Cells, Organs, and Microenvironments of the Immune System Flashcards
What type of stem cell differentiates into all the blood cells needed by the body?
Hematopoietic Stem Cell (HSCs)
Where are HSCs found in the body?
bone marrow of tibia, femur, costal bones, ribs, and sternum
True or False:
All RBCs and WBCs are decedents of HSCs.
True; HSCs are actually rare, but they make SO many cells
1 cell makes 5 x 10^4 cells!
What does multipotent mean?
Broken down, it means “multiple” and “able”, meaning HSC have the potential to become multiple (blood) cells, but not ALL cells
Hematopoiesis
“blood” “making”; process of the generation of blood cells in bone marrow
Why would HSCs need to be highly regulated?
In order to maintain a homeostatic condition; otherwise we would see cancer as a consequence
True or False:
Hematopoiesis elicits small amounts of disease fighting cells during infection via pathogen
False; there would be a HUGE amount of cells due to the initiation of the immune response.
So, hematopoiesis normally elicits a smaller number of cells bc it is not facing infection
What are the two types of common progenitor cells? Which makes the most types of cells?
Common Myeloid Progenitor (CMP); makes the most types of cells
Common Lymphoid Progenitor (CLP)
What types of cells come from CMPs?
- all RBCs
- granulocytes
- platelets
- monocytes
- macrophages
- dendritic cells
What types of cells come from CLPs?
- B cells
- T cells
- NK cells
- dendritic cells
Which progenitor involves innate immunity?
Common myeloid progenitor, as well as NK cells
Which progenitor involves adaptive immunity?
Common lymphoid progenitor cells; these are the lymphocytes
What 3 routes can HSCs take to make more cells and more of itself?
- remain HSC
- become CMP and its decedents
- become CLP and its decendents
Why do both CMP and CLP give rise to dendritic cells?
We don’t really know why, but we can acknowledge the fact that one can make up for other. If dendritic cells of CMP lineage aren’t producing enough, then CLP lineage can make up for that lack. Either way we get dendritic cells to help initiate adaptive immune responses.
Name 3 primary ways blood cells are distinguished.
- Appearance and behavior (histology)
- Flow cytometry (friggin cool)
- Fluorescence microscopy
How do we observe and identify blood cells specifically (referring to histology). How do we physically observe their appearance and behaviors?
Hematoxylin & Eosin (H&E) staining; taking advantage of pH (of cellular compartments)!
What is hemotoxylin?
Basic stain that attracts acidic structures; in this case, the DNA in cell nuclei. That’s why they are always found DEEP PURPLE on histological slides
What is eosin?
Acidic stain that binds to basic structures; in this case, the cytoplasm, vesicular content, connective tissue
What is flow cytometry?
A really cool way to test for and identify cell size, shape, granularity, or surface receptors in a heterogenous mixture of blood cells
Forward scatter = cell size
Side scatter = shape and internal complexity
What does Fluorescence microscopy entail?
Uses fluorescently labelled antibodies or dyes to label specific cells and/or cells structures and observe cell behavior
LIVE cell observation
List the granulocytes
What lineage do they come from?
- Neutrophils
- Eosinophils
- Basophils
- Mast cells
Common myeloid progenitors
Neutrophil
- 40-70% in circulation
- multilobed nuclei/trilobed (deep purple)
- phagocytic
- Neutrophil Extracellular Traps (NETs)
- recruited to site of tissue damage/infection via chemokines; capture and destroy invading pathogens
True or False:
Neutrophil count increases when there is an infection
True; numbers significantly increase. This is a key observation when testing patients for infections or disease
Eosinophil
- 1-4% in circulation
- multilobed nuclei; pink
- phagocytic/anti-parasitic
- attack parasitic infection; collaborate to cluster around pathogen and release granules to digest parasite alive
True or False:
Eosinophil granules are acidic, making their histological appearance purple
False; eosinophils are BASIC, and it is eosin that is attracted to the basic compounds of eosinophils
Result; pink appearance in H&E staining
Basophils
- <1%
- non-lobed; less spherical (deep purple)
- nonphagocytic
- release HISTAMINE from their granules to initiate inflammation due to infection (acidic contents)
- in blood*
Mast Cells
- more abundant than basophils
- non-lobed; spherical (purple)
- basophilic granules full of HISTAMINE
- phagocytic
Where do mast cells get released specifically?
bone marrow
When basophils are released from the bone marrow, are they considered mast cells yet?
Not really. They remain to be undifferentiated cells until they reach their site of maturity
When and where do mast cells mature?
They mature once they take up residence in tissues. It is here where they can finally differentiate into mast cells
In what tissues do we find mast cells?
