Unit 1 Flashcards
What is immunology?
Study of a hosts reactions to foreign substances that are introduced into the body
What is an antigen?
A substance that reacts with an antibodies or sensitized cells but may or may not be able to elicit an immune response
What is immunity?
Condition of being resistant to infection
What was the first vaccine and what is used to create it?
1st → smallpox
Composed of cowpox
Who is the father of immunology and why is he considered this?
Louis Pasteur.he created the first attenuated vaccine
What is attenuation?
- Makes pathogen less virulent
-takes place through heat, aging and chemicals
What is phagocytosis?
Cells that eat cells
What is humoral immunity?
- Protection from disease resulting from substances in the serum/plasma (antibodies and acute phase reactants)
Describe cell mediated immunity
-When recognition antigen occurs in the secondary lymphoid tissue, T cells are activated and differentiate into functionally active small lymphocytes that produce cytokines
-activities of specific cytokines include assisting B cells in commencing antibody production, eliminating tumor and other target cells, rejecting grafts, stimulating hematopóiesis in the bone marrow and initiating delayed hypersensitivity
What are the two parts of the adaptive immune response?
- Cellular
-humoral
Describe humoral immunity function
Involves production of antibodies by B cells and plasma cells
What are antibodies?
Serum protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses.
What is innate immunity?
An individuals ability to resist infection by means of normally present body functions
What are characteristics of innate immunity?
- Nonspecific
-no memory
-immediate exposure - same response for all pathogens
-influenced by nutrition, age, fatigue, stress, and genetic determinants
What is adaptive immunity?
-resistance that is characterized by specificity for each individual pathogen
List characteristics of adaptive immunity
- Delayed response
- stronger response
- specific
- has memory
What is the function of WBCs?
Defend against invasion by bacteria, virus, fungi, and other foreign substances
What are the 5 types of WBC?
-monocytes
- eosinophils
- basophils
-neutrophils
-lymphocytes
Which WBC is part of the adaptive immunity?
Lymphocytes
What are the main cells found in tissue?
- dendritic cells
- macrophages
- mast cells
What is a hematopoietic stem cells (HSC)?
All blood cell types arise from this cell
Where are WBCs produced? And how much?
- Bone marrow
- one and a half billion daily
How do WBCs form?
HSC gives rise to two distinct types of precursor cells, myeloid precursors (CMP) and common lymphoid precursors (CLP)
What do CMPs do?
-Give rise to WBC that participate in phagocytosis.
-also known as myeloid line
What is the life span of a neutrophil?
Several days
What is the size of a neutrophil?
10-15 um
Describe the nucleus of a neutrophil
- 2-5 lobes
-has lots of granules
What percentage of WBCs are neutrophils?
50-70%
What stain is used on neutrophils?
Wright stain
What is the main function of neutrophils?
Phagocytosis
What is diapedsis?
Movement through blood vessel wallsm
What are chemotaxins?
Chemical messengers that cause cells to migrate in particular direction
What do neutrophils do when an acute infection occurs?
Neutrophils increase almost immediately in the blood and go to infection site rapidly
What is the size ofan eosinophil?
10-15 um
What percentage of WBCs are eosinophils?
1-4%
What stain is used for eosinophils?
Eosin stain
Describe the nucleus of eosinophils
-bilobed/ellipsoïdal nucleus
-eccentrically located
What are the functions of eosinophils
①phagocytosis (not efficient as neutrophils)
②neutralize basophils and mast cells
③kills parasites using cationic proteins
What is the most important role of eosinophils?
Regulation of adaptive immune response through cytokine release
What percent of WBCs are basophils?
Less than 1% WBC
What is the size of basophils?
Smallest, 10-15 um
Describe the nucleus of a basophil
-deep purple- blue granules
-bilobed, hard to see
What is the life span of a basophil?
A few hours
What happens to basophils in the spleen?
Removed and destroyed by macrophages
What are the 3 functions of basophils?
①induce and maintain allergic reactions
②regulate some t-helper cell response
③stimulate B-cells to produce IgE antibody
What does histamine do?
Contracts smooth muscle
What does heparin do?
It is an anticoagulant
What is the size of a monocyte?
Largest, 12-20 um
Describe the nucleus of a monocyte
-irregular horseshoe or folded nucleus
- occupies 1/2 or more of cell
What percentage of WBCs are monocytes?
2-10%
What is the lifespan of monocytes?
30 hours, then travels to tissues and become macrophages
What are 2 types of granules in monocytes?
1st→ contains peroxides, acid phosphate, and arylsulfatase
2nd→ containsbeta-glucuronidase, lysozyme, and lipase (No alkaline phosphate)
What does monocytes contain that macrophages do not?
Peroxidase
What are macrophages in the lungs called?
Alveolar macrophages
What are macrophages called in the liver?
Kupffer cells
What are macrophages in the brain called?
Microglial cells
What are macrophages in bone called?
Osteoclasts
What are macrophages in connective tissue called?
Histiocytes
Why are neutrophils more efficient at phagocytosis than macrophages?
Macrophages are slower
Why are neutrophils more efficient at phagocytosis than eosinophils?
- Less eosinophils
- eosinophils lack of digestive enzyme
What is the lifespan of a macrophages?
A few months
What are the innate immunity functions?
① phagocytosis
②microbial killing
③anti-tumor activity
④intracellular parasite eradication
⑤secretion of cell membrane
What enhances “killing” of foreign substances?
When macrophages become activated by cytokines
How do macrophages play an important role in the adaptive system?
By presenting phagocytosized antigens to T cells
What is the lifespan of mast cells?
9-18 months
Where can mast cells be found?
- Located in variety of tissues
- resembles a basophil
What is the size of mast cells?
Larger than basophil,up to 20 um
What are the functions of mast cells?
①act to increase vascular permeability and increase blood flow to affected area
② role in allergic reactions
③ APC
Describe the appearance of dendritic cells
-Covered with long, membranous extensions that resemble nerve cell dendrites
What are dendritic cells?
-APC that links innate and adaptive immunity and are critical for the induction of immune response
- classified according to location
What is to the most potent phagocytic cell?
Dendritic cells
What percentage of WBC are lymphocytes?
20-40%
What are the size of lymphocytes?
7-10 um (similar to RBC)
Describe the lymphocytes nucleus
- Large, rounded, and indented
-has narrow ring
-chromatin stains deep blue - sparce cytoplasm
Why are lymphocytes granules unique?
They arise from HSC
What are the 3 categories of lymphocytes?
-T cells
-B cells
-innate lymphoid cells
What is the most prominent innate lymphoid cells?
Nk cells
what percent of lymphocytes are B-cells?
10-20%
What percentage of lymphocytes are T-cellsz
61-80%
What percentage of lymphocytes are Nk cells?
10-15%
What is cluster of differentiation?
Protein found on cell surfacesthat can be used to identify specific cell types and stages of differentiation
What are the primary lymphoid organs?
Bone marrow
Thymus
What is the largest tissue in the body?
Bone marrow
What is bone marrow the main source of?
HSC
What can HSC develop into?
-RBCs
- granulocytes
-monocytes
-platelets
- lymphocytes
What occurs when lymphocytes remain in the bone marrow?
Mature and become Nk cells or B cells
What occurs when lymphocytes travel to the thymus?
Mature and become T cells
Describe the thymus
Filled with epithelial cells that play central role in differentiation process
How long does it take T- cells to mature?
3 weeks
What are mature T-cells released from?
Medulla of thymus
What are the four secondary lymphoid organs?
- Spleen
- lymph nodes
-CALT
-MALT
After lymphocytes mature in primary lymphoid organs, what happens next?
They make their way to the secondary lymphoid organs
Where does main contact of foreign antigens occur?
-Secondary lymphoid organs
-T cells and B calls meet here as well
Where do lymphocytes spend most of their time?
The tissues
How do lymphocytes travel to blood stream?
Via. Thoracic duct
What is the largest lymphatic vessel?
Thoracic duct
What are T cells?’
Effector cells that serve a regulatory roles in adaptive and innate immunity
What do B cells do?
Produce antibodies
What is lymphopoiesis?
Multiplication of lymphocytes
Describe the spleens location
-upper left quadrant
-below diaphragm
- largest secondary organ
What does the spleen do?
Removes old/damaged cells and foreign antigens from the blood
What types of pulp is found in tissue?
Red and white
What is the function red pulp?
- To destroy old RBCs, platelets, and pathogens
What is rich in red pulp?
Macrophages
What is the total volume of red pulp found a in the spleen?
50%
What is the total volume of white pulp found a in the spleen?
20%
Describe white pulp of the tissues
- Contains lymphoid tissue arranged around arterioles (periarterolar lymphoid sheath: PALS)
- sheath contains mostly T cells
- primary follicles contains B cells
- marginal zone containing dendritic cells that trap antigens
Describe lymph nodes
-located along lymphatic ducts and numerous joints attacking appendages
- provide ideal environment for contact with foreign antigens that have penetrated tissue
What is the main function of the lymph nodes?
