M&I Week 1 Flashcards
Emerging Infectious Disease
An infectious disease that has newly appeared in a population or that has been known for some time but is rapidly increasing in incidence or geographic range
Endemic
A disease that is consistently found in a population at low prevalence
Epidemic
A disease that affects many people at the same time period and in the same region
Pandemic
A global epidemic
Pustule
A small pus-filled bump on the skin
Scab
A dry, rough protective crust that forms over a cut, wound, or pustule during healing
Vaccination
The induction of immunity to a pathogen by injection of a vaccine
Variolation
The deliberate introduction of a weakened form of smallpox (variola) virus into a healthy person in the hope to elicit protective immunity
Adhesin
Structure on the surface of bacteria that is utilized to bind a cellular receptor of the host
Capsule
Polysaccharide layer that surrounds the cell wall of many bacteria
Cell Wall
Rigid external covering of the cytoplasmic membrane
Colonoization
The act of establishing a colony or colonies
Endospore
A thick-walled spore formed in the bacterial cell (mother cell)
Envelope
The structures that form the surface of bacteria
Flagellum (flagella pl.)
Thin, filamentous appendage on cells composed of the protein flagellin, responsible for motility
Infection
Invasion by and multiplication of pathogenic microorganisms in a bodily part or tissue, which may produce subsequent tissue injury and progress to overt disease through a variety of cellular toxic mechanisms
Lipopolysaccharide (LPS)
Complex structures composed of sugars and fatty acids in the outer membrane of Gram-Negative bacteria
Outer Membrane Protein (OMP)
proteins in the outer membrane of Gram-Negative bacteria
Pathogen
A microorganism capable of causing disease
Pathogenicity
Ability of an organism to cause disease
Petidoglycan (or Murein)
Large polymer that provides the rigid structure of the bacterial cell wall, consisting of acetylglucosamine, acetylmuramic acid, and a tetrapeptide
Perplasmic Space
Space between the cytoplasmic and outer membrane Gram-Negative bacteria
Permease
Enzyme-like proteins in the cytoplasmic membrane that mediate nutrient transport
Pilus/Fimbria (Pili/Fimbriae pl.)
Surface appendages of certain bacteria composed of the protein pilin
Pleomorphic
Having different morphological forms within one species
Porin
Channel containing proteins in the outer membrane of Gram-Negative bacteria
Septum
A crosswall
Sporulation
The process of forming spores
Teichoic Acid
A polymer of ribitol phosphate and glycerol phosphate found in the cell walls of certain Gram-Positive bacteria
Virulence
Degree of pathology caused by an organism
Zoonosis
Disease of animals that can be transmitted to humans
Adaptive (Acquired or Specific) Immunity
The response of antigen-specific lymphocytes to antigen; it is generated by clonal selection and characterized by immunological memory
Antibody (or Immunoglobulin)
Protein produced by B cells that specifically binds with a particular substance or antigen
Antigen
A substance that can be recognized by the specific immune system, usually by antibodies
Cell-Mediated Immunity
Specific immunity mediated by T cells
CD (Cluster of Differentiation) Molecules
Cell surface molecules that are recognized by specific diagnostic antibodies. Often used as markers for specific subsets of cells. No known function for some. Often function as cell-cell interaction molecules, adhesion molecules, mediate signal transduction, etc.
CD3
A marker expressed by a T-cells and plays a critical role in T cell receptor signaling
CD4
Expressed by a subset of T lymphocytes called helper T cells that recognize peptide antigens presented by MHC class II molecules and influence the functions of other immune cells by producing cytokines
CD8
Expressed by a subset of T lymphocytes called cytotoxic T cells that recognize peptide antigens presented by MHC Class I molecules and directly kill virally infected or tumor cells
Chemotaxis
Movement of an organism in response to a chemical stimulus
Cytokines
Proteins produced by cells that affect the behavior of other cells
Interleukins
Cytokines produced by WBCs
Lymphokines
Cytokines produced by lymphocytes
Monokines
Cytokines produced by monocytes/macrophages
Interferons
Cytokines that can induce cells to resist viral replication
Chemokines
Small cytokines involved in the activation and migration of cells
Colony Stimulating Factors
Cytokines that regulate the production of leukocytes in bone marrow
Effector Lymphocyte
A lymphocyte that has been induced to differentiate into a form that is capable of mounting a specific immune response
Fc (Fragment Crystalline or Crystallizable)
Composed of the homodimer of the carboxy terminal portion of the heavy chains; fragment tends to aggregate and crystalize in solution. Fc portion of antibody differs and plays key role in eliciting the effector functions of antibodies, as it can interact with other components of the immune system
Humoral Immunity
Specific immunity mediated by antibodies
Immunoglobulin Fold or Motif
A protein motif that consists of two Beta-Pleated sheets held together with a disulfide bond, characteristic of antibodies and other proteins of the immunoglobulin superfamily
Discovery of Bacteria
Netherlands, 17th century, under a microscope witnessed “moving animals”
Development of Vaccinations
In the context of smallpox, 18th century, first disease to be eradicated altogether
Development of Antibiotics
Revolutionized treatment of infectious diseases, staphylococcal bacteria plated on petri dishes and on same plate grew mold (penicillin), which killed bacteria around it
What Impact Did Smallpox Have?
Epidemic in Europe led to selective immunity to smallpox. When Europeans emigrated, natives were introduced to smallpox and other diseases. Discovery of vaccination started with smallpox
Describe How Vaccination First Started With Smallpox?
Early forms were called variolation (blowing up the nose, poking in arm, etc.). Milking cows formed lesions/blisters on hand (cowpox), and resistance to smallpox was conferred. Edward Jenner took material out of lesion and scratched/injected it into arm. The would then variolate smallpox to see if subject was immune. First disease to become completely eradicated
Describe the HIV/AIDS Epidemic and How Vaccinations and Treatment Have Affected Different Rates?
Primarily 75%, and in eastern and southern Africa. Locations with extreme poverty more likely to have higher prevalence. Number of new infections started declining since 1995. Number of deaths have been decreasing, but number of individuals infected are increasing. Number of infected individuals on therapy also increasing. How? Therapeutics are allowing infected individuals to live longer.
Three types of infectious disease emergence and definitions?
Newly emerging (outbreaks, Zika); Reemerging (due to antibiotic resistance); Deliberately emerging (purposes of bioterrorism, particularly after 9/11, Anthrax, Category A, but also Category B and C exist
Factors and Explanations Involved in the Emergence of Diseases?
Production of Food (feed for poultry may contain antibiotics, which increase likelihood of these foods carrying salmonella); Transmission of Diseases (from other animals, Swine Flu, H1N1); Encroachment in Nature (animals can carry infectious diseases; Medical Interventions (can result in bacterial infection from improper or non-sterile tube placement, immune deficiencies due to chemotherapeutic agents, etc.)
Koch’s Postulates for Establishing a Causal Relationship Between Microoganism and Disease
1) Agent must be the direct cause of the disease as it appears naturally
2) Causal agent must be isolated in pure culture and specific characteristics determined
3) When host is injected with pure culture, characteristic symptoms of the disease myst be present
4) Causal agent must then be re-isolated and determined to be the same organism, usually by the same technique as before
Features of Prions
Disease causing protein is pathologic version of protein with function relatively unknown. Normal protein has alpha helices, where disease causing protein contains beta-pleated sheets and becomes resistant to proteolysis. Change can happen spontaneously (CJD), through genetic causes (fatal familial insomnia), or transmitted (mad cow disease, CES)
Viruses
Contain DNA or RNA and are recognized by the immune system. Encapsulated in protein capsule, sometimes has lipid bilayer. Enveloped have lipid bilayer and are sensitive to destruction in the environment
Bacteria
Prokaryotes
Differences Between Bacteria (Prokaryotes) and Eukaryotes?
Single (haploid) circular DNA, contains episomes/plasmids which can self-replicate (important for genetic engineering), do not have a nucleus or other cellular components, has one or two phospholipid bilayers and a cell wall. Protein synthesis is more efficient, transcription and translation occur at the same time, no introns. First amino acid is N-formyl-Met. Sigma factors bind DNA promoter and induce different genes. Polycistronic meaning multiple genes for multiple proteins with one single promoter
Different Shapes of Bacteria?
Spiral shaped are called spirilla, round are cocci, rod shaped are baccili. Can be a hybrid (bacilococci) or no shape (pleiomorphic). Other distinct shapes include diplococci (two balls); neisseriae (coffee-beaned shaped); tetrads (cocci in four); sarcinae (cocci in packets of 8, 16, or 32); steptococci (cocci in chains); micrococci and staphylococci (irregular clumps of balls); corynebacteria (palisades arrangement); streptomycetes (moldlike filamentous bacteria); vibrious (curved rods)
Flagella Function
Some bacteria have flagella, and strains with flagella are more likely to be pathogenic. Flagella is mad of flaggelin. For bacteria with multiple flagella, tend to bundle in counterclockwise and spread out of clockwise. In single flaggela, counterclockwise turn of left-handed helix = move forward, clockwise rotation = tumble
Pilla Structure and Function
Hollow structures made of pillin and can be used to transfer genetic information/plasmids via a sex pillus (conjugation) or adhere to cells
Gram-Positive
Thick layer of peptidoglycans above single phospholipid bilaer, bound by adherence proteins, have teichoic acids recognized by immune system, and if attached to lipids, lipteichoic acids
Gram-Negative
Has thin layer of peptidoglycans in between its inner and outer phospholipid bilayers. Also contains lipopolysaccharides, utilized for resistance, which are only seen in Gram Negative, and recognized by the immune system, associated with runaway infections (septic shock)
Peptidoglycans
N-Acetylglucosamine and N-Acetylmuramic Acid linked by short peptide chains
Sugar Capsule in Bacteria
Can protect bacteria (1) against drying, (2) prevent uptake by phagocytes, and (3) attack by the alternative complement pathway
Fungi Structure and Function
Rounded yeast cells or slender filamental hyphaae. Yeast typically divide by budding. Molds produce specialized reproductive structures called fruiting bodies, produce spores. Contain cell walls also, and can be recognized by the immune system. Lipid bilayers require sterols (ergosterol) and help direct treatment. Has layers of branched sugars (glucans) and mannoproteins, which can act as signals. B-1,3) glucan synthease can be targeted by anti-fungal theray. Chitin is the cells armor.
Thermal Dimorphism (Fungi)
Fungi can grow as rounded yeast cells at body temperature, but slender filamental hyphae (molds) at room temperature.