Skin, connective tissue, and mucosal epithelia of respiratory, genitourinary, and digestive tracts
What wonderful phenomenon do we experience thanks to mast cells doing their jobs?
Allergies; inflammation of those mucosal epithelia our nasal cavity and those pesky peanuts giving us hives
True or False:
Basophils and mast cells have the same origin and differentiate later in development.
False; they are not the same cell in different area of development. They are 2 entirely different cells, not just based on where they are found in the body, but how they appear microscopically
Neutrophil Extracelluar Traps (NETs)
When neutrophils aren’t undergoing phagocytosis, they self-sacrifice and project strands of their OWN DNA to ensnare pathogens (sick)
Why is “leukocytosis” a sign of infection?
It is an increase in circulating neutrophils, which can only be in such great amounts if there is an infection.
What is the primary cell type found in pus?
Neutrophils
NETosis
Form of cell death (apoptosis of neutrophils)
What effects does histamine release have on the body?
Histamine activates inflammation. Although our primary tissues affected by allergies don’t feel super great, it’s the mast cell keeping those pathogen at bay in those tissue using phagocytosis, inflammatory mediators, and making extracellular traps
What granulocyte if primarily responsible for “allergies”?
mast cells; specifically in mucosal epithelia
What is an antigen presenting cell (APC)?
An umbrella term describing a group of cells that function as cellular bridges between innate and adaptive immune systems
What is the purpose of APCs?
APCs PHAGOCYTOSE pathogens at the site of an infection and destroy them. What’s left of that pathogen is kept in the APC and taken to T cells in the lymph, where a T cell participates in the ANTIGEN PRESENTATION of that pathogens antigens, known as MHC II receptors, and if the T-cell is presented with its cognate antigen, it will initiate an ADAPTIVE immune response.
List the types of APCs
- Monocytes
- Macrophages
- Dendritic cells
Monocytes
- 4-8% WBCs
- large nuclei; kidney bean
- agranulocyte
- in blood and tissue (depends on infection)
- can diff. into macrophage or dendritic cell (in tissue)
Macrophages
- express receptors for ANTIBODIES
- engulf opsonized pathogens (previous adaptive immune response)
How are macrophages crazy effective after an adaptive immune response?
Well, the adaptive immune response is already going to give us antibodies against that pathogen from B-cells. If that pathogen comes back, it can be attacked and engulf immediately bc its recognizable now.
When does a monocyte become a macrophage?
When it navigates to a tissue
Dendritic cells
Capture antigen just like any other APCs, BUT their long dendritic extensions make for a large surface area, allowing more interactions with T-cells. This makes dendritic cells THE MOST IMPORTANT APCs bc they are super activators of the adaptive immune response
What APC is the most critical cell connecting innate and adaptive immunity?
Dendritic cells
Which of our 3 APCs activate naïve T cells?
Dendritic cells
What is the relationship between monocytes the other APCs?
A monocyte is in fact an APC that has not differentiated further. Monocytes are in the blood ONLY. Macrophages and dendritic cells are tissue-based APCs.
However, both do very well to efficiently seek and destroy pathogens ONCE coated with antibodies.
What cell type is responsible for forming platelets that are a necessary aspect of blood clot formation?
Megakaryocytes; big Bertha cells found in bone marrow. These guys give rise to THOUSANDS of platelets that circulate in the blood
Cluster of Differentiation molecules
Immune cell receptors/ligands used for identification and investigation of cell surface mlcs that can be measured in situ and from peripheral blood, biopsy sample, or other body fluids bc WBCs look very similar!
Boiling it down, why do we use cluster of differentiation (CD)?
We use them to differentiate between WBC subpopulations
ex: CD4, CD8
Where do activated B cells develop?
Bursa of Fabricus (birds) Bone marrow (mammals)
What do activated B cells do?
- act as APC
- express costimulatory receptors to activate T cells
- Develop in to plasma cells
What happens when B cells become plasma cells?
Those B cells lose their expression of their membrane bound BCRs, and instead they secrete them as ANTIBODIES
True or False:
Secreted BCRs from B cells become antibodies that recognize the same antigen that the previously embedded BCR’s did for that B cell.
True! This allows our body to gain memory to that specific pathogen
How many antibodies are secreted from one B cell every second during this process?
nearly 1000 antibody molecule
True or False:
Plasma cells continue to divide as they secrete their BCRs.
False; plasma cells lose their ability to divide. They have short life spans themselves, BUT, it’s the BCR-now-antibody that can remain in the body in case of future infection of that same pathogen
Where do T cells develop/mature?
