Human Disease 1

• Impairment of health, abnormal function/condition, discomfort or dysfunction, no longer healthy
• loss or limitation of function

what patient complains of; rash, pain, swelling, upset stomach; descriptive/qualitative

• quantitative changes; raised body temp, inc wbc count; measured
• defined in context of clinical tests (sometimes can see signs before symptoms- proactive)

developmental disturbance; genetic or environmental

reaction by body to an agent by means of inflammatory process

abnormal degeneration

distrubance in one or more metabolic pathways

abnormal cell growth leading to benign or malignant tumors

adaptation-->reversible injury-->irreversible injury-->cell death

• enlargemnt of cell size
• physiological and pathological conditions (chronic heart disease)

• increase in cell #
• lymphnodes, spleen

wasting of cell; decreased size

change in cell architecture and often fucntion

• digestion and exocytosis of self
• cellular self digestion

• 1. response depends on type of injury, duration, and severity
• 2. depends on type, status, adaptability and genetic makeup of injured cell
• 3. localized effect on a cell can have rapid secondary effects with result in cell injury or death
• 4. function is lost before cell death with occurs before morphological changes are observed

• Necrosis: ATP, membrane damage (mitochondria, plasma membrane, lysosome), cytoskeletal damage
• Apoptosis: mitochondria, DNA damage

• Blockage of blood flow
• Decreased oxidative phosphorylation and ATP; decrease in Na pump activity...leads to cellular swelling, blebs, ER swelling, decr glycogen; clumping of nuclear chromatin; lipid deposition

• Reversible: swelling of ER and mito, membrane blebs, clumping of chromatin
• Irreversible (necrosis): swelling of ER and loss of ribosomes, lysosome rupture, myelin figures, nuclear condensation, swollen mito with amorphous densities -- LOSS OF MEMBRANE INTEGRITY, BREAKDOWN OF GENETIC MATERIAL, LOSS OF MT FXN

• sequence of morphological changes that follow cell death in living tissues; cell swelling, denaturation of cytoplasmic proteins and breakdown of cell organelles and membranes; Loss of membrane integrity
• Release of cytoplasmic components
• Inflammation!

• programmed cell death characterized by DNA fragmentation and apoptotic bodies
• Occurs during: embriogenesis, hormone-dep physio involution, cell deletion in proliferating populations, deletion of autoreactive T cells, mild injurious stimulus that causes DNA damage
• No inflammation! Phagocytosis of apoptotic bodies

• Environmental insults-->free radicals-->damage to proteins and organelles
• Calorie restriction-->activation of DNA-stabilizing proteins--|DNA damage

• reaction by organism involving cells of immune system in response to a foreign substance
• recognition and removal of foreign substance

• Innate (natural immunity): present before exposer, does not change its response upn repeated exposure; conserved across all species; fast; macrophages, granulocytes (mast, neutrophils, basophils, eosinophils); complement; skin/mucus membranes
• Acquired (specific) immunity: stimulated by exposure; response is enhanced with each exposure; found in bony fish through mammals; slow; memory; antibodies; t and b cells

mediated by moleculres known as antibodies, released by B cells, bind foreign substances and lead to elimination

mediated by cells known as T cells which fxn to activate other immune cells and/or kill infected cells

Immune responses are specific for distinct antigens

# of lymphocytes which recognized distinct regions (or epitopes) is very large

exposure of immune system to a foreign antigen enhances its ability to respond again to taht antigen

immune response is down regulated after a period of tiem

no immune response to your own proteins or other molecules

• Antigen is molecule recognized by immune system
• epitope is section of antigen that is physically interacting with antibody or t cell receptor

• acquired immune system remembers exposure to particular antigen before- mounts stronger faster response after first exposure
• clonal expansion

• 1. Cognitive: recognition of antigen
• 2. Activation: proliferation and differentiation of lymphocytes which recognize antigens
• 3. Effector: fxnal consequenceof an active lymphocyte

• antibodies promote phagocytosis
• complement activation
• cytokines
• innate immune response results in production of protein and lipid mediators which fxn to enhance acquired immunity and vice versa

one lymphocyte = one antigen recognition (epitope)

• why we need immune cells circulating- infection or foreign body can be anywhere, so b and t cells and lymphocytes need to be everywhere to fight and control infection
• macrophage comes into contact with b and t cells in lymph node- b and t cells becomes activated and leave lymph node- find infection while circulating
• lymph node is focal point for b and t cell activation

• Helper- cytokines; MHC class II
• cytolytic- kill cell; MHC class I

• White blood cells!!
• Monocytes
• Granulocytes
• T-Helper cells
• cytolytic T cells

• 1. inflammation and wound healing
• 2. produces cytokines and chemokines which activate and recruit lymphocytes respectively, to the site of injury
• 3. antigen presenting cells
• 4. binds to and ingest particles coated with antibodies and/or complement to clear the material from circulation or from tissue

• 1. neutrophils: phagocytic, first at site of infection, short lived, activated by cytokines and by proteins of the extracellular matrix
• 2. eosinophils: receptors to a class of antibodies known as IgE. secrete granules. involved in sites of allergic reactions and contribute to tissue injury and inflammation
• 3. basophils: also have receptors for IgE and produce chemical mediators of immediate hypersensitivity

• Most polymorphic of any proteins in human population!
• Reason: different sets of MHC class I and II bind different sets of peptides; broad
• If we all expressed the same MHC class I and II molecules, then diseases would evolve so that it could avoid being bound by these molecules
• We express multiple alleles of MHC molecules. A, B, and C code for class I and differ at antigen binding site.

