Humoral and Cell-Mediated Immunity
IL-17, IL-22
*Th17* cells are CD4+ αβ T-cells that express the transcription factor *RORγt*; they produce a variety of different *cytokines* including ______ and ______.
IL-5, IL-4
*Th2 cells* typically secrete a variety of cytokines: - *IL-4, IL-5, and IL-6* promote *activation of B cells* - ______ functions in *activating eosinophils* - ______ functions in *down-regulating Th1 cells*
IL-4, IL-5, IL-6, IL-13
*Th2* cells are CD4+ αβ T-cells that express the transcription factors *GATA3 and STAT6*; they produce a variety of different *cytokines* including ______, ______, ______, and ______.
TGF-beta
*Transforming growth factors* are a main group of cytokines; the main one of these factors that is of immunological importance is _________. This cytokine is *mainly inhibitory*; it is secreted by Tregs and monocytes, inhibits macrophage and dendritic cell activation, and inhibits T cells.
TGF-beta, IL-10, IL-35
*Treg* cells are CD4+ αβ T-cells that express the transcription factor *Foxp3*; they produce a variety of different *cytokines* including ______, ______ and ______.
interferon alpha, interferon beta
*Type I Interferons* include ___________ and ___________. These are *produced by most nucleated cells of the body*. These act on neighboring uninfected cells by *inhibiting transcription and translation of viral proteins*.
interferon gamma
*Type II Interferons* are ___________. These are produced by *NK cells, Th1 cells, and Tc1 cells* (immune interferon). This promotes production of Th1 cells, inhibits production of Th2 cells, *activates macrophages, and increases MHC class I and class II expression*.
intraepithelial lymphocytes
A group of lymphocytes that has been identified as being important in protection of mucosal surfaces. They are resident within the *intestinal epithelium*, and are one of the first lines of defense of the immune system. They are a mixed population of *antigen-experienced* cells, and they comprise *both gamma-delta T-cells and alpha-beta T-cells*. Some of the cells are CD4+ while some are CD8+, but there are unusual *alpha-alpha homodimer versions of CD8* as well.
pleiotropism
A property of cytokines by which cytokine can exert different biological effects on different cell types
redundancy
A property of cytokines by which different cytokines may have the same effect on one type of cell.
antigen experienced
B cells can act as professional antigen presenting cells for _______________ T cells. In other words, *dendritic cells are required to activate naïve T-cells*.
Th2
CD4+ αβ T-cells whose primary function is to *help B cells inhibit Th1*; these cells principally target *eosinophils*, and are most important against *parasites*
Tfh
CD4+ αβ T-cells whose primary function is to *help germinal center B cells*; these cells principally target *B cells*, and are most important in *establishing memory B cells*
Th17
CD4+ αβ T-cells whose primary function is to *promote inflammation*; these cells principally target *neutrophils* and monocytes, and are most important against *extracellular bacteria and fungi*
Treg
CD4+ αβ T-cells whose primary function is to *suppress immune responses*; they suppress activity of eosinophils, basophils, mast cells, Th cells, and Tc cells.
Th1
CD4+ αβ T-cells whose primary function is to help CTL and *macrophages* (and some B cells), and *inhibit Th2*; these cells are crucial in *intracellular infections*, and most important against *viral* infections
Tc
CD8+ αβ T-cells whose primary function is to *kill infected cells*; these cells express the transcription factor *RUNX3*, and produce the *perforin, granzymes, FasL, and cytokines*
IFN-gamma, IL-12, IFN-gamma, IL-2, TNF-beta
Cytokines may act in a *cascade*. For example: 1. *Th1* cells may secrete _______ which will activate macrophages. 2. The activated *macrophages* will respond by secreting _______. 3. This secreted cytokine will then act back on the *Th1* cells causing secretion of _______, _______, and _______.
antagonistic
Cytokines may have *additive or synergistic* effects on the same cell. Cytokines may also have ____________ effects, meaning that one cytokine may reduce or eliminate the effect of another cytokine.
interferons
Cytokines that *inhibit viral replication*; there are two main types: Type I and Type II.