Protozoa
Single celled eukaryotes that lack a cell wall. Many have complex life cycles alternating between proliferative stages and dormant stages
Helminths
Parasitic worms, multicellular organisms with complex life cycles often alternating between sexual reproduction in the definite host and asexual multiplication in an intermediate host or vector. Roundworms (nematodes), Flukes (trematodes), and Tapeworms (cestodes)
Ectoparasites
Include various arthrpods such as insects (e.g lice, bedbugs, and fleas) and arachnids (e.g. ticks, mites, and spiders) which live on or in the skin. Arthropods can also serve as vectors for other pathogens. Disease vectors
Stages of Clinical Infection
Incubation: organism is replicating
Prodromal: fair amount of replication (start to not feel well, can be infectious before symptoms)
Period of Invasion: immune response
Convalescent Period: feeling better but can still remain infectious
Key Elements of An Infection Cycle
Infectious Agent, Reservoir, Portal of Exit, Transmission, Portal of Entry, Susceptible Host
Infectious Agent (Key Elements
Bacteria, Viruses, Fungi, Protozoa, Parasites, Prions
Reservoir (Key Elements)
Location where the agent normally lives and multiplies (including humans, animals, environment)
Portal of Exit (Key Elements)
The route by which the infectious agent leave the human host
Transmission (Key Elements)
from the natural reservoir to the host may occur either directly, via contact or via droplets, or indirectly (i.e airborne, vehicle borne, or vector borne)
Portal of Entry (Key Elements)
Manner by which the pathogen enters a susceptible host
Susceptible Host (Key Elements)
Susceptibility of the host depends on genetic or constitutional factors, specific immunity, and non-specific factors that influence infection
Principles of Innate Immunity
Low specificity, small diversity, no memory, does not rely on gene rearrangement, and present in invertabrates. Can recognize many different things such as LPS, DNA, proteoglycans, etc. Responds to pathogens in very similar ways. Has physical barriers such as skin and mucous membranes, but also complementary proteins which can attach to bacteria and kill them directly, or recruit other cells to come. Cytokines are produced to have regulatory effects. Phagocytes and NK cells are also a part of the innate immune system
Principles of the Adaptive/Acquired Immune System
Adapt to cells, highly specific, receptors on cells, recognize one particular component of a pathogen, large diversity, exhibits immunologic memory (where second response is larger and quicker), B cells and T cells generate millions of different receptors (gene rearrangement), only found in vertebrates. B cells are a source of antibodies and T cells. Receptors on these cells are similar but unique
Explain how the two immune systems (innate and adaptive) rely on each other?
Two systems are not exclusive and rely on each other. Adaptive immunity can only eliminate pathogens with the help of components from innate immunity system (activation of receptor on phagocyte)
Surface Epithelia (Innate)
Skin and mucosal tissue is the first line of defense; mechanical (tight junctions), chemical (short anti-microbial peptides called defensins); and microbiological (good bacteria) are barriers to infection
Complement System (Innate)
Plasma proteins that can attack and kill microbes in three different pathways, classical, alternative, and lectin binding. Recruitment of inflammatory cells, opsonization of pathogens, or killing of pathogens
Classical Pathway of Complement System
Antigen:Antibody complexes
Alternative Pathway of Complement System
Pathogen surfaces
Lectin Binding Pathway of Complement System
Lectin binding to pathogen surfaces
Phagocytes
Includes neutrophils, macrophages, and dendritic cells. Interact via pathogen associated molecular patterns (PAMPS) on the pathogen, and pattern recognition receptors (PRRs)
Neutrophils (Phagocytes)
Most abundant and kill pathogens
Macrophages (Phagocytes)
Killing machines that produce a lot of cytokines and clear up dead cells and debris
Dendritic Cells (Phagocytes)
Sentinels critically important for initiating adapative immune responses
Natural Killer Cells
Recognize and kill some virally-infected or tumor cells via conserved, non-specific receptors. Usually associated with a decreased MHC Class I expression. Recognize stressed host cells via innate receptors that bind with ligands whose expression is altered as compared with normal cells
Cytokines
Important innate cytokines include pro-inflammatory, anti-inflammatory, antiviral, and chemotactic cytokines
Other Innate Immunity Cells
Eosinophils, Basophils, and Mast Cells play critical roles in innate immune response against helminths and allergic responses to environmental antigens
Humoral Immunity
Mediated by antibodies or immunoglobulins (produced in B cells) that can be secreted and present in the fluid part of blood to bind antigens. Most effective dealing with extracellular versions of microorganisms. Can be transferred passively. Can be used for therapeutic purposes during infections or following exposure to venom
Cell Mediated Immunity
Mediated by T cells. Express T cell receptors that do not bind with intact antigen and are never secreted. Interact with processed form of protein antigens (short peptides) associated with host proteins, called major histocompatibility complex molecules, expressed at the surface of other cells. MHCI present antigen-derived peptides to CD8-expressive T-Cells (kill directly), where MHCII molecules present antigen-derived peptides to CD4-expressive T cells (secrete cytokines to recruit other cells (B-cells/Macrophages). Can be transferred passively through cells of the blood. Many issues with graft rejection
Cardinal Features of Humoral and Cell-Mediated Immune Response
Specificity, where receptors expressed by B and T lymphocytes are highly specific;
Diversity, where there is a large amount of structural variability in the receptors expressed by B and T cells, allowing them to recognize a virtually unlimited number of different antigens, generated by DNA rearrangement;
Memory, where exposure to the immune system to antigen enhances its ability to respond again to this antigen
Self-Limitation, where after elimination of the antigen, the immune response wanes down, caused by regulatory mechanisms of the immune system; and
Self/Non-self Discrimination, where the immune system is tolerant against self-antigens. Self tolerance is maintained by elimination or functional inactivation of lymphocytes. Abnormalities in this process can lead to autoimmune disease
Five Phases of an Acquired Immune Response
Recognition, where naive lymphocytes recognize the antigen for the first time, mediated by B and T cell receptors
Activation, where lymphocytes start to proliferate, and differentiate into functional effector cells
Effector, where elimination of antigen with the weapons produced by the lymphocytes occurs. Also involves components of the innate and immune system
Decline, where at the end of the immune response most of the progeny of the antigen-specific lymphocytes escapes death and differentiates into memory B and T cells. Memory lymphocytes respond more quickly and effectively to antigen than naive lymphocytes
Clonal Selection Hypothesis
A single progenitor cell gives rise to a large number of lymphocytes, each with a different specificity. Potentially self-reactive immature lymphocytes are removed by clonal deletion, leaving a pool of mature naive lymphocytes. Proliferation and differentiation of activated specific lymphocytes form a clone of effector cells
Clusters of Differentiation (CD) antigens
Cell surface molecules recognized by specific diagnostic antibodies. Used as markers for specific subsets of cells. No known functions for some
Cytokines, Interleukins (ILs), and More
Cytokines are the protein hormones of the immune system. Might be autocrine, paracrine, or endocrine. Works by interacting with specific receptors, for example IL1 recognized by IL1 receptor
Important Questions for Immunology
How does a particular immune factor or cell interact with other immune factors or cells, especially interactions between the innate and adaptive arms of the immune system? What would be the phenotype of a human or mouse lacking a particular immune factor or cell type? How could a particular immune factor or cell be targeted for immunotherapy of disease?
Lymphangitis
Inflammation of afferent lymphatic vessel
Lymphadenitis
Inflammation of a lymph node
Lymphadenopathy
Swollen lymph nodes (glands). Enlargement of a lymph node may be a sign of a distant infection or a more ominous sign of a lymphoma or the metastatic spread of a primary tumor to a metastatic location
Lymphadema
Noticeable accumulation of a lymph in a region (usually an extremity) when the outflow lymphatic pathways are congenitally absent or blocked or damaged during surgery
Lymphoma
A neoplastic growth and expansion of lymphocytes that cause enlargement of lymph nodes along regional lymphatic chains
Functions of the Lymphatic System (3)
Formation of lymph and its exit from tissue; immune defense; fat absorption
Formation of Lymph and Its Exit From Tissue (Function of Lymphatic System)
Endothelial cells in lymphatic vessels lack tight junctions. Overlapping endothelial junctions are anchored to filaments and when fluid increases in the tissue, the anchors pull open the gaps in the cells. Fluids, proteins, and particles gain access to the lumen of the lymphatic capillaries. Outflow can be obstructed
Immune Defense (Function of Lymphatic System)
If pathogens enter the body, they will be transported with the interstitial fluid and enter lymphatic capillaries. They will then enter the lymph nodes, preventing their systemic spread
Fat Absorption and Lacteals (Function of Lymphatic System)
Lacteals are highly absorptive lymphatic capillaries in the villi of the intestine. Takes up lipids and fat soluble vitamins. Lymphatic vessels converge into trunks, and these trunks become congested after eating a fatty meal. Lipophilic particles suspended in lymph are called chylomicrons. These trunks then drain the lymph into the chyle cistern.
Chylomicrons
Lipophilic particles suspended in lymph
Define the drainage regions that govern whether lymph returns to the bloodstream at either the right or left jugulovenous angle
Right arm, right chest, and right back drain into the right lymphatic duct and right venous angle, where everthing else goes through the thoracic duct and to the left venous angle
How do you plan to assess the specific anatomical sites where a primary tumor may have started
Sentinel node mapping. Can work backwards.
