Innate Immunity The inflammatory response is depicted in this graphic: Edema results from increased permeability of blood vessels. Pain is a prime symptom which results from sensitization of nerve endings by the inflammatory chemicals.

Adaptive Immunity Substances recognized as foreign that provoke an immune response are called antigens (Ag). Adaptive immunity describes the ability of the body to adapt defenses against the antigens of specific bacteria, viruses, foreign tissues… even toxins (think of the snake handler who becomes immune to the venom of snake bites).

Adaptive Immunity Two properties distinguish between adaptive immunity and innate immunity: 1.Specificity for foreign molecules which act as Ag this involves distinguishing self-molecules (normal, not antigenic) from nonself molecules 2.Memory forpreviously encountered Ag

Not all foreign substances are antigenic: We don’t make antibodies to glass, for example. Molecules, or parts of molecules tend to be antigenic if they are: Foreign – not ourselves Organic Structurally complex (proteins are usually complex and form many of the most potent antigens) Large (high molecular weight) Adaptive Immunity

Antigens can have multiple antigenic determinants called epitopes. Each epitope is capable of producing an immune response. Entire microbes may act as an antigen, but typically just certain small parts (epitopes) of a large antigen complex triggers a response. Antigens can have multiple antigenic determinants called epitopes. Each epitope is capable of producing an immune response. Adaptive Immunity

The adaptive immune response cannot get started without the aid of the nonspecific phagocytosis that occurs in the innate immune response. The phagocytic cells that initiate the process are called antigen presenting cells.

Antigen-presenting cells (APCs) are mostly dendritic cells and macrophages, and they link the innate immune system and the adaptive immune system. – Dendritic cells are usually found in tissues in contact with the external environment, and they are the most potent of the antigen-presenting cell types. Dendritic cells grow branched projections called dendrites that give the cell its name. However, these do not have any special relation with neurons which possess similar appendages Adaptive Immunity

As an antigen-presenting cell engulfs and destroys a foreign invader, it isolates the antigens those cells “display”. The APC then presents the foreign Ag to a specific T lymphocyte called a helper T cell (also known as a CD4 cell). Processed Ag is presented

Adaptive Immunity Once stimulated by antigen presentation, helper T cells become activated. Activated helper T cells are capable of activating other lymphocytes to become T cytotoxic cells (CD8 cells) which directly kill foreign invaders and B cells (which make antibodies that kill or helps kill foreign invaders).

Adaptive Immunity Activated B and T cells form the two arms of the adaptive immune response: Antibody-mediated immunity and Cell-mediated immunity. Helper T cells aid in both types, and both types work together to form specific bodily defenses. The Innate and Adaptive Immune systems are depicted

Adaptive Immunity Cell-mediated immunity involves the production of cytotoxic T cells that directly attack invading pathogens (foreign invaders with Ag harmful to us – particularly intracellular pathogens and some cancer cells). Suppressor and memory T cells are also produced. Antibody-mediated immunity involves the production of B cells that transform into antibody making plasma cells. Antibodies (Ab) circulate in extracellular fluids. B memory cells are also produced.

Adaptive Immunity B-cells can be activated by direct recognition of antigen through B-cell receptors or through T-helper cell activation. Activated B-cells undergo clonal selection to become antibody producing plasma cells.

Adaptive Immunity

MHC Molecules Our immune system has the remarkable ability, and responsibility, of responding appropriately to a wide variety of potential pathogens in our environment. The proteins that are used as cell-markers to “flag” self from non-self are called MHC molecules, and are coded for by a group of genes called the major histocompatibility complex (MHC). MHC genes are diverse, and vary greatly from individual to individual.

MHC Molecules There are two general classes of MHC molecules, and at least one or the other, or both, are found on the surface of all nucleated cells in the body. Class I molecules (MHC-I) are built into almost all body cells and are used to present non-self proteins (from bacteria or viruses, for example) to cytotoxic T cells. Class II molecules (MHC-II) are only found only on APCs.  Both classes are important for antigen processing and presentation.

MHC Molecules When APCs come across foreign antigens, they are broken down and loaded onto MHC-II molecules of APCs. The Class II MHC molecules on the APCs present the fragments to helper T cells, which stimulate an immune reaction from other cells. Clones of activated T cells (and the antibodies from plasma cells) are now “competent” to recognize similar antigenic fragments displayed by infected cells throughout the body and respond harshly.

