Cells & Organs Flashcards
Hematopoiesis
Production of new immune cells
Occurs throughout life, but declines with age
Cells of different lineage and function all develop from the pluripotent stem cell
Hematopoietic stem cells can become:
- Self-renewing stem cell
- Myeloid-Erythroid Progenitor
- Myeloid progenitor cells develop into - monocyte/macrophage, neutrophil, basophils, eosinophil, mast cell, dendritic cell
- Erythroid progenitor cells develop into - erythrocytes (RBCs), megakaryocyte/platelet - Lymphoid cell
- T cell
- B cell
- NK cell
Where does Hematopoiesis occur?
In children and adults, Hematopoiesis occurs in the bone marrow and thymus
In the fetus it begins in the yolk sac, then moves to the liver and spleen where it continues through infancy
_____________ are the only cells that express clonally distributed antigen receptors
B and T lymphocytes
Macrophages- where are they located? Where do they develop?
Macrophages are found in all organs and CT throughout the body
Like other cells of the immune system, they develop in the bone marrow from a precursor (the myeloid precursor) with the aid of specific cytokines
Subsets of monocytes
Classical/inflammatory monocytes:
- Recruited into the tissues during inflammation, infection, or tissue injury
- Produce inflammatory mediators (cytokines, CRP, etc)
Nonclassical monocytes:
- Recruited into the tissues after infection or tissue injury to contribute to tissue repair
- “crawl” or “patrol” along the the endothelial surfaces
Subsets of macrophages
M1 macrophages- these are the macrophages that phagocytose and kill pathogens
M2 macrophages- these macrophages are involved in tissue repair and remodeling
Monocytes vs macrophages
Monocytes circulate in the blood about 1-3 days
Macrophages are monocytes that have exited the blood, have become further differentiated and become fixed in the tissues (called tissue fixed macrophages)
Name the macrophages that take on specific characteristics based on location. When do they develop?
Kupffer cells- liver
Microglial cells- brain
Alveolar- lung
Sinusoidal- spleen
Develop during fetal development
Macrophage surface receptors
CR1- complement receptor 1 for complement protein C3b (aids in opsonization)
Fc- for the Fc portion of IgG and IgE antibodies (aids in opsonization or ADCC)
TLR- Toll-like receptors that recognize structures found on pathogens (ex. LPS)
MBL
Macrophages can become activated from their resting state by:
- Interferon-gamma produced by Th1, CD8+, or NK cells
- Pathogen-Associated Molecular Patterns (PAMPS: ex. LPS, mannose)
- Opsonization- enhanced phagocytosis of antibody-coated, complement coated, MBL-coated, or CRP-coated antigen
Functions of Macrophages/Monocytes (5)
Phagocytosis Tissue repair and remodeling Antigen processing and presentation Production of soluble mediators ADCC (antibody-dependent Cell-mediated cytotoxicity)
Phagocytosis
Innate immune response: phagocytosis can occur via PRR-PAMP binding or opsonization
- Opsonization: act of phagocytosis that is mediated by an opsonin (marker bound to a pathogen to make it visible to immune cells of phagocytosis) binding receptors on a phagocyte
- Opsonins in innate immunity can be soluble MBL, CRP, or complement proteins
Adaptive immune response: phagocytosis can occur via opsonization (with either complement proteins or antibodies acting as the opsonins)
- Phagocytosed pathogens are killed by cytotoxic enzymes & the oxidative burst which releases toxic oxygen & nitrogen radicals
Tissue repair and remodeling
In some instances, macrophages ingest necrotic host cells or cells damaged by toxins, trauma, or lack of circulation, as well as neutrophils that die after entering the tissues in response to an infection
Certain cytokines produced by macrophages also aid in angiogenesis and fibrosis
Antigen processing and presentation
Breaks down (“processes”) the antigen into small peptide fragments “Presents” the antigen on its surface to T cells via MHC class I or class II molecules