-filtration of interstitial fluid from around cells in tissues
-important because it -allows contact between lymphocytes and foreign antigens that have penetrated tissue
What are the layers of the lymph node tissues?
- Outer cortex
-para cortex
-inner medulla
What is lymph fluid?
A filtrate of the blood and arises from the passage of water and low molecular weight solutes out of blood vessel walls and into the interstitial spaces between cells
Describe flow of lymph nodes
- Some return to blood streams through venules
-portion flows through tissues and collected in lymphatic vessel - flow through place called sinuses lined with macrophages
What structure do lymphocytes and foreign antigens enter the lymph nodes through?
Afferent vessels
How do lymphocytes enter the lymph nodes from blood stream?
By means of the high endothelial venules
What cells could be found in a primary follicle of the lymph nodes?
-unstimulated B cells
- Macrophages
-follicular dendritic
What can be found in a secondary follicle of the lymph nodes?
Antigen stimulated proliferating B cells
What is the center of a secondary follicle of the lymph nodes called?
Germinal center
What happens when B cells come in contact with antigens?
Plasma cells and memory cells form
Where in the lymph nodes can T cells be found?
Para cortex
What structure does lymph fluid and lymphocytes exit the lymph nodes?
Efferent lymphatic vessels
What is the main function of plasma cells?
Actively secrete antibodies
What is the main function of memory cells?
Can quickly change into plasma cells
Where can MALT be found?
-appendix
-GI tract
-ileum
-peyers patch
-respiratory tract
-tonsils
-urogenital tract
Why are macrophages and lymphocytes localized in MALT?’
Mucousal surface are main ports of entry for a foreign antigen
What’s cells can be found in CALT?
- Dendritic cells
- Macrophages
- monocytes
What do all secondary organs function as?
As potential sites for contact with foreign antigens and increase probability of immune response
What are the innate phagocytic cells?
- Dendritic cells
-Macrophages
-monocytes
-neutrophils
What can recognize B cells?
-CD19
-CD20
-surface antibody
Where do T cells acquire specificity?
Thymus
What are the two subtypes of T cells?
-CD4+ (Th or treg cells)
-CD8+ (Tc cells)
What marker is present on all subtypes of T-cells?
CD3
What are NK cells?
Can kill virally infected or cancerous target cells without previous exposure to them
Which WBC is capable of further differentiation in tissues?
Monocytes
How are T cells different from NK cells?
Only NK cells are able to kill target cells without prior exposure to them
What is the most potent phagocytic cell?
Dendritic cells
What is a distinguishing feature of B cells?
Presence of surface antibody
What is the main function of T-cells?
Produce cytokines that regulate both innate and adaptive immunity
What is the function of antibodies?
Neutralize bacterial toxins
What blood cell kills parasites?
Eosinophils
What are the 2 systems of innate immunity?
- External defense system
-internal defense system
What is the external defense system?
-contains chemical, physical, and biological factors that work together to prevent most infections agents from entering the body
What is the internal defense system?
-Triggered within minutes and clears invaders as quickly as possible
Why do external and internal defense systems work together?
To promote phagocytosis
What orchestrates the healing process?
Phagocytosis and resulting inflammation brings cells and humoral factors to the injuried area
What is the barrier of the external defense system?
Skin and mucosal membrane surfaces
Describe the outer layer of the external defense barrier?
-outer layer of skin is the epidermis and contains several layers of tightly packed epithelial cells
-protein coated cell called keratin
What is the role of keratin in the epidermis?
Makes skin impermeable to most infections agents
How often does the outer layer of skin renew?
Every couple of days
What is the layer under the epidermis?
Dermis
Describe the dermis
-thicker than epidermis
- connective tissue with bloodvessel, hair follicles, sebaceous glands,and WBC
What cells are found in the dermis?
- Dendritic cells
-macrophages
-mast cells
Why does skin have several secretions?
Discourage growth of microorganisms
What is secreted on skin to maintain pH balance?
-fatty acids and lactic acids
-they prevent growth of microorganisms
What is a balanced pH of skin
~5.6
What is psoriasin?
- Produced by skin
- has antibacterial effects, especially for gram-negative bacteria
What is the respiratory tracts external defense system?
-mucous secretion block adherence
- coughing and sneezing clear out pathogens
What is the geniturinary tracts external defense systems?
-flushing out urine
- acidity helps to remove many potential pathogens
- lactic acid of vagina maintains pH of 5
What is the external defense for the digestive tract?
- Hydrochloric acid keeps pH as low as 1 to kill pathogens brought in by food and drink
What are lysosomes role in the external defense system?
- Attack cell wall of microorganisms, especially gram positive bacteria
What are microbiota?
A mix of bacteria that are normally found at species body sites and do not typically cause disease.
What is the microbiotas role in the external defense system?
Helps keep pathogens from establishing themselves
-*.3
Explain the internal defense
- Composed of both cells
- soluble factors that have specific and essential functions
What is the function of phagocytes?
They engulf and destroy most foreign cells or particles that enter the body
What is phagocytosis enhanced by?
Cell receptors on cells that capture invaders through identification of microbiota
What is the main function of soluble factors in the internal defense system?
-helps facilitate contact between microbes and phagocytic cells and bind to and recycle important proteins after phagocytosis
- soluble factors = acute phase reactants
What is the percent of macrophages and dendritic cells in total cell population of tissues?
10-15%
What are the most important cells in pathogen recognition?
- Dendritic cells
- macrophages
What is the main function of pattern recognition receptors? (PRRs)
Able to distinguish pathogens from normally present molecules in the body by means of receptors
What are pattern recognition receptors encoded by?
Hosts genomic DNA
What happens when PRRs binds to pathogen?
①phagocytic cells activate and are better able to engulf and kill organisms
② activated cells secrete proinflammatory cytokines and chemokines
③cytokines and chemokines also trigger adaptive immune response
What are pathogen associated molecular patterns?(PAMPs)
Substance that allows PRRs to have ability to distinguish self from non-self
What had a large impact on understanding innate immunity?
Toll-like receptors (TLRs)
What protein originally was discovered on a fruit fly?
Toll
Where are the highest concentrations of TLRs found?
-dendritic cell
-macrophages
-monocytes
Which TLRs are found in cytoplasm?
-TLR1
-TLR2
-TLR4
-TLR5
-TLR6
What TLRs are found in the endosomal compartment of cells?
-TLR3
-TLR7
-TLR8
-TLR9
What does TLR1 recognize?
Lipopeptides found in mycobacteria
What does TLR2 recognize?
Peptidoglycan, lipoprotein, and zymosan found in gram positive bacteria, mycobacteria, and yeasts
What does TLR4 recognize?
Lipopolysaccharides,fusion proteins, and Annan found in gram-negative bacteria, respiratory syncytial virus, and fungi
What does TLR5 recognize?
Flagellin found on bacteria with flagella
What does TLR6 recognize?
Lipopeptides, lipoteichoic acid, and zymosan found on mycobacteria - gram positive bacteria, and yeasts
What does TLR3 recognize?
Double stranded RNA found on RNA viruses
What does TLR7 recognize?
Single stranded RNA found on RNA viruses
What does TLR8 recognize?
Single stranded RNA found on RNA viruses
What does TLR9 recognize?
Double stranded DNA found on DNA viruses and bacterial DNA
What does TLR10 recognize?
Unknown
Describe the structure of TLRs
Membrane spanning glycoproteins that share a common structural element called leucine-rich repeats (LRRs)
What occurs once TLRs bind to their particular substances?
①host immune responses rapidly activated by production of cytokines and chemokines
②neutrophils are then recruitedto area because of increased capillary permeability
③macrophages and dendritic cells have expression of adhesion molecules on their surfaces
What are c-type lectin receptors? (CLRs)
- Plasma membrane receptors that bind to Mannan and beta-glucans found in fungal cell walls
-has production of cytokines and chemokines to microbes
What cells can CLRs be found on?
-B cells
-dendritic cells
-macrophages
-monocytes
- neutrophils
-T cells subsets
What are retinoisacid-inducable gene I-like receptors? (RLRs)
-recognize RNA from RNA viruses.
-induce production of inflammatory cytokines/ type I interferon
Describe serum amyloid A
-major protein who concentration can increase X1000 in response to infection/injury
-apolipoprotein synthesized in liver
-acts like cytokines, chemical messenger (activates monocytes and macrophages)
When does serum amyloid A reach peak?
24-48 hours after acute infection
Why would serum amyloid A be increased?
- Chronic inflammation
-atherosclerosis - cancer
Describe complement
- Series of serum proteins that are normally present and contribute to inflammation
What are the functions of complement?
① opsonization
② chemotaxis
③lysis of cells
Describe alpha1-antitrypsin (AAT)
- 52-KD protein that is primarily synthesized in liver
- major component of alpha-band when serum electrophoreses
-acts against trypsin
-atleast 75 alleles of gene coding for AAT
What are the functions of alpha1-antitrypsin?
-general plasma prohibitor of proteases released from leukocytes
-acts to counteract effects of neutrophils (elastase) during inflammation
-regulates expression of proinflammatory cytokines
-inhibits monocytes and neutrophils
What is elastase?