MHC Molecules Infected body cells present antigens using MHC-1 molecules

MHC Molecules Cytotoxic T cell destruction of an infected cell by release of perforins that cause cytolysis Microbes are destroyed by granulysin.

Clonal Selection Clonal selection is the process by which a lymphocyte proliferates and differentiates in response to a specific antigen. A clone is a population of identical cells, all recognizing the same antigen as the original cell. Lymphocytes undergo clonal selection to produce: Effector cells (the active helper T cells, active cytotoxic T cells, and plasma cells) that die after the immune response. Memory cells that do not participate in the initial immune response but are able to respond to a subsequent exposure - proliferating and differentiating into more effector and memory cells.

Cytokines Cytokines are chemical signals from one cell that influences another cell. They are small protein hormones that control cell growth and differentiation: Interferon Interleukins Erythropoietin Tumor necrosis factor

Antibodies Antibodies (also called immunoglobulins or Igs) are produced by plasma cells through antibody-mediated immunity. Antibodies are composed of 4 peptide chains: Two heavy chains and two light chains Disulfide bonds link the chains together in a Y-shaped arrangement. The variable region (antigen-binding region) gives an antibody its specificity. The stem is similar for each class of antibody.

Antibodies Single-Unit antibody structure

Antibodies Some of the ways antibodies are effective include: Neutralizing a bacterial or viral antibody, or a toxin by covering the binding sites and causing agglutination and precipitation (making what was soluble, insoluble) Activating the classical complement pathway Enhancing phagocytosis - a process called opsonization

Antibodies The complement system is a series of blood proteins that often work in conjunction with antibodies – it can be activated by multiple pathways in a step-wise or cascading fashion. It encourages vasodilation and inflammation, antigen opsonization, and antigen destruction. The main proteins are C1-C9.

A membrane attack complex (MAC) forms as a result of activation of the complement cascade. – The MAC results in lysis of the cell. Antibodies

There are 5 classes of antibodies: IgG – a monomer with two antigen-binding sites Comprises 80% of total antibody Only class able to cross the placenta Provides long-term immunity IgM – a pentamer with ten antigen-binding sites It is a great activator of complement, but has a short-lived response. It is the first antibody to appear in an immune response

Antibodies Classes of Antibodies IgA – a dimer with four antigen-binding sites prevalent in body secretions like sweat, tears, saliva, breast milk and gastrointestinal fluids IgE – a monomer involved in allergic reactions comprises less than 0.1% of total antibody in the blood IgD – a monomer with a wide array of functions, some of which have been a puzzle since its discovery in 1964

Antibodies Classes of Antibodies

Antibodies Thousands of memory cells exist after initial encounter with an antigen - this is called Immunological Memory. With the next appearance of the same antigen, memory cells can proliferate and differentiate within hours. This graphic shows that serum antibody titers are much higher and much faster on the second response

Gaining Immunocompetence Within the framework of innate and adaptive immunity we have discussed, there are a number of designations for the ways we can become immunocompetent: “Natural Immunity” is not gained through the tools of modern medicine, whereas ”Artificial Immunity” is. Active Immunity refers to the body’s response to make antibody after exposure to a pathogen (antigen). In Passive Immunity, the body simply receives antibodies that have been preformed. Active immunity is long-term; passive is short-term.

Gaining Immunocompetence Examples Natural active – contracting hepatitis A and production of anti-hepatitis A antibodies Natural passive - a baby receives antibodies from its mother through the placenta and breast milk. Artificial active - a person receives a vaccine of an attenuated (changed/weakened) pathogen that stimulates the body to form an antibody. Artificial passive – an injection of prepared antibody

Immunological Surveillance A current theory purports that the formation of cancer cells is a common occurrence in all of us, and that the immune system continually recognizes and removes them. There are a number of well-recognized tumor antigens which are displayed on certain cancerous cells. These cells are targeted for destruction by cytotoxic T cells, macrophages and natural killer cells. Most effective in eliminating tumor cells due to cancer-causing viruses

The Immune System and Aging Atrophy of the thymus gland results in decreased T-helper cell populations, and a diminished mediation of the specific-immune response. – There is a resulting decreased B-cell response and decreased number of T-cytotoxic cells. Compromised immune function with age results in increased titers of autoantibodies and an increased incidence of cancer (both contribute to overall mortality rates.)

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