Production of soluble mediators
Generally the first phagocytic cell to sense an invading microbe phagocytosis it and begins secreting cytokines (ex. IL-1, IL-6, TNF-alpha)
- cytokines recruit neutrophils, monocytes and other leukocytes to the infected area
Secrete complement proteins (which can kill the pathogen or act as opsonins)
ADCC
Antibody dependent cell mediated cytotoxicity (ADCC) via macrophages occurs when the target is coated with IgG antibodies
Activated macrophages directly kill the target cell without phagocytosis
Granulocytes
Neutrophils
Eosinophils
Basophils
Mast cells
Neutrophils - identification
Multilobed nucleus
Contain granules which contain various enzymes for killing pathogens (lysozyme, defensins, cathelididins)
Neutrophils - functions
Phagocytosis (best phagocyte)
Killing of engulfed pathogens- lytic enzymes, defensins (small peptides that poke holes in membranes), cathelicidins (direct toxicity to some pathogens), oxidative burst
Cytokine production
Often responsible for the immunopathology (collateral damage to host cells) associated with infection
Eosinophils
Bilobed nucleus
Major role in parasitic infections
High affinity Fc receptors for IgE and low affinity Fc receptors for IgG
Play a role in the pathogenesis of asthma
Basophils
Granules contain histamine and other vasodilator
Minor role in allergic reactions
Fc receptors for IgE
Mast cell
Granules contain histamine and multiple vasodilators
Major role in allergic reactions
High affinity for IgE
Found along CT and skin
Platelets:
Derived from ______
Function
Location
Derived from megakaryocytes
Clotting and Inflammation
2/3rd circulate, 1/3rd in spleen
Dendritic cells:
Derived from
Functions
Location
Derived from myeloid precursor
They can easily sense pathogens with their PRRs and initiate innate responses
- wider variety of PRRs than any cell type
They are also phagocytic and can kill, process and present antigen to T cells to initiate adaptive response
Some are circulating, some are found in skin (Langerhans cells), or in lymphoid tissues (to present antigen to T cells)
Subsets of Dendritic cells
Classical DCs:
- present in most tissues that interface with the external environment (skin, GI, resp)
- capture and carry tissue antigens to the T cell zones of lymph nodes
- play a role in self-tolerance of T cells
Plasmacytoid DCs:
- capture antigen in the bloodstream and transport it to the spleen for Ag presentation
- major source of type I (anti-viral) cytokines
DC functions
Phagocytosis
Antigen presentation (best APC!) - process and present peptide antigens to CD4 or CD8 T cells in the T cell zones of the LN’s or spleen (ie interdigitating DCs)
Negative selection of thymocytes
Cytokine production
Dendritic cells ID
Cytoplasmic extensions called dendrites
Follicular dendritic cells
- relation
- found?
Functionally unrelated to DC’s!
Not phagocytic
Found in germinal centers & follicles of lymphoid organs
Follicular dendritic cells- Functions
Presentation of whole, unprocessed antigen to B cells to keep them activated during affinity maturation
May also be involved in maintaining long-lived memory B cells
T lymphocytes
Have a TCR that is specific for a particular antigenic peptide
Two major subpopulations
- CD4: Become T helper cells
- CD8: become cytotoxic T lymphocytes (CTLs)
CD4 and CD8 are membrane-bound proteins that act as _________ in antigen recognition with the TCR
Co-receptors
CD4 and CD8 determine which type of antigen presentation molecule is recognized
CD4 recognize MHC class II
CD8 recognize MHC class I
CD4 T lymphocytes -
Main feature
Involved in
Main feature of CD4 T cells: they carry out their effector functions by the production of cytokines which then act on other immune cells
CD4 T cells are involved in : activation of eosinophils and neutrophils, and stimulating B cells to produce antibodies (as well as isotype switching)
Th1 cells:
- Major immune runs
- Host defense
- Role in disease
- Defining cytokines
Activate macrophages to help control intracellular pathogens.
