Chapter 43 and 44 Internal Chapter 43 and 44 Internal Environment and Body’s DefenseEnvironment and Body’s Defense

The body defends itself against pathogens and other foreign agents; the study of this process is called immunology; immune responses involve recognition of the foreign macromolecules and trying to eliminate them;

Nonspecific Defense Mechanisms (Innate) provide general protection; lysozyme-found in tears, etc.; cytokines- secreted regulatory proteins, signaling immune response to occur: 1) interferons, 2) interleukin, and 3) tumor necrosis factor

Specific Defense Mechanisms (Acquired) target specific macromolecules associated with pathogens; 1) Antibody mediated immunity and 2) Cell-mediated immunity

Cytokines are a group of intercellular regulatory proteins that ultimately control every aspect of body defense and are produced by many different cells in the body. Cytokines activate and deactivate phagocytes and immune defense cells, increase or decrease the functions of the different immune defense cells, and promote or inhibit a variety of innate body defenses. The same cytokine often carries out multiple functions that overlap with those of other cytokines and cytokines often interact in complex ways with one another.

Proinflammatory cytokines, such as Interleukin-1 (Il-1), interleukin-6 (Il-6), and tumor necrosis-alpha (TNF-alpha), promote the inflammatory response and result in the synthesis of acute phase proteins. Other cytokines, such as interleukins - 4, -5, -10, and -14 (Il-4, Il-5, Il-10, Il-14) promote antibody responses. Still other cytokines, such as interleukin-2 (Il-2) and interferon-gamma (IFN-gamma) promote cell-mediated immunity.

Antigens are recognized by the immune system

Antibodies are highly specific proteins produced in response to antigens

Animation showing antibodies blocking viral adsorption.

Animation showing interferon blocking viral replication.

Each of the cells in the innate immune system bind to antigen using pattern-recognition receptors. These receptors are encoded in the germ line of each person. This immunity is passed from generation to generation. Over the course of human development these receptors for pathogen-associated molecular patterns have evolved via natural selection to be specific to certain characteristics of broad classes of infectious organisms. There are several hundred of these receptors and they recognize patterns of bacterial lipopolysaccharide, peptidoglycan, bacterial DNA, dsRNA, and other substances.

Granulocytes- have irregular shaped nuclei with several lobes and their cytoplasm is filled with granules containing enzymes and antimicrobial chemicals. They include the following:

1. Neutrophils- phagocytic; granules contain various agents for killing microbes

2. Eosinophils- granules contain destructive enzymes for killing

infectious organisms extracellularly 3. Basophils- release histamine, leukotrienes, & prostaglandins; all promotes

inflammation

Agranulocytes- have compact nuclei and have no visible cytoplasmic granules. The following are agranulocytes:

1. Monocytes- imp phagocytes; differentiate into macrophages 2. Lymphocytes- B and T Lymphocytes; move b/t blood and lymph; only

found in vertebrates

(Acquired) Specific defense mechanisms include antibody-mediated immunity and cell mediated immunity; cells of the immune system include: phagocytes (such as neutrophils and macrophages) and lymphocytes (T-cells, B cells, and natural killer cells); In antibody mediated immunity, B cells are activated when they combine with antigen; active B cells multiply, giving rise to clones of cells; some B cells differentiate to become plasma cells which secrete specific antibodies; others become memory B cells

A: Antibodies on the surface of B-cells bind virus, leading to internalization of the virus.

B: Virus is broken down into small fragments.

C: Small fragments of virus reappear on the surface of the B-cell, bound to MHC (major histocompatibility complex) protein. T Cells recognize the MHC-fragment complex using two proteins: T-cell receptor and CD4; causing the the production of more B-cells of the same type.

D:The large population of B-cells produce lots of antibody to fight the virus.

Activation of B-cells

The recognition of cell-surface carbohydrate on neutrophils is the first stage of their migration out of the blood at sites of infection. Specialized transmembrane proteins (called lectins) are made by the cells lining the blood vessel (called endothelial cells) in response to chemical signals emanating from the site of infection. These proteins recognize particular groups of sugars carried by glycolipids and glycoproteins on the surface of neutrophils circulating in the blood. The neutrophils consequently stick to the blood vessel wall. This association is not very strong, but it leads to another, much stronger protein-protein interaction (not shown) that helps the neutrophil migrate out of the bloodstream between the endothelial cells into the tissue at the site of infection.

The macrophages roam the blood vessels and can even leave them to go to an infection site where they destroy dead tissue and pathogens. Emigration by squeezing through the capillary walls to the tissue is called diapedesis. The presence of histamines at the infection site attract the cells to their source.