An enzyme secreted by neutrophils during inflammation that can degrade elastin and collagen
What are the proinflammatory cytokines?(specific types)
- TNF-alpha
-interleukin-1beta
-interleukin-6
Describe haptoglobin
-an alpha1-globulin with a molecular weight of 100,000
-binds irreversibly to free hemoglobulin
-acts as antioxidant to protect against oxidative damage from free hemoglobin
Describe fibrinogen
-acute phase protein involved in coagulation pathway
- small portion cleaved by thrombin to form fibrils that create a fibrils clot
-340,000 daltons
What do fibrin clots do?
- Increases strength with wound and stimulate endothelial cell adhesion and proliferation
- creates barrier of microorganisms further into the body
What is the effect of fibrinogen on blood?
- Makes blood move viscous and serves to promote aggregation of RBCs and platelets
What can increased fibrinogen lead to?
An increased risk for developing coronary artery disease
Describe ceruloplasmin
- Consists of a single polypeptide chain with a molecular weight of 132,000 daltons
-copper transporting protein in human plasma
-acts as enzyme, converting the toxic ferrous ion (Fe^2+) to non toxic ferric form (Fe^3+)
Depletion of ceruloplasm is found in what disease?
Wilsons disease
What is Wilsons disease?
-autosomal recessive genetic disorder characterized by massive increase of copper in the tissues and accumulate in liver.
What is the normal range for serum amyloid A?
5-8 mg/dl
What is the normal range for haptoglobin?
40 -290 mg/dl
What is the normal range for fibrinogen?
200-400 mg/dl
What is the normal range for ceruloplasm?
20-40 mg/dl
What is inflammation?
Body’s overall reaction to injury or invasion by an infectious agent
What are the cardinal signs of inflammation?
-erythema (redness)
-edema (swelling)
-heat
-pain
What are steps of the inflammation process?
①macrophages and mast cells at site of infection release chemokines that cause vasodilation and induce selections (red/heat)
②selectins loosely bind circulating leukocytes and cause them to roll along vascular wall (swell)
③chemokine induced integrins on leukocytes and bind firmly to the endothelial cells (neutrophils)
④ integrins enable the leukocytes to crawl between endothelial cells (diapedesis)(peaks at 16-48 hours)
⑤ leukocytes then follow the chemokine concentration gradient to the site of infection (chemotaxis)
During inflammation, how long does it take for neutrophils to mobilize?
30-60 minutes
What is the acute inflammatory response?
Acts to combat the early stages of infection and also begins a process that repairs tissues damage
What is it called when inflammation occurs for an extended period of time?
Chronic inflammation
What is the main purpose of the inflammatory response?
Attract cells to the site of infectionand remove foreign cells or pathogens by means of phagocytosis
What do acute phase reactants enhance?
Phagocytosis
What cells are most active in phagocytosis ?
- Dendritic cells
-macrophages
-monocytes
-neutrophils
What are the steps of phagocytosis?
① physical contact between the WBC and foreign cell
②outflowing of the cytoplasm to surround the microorganism
③formation of a phagosome
④fusion of lysosomal granules with the phagosome
⑤formation of a phagolysosome with release of lysosomal contents
⑥digestion of microorganisms by hydrolytic enzymes
⑦release of debris to the outside of the cell by exocytosis
What are selectins?
Adhesion molecules on endothelial cells lining blood vessels
What are integrins?
Adhesion molecules on endothelial cell wall
What is chemotaxis?
- Cells are attracted to site of inflammation by chemical substances such as soluble bacteria factors and acute phase reactants
What cells already exist in tissue before phagocytosis?
- Dendritic cells
-macrophages
What enhances the binding process during phagocytosis?
Opsonins
What are opsonins?
Serum proteins that attach to a foreign cell or pathogen and make it more susceptible to phagocytosis
What do opsonins do to enhance binding?
Act by neutralizing the surface charge on the foreign particle.
What are phagosomes?
Pseudopodia fuse to completely enclose pathogen
What are phagolysosome?
Lysosomal granule fused to phagosome
What are the two processes that occur to eliminate pathogens?
- Oxygen-dependent pathway
-oxygen-independent pathway
Describe oxygen dependent pathway
-increase in oxygen consumption (oxidative burst) occurs in cell as the pseudeopodia enclose particles within vacuole
- generates considerable energy through oxidative metabolism
What is an important bacterial agent in oxygen dependent process?
Hydrogen peroxide
In oxygen dependent pathway, NAPD oxidase depolarizes the membrane when fused with phagosome. Why does this occur?
Allow hydrogen and potassium to enter vacuole, and thus alters the pH
Describe the oxygen-independent pathway
- Defensins kill gram-negative bacteria, many fungi, and some viruses
What are defensins?
Small cationic proteins that cleave segments without benefit of oxygen
What is the importance of NAPDH oxidase in the oxygen independent pathway?
Eliminate microbes
What happens after phagocytosis?
- Macrophages and dendritic cells mature and are able to process peptides from pathogens for presentation of T cells
- T cells then interact with B cells to produce antibodies
What cell is the first line of defense against virally infected cells, tumor cells,and cells infected with intracellular pathogens?
Natural killer cells (NK)
Describe NK cells
- Have ability to recognize damaged cells and target cells and eliminate them without prior exposure
-No specificity because they are early defenders
-peaks at 3 days
What is NK cell activity enhanced by?
Exposure to cytokines → interleukin-12, interferon-alpha and interferon-beta
What occurs after NK cells are activated?
-they become major producer of cytokines such as interferon-gamma and TNF- alpha that help recruit T cells
-they also release various colony-stimulating factors that act on developing granulocytes and macrophages
What is cytotoxicity?
The degree to which a substance can cause damage to a cell
What are the two main binding receptors for NK cells ?
① inhibitory receptors
②activating receptors
What do inhibitory receptors do?
Deliver inhibitor signals
What do activating receptors do?
Delivers signals to activate cytotoxic mechanism
Inhibitory signals are based on recognition of what?
Class I MHC proteins which are expressed on all healthy cells
What happens when NK cells and MHC I class react with one another?
Natural killing process is inhibited
What are perforins?
Proteins that form channels in target cell membrane
What are granzymes?
Packets of enzymes that may enter through channels and mediate cell lysis
Describe antibody-dependent cellular cytotoxicity
-NK cells recognize and lysis antibody-coated target cells
-binding occurs through surface receptors, CD16 and CD32, which bind to Fc portion of immunoglobulins
-destruction occurs outside of NK cells
What is an important contributor to the anti-tumor activity?
Antibody-dependent cellular cytotoxicity
In antibody-dependent cellular cytotoxicity, what does lysis of target cells require?
Contact with NK cells, followed by release of cytotoxic fixation
Describe innate lymphoid cells
- Growing family of immune cells that develop from the common lymphoid progenitor but does not express markers of lymphocytes lineage
-primarily found in mucosal sites
Where does the creation of hypochlorite and hydroxyl ions occur?
Oxygen dependent pathway of phagocytosis
What is the function of hypochlorite and hydroxyl ions in phagocytosis?
Damage protein irreversibly
How are phagolysomes formed?
By fusion of engulfed material and enzymatic granules within the phagocytic cell
Presence of human microbiota acts as a defense mechanism by what method?
Competing with potential pathogens
What can measurements of CRP levels be used for?
-tracking progress of organ transplant
- monitoring drug therapy with anti-inflammatory agents
-determining active phases of RA
What is the response time for C-reactive protein?
4-6 hours
What is the normal concentration of c-reactive protein?
0.5 mg/dl
How much can c-reactive proteins increase?
1000 x
What are the functions of C-reactive protein?
① ospinization
② complement activation
What is the response time for serum amyloid A?
24 hours
How much can serum amyloid A increase by?
1000X
What is the function of serum amyloid A?
Activates monocytes and macrophages
What is the response time for alpha1- antitrypsin?
24 hours
What is the normal concentration for alpha1- antitrypsin?
200-400 mg/dl
What is the function MAIN of alpha1- antitrypsin?
Proteases inhibitor
What is the response time for fibrinogen?
24 hours
How much can fibrinogen increase by?
2-5x
What is the function of fibrinogen?
Clot formation
What is the response time for haptoglobin?
24 hours
How much can haptoglobin increase by?
2- 10x
What is the function of haptoglobin?
Binds hemoglobin
What is the response time for ceruloplasmin?
48-72 hours
How much can ceruloplasmin be increased by?
2x
What is the function of ceruloplasmin?
Binds cooper and oxidizes iron
What is complement C3 response time?
48- 72 hours
What is the normal concentration for complement C3?
60-140 mg/dl
How much can complement C3 increase by?
2x
What are the functions of complement C3?
①opsonization
② lysis
What causes increased vasodilation and vasopermability?
Inflammation
Are all immunogen antigens?
Yes
Are all antigens immunogens?
No
What is a distinct difference between immunogen and antigen?
Immunogens successfully stimulate an immune response
What are factors that influence an antigens immunogenicity?
