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By mikema63
#14600303
Immunology is the study of physiological mechanisms that defend the body from pathogens. Body develops cells dedicated to defense which form the immune system.

Adaptive immunity takes time to develop, while the innate immune system is active immediatly but is less specific and less flexible.

Not all microbes are harmful, some are even helpful. The immune system plays a role in controlling indigenous microflora.

Protective immunity is developed against a specific pathogen. This is the system utilized using vaccinations with attenuated or killed infectious agents.

430 BC Thucydides recognized that only those who had recovered from the plague could nurse the sick without becoming sick again.

15th century, chinese and turks used dried crusts from small pox pustules to induced immunity.

1796 Jenner realized milkmaids who contracted cowpox did not contract small pox. Tested theory on 8 year old boy. Bioethics panel outraged.

Opportunistic pathogens cause disease if the body's defenses are weakened or it get's into a part of the body it isn't native to.

Constant evolutionary struggle between immune system and pathogen, replication times favor the pathogen.

Bacteria
Salmonella enteritidis- food poisoning
Mycobacterium tuberculosis- tuberculosis
Staphylococcus aureas- flesh eating disease

Virus
Variola- small pox
influenza- flu
HIV- AIDS

Fungi
Epidermophyton floccosum- ringworm
Candida albicans- thrush, systemic candidaisis

Protozoa
Trypaosoma Brucei- sleeping sickness
Leishmania dovani- lechmaniasis
Plasmodium falciparum- malaria

Worms
ascaris lumbricoides- ascariasis
schistosoma manosoni- schistosomiasis

Over 1000 microbial species in the human gut, these bacteria typically cause no harm to the host. They are called commensal bacteria. These bacteria are also killed by antibiotics.

Physical barriers against infection: Skin, epithelial linings of the respiritory, gastrointestinal, and urogenital tracts. Mucosal surfaces most vulnerable to infection.

Mucosal surfaces are bathed in mucus; thick fluid containing glycoproteins, proteoglycans, and protective enzymes.

Lysozyme in tears and saliva, antibacterial.

Respiratory tract mucos constantly removed to clean material out.

Stomach, vagina, and skin acidic to prevent bacterial growth.

Defnins, proteins that poke holes in pathogens.

Innate immune response

Innate immune system is determined entirely by inherited genes. Consists of two parts. Recognition and recruitment of effect mechanisms (cells).

Complement: series of proteins that act to tag an invader for phagocytosis by other immune cells or by poking holes in the microbe by completing the complement cascade.

Inflammation: the process of responding to invaders. Resident efector cells respond by releasing cytokines which induce vasodilation and vascular permiability allowing proteins, fluid, and inflammatory cells to leave blood and enter tissue.

The innate defense system is the fast first line that produces acute inflamation and has some specificity for microbes, uses different receptors to recognize pathogens.

The adaptive immune system takes longer to develope (about a week) is highly specific to antigens, uses one type of receptor. Primary response to novel pathogen, secondary response to known pathogens.

The innate and adaptive immune system work together through direct cell contact and interactions with chemical mediators (cytokines and chemokines).

Many cells of the innate immune system are the same cells used by the adaptive immune system.

Adaptive immunity-lymphocyte selection and proliferation: A single lymphocyte will have a receptor with a single specificity. When a foreign epitope is recognized by the lymphocyte receptor the cell will proliferate.

Immune cell classes:

Lymphoid cells, 20-50% of white blood cells. T cells, B cells, and NK cells.

Mononuclear phagocytes: Monocytes that circulate in blood, Macrophages.

Granulocytic cells: Neutrophils, Eosinophils, and basophiles.

Dendritic cells: main function is the presentation of antigen to T cells.

Hematophoiesis: generation of blood cells. Red blood cells, white blood cells, megakaryocytes.

Origionate from pluripotent hematopoitic stem cells whose progeny differentiate under the influence of various hematopoietic growth factors.

Hematopoetic stem cells differentiate into three lineages:

Lymphoid lineage- NK cells, T cells, adn B cells.

Myeloid lineage- Macrophages, dendritic cells, granulocytes, and mast cells.