Superficial Lower Extremities Pathway
Lymph flows distal to proximal and must move upward against gravity, flows into inguinal lymph nodes which are divided into two groups
Vertical Inguinal Lymph Nodes
Receives lymph from lymphatic vessels and nodes positioned along the great saphenous vein which includes everything in the lower extremity except the lateral thigh
Horizontal Inguinal Lymph Nodes
Receives lymph draining downward from anterior abdominal wall below the umbilicus as well as from the hip, buttocks, perineum, and upper lateral thigh
Superficial Upper Extremities Pathway
Lymph also flows distal to proximal and medially, flows into the axilla
Superficial Anterior and Posterior Trunk Pathway
In anterior body wall, skin above umbilicus drains upward to the axilla. Cutaneous lymphatic capillaries drain to nodes on the same side (i.e right thorax drains to right axillary nodes)
Superficial and Deeper Lymphatic Drainage Patterns within Head and Neck
Head is encircled with a pericervical collar of lymph nodes that can be palpated if swollen, capillaries drain downward following venous return patterns and move into deep lymphatics to form a juggular lymphatic chain alongside the internal jugular vein. Dumps lymph into the right or left jugulovenous angle
Deep Lymphatic Drainage System
Located within the pelvic, abdominal and thoracic cavities, majority of lymph is shunted towards the chyle cistern (a collecting reservoir that is located deep within the abdominal region). Receives lymph from the inguinal nodes (external iliac chain which parallel the veins of the same name). Flow upward to the common iliac nodes and these form right and left lumbar trunks. Lymph continues upwards where it collects in the chyle cistern. Intestinal trunks also drain into chyle cistern
Thoracic Duct
Begins at the upper end of the chyle cistern at the L2 level. Passes posterior to the diaphragm, enters the thorax, passes upward, receives lymph vessels draining the left intercostal spaces, bends leftward at the T5 level and dumps chyle-containing lymph into the junction of the left subclavian and left internal juggular veins. Final common pathway for 3/4 of the lymphatic system
Predict the regional pattern of lymphatic flow through the groupings of axillary lymph nodes
Anterior (Pectoral), Posterior (Subscapular), and Lateral (Humeral) nodes drain into a central and then apical node. They then move to the subclavian node and then drain into the right (or left) venous angle
Devise a simple anatomical explanation of sentinel node mapping that is suitable for use with a patient
Lymphatic drainage has a high degree of non-predictability. Sentinel node mapping has become an increasingly used technique in the staging of (breast) cancer. If cancer cells have not metasticized to anterior nodes, the prognosis is much better than if there is a central group or apical group involvement. Often spares a women the risk of having lymph node dissection
Primitive Hematopoiesis
During fetal life, erythrocytes and leukocytes are formed in several organs before the differentiation of the bone marrow. “Yolk Sac Phase” of hematopoiesis begins int he third week of gestation. Formation of “blood islands” in the wall of the yolk sac. RBCs are nucleated and express embryonic globin chains
Definitive Hematopoiesis
Begins when hematopoietic centers appear in the liver and lymphoid tissues early in fetal development (~35-42 days). Hepatic phase, RBCs are non-nucleated and express fetal or adult globins. Liver is major blood forming organ in the fetus during the second trimester. Primarily making RBCs but some WBCS are made too. Bone marrow begins developing in bones by the second trimester. After birth, blood cells are derived from precursor cells and located in red bone marrow and lymphatic tissue
Red Bone Marrow
Active bone marrow, color is due to the presence of blood and blood forming cells. It is the type of marrow found in all newborns. Main function is to produce blood cells, but also to destroy worn out RBCs and storage of iron inside macrophages. As individuals age, red bone marrow decreases and is found primarily in the epiphyses or ends of long bongs and in flat bones
Yellow Bone Marrow
Non-active bone marrow, color is due to the presence of many adipocytes. Found primarily in medullary cavities of long bones in adults. It retains hematopoietic potential (and when necessary severe hypoxia or bleeding) it can revert to red bone marrow to resume hematopoiesis
Describe How Blood Cells Are Derived From Precursors int he Bone Marrow
Pluripotent stem cells are capable of producing all blood cell types, also capable of self-renewal. They form daughter cells with reduced potentiality (unipotential or bipotential progenitor cells. Two cell lineages, lymphoid and myeloid
Lymphoid Cells
Includes lymphocytes, including B Cells and T Cells and NK Cells; and dendritic cells
Myeloid Cells
Includes platelets and RBCs, mononuclear cells (monocytes/macrophages), and polymorphonuclear (granulocytes: neutrophils, eosinophils, and basophils; phagocytes, and mast cells); dendritic cells
Describe the Factors That Regulate Hematopoiesis
Primarily controlled by cytokines (colony stimulating factors, often induced during infection to promote the generation of WBCs)
Give an Example of Regulation of Hematopoiesis
Granulocyte-Monocyte Colony Stimulating Factor (GM-CSF) promotes differentiation of granulocytes and monocytes. Cytokines such as GM-CSF can be administered to patients with failing immune systems (i.e due to chemotherapy following cancer or prior to bone marrow or stem cell transplantation)
Lymphocytes
Definitive cell type (effector) of the system, and key elements in immune response (B-Cells, T-Cells, and NK Cells). Majority (70%) are part of circulating pool and migrate back and forth between the circulation and the lymphoid tissue (immunocompetent cells). 30% are short lived, immature cells or are activated and destined for a particular tissue such as the CT underlying the epithelium of the GI and respiratory tracts
B Cells
Produced in the bone marrow, bear highly diverse receptors on their surface and secrete antibodies referred to as plasma cells
T Cells
Mature in Thymus gland, bear highly diverse receptors on their surface
NK Cells
Part of innate immune response and contributes to immunity against tumors and viruses
Myeloid Cells
WBCs consisting of granulocytes, mast cells, and monocytes/macrophages
Granulocytes
Relatively short lived, have oddly shaped nuclei often called polymorphonuclear leukocytes
Neutrophils
Most abdunant and have phagocytic properties with granules pink or neutral in color
Eosinophils
Have a role in defense against parasitic infections and contributes to allergic reactions, granules stain bright red or pink
Basophils
Have similar functions as mast cells, found primarily in circulating blood and their granules stain an intense blue/purple
Mast Cells
Reside in tissue, and are a main culprit in allergic reactions, contributes to immune response against parasites
Monocytes
Circulate in blood and when activated, differentiate into macrophages and migrate into tissues, where they are often called histiocytes
Macrophages
In the liver often called Kuppffer cells, those in the brain are referred to as microglia, and those in bone as osteoclasts
Dendritic Cells
Accessory cells critically important for the initiation of adaptive immune responses, most effective in activating naive T Cells, capable of phagocytosis and macropinocytosis. Bone marrow-derived, with subsets that originate from both the lymphoid and myeloid progenitors. Found in lymphoid and non-lymphoid tissues. Dendritic cells in skin are referred to as Langerhans Cells
Follicular Dendritic Cells
Not derived from the bone marrow, not related to conventional dendritic cells. Found within specialized lymphoid tissues, termed germinal centers of lymphoid nodules, are adept at capturing and displaying antigens at the cell surface, and are important for interacting with B cells to promote antibody responses
Central Lymphoid Organs
Include bone marrow and the thymus. B Cells originate in bone marrow, T Cells mature in thymus. After maturation, they enter the bloodstream and migrate to peripheral lymphoid organs
Peripheral Lymphoid Organs
Sites here antigens come into contact with B and T Cells of the Immune System
What 3 Characteristics Do All Lymphoid Organs Share?
(1) All have a means of collecting antigen and carrying it to the lymphoid microenvironment; (2) All have specialized vascular adapatations to recruit lymphocytes, especially lymphocytes from the blood; (3) All have distinct B and T cell zones
Describe the shape and character of the Thymus Gland?
Bi-lobed developed from the endoderm. Multipotent stem cells destined to become T cells migrate to the thymus. Lymphoid cells begin occupying spaces between the epithelial cells resulting in an “lymphoepithelial” organ of dual embryonic origin
How is the cortex and medulla of the thymus separated?
The thymus is surrounded by a dense CT capsule from which trabeculae extend penetrating through the gland, organizing it into a dense cortex and lighter medulla
Describe the Cortex of the Thymus
Contains small T lymphocytes which occupy spaces surrounded by epithelioreticular cells. Macrophages also present and are responsible for phagocytosis of T cells that do not become thymic educated
Describe the Medulla of the Thymus
Light inner portion of the thymus gland, also contains epithelioreticular cells and larger lymphocytes with paler-staining nuclei and more abundant cytoplasm
Hassall’s Corpuscles
Near terminal differentiation, the epithelioreticular cells form these, which are the characteristic histological feature of the thymus gland. Isolated masses of cells that exhibit flat nuclei, keratohyalin granules and intermediate filaments. The core often appears keratinized. Function is unknown , but increases with age
Describe the Vessels that Enter and Exit the Thymus
Both the capsule and trabeculae contain blood vessels and efferent lymphatic vessels and nerves. No afferent lymphatic vessels in the thymus gland. The Blood-Thymic barrier protects developing T Cells from exposure to antigens. As blood vessels pass from trabeculae into the substance of the thymus gland, it is ensheathed by epithelioreticular cells
Describe the Components of the Blood-Thymic Barrier
(1) Capillary endothelium; (2) Underlying thick basal lamina associated with the endothelium. Thickness makes these vessels impermeable to proteins preventing most circulating antigens from reaching the small T cells in the cortex; (3) Macrophages that will phagocytose any antigenic molecules that escape from the capillary lumen; (4) Basal lamina of the epithelioreticular cells; (5) Epithelioreticular cells that surround the capillary wall and provide further protection to developing T Cells
Lymph Nodules
Localize concentrations of lymphocytes, referred to as follicles; not encapsulated but easily defined
Describe the difference between primary and secondary nodules
Primary nodule contains small lymphocytes. A secondary nodule contains lymphocytes that have recognized an antigen and returned to the nodule to proliferate. Secondary nodules are identified by a stained or pale germinal center. Lighter staining is due to the presence of larger lymphocytes or lymphoblasts that have dispersed euchromatin. Macrophages also usually in abundance in the germinal centers. Surrounding the center is a corona or “mantle zone” of small lymphocytes. Secondary nodule indicates cascade of events has occurred
What is the Cascade of Events that a Secondary Nodule Indicates Has Happened
(1) Proliferation of lymphocytes; (2) Differentation into plasma cells; (3) antibody production
Mucosal-Associated Lymphoid Tissue (MALT), Gut-Associated Lymphoid Tissue (GALT)
When follicles are in association with mucosal epithelia or Peyer’s patches in the gut
Histological Features of Tonsils
Tonsils are incompletely encapsulated and consist of aggregates of lymphatic nodules that form a ring around the oropharynx. Three main types:
Palatine consists of diffuse lymphocytes and lymphoid nodules disposed under a stratified squamous epithelium because it projects to the lumen, Pharyngeal, and Lingual
Depict the Role of M Cells in Peyer’s Patches
M Cells are important for the intiation of an immune response, lined at the gut of the lumen with specialized epithelial cells called microfold or M cells. M Cells take up molecules and particles from the gut lumen by endocytosis or phagocytosis and then release the material at the basement cell membrane (transcytosis). Antigens may then be taken up by antigen-presenting cells, in particular dendritic cells in the Peyer’s patches
Distinguishing Structural Feature of Lymph Nodes
Small, bean-shpaed, encapsulated organs lying along the course of lymphatic vessels. Serve as lymph filters that collect and process antigens. Convex surface is where site of entrance for lymphatic vessels lie. Concave depression (hilum) is where arteries and nerves enter and veins and lymphatic vessels leave. Surrounded by a dense CT capsule. Directly underneath capsule are subcapsular and trabecular lymphatic sinuses. Remainder of organ is composed of reticular tissue filled with reticular cells, reticular fibers, lymphocytes (B and T Cells), macrophages, antigen-presenting cells, and plasma cells. Follicular cells are located in the germinal centers interdigitated between B cells
Describe the Structural Features of the Cortex of Lymph Nodes
Two regions: (a) a periphery where nodules, with or without germinal centers are located. Formed mainly of B cells embedded in a population of stromal cells. Germinal centers are of intense B cell proliferation organized around follicular dendritic cells. and (b) deeper paracortical region, without boundaries, heavily populated with T cells. Thymus dependent. High endothelial venules. Naive lymphocytes can leave blood stream and enter cortex by interacting with counter receptors expressed by high endothelial venules
Describe Structural Features of the Medulla of Lymph Nodes
Inner portion of lymph node, cords of cells separated by lymphatic or medullary sinuses. Connect to the trabecular lymphatic sinuses so that lymph moves from the periphery and percolates down towards the center of the node. Sinuses are lined by endothelium that is discontinuous where it faces the lymphatic parenchyma. Sinuses join at the hilum. Majority of lymphocytes in this region are B lymphocytes. Efferent vessels remove/take the lymph away, leaving the node through the hilar region on the concave surface of the node
Structure and Function of the Spleen
Largest accumulation of lymphoid tissue in the body and the only one where lymph is interposed with blood circulation. Plays a role in defense against foreign invaders that penetrate circulation, acts as a blood filter that removes damaged RBCs. Site of production of mature or activated lymphocytes, also site of RBC maturation. RBCs are groomed here and vacuoles or abnormal inclusions are removed from damaged RBCs to return them to normal
Supporting Tissue of the Spleen
Consists of a dense CT capsule that extends trabeculae into the tissue by dividing the pulp or parenchyma of the spleen into incomplete compartments. Trabeculae carry nerves and arteries into the splenic pulp (contains no lymphatic vessels). Few smooth muscle cells and myofibroblasts within the capsule and trabeculae. Contain contractile elements that help to discharge RBCs into the circulation. Reticular tissue containing reticular cells and fibers plus lymphoid cells and macrophages make up the remainder of the supporting tissue or stroma of the spleen
Describe Feature of the Parenchyma of the Spleen
Consists of red pump (areas of red blood cell destruction). Lymphocytes are found in white pulp, which surrounds arterioles that enter the spleen. Central part of the white pulp is called the periarteriolar lymphatic sheath (PALS), which contains mostly T lymphocytes (T Cell Zone). The PALS is flanked by B Cell Follicles (B Cell Zone), some of which contain germinal centers. The white pulp is separated from red pulp by a marginal zone, containing antigen-presenting (dendritic cells and macrophages)
Reconstruct the Pathway Taken by Lymph as it Flows Through the Lymph Nodes
The immune system continually redistributes its entire repetoire throughout the body. Naive lymphocytes in the bloodstream continually enter lymphoid organs through specialized endothelia and can then circulate within lymphatic vessels and finally return to the blood via the thoracic duct. During an infection, antigens will travel through the lymph to the local lymph nodes. There the antigens will be presented to lymphocytes, which will be activated to proliferate and differentiate. The effector lymphocytes may then leave the lymph nodes through the efferent lymphatic vessel and join the bloodstream. Activated lymphocytes may migrate to infected tissue by moving through flat venules.