- Can arise from host
-outbred/unique traits
-age, health, genetics
-dosage and route of exposure
-not all antigens are equivalentin their ability to stimulate an immune response
What is immunogenicity?
The ability of an antigen to stimulate a immune response
What factors affect the strength of immunogenicity?
① macromolecule size
② foreignness
③the ability to be processed and presented with MHC molecules
④chemical composition
⑤ molecular complexity
How large does an immunogen have to be recognized by the immune system?
10,000 daltons, (the larger, the more potent)
What occurs to prevent the immune system from attacking the body’s own cells and tissues?
- Lymphocytes are selected during development to ensure that the pool of mature lymphocytes responds only to antigens not recognized as self
The more taxonomically distant an antigen is from the host, the greater the likelihood that host lymphocytes will do what?
React to it
What are the most effective immunogens?
- Proteins (strongest)
-polysaccharides
Explain the structure of proteins
- Composed of subunits known as amino acids that are covalently linked together in polypeptide chains of various lengths
Describe the structure of a proteins primary structure?
structure made up of subunits of amino acids and covalently linked together in polypeptide chains in varying links
Describe the structure of proteins secondary structure?
Interactions between amino acids within primary structure causes chain to band/kink/ loop creating 3D shapes
What are the two common secondary structures found in proteins?
①alpha-helices
②beta- pleated sheets
Describe the alpha- helices in secondary structure of protein
Peptide chains that twist to form a spiral
Describe the beta pleated sheet secondary structure proteins
Chains of undulating zig zags that have a planar shape
Describe the tertiary structure of proteins
Secondary fold upon themselves once again, bringing distant regions of amino acid chains together and embodying the 3D orientation of the entire molecule
Describe the quaternary level of proteins
Two or more polypeptide chains come together,forming a multimeric unit.
How do activating receptors of T cells react with certain proteins?
-detect small fragments of protein (peptides) and rely on MHC molecules to cradle these peptides for antigen recognition to occur
- “sees” the primary structures
How do activating receptors of B cells react with certain proteins?
-by binding to amino acids on a proteins exterior
- “sees” tertiary and quaternary structures of a protein
An effective B cell response to most antigens requires “help” from what?
-T cells
-they must be activated so they can provide necessary physical and chemical signals to B cells
Why are polysaccharides less immunogenic than proteins?
-their small size
-T cells do not recognize carbohydrates
As immunogens, carbohydrates most often occur in what form?
- Glycolipids
-glycoproteins
What are not immunogenic by themselves?
- Pure nucleic acids
- lipids
What is required for a substance to elicit an immune response?
-must be subject to antigen processing
What is antigen processing?
-involves enzymatic digestion to create small peptides that can be completed by MHC molecules for presentation to responsiveness of an specific antigen
What is a haptan?
A substance that isn’t immunogenic by itself but is able to form a new antigenic determinant when combined with larger carrier molecule
Are haptens considered a antigen or an immunogen?
Antigen
What do haptens do once bound to a carrier?
Initiates production of antibodies that can react with the hapten even in the absence of the carrier
Who discovered ABO blood groups?
Karl Landsteiner
What is an epitope?
-part of antigen that hosts immune system recognizes, eliciting the immune response to an invading pathogen
- specifically binds to the corresponding antigen receptor on the immune cell
What are the two types of epitopes that B cells recognize?
① linear epitopes
② conformational epitopes
Describe linear epitopes
Consist of sequential amino acids on a single polypeptide chain
Describe conformational epitopes
Results from the folding of one or more polypeptide chains, bringing together amino acids that may distant fromeach other so that they are recognized together
What does triggering of a B cell response require?
-Epitopes found on the surface of a molecule
-accessible to the cell receptors, and that these sites contain more than one copy of epitopes so that cross- linking of B-cell receptors may occur
What is an autoantigen
-antigens that belong to host
- does not evoke an immune response under normal circumstances
What happens if an immune response does occur to autoantigens?
May result in autoimmune disease
What is an alloantigen?
From other members of the hosts species and are capable of eliciting an immune response
When are alloantigens important to consider?
-tissue transplant
-blood transfusion
What is a heteroantigen?
From other species, such as other animals, plants or microorganisms
What is a heterophil antigen?
- Heteroantigens that exist in unrelated plants or animals but are either identical or closely related in structures so that an antibody against either antigen will cross-react with each other
What is an important consideration in selecting the correct blood type for blood transfusions?
- The presence of naturally occurring antibodies
Describe the first laboratory assay for infectious mononucleosis (IM)
-based on a heterophil antibody reaction
- found to react with sheep RBC
- causative agent in Epstein Barr virus
Describe the current rapid screening tests for IM
-detect heterophil antibodies presentin the serum of infected patients that cross react with horse or bovine RBC antigens
How did MHC molecules get their name?
-they determine whether transplanted tissues is histocompatible and accepted by the recipientor if it is recognized as foreign and rejected
Where are MHC molecules Found?
- on all nucleated cells
What do MHC molecules play a pivotal role in?
-the developmentof both humoral and cell-mediated immunity
What is the main immune function of MHC molecules?
-Bring antigens to the cell surface for recognition by the T cells.
-only when the antigen is combined with the MHC molecules does the T cell activation occur
What is B cell recognition?
Surface receptors bind to antigen directly
What is T cell recognition?
Requires antigens to be cradled within MHC molecules
What are MHC molecules encoded by?
The most polymorphic gene system found in humans
Where does gene coding for MHC molecules in humans occur?
On short arm of chromosome 6 and are divided into 3 classes
Where are class I MHC molecules genes found?
-3 loci’s
- A, B, and C
Where are class II MHC molecule genes found?
-D region
-broken down into DR, DQ, and DP
How is gene coding of class I and class II MHC molecules different?
-class I → only one gene coding for each particular molecule
-class II → have one gene that codes for the alpha-chain of the molecule and one or more genes that codes for beta-chain
Where are class III MHC molecules found?
Lies between the class I and class II regions on chromosome 6
What complement proteins does class III genes code for?
- C4a
-C4b
-C2
-B
-TNF
Describe class III MHC molecules
-are secreted protein that have an immune function, but they are not expressed on cell surfaces
Why is the MHC system described as highly polymorphic?
There are so many possible alleles at each location.
What is codominant
All alleles that an individual inherits code for products that are expressed on cells
What is a haplotype?
- Group of alleles in an organism that are inherited together from a single parent
-one haplotype is inherited from each parent
Why does the uniqueness of the HLA antigens cause a major problem when matching organ donors to recipients?
The antigens are highly immunogenic
What is a helpful identification tool in paternity cases?
Polymorphisms
Where are class I MHC molecules found?
-on all nucleated cells
-levels of expression can vary among various cell types
Where are class II MHC molecules found?
Primarily on antigen- presenting cells (APC)
Class I expression is highest on what cells?
- Lymphocytes
- myeloid cells
Class I expression is lowest/nonexistent on what cells?
-liver hepatocytes
-neural cells
-muscle cells
- sperm
What are the most important class I MHC antigens to match for transplantation?
-HLA-A antigens
-HLA-B antigens
Describe class I antigens structure
Glycoprotein dimer made up of two noncovalently linked polypeptide chains
What is the weight of the class I alpha chain?
44,000 daltons
What is the weight of the class I beta2-microglobulin chain?
12,000 daltons
Explain the folding of the class I alpha chain
-fold into 3 domains: alpha 1, alpha 2, and alpha 3
- its inserted into the cell membrane via a hydrophobic transmembrane segement
What do the 3 external domains of class I alpha chain consist of?
90 amino acids each
Describe the transmembrane domain of the class I alpha chain?
- Has 25 hydrophobic amino acids along with short stretch of about 5 hydrophilic amino acids, as well as an anchor of 30 amino acids
Give a brief description of beta2-microglobulin
- Does not penetrate cell membrane
- essential for proper folding of the alpha chain
What structure can be found in alpha1 and alpha2 domains of class I MHC molecules?
Alpha-helix
What happens to the alpha helixes in the tertiary structure of molecules?
- Brought to together to form the walls of a deep grove
-this functions as peptide binding site (able t hold peptides between 8-11 amino acids long)
Where does the most polymorphism reside in a class I MHC molecules?
Alpha1 and alpha2 regions
Describe HLA-E and HLA-F
-non classical I class MHC that are generally not expressed on the surfaces of calls and don’t present peptide to cytotoxic T cells
- they do play an important role in immunity
Describe HLA-G
Primarily expressed on fetal trophoblasts during first trimester of pregnancy
What APCs have class II molecules?
-B cells
- dendritic cells
- macrophages
-monocytes
What are the major class II molecules?
HLA-DP
HLA-DQ
HLA-DR
Describe class II molecules structure
-consists of two noncovalently bound polypeptide chains that are encoded by separate genes in the MHC gene complex
- this protein structure is called a heterodimer
- comprises of two dissimilar polypeptide chains
What HLA-D region is expressed at the highest level and why?
-HLA-DR
- it accounts for about one-half of all the class II molecules found on a particular cell
What gene in class II MHC molecules is the most polymorphic?
-HLA-DR beta
- over 3,300 different alleles are known at this time
What gene in class II MHC molecules is found in short supply?
