Patho
What do the endothelial gaps let in?
Plasma, plasma proteins, inflammatory mediators, and complement proteins
Type I: IgE
Type II: IgM or IgG
Type III: IgG and antigen-antibody complexes
Type IV: T-Helper cells
The main purpose of RBCs is delivering oxygen to the tissues of the body.
Define -oma, -carcinoma, -sarcoma
-oma is tumor
-carcinoma is cancer of epithelial tissue (endo- or ectodermal tissue0
-sarcoma is cancer of connective tissue (mesodermal tissue)
Tidal volume: The volume of air that enters and exits the lungs during normal breathing (silent breathing)
Vital capacity: The volume of air that enters and exits the lungs after an individual’s deepest inhalation.
The lung is elastic and it is very important that it remains that way, but pathologies can result which compromise that elasticity. Intrinsic restrictive lung disease occurs due to changes (ie: scarring, chronic inflammation, microinjuries, etc) in the lung tissue between the alveoli and blood vessels which results in the lungs becoming fibrotic and stiff which makes it hard for them to expand and allow air to enter.
What do the macrophages secrete?
Cytokines, histamines, leukotrienes, prostaglandins, and other inflammatory mediators.
Self-antigens come from healthy tissue that shed component proteins and from cells that have undergone apoptosis. In the bone marrow, stromal cells and hematopoietic cells result in the production of self-antigens that are used to screen B-cells for auto-reactivity.
Erythropoietin is a hormone that is secreted by the kidneys when it senses low oxygen levels. This hormone stimulates red blood cell (RBC) production within bone marrow.
What is benign tumor?
Benign Tumor: Well-differentiated so they can continue their function, grow faster than normal cells but not as much as malignant tumors, remains localized (does not infiltrate/invade/metastasize), surrounded by fibrous capsule (which is easier to remove during resection than malignant tumors)
Air enters the upper respiratory tract through the nasal cavity. From there, it travels through the pharynx and larynx to the lower respiratory tract. Here air travels from the trachea to the primary bronchi within the lungs. The bronchi, then, narrow into bronchioles and terminates as alveoli where air will undergo gas exchange. After undergoing gas exchange, the air that was exchanged will travel through the bloodstream to the tissues that require it.
Individuals will intrinsic restrictive lung disease have reduced vital capacity, residual volume, functional residual volume, tidal volume, and total lung capacity.
What are the non-specific defenses?
There are three types: physical barriers (skin, mucous membranes, mucociliary blanket, and surface flushing), anti-bacterial agents (acidity, secretions like lysozymes in tears, and change in pH), and commensal microorganisms
APCs are the bridge between the innate an adaptive immune system. Once phagocytosis has occurred and the pathogen has been destroyed, the APC will take a portion of the foreign material (antigen) and present on its surface through MHC-II for a naïve T-cells to recognize.
Type III hypersensitivity. In this reaction, a HUGE complement response occurs which attracts cells that hope to phagocytosize the complex. Most of the time, they are unable to do and “puke” out their contents and indiscriminately destroy the surrounding tissue. The tissue damage results in inflammation and further damage which results in further inflammation and further damage which…. a vicious cycle.
Describe catabolism of red cells.
Once macrophages in the spleen, liver, or bone marrow destroy RBCs via phagocytosis. The cell will break into Globin and Heme (which will break further into Iron and Bilirubin). The Globin is reused in protein synthesis, Iron is recycled back in the erythropoiesis through metabolic processes in the liver, and Bilirubin is a by-product that is excreted via feces or urine.
Pleomorphism is cells having variation in size and shape. They have lost their differentiation and organization that they previously had. As a result, pleomorphic cells have their own autonomy and create cells whenever, wherever, and whatever shape/size they feel like with no consistency. These unstructured cells can become invasive and enter the bloodstream.
The elasticity of the lung is crucial to respiration as it allows the lungs to expand and recoil to increase and decrease pressure within the pleural space and facilitate inspiration and expiration.
Cor Pulmonale typically occurs when an individual has chronic lung disease. This causes pulmonary vasoconstriction which manifests as pulmonary hypertension. Due to the increase in blood pressure in the pulmonary blood vessels, the right ventricle of the heart pumps harder to compensate. This compensation leads to enlargement of the right side of the heart and eventually right sided heart failure as the heart is unable to keep up with the demand.