Thymus
How do CD4+ T helper cells recognize antigen?
Helper T cells recognize antigens on surfaces of APCs ONLY when there are MHC II receptors on the APC. It is the TCR of the helper T cell that attaches to the nucleated cell with MHC II receptors
True or False:
Helper T cells (CD4+) ONLY recognize APCs.
True
Which T cell looks extracellularly for antigens and which T cell looks intracellularly for antigens?
CD4 look on the surface of APC only
CD8 look inside cell; they can’t be selective like CD4 T cells
When CD4+ cells recognize the right antigen with the MHC II receptor, what happens next?
The helper T cells becomes a variety of T cell subsets (TH1, TH2, TH17)
What is the significance of TH1, TH2, and TH17?
All T cells subsets produced specific cytokines that help activate B cells, CD8 cells, macrophages, and various other cells…this is why they are HELPER T cells
What determines the CD4 T cell subset developed?
It depends on the pathogen AND a person’s genetics. Each subset produces a specific cytokine, and that cytokine elicits a change in the behavior and response of the immune system specific to THAT pathogen/genetic code.
How do CD8+ T cells recognize antigen?
They browse the surface of somatic APCs looking for the right antigen. When they find it, the CD8+ cell activates and becomes effector cytotoxic T cell, eliminating those cells that have the non-self antigen in the MHC I
We know CD8+ T cells look inside cell content for antigens. What pathogens do they look for inside cells?
virus-infected cells
tumor cells
Why can “looking inside” cells be a bad thing clinically?
Tissue transplants can be detrimental in CD8+ T cells can’t recognize the right MHC I bc this tells the CD8+ that this tissue is self. The wrong MHC I can be bad and CD8+ will recognize it as non-self, which is bad news for the patient receiving the transplant.
**What is the only difference between CD4 and CD8 T cells?
It is based on their coreceptors
Which type of cell can be formed from both myeloid progenitor and lymphoid progenitor cells?
Dendritic cells
Is a NK cell an adaptive lymphocyte or an innate lymphocyte?
Innate
How does an NK cell decide which cells to kill?
The decision to kill is based on MHC I receptor being present or not. If it’s not there, they kill it bc it is not self.
NKs can also stud themselves with antibodies to target cells that don’t belong.
True or False:
NK cells express antigen-specific receptors like most lymphoid cells.
False
How does a cytotoxic T cell decide which cells to kill?
They decide to eliminate when cells have non-self antigen in their MHCI, unlike NK cells who do not have a TCR to recognize MHCI, they just have inhibitory receptor that tells them not to kill.
Where does the majority of hematopoiesis occur in a developing fetus during the FIRST trimester?
Yolk sac
Where does the majority of hematopoiesis occur in a developing fetus during the SECOND trimester?
Liver
Where does the majority of hematopoiesis occur in a developing fetus during the THIRD trimester?
Bone marrow
What bones in a 10-year old serve as hematopoiesis zones?
- vertebral column
- pelvis
- tibia
- sternum
- ribs
What bones in a 25-year old serve as hematopoiesis zones?
- vertebral column
- pelvis
- sternum
- ribs
What bones in a 50-year old serve as hematopoiesis zones?
- Vertrbral column
- Pelvis
- Sternum
- Ribs
Describe the bone microenvironment
Bone marrow contains HSC specific site, aka stem cell niches. These niches have supportive cells that regulate survival, proliferation, differentiation, and trafficking.
List the cell types in the bone microenvironment.
- osteoblasts
- endothelial cells
- sympathetic neurons
- HSCs
Osteoblast function
generate bone and control HSC differentiation
Endothelial cells function
They line blood vessels and regulate HSC differentiation
Sympathetic neurons function
Control release of cells from bone marrow
HSCs in bone microenvironment are controlled in their production of blood cells by __________ and ________ __________.
They are controlled by streams of cytokines and growth factors
Why does bone get less and less able to perform hematopoiesis as we age?
As we age, bone marrow slowly converts into adipose tissue
Where do T cells develop? Could you point at that organ on an anatomical drawing?
T cells are created by the bone marrow but migrate to and fully mature in the thymus via blood.
It is located superiorly in the mediastinum, superior to the heart.
What happens when T cells mature in the thymus?
T cells need to pass a developmental gauntlet here so that they can learn to NOT recognize self-antigens
Briefly describe the process T cells go through to ensure they are not self-reactive and to ensure they can bind to self-MHC.