HLA-DP
How many domains are in the alpha chain and beta chain of class II MHC molecules?
-two domains each
-numbered 1and 2
Describe the heterodimic quaternary structure of class II MHC molecules
- The alpha1 and beta1 domains each contribute an alpha helix, forming the peptide binding sites
-both ends of peptide binding sites are sites are open, allowing capture of longer peptides
What are the non classical class II MHC genes?
HLA-DM
HLA-DN
HLA-DO
Describe the nonclassical class II MHC genes HLA-D
- Play regulatory role in antigen processing
-DM help to load peptides onto class II molecules
-DO modulates antigen binding
DN is unknown
Describe antigen presentation
Process by which peptide fragments derived from degraded proteins are transported to the plasma membrane, allowing recognition by T lymphocytes
What does the class I MHC molecules mainly present?
Cytoplasmic peptide antigens to CD8 T cells (cytotoxic)
What does the class II MHC molecule mainly present?
-extracellular antigens to CD4 T cells ( helper)
What is the function of class I MHC molecule?
Watchdogs of viral, tumor and intracellular bodies
What is the function of class II MHC molecule?
-help to mount an immune response to bacterial infections or other pathogens usually found outside of cells
In either class of MHC molecules, what needs to occur for a T cell response to be triggered?
-peptides must be available in adequate supply for MHC molecule to bind
- must be able to bind effectively
-they must be recognized by a T-cell receptor
Describe modern transplant HLA testing
-involves the use of molecular techniques to determine the MHC types of both donor and recipient
-also, serological testingto detect the presence of antibodies in the recipient targeting the MHC molecules of potential donor
What could happen when an individual inherits certain HLA types?
May predispose individuals to the development of autoimmunity
If an individual suffers from allergies, how does knowing a persons MHC type help?
May help predict type of allergens
What is ankylosing spondylitis?
Inflammation of the vertebrae spine
What is the HLA allele for ankylosing spondylitis? And the strength?
- B27
+++
What are symptoms of celiac disease?
- Intolerance to gluten
- diarrhea
- weight loss
What is the HLA allele for celiac disease? And the strength?
-DQ2
-DQ8
++++
What is rheumatoid arthritis?
Inflammation of multiple joints
What is the HLA allele for rheumatoid arthritis ? And the strength?
DR4
+
Describe type I diabetes
Increase in blood glucose because of destruction of insulin- producing cells
What is the HLA allele for type I diabetes?
-DQ8
-DQ2
++++
Why is the class I MHC presentation pathway also referred to as endogenous pathway of antigen presentation?
Both the peptides and MHC molecules arise from within the same cell
Describe the endogenous peptide antigens presented by class I MHC molecules
-class I MHC represents a sampling of the many polypeptide chains that compose the proteins found within the cells
-these peptides derive from host proteins
Describe the class I MHC presentation pathway
Provides cytotoxic T cells as a means of survelliancing the interiors of cells through out the body, allowing T cells to search for peptides associated with infection or malignancy
What are the steps of class I MHC presentation pathway?
① endogenous antigen within cytosol is degraded by proteasome
②peptides are transported into endoplasmic reticulum by TAP
③alpha chain of class I MHC binds B2-microglobulin
④alpha chain of class I MHC binds peptides
⑤peptide- class I MHC transported to Golgi complex and then to cell surface
⑥class I MHC peptides binds to CD8+ T cells
What is the most important chaperon protein in the class I MHC presentation pathway?
Calnexin → stabilizes the alpha chain until it binds to B2- microglobulin
Describe the 2 less significant chaperone proteins in the class I MHC presentation pathway
- Calreticulin
- tapasin
What happens once synthesis of class I MHC molecules is complete?
-their antigen-binding sites are oriented toward the interior of the endoplasmic reticulum
What are two transporters associated with antigen processing ? How are they essential?
-TAP1 and TAP2
-essential for shuttle antigen peptides into the lumen of the endoplasmic reticulum, allowing peptides to interact with newly formed class I MHC molecules
Describe TAP-driven translocation
- Dependent on ATP
- most efficient for peptides of 8 to 16 amino acids in length
- tapasin ,proton that bridges transporter and MHC, so that peptides can be directly loaded
- once alpha chain has bound the peptide,the class I MHC peptide complex is rapidly transported to the cell surface
What does class I MHC presentation pathway generate?
- Thousands of peptidesfrom proteins that have undergone proteasonal digestion, but only small fraction of these will actually become antigens
What variables dictate the binding of peptides to class I MHC molecules?
①length of peptide chain. Binding groove is closed and can only accommodate peptides no longer than 11 amino acids
②determine by complementary noncovalent interactions between peptide and the amino acids compromising of alpha helices that form
Binding groove
③different class I molecules have slightly different binding affinities, and these small differences determine the particular antigens to which an individualwill respond
How many copies estimated to be expressed in a single cell of class I MHC molecules surface?
100,000 - 200,000 copies
Describe the peptides of a healthy class I MHC molecules ?
All class I molecules contain self- peptides that are ignored by patrolling T cells
Describe the peptides of a diseased class I MHC molecules?
Some of the peptides displayed originate from microbial proteins or proteins associated with cancer
What is an immunogen?
A substance that reacts with an antibody or sensitized cell but always triggers an immune response
Where is the “foreignness” of an immunogen acquired from?
From lymphocytes in the primary lymphoid organs
What must occur for the MHC molecules of immunogens to be recognized?
Must be subject to enzymatic digestion
What is an adjuvant?
-Substances delivered simultaneously with an antigen to enhance the immune response; used in vaccines
-also prevents antigen from diffusing more immune cells to the injection site of inoculation
What does an adjuvant stimulate?
Innate immune receptors
What does longer response times with adjuvants do?
Attracts more immune cells to the injection site and increase protective immunity
What is an allele?
Alternate forms of a gene that code for a slightly different variety of the same product
What allows CD8+ T cells to continuously check the bodies cells for the presence of nonself antigen?
The display of thousands of class I molecules complexed to antigen
Describe class II MHC molecules
presentation of exogenous antigens to T cells, that is, peptide antigens that are derived from proteins found outside of the presenting cell
What needs to occur for presentation of exogenous antigens?
- Extracellular proteins accumulate within the lumen of the vesicle, resulting in peptide chains of 13 to 18 amino acids in size
Where are class II MHC moleculessynthesized?
Rough endoplasmic reticulum
What protein is associated with class II MHC molecules?
-the invariant chain → a 31-kDa protein present in great excess of the actual number of class II molecules being synthesized
What is required during production of class II MHC molecules? Why?
-the invariant chain (li)
-to prevent endogenous peptides from binding to class II peptide binding groove
Describe the invariant chain
- Serves as placeholder,ensuring that only exogenous peptide antigens will be bound to MHC II molecules
-aid in bringing alpha and beta chains together
What are the steps of class II MHC molecules presentation nothway?
① class II MHC binds invariant chain to block binding of endogenous antigen
② MHC complex goes through Golgi complex
③invariant chain is degraded, leaving CLIP fragment
④exogenous antigentaken in and degraded and routed to intracellular vesicle
⑤ CLIP fragment exchanged for antigenic peptide
⑥ class II MHC antigenic peptide is transported to cell surface
⑦ class II MHC peptide complex binds to CD4+ T cell
How is the binding groove different between class I and class II?
-class I binding groove is closed on both ends
-class II binding groove is open and can accommodated up to 30 amino acids
What is the difference between class I and class II peptide binding locations?
- Class I → occurs mostly at the amino and carbonyl terminal ends
-class II →hydrogen bonding occurs along the length of the captured peptide
Describe class II binding groove structure
- Open ends
-have pockets that can accommodate amino acids with large side chains, giving class II molecule greater flexibility in the variety of peptides that can bound
Describe helper T cells
-recognize antigen along with class II MHC protein
- Orchestrate the adaptive immune response, influencing activities of other immune cells
-express CD4 receptors
Once an antibody response is generated, haptens are capable of reacting with that antibody. Will precipitation or agglutination reactions occurr? why or why not?
Precipitation and agglutination will not occur because the complexes formed are too small.
What is a key portion of the antigens?
Epitope
How do adjuvants work?
Acts by activating innate immune cells
What is the most polymorphic gene system in humans?
HLA system
What is the function of cytotoxic T cells?
To kill cells infected with intracellular pathogens, such as viruses, bacteria, and cancerous cells
What is the function of T helper cells?
- Control the immune response through the secretion of cytokines or signaling molecules that allow communication between immune cells
What cell is responsible for producing antibodies?
B cells
What are the roles of antibodies in immunity?
① labeling targets for ingestion by phagocytes
② rendering viruses and toxins inert through neutralization
③ blocking adhesion of microbes to body tissues
What is the major difference between lymphocytes of adaptive and innate immunity?
- Gene coding for the primary receptors that activate lymphocytes under goes rearrangement during early stages of T cells or B cells development
Describe clonal expansion when infection occurs
Only lymphocytes responsive to epitopes found on/in the invading pathogens are activated and proliferate
Why is it called clonal expansion?