Exacerbation
What are the three common endpoints of the complement cascade?
Inflammation (through mast cell degranulation), opsonization (tagging pathogens with antibodies), and cytolysis (MAC attack)
An activated T-Helper cell will activate a B-cell similarly to how the T-Helper cell was activated. Recognition occurs where the antigen is presented to the B-cell. Once this occurs, co-stimulation occurs to ensure the information being communicated is correct. Lastly, chemical mediators are released which fully activates the B-cell. Once activated, clonal expansion occurs to proliferate and become B-memory cells or Plasma cells. B-memory cells “remember” the antigen that is being targeted for a faster response on subsequent exposures. Plasma cells release antibodies against the antigen and send them into circulation. These antibodies can be IgM, IgD, IgA, IgG, or IgE depending on the requirements. The antibodies will then neutralize the pathogen or opsonize the pathogen for phagocytosis
Just like T-cells, B-cells need to be checked to ensure they are not auto-reactive. If they escape, they can create antibodies to self and cause autoimmune diseases. Just like T-cells, B-cells are produced in the bone marrow. Unlike T-cells, B-cells stay in the bone marrow to mature.
Similar to how the strength of binding determines auto-reactive from normal T-cells, the same goes for B-cells. If the immature B-cell has no interaction with a self-antigen, it is allowed to exit the bone marrow and travel to the lymphoid tissue. If there is a strong interaction with self-antigens, the development of the B-cell is arrested in the bone marrow.
Once arrested in the bone marrow, three mechanisms are used to induce tolerance: receptor editing (the antigen receptor is modified through gene editing), clonal deletion (if receptor editing is unsuccessful then apoptosis occurs), and anergy (the auto-reactive B-cell stays arrested and becomes unresponsive).
Vitamin B12 is required by RBCs for condensation. In disorders like Pernicious Anemia, where B12 is not absorbed through the GI tract, abnormally large RBCs are produced which are not able to properly deliver oxygen.
Tumors attempting to invade do so by binding to the extracellular matrix and basement membrane. When bound, the tumor will release enzyme to degrade the ECM and basement membrane. In addition, due to mutations and secretions, they have reduced adhesion and release chemotactic factors. These changes allow for them to have enhanced motility which leads to invasion to neighboring tissue and through the blood.
The upper airways warm and humidify the air that enters through the nasal cavity. In addition, it removes particulate material to filter out antigens. Lastly, it protects the airways from food/drink and secretions.
The symptoms that can be experienced by individuals with intrinsic restrictive lung disease are cough, dyspnea (especially on exertion), sputum production, cyanosis (due to large concentration of deoxygenated blood), and fatigue
What are selectins and integrins?
- Selectins are surface molecules that allow for adhesin of WBCs to endothelial cells. (they slow down the WBC)
-Integrins are receptors that allow for the WBC to enter through endothelial gap junctions (they stop the roll)
Describe central tolerance of T cells – 3 possible outcomes
Central tolerance is “training camp” for T-cells. Once produced in the bone marrow, they travel to the thymus to mature. Whether the T-cell matures and can leave the thymus depends on its interactions with self-antigens that are presented by thymus cells. Thymus cells present the self-antigen for the thymus cell receptors (TCRs) on immature T-cells to recognize.
If the T-cell does not recognize the self-antigen on MHC-I molecules, they undergo apoptosis because they are not able to do their job.
If the T-cell recognizes the self-antigen and MODERATELY binds to it, this is referred to as positive selection. This guy survives and goes to the lymph node!
If the T-cell recognizes the self-antigen and STRONGLY binds to it, this is referred to as negative selection. This guy also undergoes apoptosis because there’s a chance they’ll target the self.
The bone marrow can become damaged/aplastic or infiltration by other processes, such as cancers, fat, and fibrotic tissue can lead to the bone marrow being overcrowded. Either way, pancytopenia will result which is a decreased production of all blood cells (WBCs, RBCs, and platelets).