Erythroid lineage- erythroblasts (red blood cells), Megakaryocyte (platelets)

Most abundant leukocyte is the neutrophils, followed by the lymphocytes.

Leukocytes- general term for white blood cells.

Lymphocytes, class of white blood cells that breaks down into small and large. Small lymphocytes are adaptive immune cells (B calls and T cells). Large granular lymphocytes, Natural Killer cells, innate immune cell.

Naive lymphcytes are samll lymphocytes that have not interacted with antigens.

Lymphoblasts are lymphocytes that have interacted with antigen and proliferate. Differentiate into effector cells and memory cells.

Effector cells eliminate antigen, Plasma B cells secrete antibody, cytokine producing T helper cells (CD4 cell), T cytotoxic cells (CD8 cell).

Natural Killer cells kill human cells that are infected with virus'.

Neutrophils are phagocytic cells.

NK cells are found throughout tissues but mainly in circulation. Secretes cytokins with prevent viral replication and activate T cell mediated immunity.

Neutrophils- effectors of innate immunity specialized in phagocytosis. Work in anaerobic conditions. Die at site of infection and create pus. contains toxic substances in intracellular granules.

Monocyte progenitors in the bone marrow differentiate into pro-monocytes which enter the blood where they differentiate into monocytes. Monocytes circulate in the blood for about 8 hours then mature and migrate into tissues and become macrophages. Phagocytic cells.

Dendritic cells activate T cells. Mast cells specialized in fighting parasites and are the main cause of allergies.

Dendritic cells are so called because of their many surface folds. Possess high levels of surface MHC class II molecules. Can also present MHC I. Process and present peptide antigens to T cells. Their role is to recognize antigens through innate receptors and present them to T cells.

Follicular dendritic cells Hold intact antigens in specialized areas of lymphoid tissues. Not related to regular dendritic cells. Found in germinal layers of the secondary lymphoid tissues.

Mast cells are found in the skin, connective tissue, and mucosal epithelial tissue of the respiritory and digestive tract. The origin of mast cells is uncertain but precursors differentiate in teh bone marrow and mature in tissues. When activated they degrandulate and releast pharmacological mediates like Histamine which causes inflammation.

Eosinophil, killing of antibody coated parasites through release of granules.

Basophil, controlling immune responses to parasites.

Eosinophils are granular leukocytes which stain with Eosin. They are present at low levels in circulation. Have some phagocytic activity but primarily involved in killing parasites. They usually bind to antibody coated parasites an release granules.

Basophils are granulocytes which stain with basica dyes and are present in extremely low numbers in circulation. Basophils and mast cells are very similar. both contain and release large electron dense granules during allergic responses.

Megakaryocytes in the bone marrow produce platelets. Function controlled by large number of cytokines, including thrombopoietin a glycoprotein hormone produced mainly by liver and kidney that regulates platelets.

Erythrocytes bind to immune complexes composed of antigen and antibody and carry these complexes to the liver where these are cleared by kupffer cells. Erythrocytes have an important immunological role in clearing immune complexes. Kupffer cells are phagocytic cells of the liver that line the hepatic sinusoids.

Neutorphiles are stored in bone marrow and released during infections.

Mononuclear phagocyte system, system of phagocytes located mainly in the organs and tissues.

Macrophage like cells in liver=kupffer cells
macrophage like cells in brain= microglia

Opsonization, way of making microbes more palatable to the phagocyte. Such as complement or antibody.
By mikema63
#14604509
Antigens: Any molecule or molecular fragment that can be bound by an antibody or be bound by an MHC molecule and presented to a t cell.

Antibodies: Proteins synthesized by cells of immune system, part of humeral immunity. Binds antigens.

The adaptive immune system generates a huge diversity of immunoglobulins and t cell receptors. Upon infection only the B cells with specific IG or T cells with specific receptors are stimulated to proliferate and differentiate into effector cells.

Antibodies neutralize toxins or pathogens and stop them from being able to cause harm. They also opsonize pathogens or molecules to target them for destruction by macrophages.