Proliferating lymphocytes give rise to populations of cells with genetically receptors that are specific for the same epitopeand these populations therefore represents clones of each other
Why is the delay between an initial infection and an effective adaptive response?
Because a handful of pathogen- responsive lymphocytes must undergo a massive clonal expansion before reaching the large number of effector cells needed to alter the course of an infection
What is mostly generated during clonal expansion between the innate and adaptive response?
- Effector cells
- a portion of the clones become memory cells
What are effector cells?
- Either T cells that secrete cytokines or cytotoxic
-OR B cells that produce antibodies
Describe memory cells
-enter quiescent state and become long-lived
-lie in wait for reinfection with same microbe
- when they encounter their specific epitope, they activate rapidly, resulting in faster response of greater magnitude than the primary response
Describe lymphocytes differentiation
- Production of lymphocytes by the body
- begins in early fetal development because basic adaptive immunity must be in place by birth
-progenitors of t and B cells appear in fetal liver as early as 8 weeks of pregnancy
Later in fetal development, what becomes the source of new lymphocytes?
- Bone marrow
-remains primary producer of hematopoietic cells at birth and through adult life
Describe when progenitor cell divides into two
One resulting daughter cell begins to take on the characteristics of lymphocytes where as the other dangther cell retains the stem cell
What happens once a T cell precursors formation is complete in the bone marrow?
Transported to the thymus by circulating blood
Describe the thymus’s location
- Located in the upper thorax, roughly between sternum and heart.
What are the two histologically distinct regions of the thymus?
- Outer cortex
- inner medulla
What are the T cell precusors called once they are in the thymus?
Thymocytes
Where do thymocytes enter the thymus?
Cortico-medullary junction
What do thymocytes do once they enter the thymus?
-immediately begin to migrate toward the thymus cortex under the direction of chemokines
How long does is take thymocytes to migrate from the cortex? Where do they migrate?
- Over a 3 week period
-to the medulla of the thymus
What processes occur over the 3 week period when thymocytes migrate from the context to the medulla?
①rearrangement of the T cell receptors (TCR) genes
②changes in the expression of thymocyte cell surface markers
③the selection of thymocytes with functional receptors
④The deletion of thymocytes with self-reactive potential
What is critical for the differentiation processes for Thymocytes?
-interaction with stromal cells within the thymus
-includes macrophages, dendritic cells, fibroblasts, and thyme epithelial cells
What are the stages of T cell development?
-double negative stage
-double positive stage
- mature T cells
Describe T-cell receptor structure (TCR)
- Composed of two transmembrane proteins: alpha and beta
- each chain possess 3 domains and I variable region
What are the 3 domains on each chain of TCR BY?
-intracellular signaling domain
- membrane spanning domain
- extracellular domain
What is the role of variable regions of TCR?
Responsible for recognition of antigens and are therefore the only portions of TCR genes that undergo rearrangement.
The gene encoding the variable region of the TCR beta chain are divided into 3 large sections. What are they called? What chromosome dues this occur on?
-V
-D
-J
- chromosome 7
What are early thymocytes called? Why?
- Double negative thymocytes
-thymocytes lack both CD4 and CD8
What do double negative thymocytes do?
Aggregate in the outer cortex of thymus, where the actively proliferate of the cytokines, such as IL-7
When does rearrangement of gene coding for the TCR begin?
During double negative (DN) stage of t cell development
Explain the gene coding for the DN stage of T cell development
- Shuffling and altering or TCR genes result in the expression of a unique antigen receptor by each individual thymocyte
What happens during rearrangement of the double negative stage?
Enzymes activated in DN thymocytes clip genome DNA and begin stitching it back together in a way that randomly aligns one V segment, one D segment, one J segment, and a segment encoding the constant region
In case where rearrangement leads to a faulty TCR beta chain, developing T cells employ two strategies aimed at generating functional proteins. What are these strategies?
① because T cells are diploids, the beta chain genes on both copies of chromosome 7 simultaneously under go rearrangement, doubling the probability of a functional beta chain being produced
② the enzymes that mediate TCR gene rearrangement continue clipping and stitching variable - region DNA until a functional TCR is generated
What happens when the DN thymocytes express a functional beta chain?
The pre-TCR provides survival signals to the T cells differentiation, known as double positive stage
What dues it mean when gamma and delta chains appear on TCR beta?
There was not a productive rearrangement of DNA coding for a beta chain
Describe gamma-delta T cells
Unique population of T lymphocytes proceeds down an alternative developmental pathway typically remaining negative for both CD4 and CD8
What does successful pre-TCR signaling allow?
Allows developing thymocytes to cross a developmental threshold, initiating rearrangement of TCR alpha chain
What is the alpha chain gene variable regions divided into?
-one V segment
-one J segment
What happens when there is an appearance of a functional alpha chain on cell surface?
- Sends signal to suppress any further TCR gene rearrangements
- concurrently, thymocytes become both CD4+ and CD8+
Describe the CD3/TCR complex
-TCR alpha and beta chains occur in this complex with 6 other molecules common to all T -cells
-6 chain of nonspecific CD3 portion of the complex assist in intracellular signaling when an antigen binds to the TCR
The CD3 complex chains occur in 3 pairs. What are the 3 pairs?
-delta-epsilon
-gamma - epsilon
-tau-tau
What type of antigen is not recognized alone by T cell receptors?
Peptide antigens
How are peptide antigens recognized by the T cell receptors is they cannot be recognized alone?
-peptide antigen must be held in an MHC molecule or “presented” to T cells, a requirement known as MHC restriction
-this property is established during DP stage of thymocyte development
Describe thymocytes encounter with stromal cells
- Occurs during DP stage
-encounter occurs in the thyme cortex that express MHC class I and II proteins
-these initial interactions determine the thymocytes fate: high affinity MHC molecule will fail to bind and die by apoptosis
What CD markers are expressed in the DP stage of thymocytes?
- Both are expressed
-depending on which class of MHC molecule a positively selected thymocyte recognizes, the expression of the opposite marker begins to decrease sustainability
What CD marker is expressed on MHC I?
CD8
What CD marker is expressed on MHC II?
CD4
Where does negative selection occur?
In the corticomedullary and medulla region of the thymus
Describe the stromal cell activity in negative selection
- Express a variety of self-antigens to positively selected thymocytes
-A strong reaction between TCR and any of the self- peptides presented by stromal cells indicates a high potential for autoreactivity
What prevents self reactive T cells from leaving thymus?
Thymocytes with strongly binding TCR are negatively selected and undergo apoptosis
When is a T cell considered mature?
When it exits the thymus
What is a “naive” mature T cell?
- Mature T cell that have not yet encountered the specific peptide epitope recognized by their TCR
-to enhance probability of a mature naïve T cell encountering its specific antigen, these cells recirculate between the blood stream and lymphatics
What influence which cytokines are produced by the Th cells?
The signals found within the environment where Th cell activation occurs which cytokines are released
What are B cells derived from?
Hematopoietic stem cell
What is antigen- independent phase?
-first phase of B cell development in bone marrow that result in mature B- cells that have not been exposed to antigens
What are the subpopulations of antigen independent phase?
- Pro-B cells
-pre-B cells
-immature B cells - mature B cells
What is antigen dependent phase?
- if B cells ave stimulated by antigen, it undergoes transformation to a blast stage that forms memory cells and plasma cells
Describe pro B cells
- Stage in B -cell development in which rearrangement of the genes that codefor the heavy-chain region of an antibody occurs
-b-cell progenitors receive signals from bone marrow stromal call to cell contact as well as soluble cytokines (such as IL -7)
What is the earliest developmental stage of B cells?
Pro B cells
What are important transcription factors expressed within pro-B?
-E2A
-easy b-cell factor (EBF)
-interferon regulatory factor 8 (IFR8)
- paired box protein 5 (PAX5)
What is one of the most important events of the pro B cell phase?
Rearrangement of the B- cell receptor (BCR) genes
Describe B-call receptors (BCR)¡
Simply a cell surface version of an immunoglobulin or antibody molecules
What are the similarties of BCR and TCR?
①composed of a different chains
②have variable regions which determine their specificity
③ have constant regions, which allow for intracellular signaling activation of the lymphocyte expressing them
④ have similar gene regions (V, D, and J)
⑤use similar mechanisms for gene rearrangement
What are the two chains in BCR?
Light and heavy
What genes in BCR contain multiple V, D, and J segments?
Heavy chain genes
Like TCR, what occurs once heavy-chain rearrangement is completed successfully on one chromosome?
- Allelic exclusion silences expression of the heavy chain gene on the opposite chromosome
What needs to occur for a pro-B cell to progress to the next phase of differentiation?
At least one heavy chain gene must undergo successful rearrangement
Describe the pre-B cell phase
The stage of B cell development where the heavy chain part of the antibody molecule is present
How are pre-BCRs formed?
- Some heavy chains travel to cell surface and combine with a surrogate light chain as well as two shorter chains, Ig - alpha and lg- beta, which are signal- transacting subunits to form pre-BCR
What happens to pre-B cells before they assemble the pre-BCR?