G0: The resting state of the cell (out of the cycle of division) where it performs it function
G1: When ready for division, the cell will enter this phase where it will grow and prepare. To do this, organelles and cytoplasm of the cell begin to duplicate along with performing transcription and translation of DNA.
S: DNA synthesis and duplication occurs here
G2: The cell continues to prepare for cell division by duplicating organelles and cytoplasm.
M: Mitosis
Cytokinesis: After completing mitosis, the two daughter cells split and become individual cells
Once completing mitosis and cytokinesis, the cell can either remain in the cycle to divide again, or it may leave and return to G0.
Passive breathing: You “suck” air. The pressure of the lungs is equal to the pressure of the atmosphere outside the body, but the intrapleural space (the space between the membrane surrounding the lungs and the lungs themselves) has a negative pressure. The elasticity of the lung and chest walls allow for that negative pressure to exist. When the diaphragm expands downwards and the chest wall expands outwards, the volume of the lungs increases (which further cause the pressure to decrease). This negative pressure allows for air to enter effortlessly.
Active breathing: When not enough O2 is being delivered to the tissue or other circumstances arise where an individual needs to breathe harder than passively, the diaphragm will work harder and faster to allow the respiratory rate to increase. In addition, the intercostal muscles will be recruited to further expand the size of the pleural cavity (which causes an even greater negative pressure) and allow more air to enter. In addition, the abdominal muscles will assist in pushing air out. If this is not enough and extreme circumstances arise, the accessory muscles within the neck and spine will also assist.
The causes are occupational/exposure (particles that get trapped in the lung that lead to an immune response), drugs, autoimmune diseases (Lupus, Rheumatoid arthritis, scleroderma, etc), idiopathic (pulmonary fibrosis, interstitial pneumonia, etc), or smoking.
What is the first thing the body does when injury and contamination occur?
Vasoconstriction occurs to prevent the harmful agents from entering the blood stream. Fibrin is also deposited at the site to stop bleeding and prevent pathogens from accessing the circulation.
While central tolerance does a good job of catching the T-cells that shouldn’t be allowed to live, it’s not always perfect. Some auto-reactive T-cells escape to the lymph nodes. To stop these T-cells from reacting and attacking the self, peripheral tolerance is a method to stop their attack. The overall goal of peripheral tolerance is to either prevent their activation or control the immune response.
Normally recognition, co-stimulation, and release of chemical mediators is required to activate T-cells. To prevent activation, T-cells that do not co-stimulate due to their strong affinity for self-antigens, peripheral clonal deletion occurs where the T-cell undergoes apoptosis or anergy occurs where the T-cell is “put to sleep”.
In addition, the immune response can be controlled to further protect against the auto-reactive T-cells. These methods include an immune deviation (a less harmful response results), immune privilege regions exist where no immune cells are found (eyes, CNS, testes), cytokines are immunosuppressed, and regulatory T-cells further control the response.
Why does iron deficiency cause problems for red blood cells?
Key components of RBCs are hemoglobin and iron. There are tons of molecules of heme that are bound to iron. This interaction allows for iron to bind to oxygen molecules which then allows RBCs to carry and deliver oxygen to various tissues of the body. With a deficiency of iron, RBC production becomes compromised, and they often are smaller in size which decreases their ability to deliver oxygen.
There are multiple checkpoints within the cell cycle that monitor the progress of the cell through the different phases and attempt to prevent mutant replication and detect DNA damage. If damage is detected, the cell will attempt to repair it, enter G0, or undergo apoptosis.
The first checkpoint is found between the G1 and S phases to ensure the DNA is ready for duplication and so that the cell size, nutrients, and growth factors can be checked. The second checkpoint is found between the G2 and M phases to ensure everything is ready for mitosis and ensuring DNA replication didn’t lead to damage or errors. There is also one last checkpoint during mitosis that ensures the spindles (attach the chromosomes to the metaphase plate) are functioning properly.
Active exhalation is used when breathing needs to occur harder and recruits the abdominal and accessory muscles to breath in that manner. In comparison, quiet breathing is the natural mechanism of respiration where those muscles are not activated.