Mechanical Role Surface Epithelium
Joined by tight junctions to form a physical barrier. The longitudinal flow of air (in lungs) or fluid (in GI) prevents microbial colonization. The movement of mucous by cilia in the respiratory tract provides an upward motion to expel particles
Biochemical Role of Surface Epithelium
Fatty acids produced on the skin. Productoin of antimicrobial enzymes: lysozyme (active against peptidoglycan, which is most abundant in the cell wall of Gram Positive Bacteria) by saliva and tears; pepsin by the stomach. The low pH of the stomach. Defensins and cathelicidins are two families of antimicrobial peptides secreted at mucousal surfaces and skin, which are active against bacteria, fungi, and viruses. Defensins are particularly abundant in the gut
Microbiological (Ecological) Role of Surface Epithelium
Normal flora compete for nutrients and attachment to epithelium and often produce antibacterial substances (e.g colcins produced by E. Coli). Antibiotic treatments that kill the normal flora can make an individual susceptible to infection by pathogens
Classical Pathway (General)
Indirect activation of complement by binding with antibodies that have attached to microbes. This function of complement contributes to the effector phase of the adaptive immune response
Lectin Pathway (General)
Activated by plasma proteins such as mannose-binding protein, which bind to pathogen surfaces and activate complement. Part of innate immune response
Alternative Pathway (General)
Direct activation of complement by binding with bacterial cell wall components. part of the innate immune response
Membrane Attack Complex (MAC)
Where activation of any of the three pathways can lead to the formation of the membrane attack complex, which forms a pore in microbial membranes leading to osmotic lysis. Host cells are protected against complement activation by a variety of complement control proteins
Opsonization
Where complement components also prepare pathogens for uptake by phagocytes and contribute to the inflammatory response
Classical Pathway Specific Mechanisms
C1qrs binds to Fc domain of antibody (IgM or IgG) when bound to pathogen. Binding of C1q results in conformational change that activates C1r to cleave C1s to generate an active serine protease. C1s cleaves C4 into C4b, which covalently binds to the pathogen surface (via thioester bond). C4b then binds to C2, which is cleaved by C1s to generate C4b2b, which is a C3 convertase
Lectin Pathway Specific Mechanism
Mannose-binding lectin is produced by the liver in response to an acute phase response. Binds with mannose and few other sugars on bacterial but not mammalian cells. Mannose-binding lectin binds with MASP-1 and MASP-2. MASP-2 cleaves C4 and C2, resulting in the covalent attachment of C4b2b (C3 convertase) to bacterial surfaces
Alternative Pathway Specific Mechanism
Spontaneous hydrolysis of C3 into C3b, which can covalently bind with repeated structures (e.g LPS) of the pathogen surface. C3b binds factor B, allowing its cleavage by factor D, regulated by factor P, generating C3bBb (covalently bound to pathogen surface). C3bBb is a C3 convertase
C3 Convertases
C3 is cleaved into C3b and C3a, which feeds back into the alternative pathway, resulting in more C3b deposition. The alternative pathway amplifies the classical and lectin pathways. C3b binds with C3 convertases, resulting in complexes that are C5 convertases. C5 is cleaved to generate C5b, which attaches to the pathogen surface. C5b initiates assembly of the later complement components (C6-C9) and their insertion into the cell membrane
Four Functions of Complement System
(1) Punch holes in microbial cell walls and cellular membrane
(2) Induce inflammation
(3) Prepare microbes for phagocytosis
(4) Remove circulating immune complexes
MAC Punching Holes In Bacteria
C5b binds with C6, which binds with C7 causing a conformational change in C7, allowing insertion into lipid bilayer. Complex binds C8, which also inserts into membrane. Induces polymerization of 10-16 C9 molecules into a pore forming structure called the membrane attack complex (MAC)
Promotion of Inflammation by Small Complement Components
C3a, C4a, and C5a promote inflammatory responses. C3a and C5a specifically are anaphylatoxins and act on mast cells to release histamine, resulting in smooth muscle contraction and vascular leaking. C5a is also a chemokine, resulting in the recruitment of neutrophils to enter the site of infection.
Opsonization of Pathogens by Complement Components
C3b and C4b function as opsonins. Phagocytes have multiple complement receptors including CR1, CR3, and CR4 that can bind with C3b and/or C4b on pathogen surfaces. C5a is needed to activate phagocyte
Clearing of Small Immune Complexes via Complement Components
C3b (or C4b) bind to antigen-antibody complexes with CR1 on RBCs, which transport the complexes to the liver or spleen where they are removed and digested by macrophages expressing complement receptors (CR1, CR3, and CR4) and Fc receptors (binds with Fc domain of antibodies)
Three Examples of Protection of Host Cells Against Complement Activation
(1) C1 inhibitor (C1INH) binds with the active components of C1, thus inhibiting its activation in plasma (inhibitor of classical complement pathway)
(2) Factor 1 specifically cleaves C3b and C4b, and this process is positively regulated by several other factors, thus inhibiting all complement pathways
(3) CD59 (protectin) prevents the formation of the MAC
Defects in Components of the Classical Pathway
Deficiencies in these complexes are often associated with immune complex disease because these components are important for clearance of immune complexes
Defects in Components Specific to the Lectin Pathway
Enhance suceptibility to bacterial infection in early childhood
Defects in Components that are Shared Between the Classical and Lectin Pathways, But Not Alternative
Enhance susceptibility to bacterial infections, and are associated with immune complex disease
Defects in Components Specific to Alternative Pathway
Enhance susceptibilty to infection by pus-forming bacteria and Neisseria species
Defects in Complement C3 Component
Lead to infection by pus-forming bacteria and Neisseria species and may sometimes cause immune complex disease (because C3 also contributes to clearance of immune complexes
Defects in Components of the MAC
Only enhance susceptibility to Neisseria species, suggesting that MAC is redundant with other immune defense systems
Hereditary Angioneurotic Edema
Defects in the C1 inhibitor. Normally inhibits C1r and C1s and enzymes that participate in the clotting and kinin systems. Subject to recurrent edema in intestinal, skin, and airways
Paroxysmal Nocturnal Hemoglobinurea
Acquired defects in synthesis of glycoslyphosphatidylinositol (GPI) in hematopoietic stem cells, causing defective expression of CD59, DAF, and HRF, on RBCs, which results in the destruction of RBCs
Function of Phagocytes
To recognize, contain, and destroy microbial invaders. Recognition is non-specific and non-clonal
Neutrophils or Polymorphonuclear Phagocytes
Most prevalent phagocytes and are present in lymphoid tissues and circulation, are produced continuously and have a short lifepsan. Only enter tissues that have an ongoing infection
Monocytes and Macrophages (mononuclear phagocytes)
Macrophages mature continuously from circulating monocytes and leave the circulatoin to migrate into tissues. Activated macrophages are killing machines, important to cytokines and chemokines, and can present antigens to naive T Cells. Macrophages are also critically important for removing dead cells and debris. Some macrophages have a strong phagocytic and pro-inflammatory functions, whereas others have more anti-inflammatory and wound-healing functions
Dendritic Cells
Present in lymphoid and non-lymphoid organs. Upon antigen uptake in tissues, dendritic cells mature and move to the draining lymp node. Not very effetive in killing microbial invaders, but are very effective in presenting antigens to naive T Cells. Several dendritic cells subsets with distinct functions have been identified
Reticuloendothelial System
What the mononuclear phagocyte system was once referred to as
Extravasation
When neutrophils and other phagocytes leave the bloodstream and enter the infected tissue. Involves three sets of receptor-ligand interactions. Attachment, Activation, Tranendothelial Migration, and Migration
Attachment in Extravasation
The tethering or adhesion of leukocytes to activated endothelium and their rolling along the endothelial cells. Events are based on cell adhesion, mediated by E and P selectins on endothelial cells that interact with their carbohydrate ligands on phagocytes
Activation of Leukocytes in Extravasation
In response to engagement of chemokine receptors with chemoattractants made of chemotactic properties. Can be generated by bacteria themselves (i.e N-formly-Met), generated as by products of complement activation (C5a), or chemokines (IL-8) produced by phagocytes, endothelia, etc. at the site of infection. Upregulates cell adhesion molecules termed integrins (LFA-1), which bind to counter receptors (ICAM-1) on endothelial cells resulting in arrest and strengthening of adhesion
Leukocyte Adhesion Deficiency (LAD) in Extravasation
Genetic deficiency in beta-2 integrin, resulting in defects of phagocyte entry
Transendothelial Migration in Extravasation
Diapedesis, where the neutrophil slips in between two endothelial cells
Migration in Extravasation
Migration to the site of infection/inflammation. This step also involve chemokines, which have a tendency to “stick” to the extracellular matric
Recognition of Pathogens and Damaged Cells By Phagocytes
Phagocytes can recognize microbial products via (1) pattern recognition receptors (PRRs); (2) complement receptors; or (3) Fc antibody receptors
Pattern Recognition Receptors (PRRs)
Recognize pathogen-associated molecular patterns (PAMPs). During tissue injury or stress, cells release products, referred to as damage-associated molecular patterns (DAMPs) that are similarly recognized by PRRs and promote inflammation
Endocytic/Phagocytic Pattern Recognition Receptors
Promote phagocytosis, many are C-type lectin receptors (CLRs). Examples include recognition of mannose in the cell wall of bacteria by the mannose receptor, recognition of modified lipoproteins by the scavenger receptor, recognition of LPS in Gram Negative Bacteria by CD14, and recognition of Beta-Glucans in the cell wall of fungi by dectins
Signaling pattern Recognition Receptors
Promotes activation of gene expression in phagocytes, leading to the production of cytokines, other inflammatory mediators, and co-stimulatory molecules. Multiple familites of these receptors, including Toll-like receptors, NOD-like receptors, and RIG-I-like receptors
Toll-Like Receptors (TLRs)
Most TLRs can directly interact with pathogen-associated molecular structures, however TLR4 signals the presence of LPS by assocation with the LPS receptor CD14. Can induce a variety of responses, including phagocytosis and/or cytokine production. Some expressed at the cell surface, whereas others are expressed on endosomal membranes
NOD-Like Receptors (NLRs)
NLRs are present mostly in the cytoplasm and recognize bacterial or damage-associated molecular patterns. Some of the NOD-like receptors, including NOD1 and NOD2 recognize components of the peptidoglycan layer of bacteria. Other NLRs (NLRP3) function as important sensors of cellular injury and stress and signal through a large signaling complex referred to as the “inflammasome”, resulting in IL-1 production
RIG-I-Like Receptors (RLRs)
