2. Chapter 6 - (Kabwe) PDF

Preview

Summary

Chapter 6: Genes and the Immune SystemAbstract Humans have three defenses against infection: the skin and mucous membranes, the innate immunity and the adaptive immune system.  The adaptive immune response has two components: antibody-mediated immunity and cell-mediated immunity.  The A and O blo...

Description

Chapter 6: Genes and the Immune System Abstract    

Humans have three defenses against infection: the skin and mucous membranes, the innate immunity and the adaptive immune system. The adaptive immune response has two components: antibody-mediated immunity and cell-mediated immunity. The A and O blood type are the most common and the B and AB are the rarest. Disorders of the immune system can be inherited or acquired by infection.

Key Points   

       

 

Histamine: A chemical signal produced by mast cells that trigger dilatation of blood cells. Inflammation Response: the body’s reaction to invading microorganisms, a nonspecific active defense mechanism that the body employs to resist infection. Complement System: a chemical defense system that kills microorganisms directly, supplements the inflammatory response and works with (complement) the immune system. Lymphocytes: White blood cells that originate in bone marrow and mediate the immune responses. B cells: A type of lymphocyte that matures in the bone marrow and mediates antibody – directed immunity. T cells: A type of lymphocytes that undergoes maturation in the thymus and mediates cellular immunity. Stem cells: Cells with two properties: the ability to replicate themselves and the ability to form a variety of cell types in the body. Antibody-mediated immunity: Immune reaction that protects primarily against invading virus and bacteria using antibodies produced by plasma cells. Cell-mediated immunity: Immune reaction mediated by T cells directed against body cells that have been infected by viruses or bacteria. Antibody: A class of proteins produced by B cells that bind to foreign molecules (antigens) and inactivate them. Immunoglobins (Ig): The five classes of proteins to which antibodies belong. They include IgG, IgA, IgM, IgD and IgE. IgG represents 80% of all antibodies in the blood and it is the most characterized. Each antibody molecule consists of two types of chains of polypeptides, each in two copies. The heavy chain = H has 40 amino acids and the light chain = L has 220 amino acids. Antigens: Molecules usually carried or produced by viruses, microorganisms or cells that initiated antibody production. T-cells receptors (TCRs): Unique proteins on the surface of T cells that bind to specific proteins on the surface on T cells that bind to specific proteins on the surface of cells infected with viruses, bacteria or intracellular parasites.



    

Major Histocompatibility complex (MHC): A set of genes on chromosome 6 that encodes recognition molecules that prevent the immune system from attacking a body’s own organs and tissues. Helper T cells: A lymphocyte that stimulates the production of antibodies by B cells when an antigen is present and stimulates division of B cells and cytotoxic T cells. Plasma cells: Daughter cells of B cells, which synthesize and secrete 2000 to 20, 000 antibody molecules per second into the blood stream. Memory B cells: A long-lived B cell produced after exposure to an antigen that plays an important role in secondary immunity. Blood type: One of the classes into which blood can be separated on the basis of the presence or absence of certain antigens. Hemolytic Disease of the Newborn (HDN): A condition of immunological incompatibility between mother and fetus that occurs when the mother is Rh- and the fetus is Rh+.

A. Innate Immunity  Refers to nonspecific defense mechanisms that come into play immediately or within hours of an antigen’s appearance in the body. These mechanisms include: o Physical barriers such as skin, o Chemicals in the blood, and o Immune system cells that attack foreign cells in the body.  Responses are not specific to a particular pathogen. o They depend on a group of proteins and phagocytic cells that recognize conserved features of pathogens and become quickly activated to help destroy invaders.  Stages in the inflammation response after a bacteria infection.



Inflammation response after a bacteria infection.



Complement System: can be activated by binding directly to the surface of an invading bacterial cell, starting a cascade reaction. This pathway leads to the formation of membrane-attack complexes (MAC) and the destruction of the invading cells.



The complement system responds in several ways to infection. A) One way begins with binding to antibodies. In this example, the antibodies are bound to the surface of bacterial cells. B-E) The complement system also can be activated by binding directly to the surface of an invading bacterial cell. Both pathways lead to the formation of membrane attack complexes (MACs) and the destruction of the invading cell.

Inflammatory Response 

Mutations in genes encoding proteins involved in the inflammatory response can produce clinical symptoms of an inflammatory disease: o Inflammatory bowel disease o Ulcerative colitis o Crohn disease

B. Adaptive Immune Response  Adaptive immunity refers to antigen-specific immune response. The adaptive immune response is more complex than the innate.  The antigen first must be processed and recognized. Once an antigen has been recognized, the adaptive immune system creates an army of immune cells specifically designed to attack that antigen.  The adaptive immune response has two components: o Antibody-mediated immunity; o Cell-mediated immunity.

Lymphocytes 

Immature lymphocytes (lymphoblasts) produced in bone marrow that travel to the thymus for maturation become T cells. Those that remain and mature in bone marrow become B cells. Once mature, T and B lymphocytes migrate through the body in the circulatory system as part of the immune system.

Stem Cells in Bone Marrow 

Stem cells in bone marrow give rise to the precursors of T cells, macrophages and B cells of the immune system.

Antibody Molecule 

Antibody molecules are made up of two different proteins (an H chain and L chain). The molecule is Y-shaped and forms a specific antigen-binding site at the ends.