Naïve thymocytes travel to thymus via blood. Once in thymus, thymocytes lack CD4, CD8, and TCRs, making them DN thymocytes. These DN thymocytes migrate to the subscapular cortex where they proliferate and generate CD4+, CD8+, and TCRs. Now they are DP thymocytes and travel to the cortex, where they are tested for their ability to bind to MHC complexes via cTECs. If they can recognize self this way, then they move to the medulla where they become SP thymocytes, (CD4+ and CD8+ T cells). At this point, they are tested for the ability to bind to proteins found on other organ types via mTECs.
What is negative selection of T cells?
It’s when T cells are selected AGAINST if they bind too tightly or recognize self-peptides
In this case, cells will be killed bc they are not supposed to recognize self, if they do, they will elicit an immune response to self-peptides
What is positive selection of T cells?
If DN bind just right to MHC complexes in cTECs, those cells will continue to mature. If they bind incorrectly to don’t bind at all to MHC, they are killed.
What are the three primary secondary lymphoid organs (SLOs) discussed in lecture?
- lymph nodes
- spleen
- X-associated lymphoid tissue (XALT)
What is included in XALTs?
The lining of multiple organ systems:
- Tonsils
- adenoids
- Peyer’s patches
- appendix
What do all secondary lymphoid organ have, despite their different overall anatomies?
- Distinct regions or B cell and T cell activity
- Lymphoid follicles
What are lymphoid follicles?
Organized microenvironments that are responsible for the development and selection of B cells that produce high-affinity antibodies
How are SLOs connected?
Via blood and lymphatic circulatory systems; lymph is just plasma that has leaked from blood vessels into tissue
How much lymph fluid is returned to the circulatory system each day?
2.9 L per day
What can occur when lymph is not efficiently returned to the circulatory system?
Lymphedema; see physical effects of immune reaction
What is the importance of lymph vessels?
They provide routes for antigens and activated immune cells from sites of infection to secondary organs so that lymphocytes can be activated
Where do T cells enter the lymph node?
Naïve T lymphocytes enter via high endothelial venules of the blood stream to enter the paracortex
Where do B cells enter the lymph node?
B cells enter through high endothelial venules
Where do antigens/APCs enter the lymph node?
incoming (afferent) lymphatic vessels
Where are T cells found when they are searching for antigen?
Paracortex of lymph node (takes about 16-24 hrs for each node)
How do these naïve T cells search for APCs? What system do they take advantage of to search?
APCs themselves are already located on a network of fibers called fibroblastic reticular cell conduit system (FRCC), made up of fibroblastic reticular cells (FRCs). The FRCC serves as a highway for naive T cells to travel on; it guides them via adhesion mlcs and chemokines
Where are B cells found when they are searching for antigen?
Follicles! They browse for antigen here using follicular dendritic cells (FDCs) or by using soluble antigen that enter via the afferent lymphatics
Where do nonactivated lymphocytes exit?
efferent lymphatics (T cells); this occurs when lymphocytes do not find their MHC peptide match
What occurs in germinal centers?
Here, the generation of B cells is facilitated, where they go through somatic hypermutation to mutate in a way that makes their receptors more effective to bind to antigen…bc if they don’t bind, they don’t live. If they are the winners and bind with the antigen, they make even better antibodies and move to the medulla to be secreted into the blood stream
What dictates which B cells live to become effector plasma cells?
How well they bind to the antigen, meaning they went through somatic hypermutation and adjusted their BCRs to be more effective. The more effective binding tells who will bind with the antigen and secrete those BCRs as antibodies from plasma cells
What types of T memory cells are created? Where do you expect to find them in the body?
Effector memory cells: cont. to circulate among all tissues
Central memory cells: take up residence in SLOs
Resident memory cells: Take up residence in nonlymphoid tissue (NLT)
Where do T cells enter the spleen?
Splenic artery
Where do B cells enter the spleen?
Splenic artery
Where do antigens/APCs enter the spleen?
Splenic artery
Where are T cells found when they are searching for antigen?
They are found browsing in the periarteriolar lymphoid sheath (PALS), aka WHITE PULP
Where are B cells found when they are searching for antigen in the spleen?
Encounter antigens in follicles, find their T helper cell match, and create germinal center in follicles
Where do nonactivated lymphocytes exit?
via splenic vein
White pulp
B-cell follicles
PALS (T-lymphocytes)
Red pulp
RBCs
Macrophages
Lymphocytes
Marginal zone
separation area between red pulp and white pulp
It houses dendritic cells, macrophages, and marginal zone B cells (MZ B cells)
Is the subtype of B cells (called MZ B cells) innate immune cells or adaptive immune cells?
Yes…MZ B cells have both BCRs and PRRs that recognize PAMPs and express antibody in response