The RLRs including RIG-1 and MDA-5 are specific for viral nucleic acids and induce Type 1 interferon production
Secreted Pattern Recognition Receptors
Secreted to bind to antigen. Example include C3b, generated in the altenrative complement activation pathway is secreted to bind with repeated molecular structures like LPS on bacterial surfaces. In acute phase, proteins are produced in hepatocytes through the action of IL-6, which can be produced by activated macrophages. C-reactive protein binds to phosphory choline and activates complement and mannose binding prortein (mannose binding lectin), specifically binds with mannose and similarly activates the lectin pathway of complement
Chemotactic Pattern Recognition Receptors
The N-Formyl-Met receptor permits leukocytes to “chase” bacteria producing N-formylated peptides
Complement Receptors
Bacteria may be coated with complement by any of the 3 pathways to be recognized by phagocytes, because phagocytes have complement receptors. Complement not alone sufficient for phagocytosis, need C5a to activate the act of phagocytosis
Fc Receptors
Bacteria coated with antibodies (mostly IgG or IgM) can be recognized by phagocytes because they have receptors, called Fc receptors
Two Steps of Phagocytosis
Engulfment where bacteria are surrounded by the plasma membrane of the phagocyte to form a phagosome; and Fusion of the phagosome with the lysosome to form a phagolysosome
Chediak-Higashi Syndrome (CHS)
Where individuals have defects in the fusion of phagosomes with lysosomes, resulting in defects in phagocyte function
Ways Ingested Material is Damaged (6)
Acidification: lysosomal enzymes (lysozyme is most active against Gram Positive bacteria)
Antimicrobial peptides: defensins have activity against bacteria, fungi, and viruses
Generation of ROS: vigorous or respiratory burst leads to superoxide, H2O2, or oxygen radicals, defects in ROI generating enzymesin host can lead to lack or impaired killing of ingested organisms and results in a disease referred to as chronic granulomatous disease (CGD)
Generation of Reactive Nitrogen Intermediates: in macrophages, production of NO via inducible nitric oxide synthase
Sequestration of Nutrients: sometimes referred to as nutritional immunity
Chronic Granulomatous Disease
Defects in ROI generating enzymes leads to lack or impaired killing of ingested organisms
Action of Cytokines and Other Mediators Produced by Phagocytes
Cytokines, ROIs, bradykinin, and lipid mediators such as prostaglandins and leukotrienes produced by macrophages have important local and systemic effects. Act as danger signals to alert the adaptive immune response that a foreign invader is present
Inflammation and Systemic Vascular Effects
Results at local site of infection due to combined local effects of cytokines and other mediators such as leukotrienes. Increase in vascular diameter, increase in vascular permeability; increase in expression of adhesion molecules
TNF-Alpha (Tumor Necrosis Factor Alpha)
Plays a critical role in inflammation. Systemic release of this cytokine can lead to septic shock and disseminated intravascular coagulation
Induction of Fever
IL1, IL6, and TNF-Alpha are endogenous and induce fever by stimulating the production of prostaglandin E2, a metabolite of arachidonic acid. Acts on the hypothalamus. Raising body temperature is thought to help eliminate infections
Activation of the Acute Phase Response
IL6 induces the production of acute phase proteins such as C-Reactive protein and mannose binding protein by hepatocytes, which can activate complement and opsonize bacteria. CRP can be used as a surrogate maker for inflammatoin
Chemotaxis
One important function of innate immune system is to recruit more phagocytic cells and lymphocytes to the site of infection. Process is called chemotaxis and mediated by a group of small polypeptides, termed chemokines. IL8 belongs to this group of cytokines
Activation of NK Cells
IL12 is a potent activator of NK cells, destroy viral or tumor cells by recruiting T-lymphocytes
Influencing the Activity and Quality of the Adaptive Immune Response
Activated macrophages and dendritic cells expression co-stimulatory molecules that are important for the initiation of an adaptive immune response mediated by T-Cells
IL1
Activates vascular endothelium, activates lymphocytes, local tissue destruction, fever production of IL-6
TNF-Alpha
Activates vascular endothelium and increases vascular permeability, fever mobilization of metabolites, shock
IL6
Lymphocyte activation, increased antibody production, induction of fever, acute phase protein productoin
IL8
Chemotactic factor recruits variety of leukocytes to site of infection
IL12
Activates NK Cells and induces the differentiation of CD4 T Cells into TH1 cells
PGI2
Causes vasodialation, inhibits platelet aggregation
TXA2
Causes vasoconstriction, promotes platelet aggregation
PGD2 & PGE2
Vasodialation, increased vascular permeability
5-HETE & LTB4
Chemokines (chemotaxis)
LTC4, LTD4, LTE4
Bronchospasm, increased vascular permeability
LXA4 & LXB4
Inhibit neutrophil adhesion and chemotaxis
Type I Interferons
Produced when cells are infected with viruses, developed to interfere with viral replication. Induce the expression of MHC molecules, enhancing the ability of infected cells to present viral peptides to CD8 T Cells. Also strongly activate NK Cells. The Type I Receptor is a TKR of the JAK family
What do Type I Interferons Respond To
Produced in response to dsRNA or ssRNA, which is found as part of the infectious cycle of most viruses, and interacts with endosomal and cytoplasmic PRRs
NK Cell Structure
Large granular lymphocytes that can kill certain virally infected cells and certain tumor cells, without significant prior stimulation. Strongly enhanced by IL12 and Type I Interferons
How do NK Cells Destroy Other Cells
They poke holes into cells using the protein perforin, recognizes these cells via a variety of activating receptors (either expressed self-proteins and stress induced proteins expressed by tumor or virally infected cells). Another activating receptor of NK cells is the Fc receptor of IgG antibodies
Resistance to NK Cells
Autologous cells resistant to NK cells because they express MHC Class I molecues, which engage inhibitor receptors on NK cells. Tumor cells have reduced levels of MHC I. NK cells activated this way, release Type II Interferons, which activates macrophages
What is the importance of innate immune response for the clearance of viral infections
IFN-Alpha and -Beta and NK Cells keep infection under control, while giving time for CD8 T Cells to develop and eliminate the virus. Innate immunity alerts and shapes the adaptive immune response
Manifestations of Inflammation
Heat, redness, swelling, pain, and loss of function. Largely due to consequences of the vascular changes and leukocyte recruitment and activation, induced by inflammatory mediators
Difference Between Acute and Chronic Inflammation
Acute inflammation is fast (minutes or hours), mainly neutrophils, usually mild and self-limited, local and systemic signs are prominent
Chronic inflammation: slow (days), monocytes/macrophages and lymphocytes, often severe tissue injury and progressive, local signs and systemic signs less prominent and may be subtle
Triggers of Inflammation
Infection (bacteria, viruses), immune-mediated reactions (cytokines), hypoxia (oxygen deprivation), various physical events (trauma, pressure, radiation), and chemical agents (endogenous or exogenous, drugs, environmental factors)
Mediators of Acute Inflammation
Histamine, prostaglandins, and leukotrienes, platelet activating factor, Reactive Oxygen Species, NO, Various cytokines and chemokines, etc. Different sets of mediators may lead to the development of different “flavors” of inflammation
Histamine
Mast cells, basophils, platelets, vasodialation, increased vascular permeability
Serotonin
Platlets, increased vascular permeability
Prostaglandins
All leukocytes, mast cells, vasodialation, fever, pain
Leukotrienes
All leukocytes, increased vascular permeability, chemotaxis, leukocyte recuitment and activation
Platelet Activating Factor
All leukocytes, EC
ROS
All leukocytes, tissue damage
NOS
Macrophages, EC, tissue damage
Cytokines
Macrophages, lymphocytes, EC, mast cells, chemotaxis, leukocyte recruitment
Neuropeptides
leukocytes, nerve fibers, chemotaxis, leukocyte recruitment and activation
Plasma Protein Derived Mediators of Inflammation (Complement Activation)
C3a, C5a (anaphylatoxins), C3b, and C5b-9 (membrane attack complex), increased vascular permeability, chemotaxis, and leukocyte recruitment and activation
Plasma Protein Derived Mediators of Inflammation (Factor 12)
Kinin system (bradykinin), coagulatoin/fibrinolysis system
Outcomes of Acute Inflammation (Resolution)
Termination of the inflammatory process because inflammatory mediators are short-lived or destroyed, and by production of mediators that counteract inflammatory processes. Debris and edema cleared by phagocytes and lymphatic damage. Cytokines initated repair process
Outcomes of Acute Inflammation (Chronic Inflammation)
May occur if the offending agent is not removed
Outcomes of Acute Inflammation (Scarring)
May occur if the inflammation induces substantial tissue destruction resulting in replacement of the injured tissue with connective tissue (fibrosis)
Chronic Inflammation and Granuloma Formation
Prolonged host response to a persistent stimulus. May be caused by microbes and resist immune attack, immune response against self-antigens or environmental antigens, or some toxic substances. Cellular infiltrate often consists of macrophages, lymphocytes, and plasma cells, with substantial fibrosis
Granulomas
Chronic inflammation may cause the aggregation of activated macrophages and lymphocytes. Characteristically produced following infection with Mycobacterium tuberculosis, but may also be produced following some other infections, immune mediated inflammatory diseases such as Chrons and Sarcoidosis, and in response to foreign bodies
Adhesion Moleules
Integral membrane glycoproteins forming monomeric or heterdimeric receptors mediating cell-cell interaction and cell-extracellular matrix interaction
Anaphylatoxins
Small fragments of complement proteins (C3a, C4a, and C5a) that when injected into experimental animals cause fatal shock resembling anaphylaxis
Antibody-Dependent Cellular Cytotoxicity (ADCC)
The killing of anti-body coated cells by Fc receptor positive cells; most ADCC is mediated by NK Cells
Chemokines
Small cytokines that are involved in the migration and activation of cells
Chemotaxis
Recruitment of cells; predominantly mediated by chemokines
Convertases
C3 convertase and C5 convertase are complexes of a complement component enowed with enzymatic activity, including cleavage of C3 and C5, respectively
Cytokines
Proteins produced by cells that affect the behavior of other cells. Cytokines produced by WBCs are called interleukins; produced by lymphocytes are called lymphokines; monocytes/macrophages are called monokines; cytokines that can induce cells to resist viral replication are called interferons; small cytokines involved in the activation and migration of cells are called chemokines; cytokines that regulate production of leukocytes in bone marror are called colony stimulating factors
Damage-Associated Molecular Patterns (DAMPs)
Molecules derived from injured tissues or cells that can drive inflammatory responses by interacting with patter recognition receptors. Their function is therefore similar to pathogen-associated molecular patterns (PAMPs)
Eiconsanoids