colony stimulating factors
Cytokines that are secreted by a variety of cell types, including bone marrow stromal cells (e.g., fibroblasts and macrophages). *There are three main types:* 1. Granulocyte-macrohage - acts early in myeloid development 2. Monocyte macrophage - induces monocyte differentiation. 3. Granulocyte - induces granulocyte differentiation*
gamma delta T cells
Diversity in these types of T cells is created by recombination of TCR genes in the thymus. They recognize *antigens alone, and lipoprotein and glycolipids presented by MHC-like molecule CD1*. These cells comprise *less than 5%* of T cells, and are present mostly in the gut mucosa, skin, lungs, and uterus.
alpha beta T cells
Diversity in these types of T cells is created by recombination of TCR genes in the thymus. They recognize *peptides presented by MHC molecules*.
T-dependent antigens
The vast majority of antigens are ___________________. In these cases, B-cells can be induced to *class switch* following interaction with appropriate helper T-cells. On the surface of the naive B-cell, the MHC Class II peptide and the molecule CD40 are expressed. In the presence of helper T-cells, the *CD40 ligand molecule on the surface of the T-cell* interacts with the CD40 on the surface of the B-cell. This interaction will cause the helper T-cell to *release cytokines* and this combination of CD40 ligand binding to CD40 on the B-cell together with cytokines will cause the *B-cell to class switch*.
monoclonal antibodies
Therapeutic agent antibodies that can block the activity of cytokines. They may be directed against the cytokine themselves, or alternatively they could be directed against cytokine receptors to prevent binding of the cytokine to the receptor. They should not trigger the receptors.
IL-2 diptheria toxin
Therapeutic blocking of pathological cytokines: Indicated for use in CD25+ cutaneous T cell lymphoma.
anti-IL-2 receptor
Therapeutic blocking of pathological cytokines: Indicated for use in acute kidney rejection.
anti-IL-1-beta
Therapeutic blocking of pathological cytokines: Indicated for use in cryopyrin-associated periodic syndromes and juvenile idiopathic arthritis.
anti-IL-6
Therapeutic blocking of pathological cytokines: Indicated for use in multicentric Castleman disease.
anti-IL-12, anti-IL-23
Therapeutic blocking of pathological cytokines: Indicated for use in plaque psoriasis and psoriatic arthritis.
IL-1RA
Therapeutic blocking of pathological cytokines: Indicated for use in rheumatoid arthritis and cryopyrin-associated periodic syndromes.
anti-IL-6 receptor
Therapeutic blocking of pathological cytokines: Indicated for use in rheumatoid arthritis and polyarticular or systemic juvenile idiopathic arthritis.
anti-TNF-alpha
Therapeutic blocking of pathological cytokines: Indicated for use in rheumatoid arthritis, plaque psoriasis, Crohn's disease, ulcerative colitis, anklosing spondylitis, psoriatic arthritis, and polyarticular juvenile idiopathic arthritis.
anti-BLyS
Therapeutic blocking of pathological cytokines: Indicated for use in systemic lupus erythematosus.
IFN-alpha
Therapeutic cytokine: Effect - antiproliferative, antiviral Indications - chronic hepatitis C, AIDS-related Kaposi sarcoma, hairy cell leukemia, chronic myelogenous leukemia, metastatic melanoma
IFN-beta
Therapeutic cytokine: Effect - antiproliferative, antiviral Indications - relapsing multiple sclerosis
IL-2
Therapeutic cytokine: Effect - immunostimulatory Indications - metastatic renal cell carcinoma and metastatic melanoma
IFN-gamma
Therapeutic cytokine: Effect - immunostimulatory, antiviral Indications - control of infection in chronic granulomatous disease, delay of progression in severe malignant osteopetrosis
autocrine, paracrine, endocrine
There are *3 main ways in which cytokines signal other cells*: 1. ____________ signaling = The cell type producing the cytokine is the same cell type that responds to the cytokine. 2. ____________ signaling = cytokines are produced by a type of cell and affect different types of cells that are close by. 3. ____________ signaling = cytokines can enter the circulation and act on cells that are distant.
tumor necrosis factors
There are two main types of these inflammatory cytokines, *alpha (α)* and *beta (β, also known as lymphotoxin)*. They are produced by many cell types, including macrophages, monocytes, T cells, B cells, and NK cells. These cytokines have multiple effects, including *macrophage activation*, *induction of endothelial cell adhesion molecules in acute inflammation*, and stimulation of production of other cytokines.