How does the fibrosis develop? Explain the pathophysiology
Foreign materials or a chronic irritant can lead to an immune response to be mounted. Macrophages that are present in the area attempt to engulf the foreign material and clear the alveoli. Unable to do, macrophages may undergo oxidative burst or disintegrate to clear it instead. This leads to a buildup of fibrous tissue (collagen) within the alveoli. This tissue affects diffusion and stiffens the lung as collagen is not as elastic.
Low intensity heat/extreme heat, cold/extreme cold, UV radiation, electric current, viruses, drugs/toxins
Describe each of the steps of the inflammatory response.
Triggers: An injury, exposure, allergen, or infection that results in a reaction
Activation of first responders: The innate immune response is triggered by pathogen associated molecular patterns (PAMPs) to eliminate the cause, remove dead tissue, and repair the damage. Pattern recognition receptors (PRRs) on first responders (mast cells and macrophages) detect PAMPs which activates them.
Chemical efflux: The first responders degranulate and efflux of cytokines (such as histamine) results to ‘ring the alarm’
Chemical influx: The alarm has now been rung. Vasodilation occurs to bring plasma, plasma proteins, inflammatory mediators, and complement proteins to the site where they are needed.
Cellular phase: The ‘reinforcements’ arrive to the scene of the battle. Vasodilation has also caused a decrease in blood flow that allows for WBCs to cross the endothelial barrier and ‘join the fight’.
Self-Discrimination
In the bone marrow, hematopoiesis leads to the production of megakaryoblasts. When undergoing mitosis, they do not cleave (cytokinesis) and instead remain fused. This results in the multinucleated megakaryocyte. This cell breaks off pieces of itself that are anucleated. These broken off pieces are platelets. Once broken off, platelets circulate in the blood for ~10 days in an inactive form. When bleeding occurs in the body, they become active to make fibrin clots to stop it.
There are many findings, these include: cachexia (weakness), anemia (due to chronic loss and suppression of bone marrow), infection (due to suppression of immune system), pain (due to pressure, destruction, and nerve involvement), anorexia (loss of appetite/weight loss), pallor, depression, anxiety
The respiratory center within the brain is in the brain stem (specifically within the medulla oblongata). There are chemoreceptors that monitor the O2 and CO2 concentration within the body and cause an increase in breathing or a decrease in breathing rate depending on the needs of the body.
In addition to the medulla controlling respiration, the pons plays a role as well to fine tuning respiration.
Granulomas are clumps of immune cells. Chronic infection/inflammation leads to multiple immune cells to be present at the site. These immune cells clump in such a way that a necrotic core and fibrotic capsule forms that walls off the pathogen from the rest of the body.
The stimulus that results in disruption of homeostasis are noticed by the body through sensors/receptors which cause a response by the cell. The responses could be adaptive or injury can occur if the cell is unable to adapt. If the injury is still reversible, the cell can return to normal functioning. If the injury is not reversible and the cell is unable to adapt, apoptosis or necrosis will result.
Describe the steps of the cellular phase
Due to vasodilation, the flow of blood decreases which allows for WBCs to arrive at the area of ‘attack’. Once they arrive, selectins on endothelial cells cause WBCs to slow down. As a result, WBCs roll and marginate until integrins stops them and, through the endothelial gap junctions, allows for diapedesis (slipping through). Once they have entered, chemotaxis allows for the WBCs to be attracted towards the ‘battle site’. Upon arriving, phagocytosis occurs where macrophages envelope and destroy the pathogen.
IgM
It is a pentamer that is seen earlier in infection. It results in opsonization, activation of complement cascade (C1), or agglutination
Describe the type of hypersensitivity with examples. Type III
This type of hypersensitivity is mediated by immune complexes (antigen-antibody complexes). This occurs due a double failure of tolerance. Not only did a self-recognizing T-cell escape, but a self-recognizing B-cell escaped as well. Due to co-stimulation, B-cells produce IgG antibodies and bind to antigens that are soluble (free-floating and not attached to cell). If the antibody is binding to an antigen on a cell that is Type 2 hypersensitivity. Since the antibodies formed are binding to small antigens, macrophages aren’t attracted as they would be if it were a cell. This results in the complexes floating in circulation for a while before getting trapped in spaces (ie: blood vessel walls, glomeruli, synovium). Once trapped, a HUGE complement response occurs which attracts cells that hope to phagocytosize the complex. Most of the time, they are unable to do and “puke” out their contents and indiscriminately destroy the surrounding tissue. The tissue damage results in inflammation and further damage which results in further inflammation and further damage which…. a vicious cycle.