Any class of compounds (as the prostaglandins, leukotrienes, and thromboxanes) derived from polyunstaurated fatty acids (such as arachidonic acid) and involved in cellular activity
Extracellular Matrix
The scaffolding made of multiple proteins such as collagens, fibronectin, laminin, vitronectin, thrombospondin, and many more, to organize cells into tissue or organs. ECM proteins are recognized by integrin receptors
Fc Receptors
Receptors expressed by a variety of cell types that interact with the constant portion (termed Fc porion) of antibodies. Engagement of an Fc receptor with antigen-bound antibody mediates various effect functions such as phagocytosis
ICAM1, ICAM2
Intracellular cell adhesion molecules 1 and 2. They contain 5 and 2 immunoglobulin-like domains. They interact with other adhesion receptors (integrins) and bind with common cold viruses and malarial parasites
Inflammation
A general term for the local accumulation of fluid, plasma proteins, and WBCs during infection, injury or local immune response. It is characterized by redness, swelling, pain, fever, and loss of function
Integrins
Cell membrane glycoproteins made of two non-covalently linked polypeptide chains, alpha and beta that form heterodimers usually with a common beta subunit. Together they function as receptors for ECM proteins, complement proteins, and cell adhesion molecules on the membranes of other cells (counter-receptors, such as ICAM1, ICAM2)
Janus Kinases (JAXs)
Tyrosine kinases activated by cross-linking of cytokine receptors: phosphrylate signal transducers and activators of transcription (STATs). JAK inhibitors are employed clinically for treatment of inflammatory diseases
Leukotrienes
Any group of eiconsanoids that are generated in basophils, mast cells, macrophages, and human lung tissue by lipoxugenase catalyzed oxygenation especially of arachidonic acid and that participate in allergic responses
Membrane Attack Complex (MAC)
Composed of terminal components, which form a pore through the membrane of the target cell
NK Cells
Large granular lymphocytes, distinct from B and T Cells that can lyse some virally infected or tumor cells
NLR (Receptors)
Nod-Like Receptors, present mostly in the cytoplasm and recognize bacterial or DAMPs. Some including NOD1 and NOD2 recognize components of the peptidoglycan layer of bacteria. Other NLR function as important sensors of stress and signal through a large signaling complex, referref to as the “inflammasome”, activating caspase1 and IL1 productoin
Opsonization
Alteration of a surface pathogen, so that it can be taken up by a phagocyte
Pathogen-Associated Molecular Patterns (PAMPs)
Common structures of pathogens that are absent in mammlian cells (LPS)
Pattern Recognition Receptors (PRRs)
Receptors expressed by cells of the innate immune system that recognize components common to many pathogens
Perforin
A protein expressed in the cytotoxic granules of NK cells and cytotoxic T lymphocytes. Upon target cell recognition, perforin is released from NK cells and cytotoxic T cells and polymerizes in the membrane of the target cell, forming a pore
Prostaglandin
An of various oxygenated unsaturated cyclic fatty acids of animals that are formed as cycooxygenase metabolites especially from unsaturated fatty acids (such as arachidonic acid), composed of a chain of 20 carbon atoms and that perform a variety of hormone-like actions
Pyrogens
Agents that increase body temperature
Reticuloendothelial System
The mononuclear phagocyte system located in the reticular connective tissue; it consists predominantly of monocytes and macrophages
RIG-I-like Receptors (RLRs)
A family of PRRs with an RNA-helicase like domain that binds with viral RNA. Activation of the RIG-I-like receptors induces type I interferon production
Selectins
Cell adhesion molecules expressed on lymphocytes. PMN leukocytes, monocytes, and endothelial cells. They recognize complex carbohydrates through the N-terminal “lectin-like” domain
Signal Transducers and Activators of Transcription (STATs)
Induce new gene transcription in response to activation by JAKs
T-helper type 1 (Th1) cells
TH1 cells are CD4-expressing effector T cells that are most effective in activating the cellular arm of the adaptive immune system (macrophages and CD8 T Cells), by producing the cytokines IFN-gamma and TNF
Toll-Like Receptors (TLRs)
A group of pattern-recognition receptors expressed by cells of the innate immune system that activate the transcription factor NF-kB. All mammalian TLRs are homologous to a receptor
Inflammation in Wound Healing
Clot formation and inflammation
Proliferation in Wound Healing
Re-epithelializatoin, angiogenesis and granulation tissue, provisional matrix
Maturation in Wound Healing
Collagen matrix and wound contraction
Macrophages in Wound Healing
Clear out debris and promote angiogenesis and ECM deposition
Vascular Endothelial Cells in Wound Healing
Proliferate and form granulation tissue which is comprised of new blood vessels, fibroblasts, and early collagen deposition. Amount of granulation tissue that is formed depends on the size of the injury
Fibroblasts in Wound Healing
Proliferate and form granulation tissue comprised of new blood vessels, fibroblasts, and early collagen deposition. Fibroblasts produce collagen and epithelial cells start to move away from the wound edge and secrete basement membrane material. Makes up avascular scar
Myofibroblasts in Wound Healing
Myofibroblasts play an important role in closing the wound by decreasing the gap between the dermal edges. Myofibroblasts contain smooth muscle and can therefore contract
Extracellular Matrix in Wound Healing
Connective tissue remodeling, where the scar replaces the granulation tissue. Balance between ECM degradation synthesis by Matrix Metalloproteinases
Matrix Metalloproteinases in Wound Healing
Degrade collagen and other ECM proteins, and growth factors that stimulate synthesis of collagen and ECM modulate activation of metalloproteinases
Primary Union Healing
Occurs with a clean, small incision that injures only a limited number of epithelial and connective tissue cells. Re-epithelialization to the wound occurs with a scar underneath
Secondary Union Healing
Occurs when there are large defects that result in extensive loss of tissue. Healing involves a more intense inflammatory reaction formation of abundant granulation tissue, and extensive collagen deposition resulting in a large scar
List Local Factors that can Adversely Affect Wound Healing
Infection, Mechanical Factors such as separate wound edges and compressed vessels, Foreign bodies; Size, Location, and Type of Wound
List Systemic Factors that can Adversely Affect Wound Healing
Nutrition, Metabolic Status, and Circulatory Status, Hormones
Normal Wound Healing
Formation of Blood Clot
Formation of Granulation Tissue: fibroblasts and vascular endothelial cells proliferation
Cell Proliferation and Collagen Deposition: Fibroblasts produce collagen
Scar Formation: by the end of the first month, the granulation tissue is replaced by an avascular scar comprised of fibroblasts, dense collage (type I), fragments of elastic tissue, and other ECM components
Wound contraction: decreasing dermal edges, myofibroblasts
Deficient Scar Formation
Inadequate formation of granulation tissue or scar can result in (A) wound dihiscence and (B) ulceration. Dehiscence is most common after abdominal surgery and is due to increased abdominal pressure. Wounds can ulcerate because of inadequate blood supply and loss of sensation
Excessive Formation of Scar Tissue
Accumulation of excessive collagen can cause a hypertrophic scar. If the scar goes beyond the boudnaries of the original wound and does not regress, it is a keloid. Formation of keloids is determined by individual predisposition
Contract of Scar
Although contraction is normal component of wound healing, it can be exaggerated and result in a contracture leading to deformity of surrounding tissues. Contractures are prone to develop on the palms and soles after serious burns
Fibrosis and TGF-B
Denotes excessive deposition of collagen and other ECM components. Most often in chronic diseases. Mechanisms of excessive collagen deposition is the same as for wound healing, however persistence of chronic inflammation results in prolonged activation of macrophages and production of inflammatory growth factors. TGF-B is the most common fibrogenic agent. It is produced by most cells in granulation tissue and casues fibroblast migration and proliferation, increased collagen synthesis, and decreased degradation of ECM
Structure of Eicosanoids
20-chain fatty acids (containing double bonds)
Eicosanoid Induction and Derivation
Induced following cellular damage or stimulation such as during trauma, infection, inflammation, ischemia, etc. Derived by oxidation of omega-3 and omega-6 polyunsaturated fatty acids
Function of Eicosanoids
Function as signaling molecules (hormones) that regulate the functions of other cells. Short half-life local acting. Enzymes responsible for the synthesis of individual eicosanoids are often expressed at highly divergent levels in distinct cell types, resulting in large variations in eicosanoid production by different cell types. Activates several GPCRs, different functions
Classification of Eicosanoids
Classical and nonclassical eicosanoids. Classical include prostanoids (P) and the leukotrienes (LT). Can further be divided into prostaglandins (PG) and thromboxanes (TX). Nonclassival includes lipoxins, isoprostanes, resolyins, epoxyeicosatrienoic acids, and others
Nomenclature of Eicosanoids
Characters 1 and 2 are the subtype of eicosanoid (PG, TX, or LT); character 3 is the subtype based on order of discovery; and character 4 is a subscript indicating the number of double bonds (2 for prostanoids and 4 for leukotrienes derived from arachidonic acid)
Overview of Eicosanoid Pathway
PLA2 becomes activated in response to trauma or cellular stimulation. It is trafficked from the plasma membrane to the nuclear membrane where it converts membrane phopholipids into arachidonic acid (AA), which ends up in the cytoplasm. AA is converted via oxidation to a variety of classical and non-classical eicosanoids. COX enzymes covert AA to prostanoids (PG and TX), where as 5-LO converts arachidonic acid into LTs. These are then released by the cells
COX conversion of AA
Converts AA into PGG2 and subsequently PGH2, which is a substrate for many enzymes leading to the production of other prostaglandins (PGD2, PGE2, PGF2a, PGI2, and TXA2
COX1
Constitutively expressed at relatively low levels in many tissues and is thus involved in homeostatic prostanoid synthesis, which controls platelet clotting actions and protects the GI mucosa against damage
COX2
Inducible by inflammation (LPS, TNF, IL1) and promotes pain and inflammatoin. Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen block prostanoid synthesis by inhibiting the activity of one or both COX enzymes
PGD2
Main prostaglandin produced by mast cells and is also in the brain. Important for recruiting a variety of cell types such as eoisinophils, basophils, and T cells. Plays a role in allergic response and asthma, promotes contraction of bronchial airways, male pattern baldness
PGE2
Causes induction of fever, vasodialator relaxing smooth muscle in blood vessels, but promotes smooth muscle constriction in the GI tract, protects the gastric and intestinal mucosa against damage. Inhibits 5-LO, which causes aspirin-exacerbated respiratory disease in patients with asthma
PGF2A
Role in reproduction, renal physiology, and modulation of intraocular pressure
PGI2
Also known as prostacyclin, major prostaglandin produced by vascular endothelium, inhibits platelet activatoin during clot formation. Also provides protection against mucosal damage in the GI tract