Organs of the immune system. Primary and secondary lymphoid organs. Thymus and bone marrow are primary organs where lymphocytes matures. Lymph nodes, spleen, and mucosal associated tissues are secondary organs which trap antigen and promote lymphocyte activation.

B cells mature in bone marrow, T cells mature in thymus.

Lymphatic system. Small lymphocytes travel in blood and lymph. Antigens are carried to lymph nodes, as are lymphocytes enabling ineractions. When an antigen is encountered they lymphocytes will no longer recirculate.

Secondary lymphoid organs are a meeting place where lymphocytes circulating in blood encounter antigens brought from site of infection. Antigens derived from infections originating in connective tissues are carried by the lymphatics to the nearest lymph node. Dendritic cells activated by infection also carry antigens.

Lymphocytes leave blood and enter lymph nodes where they are activated. Pathogens drain from site of infection to lymph nodes via afferent lymphatic vessels. Activated lymphocytes stay in lymph nodes and divide and idfferentiate into effector cells while non-activated cells leave through efferent lymphatics. Lymphocytes recirculate at a rate of 5x10^6 cells a minute.

Lymph node architecture.

Kidney shaped, packed with lymphocytes and macrophages through which lymph percolates. Pathogesn and dendritic cells carrying pathogens arrive in afferent lymph. Pathogens are degraded and used to stimulate lymphocytes. Lymphocytes arrive at lymph nodes in arterial blood. Extravasate from capillaries.

In lymph nodes there are discrete sites where B cells and T cells congregate. Effector B cells, plasma cells, secrete antibodies. Lymph node increases in size due to dividing lymphocytes, swollen glands. Expansion occurs in the lymphoid follicles. As lymphocyte development proceeds, follicle shape changes, germinal center.

The spleen.

Filter for blood that removes old or damaged cells= red pulp. Site where blood borne pathogens encounter lymphocytes= white pulp. Blood is the only way in and out for lymphocytes as well as pathogens. Spleenic macrophages and dendritic cells in the spleen take up antigen and stimulate b and t cells.

White pulp of spleen consists of sheath of lymphocytes called the periarteriolar lymphoid sheath surrounding a central arteriole. T cells are closest to the CA while B cells are more peripheral forming a B cell corona.

Mucosal associated lymphoid issue.

Mucosal surfaces lining digestive, respiratory, and urogenital tracts are the major sites of entry for pathogens and are defended by MALT. Tissues range from loosly organized clusters of lymphoid cells to well organized structures-tonsils, appendix.The gut associated lymphoid tissues include tonsils, adenoids, appendix, and peyer's patches that line the gut. lymphocytes activated in the MALT tend to stay in MALT and the memory cells serve the MALT in the future.

Pathogens arrive through direct delivery across mucosa mediated by specialized cells called M cells. Lymphocytes enter from the blood, if not activated, leave in the lymphatics.

Lymphocytes that expand persist, providing long term memory. First time infection results in a primary response which leads to memory T and B cells of the pathogen. Subsequent infections with the same pathogen, having hte same antigens, will elicit a secondary response which is much faster and stronger.

Immunodeficiency.

Mutation in immune function genes or from disease such as AIDS.

Physical barriers of the immune system. Outer epithelial, colonization by nonpathogenic resident microorganisms. 1000 different species of bacteria inhabit human gut.

4 classes of pathogens. Viruses, bateria, fungi, and parasites. Can infect cells intracellularly or extracellularly.

Complement. Tags pathogens and extracellular molecules for destruction by phagocytic cells such as macrophages. Can destroy pathogens directly by poking holes in the outer membrane or cell wall with membrane attack complex. Three pathways: alternative, lectin, and classical.

Alternative pathway. Complement is ubiquitous in blood and lymph. SOluble proteases that circulate in an inactive form called zymogens. A molecular defense that can be immediately utilized.

The alternative pathway's process occurs continuously at a low rate in blood, lymph, and extracellular fluids. Rate increases in vicinity of certain pathogens. iC3 is the product of C3 hydrolysis but there is no cleavage of C3. iC3 binds to factor B in the blood or ECF making factor B susceptible to cleavage by factor D. At pathogens surface. iC3Bb is produced (soluable form of C3 convertase). iC3Bb cleaves C3 into C3a and C3b. some of C3b becomes bound to pathogens surface.