Involved in AI and chronic inflammatory diseases
Defining cytokines: IFN-gamma
Th2 cells:
- principal target cells
- major immune reactions
- role in disease/host defense
- defining cytokines
Activate eosinophils —> immunity to helminthic worms
Activate mast cells —> classic allergic reactions
Cytokines: IL-4, IL-5, IL-13
Th17:
- principal target cells
- major immune runs
- host defense
- role in disease
- defining cytokines
Neutrophils recruitment and activation which increases inflammation
Immunity to extracellular pathogens
Inflammation and AI disorders
Defining cytokines: IL-17 and IL-22
Tfh:
- Principal target cells
- Major immune rxns
- Host defense
- Role in disease
- Defining cytokines
B cells —> antibody production
Extracellular pathogens
AI (autoantibodies)
IL-21 (and IFN-gamma or IL-4)
Treg:
Suppression of immune response
Development/maintenance of self-tolerance
CD8 T lymphocytes:
- become ________
- utilized for ________
- kills __________
Activated/differentiated CD8 T cells become cytotoxic T lymphocytes (CTL)
- Utilized for intracellular pathogens
- Direct killing of infected target cells (ie the CTL kills the infected host cell which results in killing of the pathogen)
- cells mostly responsible for killing grafted/transplanted tissue
B lymphocytes: effector function
Production of antibodies - to aid in the removal of pathogens and their products
Subsets of lymphocytes
B-1 B cells
B-2 B cells
- Follicular B cells
- Marginal Zone B cells
B-1 B cells:
- provide?
- respond to?
Less diverse BCR’s than follicular B-2 cells
The anti-A/B blood antibodies found in serum are generated by B-1 B cells
Provide antibodies for much of our mucosal immune responses
Typically respond to T-independent antigens
B-2 Follicular B cells: explain general purpose
Naive cells express IgM and IgD (same Ag specificity)
Memory cells express only 1 isotype (IgM, IgG, IgA, or IgE - not IgD)
Express MHC class I and class II molecules for Ag presentation to T cells in lymphatic organs
Very diverse BCRs from one cell to another
B-2 follicular B cells:
- Found where?
- Respond to?
- CD80 or CD86 on these cells involved in __________________
These B cells circulate through the body
They respond mainly to T-dependent (protein) antigens
CD80 or CD86 on these cells is involved in activating naive T cells in the lymphatic organs
B-2 Marginal Zone B cells:
- found?
- respond to?
- naive cells do not express _______
Found mostly in the marginal sinuses of the spleen and LN’s
Can respond to T-independent antigens and lipid antigens
Naive cells do not express IgD
B cell type with the most diverse BCRs?
Follicular B-2 B cells
B cell functions
Production of antibodies by differentiated plasma cells (all B cells)
Follicular B cells Functions
Immunologic memory- some activated B cells differentiate into memory B cells
Antigen presentation via MHC Class I or II
B cell process
Antigen load onto Antigen receptor of Naive lymphocyte —> Proliferation (clonal expansion) —> Differentiation into Effector cell (terminally differentiated) + Memory lymphocytes
- Note: memory lymphocytes can become activated and go through the process again
NK cells (null lymphocytes):
- receptor
- express?
No antigen receptor (like BCR or TCR). Do not require antigen presentation!!!
