective against fungi but very few drugs that are effective against viral diseases. Bone marrow transplantation can in most cases, completely correct the immunodeficiency.

29. References