Undergo several rounds of cell division resulting in many clones of original cell, all of which express an identical heavy chain
What occurs simultaneously with the appearance of the pre-BCR at the cell surface?
Light chain gene rearrangement begin
What are the two types of light chains possessed by humans?
-kappa
- lambda
Similar to TCR alpha genes, the kappa and lambda light chains are composed of what?
V and J segments
What happens to V segments, J segments and light chain constant region during rearrangement?
-these segments are stitched together
What occurs once successfully rearranged light chains are expressed?
-macromolecular complexes comprised of two light chains and two heavy chains formed
-immunoglobulins are fastened together by disulfide bonds and journey to the cell surface to replace the pre-BCR
What is the first immunoglobulin produced?
IgM
What signifies the pre-B cells entry into the next phase, immature B cells?
The appearance of a functional BCR on the b-cell surface
What does the appearance of a functional IgM BCR on the cell surface indicate?
-rearrangement of the genes encoding the receptors is now complete and that a new B cell exists with the potential to produce antibody for a specific and unique epitope.
What determines the antigen specificity of immature B cell and its IgM BCR?
The immunoglobulin variable region, found on both the light and heavy chains
What happens to prevent BCRs from responding to self- antigens?
Negative selection
What happen when the B cell reaches maturity?
B-cells respond to binding of antigen to the BCR by activation, proliferation, and antibody production
What is the reaction of immature B cells when signaled?
Halting their development and undergoing apoptosis
What is central tolerance?
- Elimination of B cells that bear self -reactive receptors
- it is estimated that more than 90% of B-cells die in this manner
What surface markers begin to make an appearance during the immature B cell phase?
-IgM
-CD21
-CD40
- class II MHC molecules
Why ave cell surface markers of an immature B cell phase important?
- Useful for laboratory identification of B cells
- also essential to The function of B cells - especially
Their role in antigen presentation to CD4+ Th cells
Describe the CD21 cell surface marker
-acts as a receptor for a breakdown product of the complement component C3 ( known as CD3)
- presence enhances the likelihood of contact between B cells and antigens frequently become coated with complement fragments during the immune response
When is a B cell considered mature?
Expresses a functional IgM BCR, survives selection by not reacting to self antigens and begins to display certain B cell markers
What happens once a b-cell is considered mature?
- Exit the bone marrow and are carried in the blood to the spleen for next stage of development
What are the two types of mature B cells that develop in the spleen?
-follicular B cells
- marginal-zone B611
Where can follicular B cells be found?
- Constantly recirculate between blood and secondary lymphoid organs in search of their specific antigens
Where can marginal-zone B cells be found?
Remain in spleen to respond quickly to blood- borne pathogens
The majority of mature B cells are destined to be what type of B cell?
Follicular B cells
What does follicular refer to?
To the region of the lymph mode where this type of B cell tends to localize
Describe lymphoid follicles
- Represent dense clusters of naïve B cells awaiting exposure to their specific antigens
Describe follicular B cell activity during antigen recognition
Follicular B cells make contact with CD4 + follicular helper cells
Why is cooperation between antigen activated B cells and Tfh cells critical?
Formation of immunologic memory
Where in the spleen are marginal-zone B cells located?
Marginal sinus
What happens when marginal-zone B cells contact their specific antigen?
They differentiate into IgM secreting plasma cells, each producing vast quantities of anti- microbial IgM and only stopping once the invading microbes have been eliminated
-response must begin a new upon each exposure to a particular polysaccharide antigen.
What does the presence of both lgM and IgD on the cell membrane signify?
A mature B cell
What occurs when a BCR binds to its specific antigen?
-multiple BCR molecules are brought together, initiating an intracellular signaling cascade
-these signals drive the B cell to enter a proliferative stage where it divides rapidly to produce both antibody- secreting plasma cells and for follicular B cells, memory B cells
What are plasma cells role?
A differentiated B cell that actively secretes antibodies
Where would immunoglobulins be found in plasma cells?
-little expressed on cell surface but has abundant cytoplasmic immunoglobulin
What do plasma cells have to accommodate translation and post-translational processing the large quantity of antibodies?
Possess ample endoplasmic reticulum and a well defined Golgi
What is a common resident of bore marrow and the germinal centers of peripheral lymphoid organs?
Plasma cells
How do plasma cells survive in the bone marrow?
-plasma cells survive in bone marrow niches surroundedby stromal cells, which provided stimulation to plasma cells via cytokines
- stromal en support allows plasma pens to being long lived and fosters their continual production of antibodies
What is a key surface marker found on plasma calls?
CD138
What happens when an infection occurs in the body tissues?
-APCs such as macrophages and dendritic cells, are among the first immune cells to respond
- APCs engulf pathogens at these distal sites of infection and carry associated antigensto local lymph nodes
What happens upon the arrival of APCs at the lymph nodes near the site of infection?
- Antigen- laden APCs encounter naive T cells in the process of patrolling for antigen.
What does the continuous recirculation of naive B cells between the blood and lymph nodes greatly increase the chance of?
The likelihood of an APC connecting with one or move of the few T cells whose TCRs recognize the antigen carried by the APC
What is the primary mode of communication between T cells and APCs?
Direct cell to cell contact
Describe antigen presentation of APCs?
- Display peptide antigens to T cells via MHC
-MHC molecules antigenic peptides and allow the TCR to bind along the entire length of the peptide
What do class I MHC molecules present in a healthy cells ?
Peptide antigens derived from cytoplasmic sources such as endogenous peptides manufactured by healthy cells
What do class I MHC molecules present in diseased cells?
Peptides associated with intracellular bacteria, viruses, or even proteins associated with cancer
What type of cell does class I MHC molecule antigens present to?
- Cytotoxic T cells
What T cell population most useful for destroying malignant cells or infected cells?
Cytotoxic T cells
The interaction between the cytotoxic TCRand class I MHC is stabilized by what?
CD8
What do class II MHC molecules present in healthy cells ?
- Peptides captured from the extracellular space, such as those derived from extracellular microbes
-allow APCs to present such extra cellular derived peptide antigens to Th cells
What additional protein is required to stabilize the interaction between class II MHC molecule and Th TCR?
CD4
CD4 is commonly used as a marker to identify what type of cell?
Th cell
What happee3ns when a naive T cell enters secondary lymphoid tissues and encounters APCs?
-multiple contacts occur between the T cells TCR and peptides presented in MHC molecules on the surfaces of APCs
-if TCR recognize one of the many antigens being presented by an APC, an infracellular signaling cascade is initiated within the T cell
Will TCR signaling activate a naive T cell?
- No, for activation to occur, the APC must also provide costimulation to the T cell by expressing CD80 and CD86
What do CD80 and CD86 legate?
-CD28, T cell surface protein
What transforms a naive T call to on activated T cell?
-The combination of signals that arises when the TCR recognizes its specific peptide and CD28 is ligated
Why are Th cells considered the most important cells of the adaptive response?
- Role in driving activities of other immune cons that act directly fight infection
-when activated by APCs,Th cells travel to infected tissues orchestrate the immune response via the secretions of cytokines
What are the most prominent subsets of Th cells?
Th1
Th2
Th17
What influence the type of Th cell subset that is produced after differentiation?
Influenced by the cytokines present during activation
Describe role of Th1
-produce INF-gamma, IL-2, and TNF-alpha which protect cells against intracellular pathogens by activating cytotoxic lymphocytes and macrophages
Describe role of Th2
-essential role is to help B cells produce antibodies against extracellular pathogens and to generally regulate B cell activity
-produce a variety of cytokines, including IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13
-also thought to play a role in allergies
Describe the role of Th17
- Produce cytokines IL-17 and IL-22, which lead to the recruitment of granulocytes in response to an extracellular bacterial infection damage
Why is the Th17 response often associated with pathology?
The granulocytes activity can sometimes cause immune-mediated damage
Describe T regulatory cells (Treg cells)?
- Subset of T cell
- possess the CD4 and CD25 antigens
-play important role in suppressing the immune response to self-antigens and harmless antigens
How do Treg cells suppress the immune response to self and harmless antigens?
They proliferate of other t-cen populations by secreting inhibitory cytokines
Why is the response of Treg cell antigen-specific?t
They possess TCRs that recognize antigenic peptide in MHC class II
How do T follicular helper cells assist B cellsin antibody production?
-remains in lymph nodes and interacts with B cells and plasma cells there
-Tfh cells provide essential signaling to B cells as they undergo processes such as activation immunoglobulin class switching, affinity maturation, and formation of B cells memory
What are the two distinct populations created after cell division of Th cells?
① most Th cells begin to secrete cytokines and may travel to infected tissues where their activities are most needed.
② A small percentage of Th cells generated after activation will differentiate into memory cells
What do memory Th cells du after creation?
-enter a quiescent state and await re-exposure to their specific antigen
-if/when contact with antigen occurs again, memory cells respond rapidly by re-entering cell division and immediately secreting appropriate cytokines
What are the roles of cytotoxic T cell?