Cells of the Immune System

1. Antibody mediated immune response.

   

APC = Antigen Presenting Cells TCR = T-Cell Receptor BCR = B-Cell Receptor Helper T-Cells link the T-Cell and B-Cell responses.

Cells vs. Antibody Mediated Response

2. Cell mediated immune response.

Helper T-Cell  



Helper T cells are arguably the most important cells in adaptive immunity, as they are required for almost all adaptive immune responses. They not only help activate B cells to secrete antibodies and macrophages to destroy ingested microbes, but they also help activate cytotoxic T cells to kill infected target cells. As dramatically demonstrated in AIDS patients, without helper T cells we cannot defend ourselves even against many microbes that are normally harmless.

Diseases of the Immune System The immune system is a complex and highly developed system, yet its mission is simple: to seek and kill invaders. If a person is born with a severely defective immune system, death from infection by a virus, bacterium, fungus or parasite will occur. In severe combined immunodeficiency, lack of an enzyme means that toxic waste builds up inside immune system cells, killing them and thus devastating the immune system. A lack of immune system cells is also the basis for DiGeorge syndrome: improper development of the thymus gland means that T cell production is diminished. Most other immune disorders result from either an excessive immune response or an 'autoimmune attack'. Asthma, familial Mediterranean fever and Crohn's disease (inflammatory bowel disease) all result from an over-reaction of the immune system, while autoimmune polyglandular syndrome and some facets of diabetes are due to the immune system attacking 'self' cells and molecules. A key part of the immune system's role is to differentiate between invaders and the body's own cells - when it fails to make this distinction, a reaction against 'self' cells and molecules causes autoimmune disease.          

Asthma Ataxia telangiectasia Autoimmune polyglandular syndrome Burkitt lymphoma Diabetes, type 1 DiGeorge syndrome Familial Mediterranean fever Immunodeficiency with hyper-IgM Leukemia, chronic myeloid Severe combined immunodeficiency

Immunity is in the Genes Recent studies: Researchers discovered 89 independent gene variants over 53 sites that were linked to the genome associated with regulating the production of immune system cells. The team discovered that variants in particular genes had significant effects on the levels of one or more specific types of immune system cells.

Some of these genes are also involved in the risk of various autoimmune diseases, including ulcerative colitis, multiple sclerosis, rheumatoid arthritis and celiac disease. Blood Transfusion and Immune Response The immune system never rests—its cells constantly patrol the circulation. Without the immune system, the body would be overwhelmed with infections. With it, blood transfusions must be performed with great care. If incompatible blood is given in a transfusion, the donor cells are treated as if they were foreign invaders, and the patient's immune system attacks them accordingly. Not only is the blood transfusion rendered useless, but a potentially massive activation of the immune system and clotting system can cause shock, kidney failure, circulatory collapse, and death. A transfusion reaction resulting from transfusion type B into a recipient with type A blood.

Blood Types

Hemolytic transfusion reaction (RBC incompatibility): HTRs are reactions in which donor RBCs are destroyed by antibodies in the recipient's circulation. They occur when antigenpositive donor RBCs are transfused into a patient who has preformed antibodies to that antigen. The donor RBCs may be destroyed immediately (a potentially serious reaction) or may have a shortened or even normal survival time (milder reactions). Hemolytic Disease of the Newborn: Rhesus Factor (Rh)

The Rh factor and pregnancy. A) Rh+ cells from the fetus can enter the maternal circulation at birth. The Rh- mother produces antibodies against the Rh factor. B) In a subsequent pregnancy, if the fetus is Rh+, the maternal antibodies cross into the fetal circulation and destroy fetal red blood cells, producing hemolytic disease of the newborn (HDN).

Allergens and Immune Response: Steps in Allergic Reaction

The Human Leukocyte Antigen (HLA) and the Immune System The human leukocyte antigen (HLA) system is the name of the loci of genes that encode for major histocompatibility complex (MHC) in humans. The super-locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6 and encodes cell-surface antigen-presenting proteins and has many other functions. The HLA genes are the human versions of the MHC genes that are found in most vertebrates (and thus are the most studied of the MHC genes). The proteins encoded by certain genes are also known as antigens, as a result of their historic discovery as factors in organ transplants. The major HLA antigens are essential elements for immune function. Different classes have different functions:

The HLA region on human chromosome 6, showing the organization of the Class I and Class II regions. Haplotype: a cluster of closely linked genes or markers that are inherited together.

The outcome of kidney transplants with (upper curve) and without (lower curve) HLA matching. HLA Allele and Diseases Disease

HLA allele

Risk Factor

Ankylosing spondylitis

B2-

>100

Systemic lupus erythrematosus

DR3

3

Psoriasis

B1-

6

Rheumatoid arthritis

DR4

6

Reiters syndrome

B2-

50

Multiple Sclerosis

A3

3

Chronic active hepatitis

B8

6

Cell Types Affected in Immune Disorders Immune disorders

Affected cell type

X-linked agammaglobulinemia

B cells missing

Nucleotide phosphorylase deficiency

T cells reduced after birth

Severe combined immunodeficiency

T and/or B cells missing or non-functional

DiGeorge syndrome

T cells missing

Acquired immunodeficiency syndrome

T cells decline after infection...