Thromboxanes
Clot formation
TXA2
Main product of arachidonic acid produced in platelets and potently aggregates platelets during clot formation. Constructs smooth muscle in blood vessels and the bronchial airways
Synthesis of Leukotrienes
5-LO converts AA into LTA4, resulting in the synthesis of LTB4, LTC4, LTD4, and LTE4. LTC5 LTD4, and LTE4 are referred to as cysteinyl leukotrienes, as they bind to the cysteinyl leukotriene receptors cysLTI and cysLT2
Cysteinyl Leukotrienes
LTC4, LTD4, and LTE4 bind to cysLT1, and cysLT2
Inhibition of Leukotrienes
Montelukast, used to treat asthma and seasonal allergies blocks the cyLT1 receptor, thus inhibiting the action of cysteinyl leukotrienes (LTC4, LTD4, and LTE4) on cells that express this receptor
Leukotrienes
Named for their production by leukocytes and containing three conserved double bonds
LTB4
Predominantly expressed by activated leukocytes and is critical for recruitment of neutrophils and other leukocytes
LTC4, LTD4, and LTE4
The cysteinyl leukotrienes, produced by mast cells and a variety of other cell types. They play a critical role in asthma and other allergic diseases such as anaphylaxis by promoting bronchoconstriction, mucus production, and eosinophil recruitment
Glucocorticoids
Corticosteroids produced naturall or synthetically. Hormones with multiple functions. Naturally produced by the body to suppress inflammatory responses, suppression of eiconsanoid synthesis by inhibition of PLA2
NSAIDs
Analgesic, antipyretic, and anti-inflammatory effects. Inhibits the activity of both COX1 and COX2 and are thus non-selective. Blocking of COX1 may cause GI bleeding and ulceration (due to inhibition of PGE2 and PGI2 synthesis). Aspirin irreversibly inhibits COX1 which may inhibit platelet aggregation. Selective COX2 inhibitors have been associated with adverse cardiovascular effects
Acetaminophen
Selective COX2 inhibitor, predominantly in the CNS. Inhibits the reuptake of endogenous cannobinoids, leading to increased cannabinoids in neural synapses, thus reducing pain. Assocated with substantial toxicity, metabolized by the liver and is hepatotoxic
Leukotriene Receptor Antagonists
Montelukast used for treatment of asthma and to relieve symptoms of seasonal allergies. Also an antagonist of the cysLT1 receptor
5-LO Inhibitors
Inhibits 5-LO inhibiting leukotriene formation and are used to treat asthma
Prostacyclin and Synthetic Analogs
Acts of PGI2, used as vasodialators and in pulmonary hypertension
Dinoprost Analog
Acts of PGF2A used to start labor and induce abortions
Dinoprostone
Acts of PGE2 used to start labor and induce abortions
Follicle
A spherical mass pf lymphocytes, measuring 2-3mm in diameter. An active nodule consists of two zones and is actively producing lymphocytes. The outer zone or corona stains dark and contains immature B lymphocytes. The inner zone or germinal center appears pale and contains many cell types including small lymphocytes, medium mature B lympphocytes (blastic transformation), plasma cells, macrophages, and reticular cells
Structure of the Lymph Node
Round, Ovoid, or bean-shaped. Nodes are widely distributed and may occur as singly or as anatomically recognizable and clinically important groups among blood vessels or areas of flexion (popliteral, axilla, inguinal) May enlarge during infection or disease
Function of Lymph Nodes (4)
Produce lymphocytes and antibodies
Filter the lymph: removing dead bacteria and other foreign bodies
Serve as a Defense Mechanism to Prevent the Spread of Malignant Cells
Represent Potential Hematopoietic Organs
Connective Tissue Fiber in Lymph Node For Support of Cellular and Sinusoidal Components
The capsule is a dense irregular connective tissue forming the capsule consists mostly of collagenous fibers with an intermingling of elastic fibers, fibroblasts and an occasional smooth muscle fiber. Trabeculae are projections of connective tissue which extend from the capsule into the substance of the lymph node. They are straight in the cortex and branched in the medulla. They separate the cortex of the node into incomplete compartments
Circulation Through the Lymph Node
Affterent Lymph Vessels -> Subcapsular Sinus -> Peritrabecular Sinus -> Medullary Sinus -> Efferent Lymph Vessels. The efferent lymph vessels have open ends and collect the lymph from the medullary sinuses. All sinuses have macrophages, which remove particulate matter and degenerating cells from the lymph. Medulllary sinuses are extremely broad and this slows the lymph, allowing for greater phagocytic action by the macrophages. Lymphocytes are added to the lymph as it passes through the lymph node
Location of the Thymus Gland
In close association with the great vessels at the base of the heart: Mediastinum
Structure of the Thymus Gland
Bilobed mass, greatest relative weight at birth and greatest absolute weight at puberty. Begins to involute after puberty. Lacks afferent lymph vessels and lymph sinuses, has a framework of cytoreticular cells rather than a stroma or reticular connective tissue
Function of the Thymus Gland
Maturation of T Lymphocytes
Distinguishing Feature of the Thymus Gland (Cell Type)
Hassall’s Corpsuscles (Thymic Corpuscles). Aggregates of degenerating cytoreticular cells, which are located in the medulla and are unique to the thymus. Acidophillic and their centers may appear hyalinized (glassy)
Structure of Spleen
Large lymphatic organ, located on the left side of the body behind ribs 9-11. Connected to blood vessel and represents the only blood-filtering organ in humans. Has a soft tecture, is filled with blood, and if ruptured it must be removed to stop the bleeding. Surrounded by a capsule and contains a hilus where nerves and branches of the splenic artery and vein enter and leave the spleen
Function of the Spleen
RBCs monitored and destroyed via lymphocytes and other cells because of open circulation, groomed and recycled
Circulation Through Spleen
The spleen has white and red pulp, and it is the one organ that has “open circulation”. The blood and lymphocytes are open to each other. It has a capsule which brings in the blood supply. Also contains PALs, which are T-lymphocytes surrounding arterioles. Has only blood vessels (no lymph vessels). Sinuses of red pump contain high number of macrophages and discontinuous epithelia allows cells to enter and exit
Difference Between Palatine and Pharyngeal Tonsils
Distinguish between tonsils by their non-encapsulated epithelial layer. The pharyngel tonsils will demonstrae pseudostratified columnar epithelia with cilia and goblet cells. The Palatine tonsils are made of stratified squamous epithelia (non-keratinized) for protective measures. The tonsil’s location determines the type of epithelial layer and function
Peyer’s Patches and Identification
Peyer’s Patches are aggregates of lymphoid tissue in the ielum of the small intestine. The duodenum and jejunem do not have Peyer’s Patches. Many of these lymphoid aggregates are secondary follicles
What Cell Type is Affiliated With Peyer’s Patches and Aids in Presenting Foreign Materials to Lymphocytes
M-Cells (Microfold Cells) which are wedged in between the epithelial layer (simple columnar with microvilli brush border) of the GI tract. It sample material from the GI lumen and exocytoses it to the lymphocytes underneath (transcytosis)
Plasma Cell Identification
Plasma cells have the “clock-shaped” nucleus and will be found in the germinal center of a secondary follicle as B-lymphocytes will often degenerate into plasma cells
Hydrocortisone/Cortisol
Important modulator of metabolic activity including carbohydrate and lipid metabolism. Enodgenous production is 10-15mg per day but can increase 10-fold with stress. Glucocorticoids have anti-inflammatory and immunosuppressive effects even at physiological concentrations (i.e these effects are not merely seen at higher “pharmacological” doses)
Prednisone
4x more potent than hydrocortisone. Most common oral steroid in the US, double bond decreases metabolism and increases half-life
Methylprednisone
5x more potent than hydrocortisone, 1/5 equivalent dose, IV/IM
Dexamethasone
25x more potent, 1/25 equivalent dose of cortisol, IV/IM
11-Keto Glucocorticoids Activation
Must be hydroxylyzed to 11-OH to become activated
How do Glucocorticoids Express Most of Their Metabolic/Anti-Inflammatory Activity
Metabolic effects are initiated by glucocorticoid receptors transporting to the membrane to which glucocorticoids response elements bind. This creates downstream signaling and activation of different transcription factors. These same receptors also decrease AP1 and NF-kB (pro-inflammatory) by interfering with transcription factors. In addition, glucocorticoids decrease the stability of mRNA of COX-2 and NO synthesis (other components of inflammation)
Anti-inflammatory glucocorticoids are not without ____ and thus not without _____
metabolic activity, side effects
Metabolic Side Effects of Glucocorticoids
Glucose intolerance, muscle weakness, fat redistribution, fluid retention, hypertension, poor wound healing
Azathioprine/6-mercaptopurine
AZA is the pro-drug of 6-MP, both prevent clonal expansion of B and T Cells by inhibiting de novo purine synthesis
Competing pathway for 6-MP and effects of genetics and drug interaction of efficiacy and toxicity
An example of pharmacokinetics. Three pathways for how drug is dealth with: if patients are homozygous recessive for TMPT enzyme, AZA can wipe out bone marrow. If patient is also taking allopurinol for gout, and to stop the production of uric acid, pathway will also be shifted towards metabolites
Key toxicities of AZA/6-MP
Myelosuppression, pancreatitis, hepatitis, naesea, myalgia, rashes malignancy
Methotrexate
Was originally used to treat cancer in high doses. Inhibitor of folate related enzymes. Inhibits cell proliferation, cell-mediated immune reactions, and some cytokine production. Was used to treat RA and psoriasis
Major Toxicities of Methotrexate and Renal Dysfunction
Naesea, Anorexia, Stomatits, Diarrhea, Hepatic Steatosis, Fibrosis, Pulmonary Fibrosis, Myelosuppression. Eliminated by the kidney and renal dysfunction increases risk of toxicity
Two Calcineurin Inhibitors (Cyclosporin and Tacrolimus) and Their Mechanism of Action
Cyclosporin is a member of a clas of potent immunosuppressive agents responsible for success of solid organ transplantation. Tacrolimus was the second drug to be approved by the FDA. Structurall dissimilar, but both have a selective inhibitory effect on T Lymphocytes, suppressing the early cellular response to antigenic and regulatory stimulus. Both drugs decrease calcineurin function
Transformative Role of Calcineurin Inhibitors
Calcineurin-Serine/Threonine Phosphatase: T-cell receptor activation increases intracellular calcium activing calcineurin. Calcineurin, dephosphorylates NFAT (nuclear factor of activated T Cells), which leads to increased transcription of certain genes (IL2, GmCSF, TNF-Alpha, Interferons, other ILs)
Calcineurin Inhibitors and Drug Interaction
Cyclosporin binds to cyclophilin which then binds to calcineurin. Tacrolimus binds to FK binding protein which then binds to calcineurin and hibits downstream activation
mTOR inhibitors and Role of Transplantation and Anti-Neoplastic Therapy
Rapamycin derived from Streptomyces hydrocopicus. Everlimus. Mechanism of activation is related to biding of FK binding protein, but this does not alter calcinurin activity. Instead binding to mTOR to inhibit the second phase of T Cell activatoin that normally involves signal transduction and clonal proliferation of T-Cells. This is similar to AZA and 6-MP.