In normal RBC development, Hgb A is present that allows RBCs to be flexible and slip through tiny gaps (such as the ones in capillaries) without any issues. In sickle cell, however, there is a mutation which turns Hgb A into Hgb S. This mutation results in RBCs to more rigid and form in a crescent shape. Due to these changes, RBCs undergo premature hemolysis and only circulate the body for ~20 days compared to the normal ~120 days. Since turnover occurs more often, the body can’t produce enough RBCs needed to deliver the appropriate amount of oxygen to the tissues that is required. This results in the individual experiencing hypoxia and feeling cold. In addition, due to the crescent shape, the sickled RBCs can no longer slip through gaps. This results in them getting stuck in places like capillaries, the spleen, kidneys, and etc further resulting in the symptoms described earlier along with the possibility of blocking blood flow and resulting in necrosis of tissues which causes pain, inflammation, and increased risk of infection for the individual.
In normal conditions, there checks that keep the cell from dividing uncontrollably. The cyclin-CDK complex activate the proteins required to continue through checkpoints and proceed through the cell cycle. If there is damage to DNA, cyclin is not present and the cell cycle will be halted to repair DNA, return to G0, or undergo apoptosis.
In oncogenesis (development of a tumor), this mechanism is broken and results in excessive cell division, reduced cell loss, and an increase in retention of cells. Proto-oncogenes are required in normal cell growth and division, but in oncogenesis these genes become defective and become oncogenes. These oncogenes are like pressing on the gas pedal and continuously speeding through checkpoints. There are suppressor genes (ie: p53), however, that act as brakes and promote DNA repair and apoptosis.
In oncogenesis, suppressor genes can become inhibited and damaged DNA is allowed to replicate, or oncogenes can be activated by excess of promoter growth factors can override suppressor genes and lead to tumor production (without the promoter, this would not be possible).
Gas exchange occurs within the alveoli of the lungs. Within the alveoli, waste (CO2) needs to diffuse from the blood into alveoli and nutrients (O2) need to diffuse from the alveoli into the blood. The epithelium of the alveoli is very thin and allows for this diffusion to occur. CO2 will be expelled upon expiration and O2 will travel through the bloodstream to the necessary tissue.
In the lumen: This type of obstruction is where an object is blocking the passageway of the lumen itself.
Outside the lumen, pushing in: This type of obstruction is where an object is blocking the passageway of the lumen from outside.
In the wall: This type of obstruction is where an object is blocking the passageway from the wall of the lumen.
How do WBC’s know where to go once in the interstitium?
Through chemotaxis. Cytokines expelled by other inflammatory mediators draw WBCs to where they need to be.
IgE
It is a monomer that is seen in allergic reactions. Associated with Eosinophils
Describe the type of hypersensitivity with examples. Type II
This type of hypersensitivity occurs due to a failure of central tolerance that is antibody mediated and generally leads to cytotoxicity. Normally, central tolerance takes care of T-cells and B-cells that are auto-reactive, but some escape and circulate the system. These cells produce IgM antibodies that can bind to molecules they shouldn’t have and create an antigen-antibody complex. These complexes can result in different mechanisms to kill the cell. First, they can activate the complement system (C1 binds to the antibody) which will result in the destruction of the cell through the MAC (membrane attack complex). Second, they can opsonize the cell which will attract immune cells a macrophage to phagocytosize the cell and destroy it. If phagocytosis cannot be done, macrophages or neutrophils “puke” out perforins, enzymes, or free radical species (found in lysosomes and peroxisomes) and indiscriminately destroy the area the antigen is in.
Destruction of platelets by the immune system is known as ITP (immune thrombocytopenia purpura). In this autoimmune disease, antibodies are created against platelets. Their destruction can result in purpura (small bleeding spots beneath the skin) or, in severe cases, epistaxis (nose bleeding). Normally, hemostasis occurs where bleeding is stopped by plugging the vessel that is leaking through platelet clumping at the site. In ITP, due to destruction of platelets, bleeding becomes harder to stop.