• 1. produced during effector phase of both innate and acquired immune response and regulate immune and inflammatory responses
• 2. secretion is brief and regulated
• 3. produced by multiple cell types
• 4. act on different cell types
• 5. stimulation may have multiple effects on target cells
• 6. different cytokines can have similar effects
• 7. can influence synthesis of other cytokines
• 8. can influence synthesis of other cytokines
• 9. initiate their action of other cytokines
• 10. receptor expression is also regulated
• 11. production usually requires new mRNA and protein synthesis
• 12. act as growth factor

• random somatic recombination
• V-D-J rearrangement during development

• TNFalpha and IL-1: Inflammation
• Increase leukocyte adhesion by upregulation of selectins and ICAM-1
• INFgamma- produced by t cells and is an important cytokine for activating macrophages

• Chemo-attractant
• IL-8: produced by macrophages, important mediator of the immune reaction in the innate immune system response.

transplant btwn 2 genetically different individuals of same species

• immune response to allograft
• MHC class I and II are major antigens that stimulate this

Alloreactive CD4+ or CD8+ T cells or specific alloantibodies are capable of mediating allograft rejection

• 1. Suppresion of recipients immune system: inactivation of T cells using immunosuppressive drugs; total lymphoid irradation; use antibodies to block T cell activation; graft recipient may be made tolerant to allograft
• 2. graft may be made less immunogenic

• initiated mature T cells in donor's bone marrow which recognizes host alloantigens
• tissue destruction is thought to be mediated primarily be NK cells

• protective response induced by the body due to some insult with the idea of removing whatever caused the insult and heal the resulting damage associated with it
• both immune mediated and nonimmune mediated
• Trauma: not antigen driven

• quick to respond- with in minutes
• neutrophils
• edema- build up of fluid and proteins in tissue; breakdown of epithelium

• longer duration
• macrophages and lymphocytes
• increased damage to tissue and fibrosis

heat, redness, swelling, pain, and loss of fxn

• main mechanism of vascular permeability associated with acute inflammation
• break down of cell-cell jxns

• 1. cell brought in can eliminate problem
• 2. inflammatory process can cause damage, so want it kept in small area

• selectins bind carbohydrates- low affinity binding allows for rolling
• upregulated by granules and exposure to inflammatory mediators

• found on leukocyte in inactive form.
• when exposed to TNF, will change conformation and bind to ICAM-1 and PECAM
• diffusion mediated process- adhesion happens in close proximity to where damage is

• Chemotactic gradient- move toward higher concentration. fMLP, C5a, LTB4, IL-8
• proteases degrade matrix so leukocytes can make their own road- causes some tissue damage

• 1. very important anti-microbial. produced with phagosomes (macrophages and neutrophils)
• 2. cause tissue damage- produced locally to constrain this

• histamine: inc vascular permeability-edema (mast cells)
• lysosomal enzymes: (macrophages and neutrophils)

• Cell membrane phospholipids-->arachidonic acid
• 1. 5-lipoxygenase-->5-HPETE-->Leukotriene (vasocontriction, increased permeability)
• 2. Cyclooxygenase-->Prostaglandin (potentiate edema)

increase vascular permeability

• wound healing and drive fibrosis
• increase leukocyte adherence

• 1. lectin: mannose binding lectin
• 2. classic: most active and efficient pathway; antibody mediated (effector molecule made in liver)
• 3. alternative: inefficient

• C3a chemotaxis, stimulates mast cell degranulation
• C3b coats microbe to enhance ability to be phagocytosed
• C5a stimulates vasodilation by causing histamine relase; promotes leukocyte adhesion by upregulating expression of selectins and activating integrins

lysis of microbes

• 1. mononuclear phagocytes, t lymphocyes, plasma cells, and mast cells
• 2. tissue destruction
• 3. new vessel formation and fibrosis
• - persistent infection, continual exposure to toxic material, autoimmune diseases, interference with normal repair process

• Giant cell, epitheliod cell, macrophage, lymphocyte, fibroblast.
• wall off substances that it perceives as foreign but is unable to eliminate
• special type of inflammation

• removal of edema fluid and proteins by drainage into lymphatics or by macrophage pinocytosis
• phagocytosis and apoptotic neutrophils and necrotic debris by macrophages
• removal of macrophages

• Regeneration of cells lost during the inflammatory process
• replacement of cells with connective tissues- results in scarring

• 1. Epidermal GF
• 2. Platelet derived GF
• 3. Fibroblast GF
• 4. Transformting FGbeta

• Basement membrane: fibrous structural proteins- collagens, laminin and proteoglycans
• Interstitial matrix: fibronectin, laminin, elastin, vitronectin and collagen; proteoglycan and hyaluronan

• 1. support for cells
• 2. control of cell growth
• 3. cell orientation
• 4. cell differentiation
• 5. scaffolding for tissue renewal
• 6. cell migration
• 7. storage and presentation of regulatory molecules

wound healing. fibrosis occurs when wound is too deep