mTOR inhibitors and wound healing
mTOR inhibitors are not started until 2 to 4 weeks post-operatively because wound healing is inhibitied by these drugs
Resurgent Role of Antibody Therapy in Modern Medicine
Anti-lymphocyte antibodies are commerically produced antibodies directed against lymphocytes that enables rapid lowering of the number of lymphoid cells as well as suppressing the function of specific lymphocyte populations. Used to treat steroid resistant rejection in solid organ transplantation or replace cyclosporine or tacrolimus in initial phase of transplantation. Anti-IL2 Receptor antibodies, Anti-IL-6 Receptor antibodies, anti-TNF-alpha antibodies
Definition of Sepsis
A life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock is defined as a subset of sepsis in which particularly profound circulatory, cellular, an metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Can only be called sepsis when infection is confirmed
Etiology of Sepsis
Bacterial infections most common, but can also be caused by viruses, fungi, and parasites. Gram-Negative sepsis has diminished, where Gram Positive has increased, likely due to increased incidence in pneumonia and the use of intravascular devices. Primary infections of the chest, abdomen, genitourinary system, and the bloodstream account for more than 80% of all cases of sepsis
Epidemiology of Sepsis
750,000 cases per year, with an overall mortality of 215,000. Increased risk: young or old age, underlying disease (neutropenia, solid tumors, leukemia, cirrhosis of the liver, diabetes, AIDS, COPD); surgeyr or instrumentation (infection), prior drug therapy (immunosuppresive), other (childbirth, abortion, trauma, burns)
Pathogenesis of Sepsis
Initiated by a variety of PAMPs that induce a cytokine storm and numerous other inflammatory mediators resulting in acute vascular injury and activation of multiple plasma protein cascades (kinin-kalikrein, complement, coagulation, fibrinolysis). During the late stages of sepsis, anti-inflammatory cytokines and antagonists of pro-inflammatory cytokines gain the upper hand, resulting in immune suppression and susceptibility to secondary infection
PAMPs LPS in Sepsis
LPS part of gram-negative cell wall, protecting bacteria against environment. Lipid A, a part of the LPS is the toxic principle of LPS, and it can replicate the toxic effects of LPS both in vitro and in vivo. LPS is a potenti activator of macrophages (as well as dendritic cells and B cells), binds with the LPS receptor CD14 and signals through TLR4 to activate a variety of TFs (NF-kB), resulting in the induction of a variety of inflammatory mediators
Other PAMPs in Sepsis
Macrphages expressing signaling receptors for a variety of PAMPs, include TLRs, NLRs, and RIG-I-like receptors. Because the signaling pathways employed by these receptors are divergent, this leads to the induction of divergent inflammatory responses
PAMPs Superantigents in Sepsis
Some Gram Positive organisms including pathogenic stretococci and staphylococci, produce superantigens that activate large populatoins of T cells in an antigen-independent manner, by binding with both MHC Class II and certain beta chains of the T cell receptor. Leads to cytokine storm resulting in sepsis, often referred to as toxic shock syndrome
DAMPs in Sepsis
Some pattern recognition receptors can also be activated by endogenous molecular patterns, termed DAMPs, that might be released during tissue damage, causing severe systemic inflammatory response syndrome similar to sepsis
Systemic Inflammatory Responses in Sepsis
Induction of a variety of signaling pathways and TFs, resulting in the induction of a variety of cytokines, adhesion molecules, and other inflammatory mediators. Best understood thorugh LPS. Injection of LPS into mice induces cytokine storm, most notably the production of TNF-alpha, IL1, and IL6. Cytokine storm induces a variety of effects on vascular endothelium (systemic increase in vascular diameter, leading to vasodialation and drop in BP; increased vascular permeability leading to vasclar leak and loss of plasma volume; increase in expressoin of adhesion moelcules, which bind to the surface of phagocytes and can now enter tissues. Other inflammatory mediators are released including cytokines, prostaglandins, leukotrienes, toxic oxygen products, adhesion molecules and proteases
Inflammation-Induced Activation of Plasma Protein Cascades (Complement Cascade)
Microbes can activate the complement cascade, resulting in production of C5a, which has chemoactive activities and more importantly, causes mast cell activation and production of histamine, which induces further vasodialation
Inflammation-Induced Activation of Plasma Protein Cascades (Kinin-Kallikrein Cascade)
Endothelial injury will activate kallkrein to generate kinins such as bradykinin, which lowers blood pressure
Inflammation-Induced Activation of Plasma Protein Cascades (Coagulation Cascade)
Endothelial damage results in binding of platelets to collagen and initation of the coagulation cascade through activation of Hageman factor, which leads to activation of thrombin and formation of fibrin strands. Results in clot formation in small blood vessels referred to as disseminated intravascular coagulation (DIC), preventing blood flow and delivery of oxygen to vital organs, thus leading to failure of multiple organs
Inflammation-Induced Activation of Plasma Protein Cascades (Fibrinolysis Cascade)
Endothelial damage activates the function of tissue plasminogen activator, thus promoting plasmin formation, fibrin degradation and clot resolution. During sepsis, this pathway is inhibited and therefore insufficient to suppress dissemintated intravascular coagulation
Late Stages of Sepsis
During inflammatory response, countermeasures are undertaken to restore homeostasis. Pro-inflammatory cytokines followed by anti-inflammatory cytokines and antagonists of pro-inflammatory cytokines, which may take upper hand in later stages of sepsis resulting in overall state of immune suppression and paralysis. Termed compensatory anti-inflammatory response syndrome
Clinical manifestations of Sepsis
Most symptoms due to capillary leak, hypotension, and disseminated intravascular coagulation
Nonspecific Symptoms of Sepsis
Fever, chills, fatigue, malise, anxiety or confusion, increased heart rate, increased repiration
Organ Dysfunction Associated with Sepsis and Septic Shock
Lungs: acute respiratory distress syndrom, tacypnea, hyperpnea
Kidneys: oliguria, anuria, proteinuria
Liver: elevated serum bilirubin, jaundice
Digestive Tract: nausea, vomiting, diahhrea
Heart: cardiac output normal then elevated
Skin: starts warm or flushed but then becomes cold and turns blue
Brain: confusion, delirium, coma
Systemic Effects: lactic acidosis, generalized edema
Virus Reactivation and Secondary Infection in Sepsis
During the later stages of sepsis, when immune suppression ensues, patients might become susceptible to virus reactivation and secondary infection
Death in Sepsis
Mortality due to sepsis is about 30% and increases with disease severity
Treatment of Sepsis
Immediate stabilization of the patients: protection of airway, BP and tissue perfusion, cardiac output, kidney function - dialysis
Clearing out of microoganisms from blood: appropriate antimicrobials
Removal of the original focus of infection: drain eudate, remove foreign body, removed infected organ
Many other treatments aimed at halting inflammatory responses and vascular damage have been not as promising
Acute Respiratory Distress Syndrome
A life threatening lung condition that prevents enough oxygen from getting into the blood; might be caused by any major swelling (inflammation induce) or injury to the lung
Bacteremia
The presence of viable bacteria in the blood
Compensatory Anti-Inflammatory Response Syndrome
An immunological phenomenon occurring in sepsis that is meant to curb inflammation caused by SIRS to resotre homeostasis
Disseminated Intravascular Coagulation (DIC)
A syndrome due to generation of thrombin in the circulation resulting in activation of clotting factors and platelets; their consumption is accompanied by formation of platelet-fibrin thrombi in the microcirculation followed by activation of fibrinolysis and development of a diffuse bleeding tendency in the skin and mucous membranes
Endotoxemia
Presence of endotoxins (LPS) in the blood
Infection
Microbial phenomenon characterized by inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms
Lipid A
A glycolipid that confers toxicity to LPS
Multple Organ Dysfunction Syndrome
Presence of altered organ function in an acutely ill patient such that homeostaisis cannot be maintained without intervention
NF-kB
a nuclear factor-kB is a transcription factor that is activated in response to inflammatory and immune stress; it is sequestered in the cytoplasm by its inhibit IkB; upon removal of IkB, NF-kB is important to the nucleus and activates multiple genes encoding mediators of inflammatory and immune responses
Petichia
A small red or purple spot caused by bleeding in the skin
Shock
A life threatening medical condition that occurs due to inadequate substrate for aerobic cellular respiration. Typical signs of shock are low BP, rapid HR, and signs of poor end-organ perfusion. Different types of shock include hypovolemic, cardiogenic, and distributive shock. Septic shock is a form of distributive shock
Systemic Inflammatory Response Syndrome
The systemic inflammatory response to a variety of severe clinical insults; the response is manifested by two or more of the following conditions: (1) temperature >38 degrees or 90; RR >20 or PaCO2 12,000 or 10% of immature band forms
Sepsis
The systemic response to infection. In the classical classification system it is manifested by two or more of the following condiions as a result of infection: (1) temperature >38 or 90; (3) RR >20 or PaCO2 12,000 or 10% of immature band forms. Life threatening organ dysfunction caused by a dysregulated host response to infection, where the organ dysfunction involves an increase in total SOFA score of 2 or more points
Severe Sepsis
Sepsis assocatied with organ dysfunction, hypoperfusion, or hypotension; hypoperfusion and perfusion abnormalities may include but are not limited to lactic acidosis, oliguria, or an acute alteration in mental status. In new classification scheme the term “severe sepsis” has been abandoned
Septic Shock
Was defined as sepsis-induced with hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include but are not limited to lactic acidosis, oliguria, or an acute alteration in metnal status; patients who are receiving inotropic or vaspressor agents may not be hypotensive at the same time that perfusion abnormalities are measured. Now its defined as a subset of sepsis in which particuarly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone; patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2mmolL in the absence of hypovolemia
Sequential Organ Failure Assessment Score
Score is used to track a person’s status during the stay in an ICU. Extent of a person’s organ function or rate of failure. Six different scores, respiratory, cardiovascular, heptaic, coagulation, renal, and neurological systems. Good predictors of outcome
LAD Disease
C2, Extravasation, Bacteria
CHS
CHS gene, vesicle trafficking, bacteria bleeding partial albinism
CGD
NADPH Ox, oxidative burst (ROS), bacteria + granulomas
NK Cell Defects/Deficiency
?, No NK Cells, Viruses (herpes)
C1 Deficiency
Specific Gene Mutation, Classical C, Immune Complex
MBL Deficiency
Specific Gene Mutation, lectin C, Bacteria (childhood)
C2 or C4
Specific Gene Mutation, Classical + Lectin C, Bacteria + Immune Response
D or P Deficiency
Specific Gene Mutation, Alternative C, Bacteria
C3 Deficiency
Specific Gene Mutation, All C, Bacterial + Immune Response, recurrent pyogenic sinus and respiratory tract infections, susceptibility to hypersensitivity
C5-C9 Deficiency
Specific Gene Mutation, MAC, Neisseria
PNH/DAF
GPI Synthesis, DAF CD59 HRF on RBCs, RBC destruction
Hereditary Angioedema
C1 INH, No inhibition of C1 Factor 12 Kalikrein, Swellin