C3 convertase of the alternative pathway. Factor B binds to c3b fragments and is cleaved by factor D, the complex of C3bBb is formed on the pathogen's surface= C3 convertase of the alternative pathway. Assembly of some C3 convertase molecules results in more C3 being cleaved and more C3b attached to teh pathogen's surface. Assembly of even more convertase, process of progressive amplification that rapidly coats the pathogen with C3b. High density C3b fragments on the pathogens surface form effective ligands for complement receptors of macrophages in infected tissue. Conalently coupled C3b fragments tag the pathogen for destruction by phagocytosis.

C3b tags pathogens for phagocytosis. Opsonin- a protein bound to the surface of a pathgen that facilitates its phagocytosis. CR1- complement receptor 1- bind to C3b deposited on microbial surfaces. Also plays a protective role on human cell surfaces by disrupting C3 convertase.

Binding of C3b to existing C3bBb complexes at pathogens surface forms the alternative C5 convertase C3bbBb (C4b2a3b in classical pathway). activates C5, terminal compnenets of complement (C6-C9). C3a recruits neutrophils to infection cyte. Most potent anaphylatoxin.

CR1 recognizes C3b. CR1 can also play a protective role by C3 susceptivile to factor 1 iC3b.

CR2 is a B cell co receptor and recognizes C3d.

CR3 and 4 recognize iC3b. iC3b can be recoognized by phagocytic cells.

C3a and C5a contribute to acute inflammation. Also referred to as naphylatoxins. C5a is more potent and stable. They bind to mast cells, phaocytes, and endothelial cells. Release of histamine from mast cells. Histamine increases blood vessel permeability and blood flow. Activate endothelial cells which direct phagocytes to site of infection. C5a increases the adherence of monocytes and neutrophils to blood vessel walls and acts as a powerful chemotactic factor.

Proteins that control complement activation ensure C3b is densily deposited on microbial surfaces but not human cells. Plasma protein= properdin (factor P).

Factor P binds to C3 convertase (C3bBb) on microbial surfaces and protects it from inhibition by factor H. Factor H plasma protein reduces complement reaction s by making C3b susceptable to clevage by factor 1 creating iC3b fragment that is incapable of forming C3 convertase. On human cells the complement pathway is stoppped by human cell surface proteins decay accelerating factor and membrane co factor protein. DAF and MCP control proteins destroy C3 convertase activity by binding to C3b and displaces Bb and or reders C3b susceptable to cleavage by factor 1.

C3bBb is formed on human cell surface it is rapidly disrupted by the action of one of the regulatory membrane proteins, decay accelerating factor or membrane cofactor protein. These regulatory proteins esure that a lot of complement is fixed to pathogen surface and little is fixed to human cell surfaces. CR1 also plays a protective role on human cells.

Complement activation limits bacterial infection sbut some bacteria mimic human cells to evade complement. Ex. S. Pyogenes and S. aureus. C3b bound on these pathogen's surfaces is readily inactivaded by factor H. Abs coat the bacterial surface and mask sialic acids before complement is bound. therefore these bacterial cells are only resistant to the effects of complement when no specific antibacterial antibody is present.

Several classes of plasma protein limit the spread of infection. Protease inhibitors such as alpha 2-macroglobulin inhibit potentially damaging proteases. Microbe invasion and colonization of human tissues is dependent on microbial proteases. In response human plamsa is loded with protease inhibitors. alpha2-macroglobulins first trap the protease with a bait region, when the protease cleaves the base the alpha2-macroglobulin binds covalently. Surrounds the protease.

Definsins alpha and beta. Amphipathic, both hydrophobic and hydrophilic regions. Penetrates the microbial membrane and disrupts it. alpha definsins, produced mainly by neutrophis and pneth cells. beta defensins, expressed mainly by epithelial cells of the respiratory tract the urogentital tract and the skin.

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