-activated cytotoxic T cells migrate to sites of infection and initiate apoptosis in cells infected with intracellular parasites and viruses
-the activity of cytotoxic T cells is driven by TCR recognition and is therefore antigen-specific
There are two primary strategies that are cytotoxic T cells use once recognition of peptide antigen on surface of MHC I occurs. What are these strategies?
①The release of cytotoxic granules from the T-cell cytoplasm
② ligation of death receptors on a target cell surface
-either Case, the target all rapidly undergoes apoptosis
What are the two toxic substances found in cytotoxic T cell granules?
-perforins
-granzymes
Describe now performs and granzymes work together
-TCR recognition of antigen by a cytotoxic T cell cause accumulation of granules in the T cell cytoplasm adjacent to the target cell
-granules are released by the T cell in the direction of the target cell
-almost immediately, perforins begin forming holes in the target cell membrane, through which gránzymes can enter
- once in target cell, granzymes that cleave DNA and disrupts mitochondria. With its genetic material shredded and energy levels dropping, the target cell quietly dies by apoptosis
Describe cytotoxic T cells ability to induce apoptosis by ligation of death receptors
-TCR recognition of antigen complexed with target- cell MHC leads to expression of the death-inducing protein Fas-ligand (FasL) by the T cell
- when FasL binds to Fas on the target cell membrane, apoptopic pathways similar to those activated by the granzymes are set in motion
What is the essential first step in the activation of a mature B cell?
Exposure of the IgM BCR to its specific antigenic epitope
Antigen recognition by the different types of mature B cells occur in different anatomical regions. What are these regions?
- Lymph nodes
- spleen
How did T-dependent antigens get their name?
The follicular B-cell response depends heavily on the activity of Tfh cells to promote an effective antibody response, antigens that provoke this type of response
How did T- independent antigens get their name?
-marginal-zone B cells don’t require the help of Tfh cells
T-dependent antigens are almost always what? Why?
-proteins
-proteins are the only type of antigen that can stimulate a T cell response.
How do protein antigens reach the lymph nodes?
- May travel suspended or dissolved within lymphatic fluid, or they may be carried by macrophages or dendritic cells
-regardless, they arrive at the B cell rich follicles in their state
Explain what happens once a follicular B cell and its specific antigen are united
- The BCR locates its epitope and binds the antigen securely via surface immunoglobulin
-BCR antigen recognition initiates a cascade of intracellular signaling within the B cell, driving the cell into an activated state.
What is the response of the B cell cytoskeleton to BCR signaling?
- B cell cytoskeleton is mobilized to internalize the bound antigen using endocytosis
-antigen uptake allows for digestion of the antigen and presentation of its constituents peptides on class II MHC molecules on the B cell surface
What do B cells do after activation?
- B cell migrate to the edges of the follicle, where they ‘ begin to interact with Tfh cells
-in this context, B cells act as APCs, presenting peptide fragments derived from internalized antigen to Tfh cells
-if TCR binding to antigenic peptides occurs, a T cell- B cell pair is formed, and the T- dependent phase of the B cell response begins
How does Tfh cells complement BCR signaling?
Tfh cells provide activated B cells with two additional signals that contribute to the B cell response
What does the first signal provided by the T cell require?
Physical contact between T cells and B cells
What does TCR recognition of peptide antigens cause Tfh cells to do?
To express CD40 ligand which binds to CD40 on B cells
Describe T cells ability to signal B cells through the secretion of cytokines
-T cells secrete IL-2, which secrete CD25 expressed on B cells and spurs them to enter a phase of rapid cell division
-each dangther en produced during this replicative explosion will inherit an identical BCR to that of the parent B cell and will therefore recognize the same antigen
What are the two possible fates of dangther B cells that are produced during proliferative phase of T dependent response?
① some remain in contact with T cells and differentiate into IgM secreting plasma cells
② others form germinal centers within follicles and participate in a series of processes that enhance the antibody response through time
What are the 3 overlapping processes of the germinal center reaction?
① immunoglobulin isotope switching
② activity maturation
③memory cell generation
What does germinal center formation require?
-interaction with T cells, specifically the affiliation of CD40 with CD40L and secretion of cytokines
What is the most common class of immunoglobulin molecule incorporated into BCRs of marginal- zone B cells and follicular B cells before and at very early times after antigen recognition? BY
IgM
Describe IgG
-predominant form of antibody found in blood
-found in intestines and the body’s secretion
-associated with allergies
What is isotype switching?
-under the direction of T cells, germinal center B cells can change which class of antibody they express
-also determines the class of antibody secreted once the B cell differentiates into a plasma cell
What is affinity maturation?
- Immunologlobulins bind antigen with increasing strength (affinity) through the course of an immune response, resulting in the production of even more effective antibodies
- this is accomplished through somatic hypermutation
What is somatic hypermutations?
Appearance of mutations in immunoglobulin gene variable regions
What causes dangther cells to be produced with slightly different antigen -binding abilities?
- Somatic hypermutation
What happens to daughter cells whose BCR have a greater affinity? What about lesser affinity?
-greater affinity for antigen receive survival signals
-lesser affinity for antigen die of apoptosis?
For each generation of daughter cells produced within the germinal center, there are 3 basic populations of cells formed. What are these cells?
①plasma cells
② memory cells
③ B cells that remain in the seminal center to continue the process of affinity maturation
Describe plasma cell activity after being formed
- Plasma cells exit lymph nodes and secrete large quantities of antibody of isotype and affinity achieved during that replicative generation
Describe memory cell activity after being formed
- May remain lymph modes or travel to tissues
-do not require antigen stimulation for survival, allowing them to lie in wait for re-exposure
What happens when a memory B cell is re-exposed to antigen?
It can rapidly respond with the production of high affinity, class-switched antibody
What are the pro-B cell key CD markers?
CD10 and CD19
What are the pre-B cell key CD markers?
CD10, CD19, and CD20
What are the immature B cells key CD markers?
CD10
CD19
CD20
CD21
CD40
What are the mature B cell key CD markers?
CD19
CD20
CD21
CD40
What are the pro-B cell receptors?
None
What is the pre-B cell receptor?
Pre-BCR: immunoglobulin heavy chain and surrogate light chain
What is the immature B cell receptors
Functional BCR: IgM heavy chains and kappa or lambda light chains
What is the mature B cell receptor?
Functional BCR: IgD or IgM heavy chains and kappa and lambda light chains
What is the double negative key CD marker?
CD3
What is the double negative T cell receptors?
None
What are the double positive key CD markers?
CD3
CD4
CD8
What are the double positive T cell receptors
TCR alpha and TCR beta
What are the single positive key CD markers?
CD3
CD4
CD8
What are the single positive T cell receptors?
TCR alpha and TCR beta
What is a characteristic of immune response to a T-independent antigen?
- Antigens are often polysaccharides
How does humoral immunity produce antibodies?
By plasma cells
What is negative selection?
-Process that takes place among surviving DP T cells in the corticomedullary region and the medulla of the thymus
- strong reactions with self-peptides other than MHC antigens triggers apoptosis
What are thymocytes?
Lymphocyte precursors in the thymus that are committed to becoming T cells
Describe immature B cells
A phase in the growth of B cells characterized by the appearance of complete IgM antibody molecules on the cell surface
What are variables?
-Contained by both alpha and beta chains on TCR
- recognizes specific antigens
Describe T-independent antigens
T cell help is required in order for B cellsto respond to antigen
What is MHC restriction?
Selection of thymocytes that will only interact with the MHC antigens found on host cells
What is surrogate light chain?
Consists of two shout polypeptide chains that are noncovalently associated with each other along with two shorter chains, Ig-alpha and Ig-beta
What is allelic exclusion?
Selection of an allele on one chromosome only
What is a cytotoxic T cell?
-Express CD8 receptor
- interact with antigen and class I MHC protein
What is clonal deletion?
Process of elimination of clones of cells that would be capable of an autoimmune response
What are T regulatory cells?
-Possess the CD4 antigen as well as CD25
-play important role in suppressing the immune response to self antigens
Describe cell flow cytometry
Automated system for identifying cells based on the scattering of light as cells flow single file in a stream of fluid by a laser beam
What is positive selection?
Process that takes place when the CD3-alphabeta receptor complex (TCR) is complete and expressed on cell surface that allows only DP cells with functional TCR receptors to survive.
Describe process used by cytotoxic T-cells to kill target cells
Producing granzymes that stimulate apoptosis
Where do germinal centers occur?
Spleen and lymph nodes
What is a distinguishing feature of pre-B cells?
Mu chains in the cytoplasm
What is acute phase reaction that helps to prevent formation of peroxides and free radicals that can cause damage to tissues?
Haptoglobin
What are the 3 characteristics of acute phase reactants?
① rapid increase following infection
② enhancement of phagocytosis
③ nonspecific indicators of inflammation
What are 3 characteristics of on immunogen?
① large molecular weight
② internal complexity
③ presence of numerous epitopes
Where are class II MHC ANTIGENS found?
B cells and macrophages
Pattern recognition receptor act by what?
Recognizing molecules that are unique to pathogens
What type of cells would be found in a primary follicle?
Unstimulated B cells