Constitutively express IL-2 receptor for increased activation and killing when an infection occurs
- IL-2 is made by APCs and activated T cells in response to infection
NK cells receptor
Fcgamma receptor (for ADCC)
NK cells- Functions
- Killing of infected cells and tumor cells is done through a receptor on the NK cell (NKG2D) which recognizes MICA or MICB expressed by sick/stressed cells or cancer cells
- NK cells also kill target (host) cells when their KIRs are not engaged by MHC I molecules on the target
NK KIRs
Inhibitory receptor engaged (Self class I MHC) —> removal of phosphate —> NK cell not activated; no cell killing
Inhibitory receptor not engaged (virus inhibits class I MHC expression) —> phosphate not removed —> NK cell activated —> killing of infected cell
Lymphoid organs
Support the development and function of immune cells
Immune cells are concentrated in the lymphoid organs
Primary Lymphoid Organs
Where lymphocytes are generated and mature
Bone marrow:
- B cell development/production
- leukocyte production
Thymus:
- T cell development
Secondary Lymphoid Organs - promotes interactions between
Promotes interactions between B cell and antigen, T cell and antigen, and B and T cells
Secondary Lymphoid Organs: function
Mature B and T cells become activated, proliferate, and differentiate into effector cells or memory cells
Functions:
- bring lymphocytes into contact with their cognate antigen
- bring antigen-specific lymphocytes into contact with each other
- provide appropriate environment
Secondary Lymphoid Organs- name them & their function
Spleen: filters Ag’s from blood
Lymph Nodes: filters Ag’s from tissues & interstitial fluid
MALT (ex. Adenoids, tonsils, gut): contain specialized cells for taking up pathogens in mucosal tissues
Spleen
Antigen enters the spleen in red pulp (carried in blood)
Immune cells encounter antigen in the white pulp
White pulp has B cell and T cell zones which facilitate necessary interactions
Lymph Node
Filters antigens from tissues and interstitial fluid
LNs have B and T cell zones
- B cell zones are divided into areas where activated and naive or memory cells are located
Lymphocyte recirculation
Naive T cells - migrate into the T cell zone within the Lymphoid organ where antigens are displayed by APCs. If activated, it becomes an effector T cell or memory T cell, if not activated, it can renter the lymphatic or the bloodstream to continue to the next LN or the spleen.
Effector T cells: once activated, they lose the receptors that allow them into LNs so they will not reenter other LNs to search for antigen. The vast majority of these cells leave the LN and reenter circulation. They preferentially migrate into tissues that are colonized by infectious microorganisms.
Memory T cells: Now that they have been activated, they seek out their activating antigen by circulating through sites in the body where the antigen might be found - skin, mucosal tissues (respiratory tissues, gut), Lymphoid organs
Lymphocytes are activated ________
In the secondary Lymphoid tissues
Mutations in FOXP3 results in
Deficiency of Treg cells which leads to an AI disease called immune dysregulation polyendrinopathy, enteropathy, X-linked (IPEX)
What is the term used to describe the production of immune cells?
Hematopoiesis
Where does immune cell production occur and is it the same for all cells?
All immune cells develop from the pluripotent stem cell in the bone marrow
Where do immune cells differentiate?
B cells differentiate in the bone marrow
T cells differentiate in the thymus
Which cell type is the best phagocyte?
Neutrophil
Which cell type is the best APC?
Dendritic cell
T/F: A follicular dendritic cell is a differentiated form of a Langerhans cell.
False!
Functionally unrelated to dendritic cells
Which type of B cell produces antibodies?
B-1 B cells
Which T cells are the fundamental mediators of a cell mediated immune response?
CD8 T lymphocytes
Which T cells are the fundamental mediators of a humoral immune response?
CD4 T lymphocytes
Which cells are considered the APCs?
Dendritic cells
Macrophages
B-2 Follicular B cells
Which T cells can induce B cells to change their antibody isotype (isotype switching)?
CD4 T cells
Describe the difference in functions between the primary and secondary lymphoid organs.
Primary lymphoid organ- where lymphocytes are generated and mature. Bone marrow and thymus
Secondary Lymphoid organ- promotes interaction between lymphocytes and their antigen, antigen-specific lymphocytes with each other. Spleen, LN’s, and MALT (adenoids, tonsils, gut)
How do dendritic cells and follicular dendritic cells differ? What are their roles and where are they located?
Dendritic cells- some are circulating, some in skin or lymphoid tissues (to present Ag to T cells)
- Fxns: Phagocytosis, APC, negative selection of thymocytes, cytokine production
Follicular Dendritic cells- found in germinal centers and follicles of lymphoid organs.
- Fxns: Presentation of whole, unprocessed antigen to B cells to keep them activated during affinity maturation. May also be involved in long-lived memory B cells
NOT Phagocytic!