Nonspecific defense mechanisms include 1) physical barriers (mucous, skin, cuticle), 2) Cytokines are regulatory proteins mediating interactions between cells: interferon, interluekins, tumor necrosis factors; Methods include: A) complement proteins lyse the CW of pathogens, B) coat the pathogen, some attract WBC to the site of infection; and C) some engulf and destroy bacteria, neutrophils and macrophages A) complement proteins lyse the CW of pathogens, B) coat the pathogen, some attract WBC to the site of infection; and C) some engulf and destroy bacteria, neutrophils and macrophages

Antibodies are highly specific proteins also called immunoglobulins (Ig), that are produced in response to specific antigens; antibodies are typically Y-shaped, with the two arms attaching to the antibody; antibodies consist of four polypeptides: 2 heavy chains and 2 shorter, light chains; each chain has a C region, a J region, and a V region

Five classes of antibodies, based on differences in the constant regions of the heavy polypeptide chains: IgG and IgM defend against pathogens within the blood; IgA prevents pathogens from attaching to epithelial surfaces; IgD activates B cells after they bind with antigens; IgE is important in allergic reactions; each antibody may bind with different affinities to the antigens, higher affinities are exhibit in immune responses; form antibody-antigen complex

Antibody-mediated ImmunityStages in this process are:

1.antigen detection

2.activation of helper T cells

3.antibody production by B cells

Each stage is directed by a specific cell type.

human IgG1 model

L-H=H-L(Fab)2

-----------Fc

Fc Receptor binding region

carbohydrate

Model of human IgG

Cell-mediated immunity specific T-Cells are activated; certain T Cells differentiate to become cytotoxic T Cells, which migrate to the site of infection and chemically destroy cells infected with viruses; some of these T-Cells remain in the lymph nodes as memory T Cells; others become helper T-Cells

Cell-mediated immunity (CMI) is an immune response that does not involve antibodies, but rather involves the activation of macrophages and NK-cells, the production of antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.

Cellular Immunity Protects the Body By: 1. Activating macrophages and NK cells, enabling them to destroy intracellular pathogens

2. Activating antigen-specific cytotoxic T-lymphocytes (CTLs) that are able to lyse body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens

3. Stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses

Cell-mediated immunity is directed primarily against antigens embedded in the membranes of cells. It is most effective in removing virus-infected cells, but also participates in defending against fungi, protozoans, cancers, and intracellular bacteria. It also plays a major role in transplant rejection.

Memory B and T Cells are responsible for long term immunity; the first exposure stimulates primary response; the second exposure evokes a secondary immune response which is more rapid and intense

Upon recognition of specific antigen, T cells expand dramatically through cell division. While most of these cells subsequently die by apoptosis, some survive long term as memory T cells.

Generation of T Cell MemoryThe vast majority (>95%) of T cells activated during an acute immune response die, with the remainder surviving long-term and carrying immunological memory. Remarkably, very little is known about the factors that allow for the establishment of the memory T cell pool.

Active immunity develops as a result of exposure to antigens; occurs naturally after exposure to a disease or artificial exposure (immunizations); monoclonal antibodies are identical antibodies produced from a single cell; graft rejection is an immune response

Malfunction of the immune system can lead to allergic reaction, autoimmune disease; or immunodeficiency.

Allergic reactions are stimulated by allergens which can stimulate IgE that combine with mast cells; when combined with IgE the mast cells release histamines which cause inflammation; rapid, widespread allergic responses that may lead to death are termed systemic anaphylaxis

For patients with a food allergy, places such as supermarkets, restaurants, and even a home dining room can be a minefield. Unable to be certain that what they eat is free of allergen, many patients do not dine at restaurants at all and become uneasy whenever human sociability includes food consumption. In these ways, food allergy can profoundly alter a person's life. Until now, physicians have had no means to manage the problem other than educating patients in avoiding allergen and in responding to exposure. Strategies such as anti-IgE therapy may signal the beginning of specific treatment. Although a given intervention might not permit unfettered allergen intake, it might provide a degree of protection. Even an assured ability to weather small, inadvertent exposures would be a great boon.

As such treatments come to public attention, physicians can expect to see increasing numbers of patients who would otherwise have simply resolved to avoid a food. Such numbers, along with accurate differentiation of true food allergy from a patient's misimpressions, will give a better idea of the actual prevalence of a wide range of allergy syndromes. In the meantime, there are certainly precautions and education that can make a patient's life safer.

A new experimental approach to treating and preventing Type-I hypersensitivity involves giving the person with allergies injections of monoclonal antibodies that have been made against the Fc portion of human IgE. This, in turn, blocks the attachment of the IgE to the Fc receptors on mast cells and basophils and the subsequent release of histamine by those cells upon exposure to allergen. (This illustrates the previous slide!!)

Autoimmune diseases cause the body to react against its own tissues; AIDS is caused by a retrovirus known as HIV; destroys helper T-cells and the ability to resist infection is diminished

Examples of Autoimmune Diseases:Examples of Autoimmune Diseases:(Listed by the Main Target Organ)(Listed by the Main Target Organ)Nervous System: Gastrointestinal System:Multiple sclerosis Crohn's DiseaseMyasthenia gravis Ulcerative colitisAutoimmune neuropathies Primary biliary cirrhosis   such as Guillain-Barré Autoimmune hepatitisAutoimmune uveitis

Endocrine Glands:Blood: Type 1 or immune-mediated

Autoimmune hemolytic anemia    diabetes mellitusPernicious anemia Grave's DiseaseAutoimmune thrombocytopenia Hashimoto's thyroiditis

Autoimmune oophoritis andBlood Vessels:    orchitisTemporal arteritis Autoimmune disease of theAnti-phospholipid syndrome    adrenal glandVasculitides such as   Wegener's granulomatosis Multiple Organs Including theBehcet's disease Musculoskeletal System:*

Rheumatoid arthritisSkin: Systemic lupus erythematosusPsoriasis SclerodermaDermatitis herpetiformis Polymyositis, dermatomyositis

Pemphigus vulgaris Spondyloarthropathies such asVitiligo    ankylosing spondylitis

Sjogren's syndrome