By definition benign tumors are not cancerous and will not lead to metastasis. However, these cells can continue to grow and crush/damage neighboring cells (this phenomenon is known as mass effect).
There are places in the body where space is limited (ie: the skull) where a benign tumor can grow large enough to damage brain cells, disrupt flow of CSF, and other devastating effects. Another example is obstruction of passageways (ie: respiratory tract where the benign tumor can result in blockage of air).
The multiple C-shaped cartilaginous rings provide support and stabilize the trachea so that it does not collapse during respiration. In addition, it allows for flexibility to allow for mobility in the neck to turn and move.
Give an example of reversible cell injury
An example is an individual getting a sunburn. Overtime, the cell will repair the injury and return to their normal state.
Describe the steps of the vascular phase
Local vasoconstriction and clotting occurs at the site of injury to prevent contamination. First responders (masts cells and macrophages) are activated by PAMPs and degranulate to ‘ring the alarm’. Triggered by the cytokines released, vasodilation occurs to decrease blood flow and bring ‘back up’ (more WBCs) to the site. The vasodilation results in redness (RUBOR) and the increased blood flow to the area results in warmth (CALOR). Vasodilation also results in the endothelial junction to widen and allows for plasma, plasma proteins, WBCs, and complement proteins to leak through. This results in swelling (TUMOR).
IgA
The most abundant type of antibody. It is a monomer that is produced by plasma cells to either 1) precipitate, 2) activate MAC, or 3) neutralize the pathogen
Describe the type of hypersensitivity with examples. Type IV
This type of hypersensitivity is referred to as T-cell mediated hypersensitivity. Certain foreign molecules are very small and can cross through barriers and be picked up by APCs. If a naïve T-Helper cell recognizes the antigen, activation of the T-Helper cell can occur (recognition, co-stimulation, and release of chemical mediators). The now activated T-Helper will proliferate and activate other immune cells like macrophages to release cytokines. The cytokine release widens the endothelial gaps and allows for immune cells to enter (the 4 pillars of inflammation - swelling, redness, heat, and pain occur!).
CD4+ cells are not the only players in this type of hypersensitivity though! Killer T-cells (CD8+) are present and can directly destroy cells like a silent assassin. They scan cells and monitor their MHC-I receptor. When changes occur to the MHC-I molecule, CD8+ cells bind to it and release perforins and granzymes to induce apoptosis in the infected cells.
Examples include poison ivy, TB, type 1 diabetes mellitus, multiple sclerosis, and rheumatoid arthritis. This hypersensitivity takes the longest to occur.
Describe TTP and its clinical findings
TTP (Thrombotic thrombocytopenia purpura) is a blood disease where small blood clots occur throughout the body. During blood clot formation, von Willebrand factor sticks to exposed tissue and acts like a glue for platelets to stick to. Once the clot needs to be broken down, an enzyme breaks down von Willebrand factor but in TTP, there is a deficiency of that enzyme. Without the regulatory effects of this enzyme, small blood clots form frequently throughout the body. These blood clots can block blood flow and lead to the clinical findings of decreased platelet count, purpura (small bleeding spots beneath the skin), brain dysfunction, GI problems, and heart-related symptoms.
In oncogenesis (development of a tumor), the mechanism that checks before continuing through the cell cycle is broken and results in excessive cell division, reduced cell loss, and an increase in retention of cells. Proto-oncogenes are required in normal cell growth and division, but in oncogenesis, initiators cause these genes to become defective and become oncogenes.
Compared to normal functioning cells, promoters have a stronger effect in cancerous cells and oncogenes can be activated by excess of promoter growth factors which overrides suppressor genes and lead to tumor production.
Extrinsic lung disease are pathologies that decrease the amount of air that can be “sucked” in. These can affect the diaphragmatic excursion or can restrict the chest wall.
Examples: Guillan-Barre Syndrome, Mysthenia Gravis, rib fractures, circumferential burns, Air/pus/water/blood/lymph in the lung (Hemothorax, Empyema, Pleural effusion, Hemothorax, Chylothorax)
The toxic causes of shortness of breath are CO2, CO, cyanide, and particles that result in the fibrosis of the lung (as listed above).