Fas, FasL
There are two ways in which the *Tc* killing process can function. In the first, the infected cells have on their cell surface the molecule ______, and this can interact with the molecule _______ on the surface of the cytotoxic T-cell. Upon engagement of these molecules, a signal is sent into the infected cell which *activates caspases*, which are enzymes that are involved in inducing apoptotic cell death in the infected cell.
granzymes, perforin
There are two ways in which the *Tc* killing process can function. The second method relies on the release of enzymes called __________ from the cytotoxic T-cell, and also molecules called __________ (which cause pores to be formed in the membrane of the infected cell); this pathway also leads to caspase activation and apoptotic cell death of the infected cell.
homeostatic, inflammatory, angiogenic
There is a *Functional Grouping* of *chemokines*: 1. ______________ chemokines: Control the migration of cells during the normal development and maintenance of tissues and lymphoid organs. 2. ______________ chemokines: Produced in response to infection or injury and direct the migration of leukocytes into the infected or damaged site. 3. ______________ chemokines: Promote the development of blood vessels (pro-angiogenic) while others prevent the development of blood vessels (anti-angiogenic).
chemokines
These are *chemotactic cytokines*, but with multiple other effects. They are secreted by many different types of cells. There are *4 families* grouped according to arrangement of cysteines in their structure.
Th0
These are *precursor cells that give rise to subtypes of Th cells*. T cells need to recognize the antigen presented on the dendritic cell, and that dendritic cell will secrete cytokines depending on the type of pathogen. *The Th cell response (the optimal response) depends on what types of PAMPs activated the dendritic cell (guiding differentiation)*. Th differentiation will also depend on other cell types that are present (ex. NK cells secreting IFN-gamma).
CTLA-4, LAG-3
Treg cells are *suppressive cells*. They secrete suppressant cytokines TGF-beta, IL-10, and IL-35. Besides this indirect inhibition via cytokines, Treg cells can also *suppress dendritic cells by direct cell-to-cell contact* via Treg cell surface ________ and ________.
TNF-alpha
Use of antibodies (Cytokine Therapy): *Anti-TNF-α IgG1 mab's* (Remicade, Humira) *bind to circulating _________*, preventing it from binding its receptors on the cells. This reduces inflammation of *RA, Crohn's disease, and ulcerative colitis*, but suppressing the cytokine activities increases the risk of infection
C, CC, CXC, CX3C
What are the *4 families* of chemokines? - _________ (example = *lymphotactin*) - _________ (example = *RANTES*) - _________ (example = *IL-8*) - _________ (example = *fractalkine*) Note: chemokines are grouped according to the arrangement of cysteines in their structures, and the 'X' represents any different amino acid separating the two cysteine residues.
interleukins, colony-stimulating factors, chemokines, interferons, tumor necrosis factors
What are the *5 major groups* of cytokines?
JAK kinase, STAT
When a cytokine binds to a cytokine receptor (often a dimer) on the surface of a cell, it causes *dimerization* of the receptor which leads to a *signaling cascade*. ___________ will cause phosphorylation of sequences within the cytoplasmic region of the cytokine receptors. This leads to the recruitment of _________, which will cause further phosphorylation events occur and dimerization of this molecule. Ultimately, the result will be *gene transcription*.
Phosphatidylserine
When the apoptotic signals are sent into the infected cell by the Tc cell, either via the Fas-Fas ligand pathway or the perforin-granzyme pathway, there is a *flipping* of the cell membrane, so that *surface membrane of the cell that was originally on the inside of the cell is now on the outside of the cell*. An example of such a molecule is ________________. *Macrophages* have on their cell surface, receptors for this molecule, allowing them to recognize the fact that this is a dead or dying cell, and they will engulf it and destroy it.
IL-17, IL-22
Which *two interleukins* are *produced by Th17 cells*, and are primarily *pro-inflammatory* cytokines?
IL-4, IL-5, IL-10, IL-13
Which cytokines are involved in *allergic reactions and asthma*?
IL-1, IL-6, TNF-alpha
Which cytokines are mediators of the acute phase response (acute inflammation)?
IL-2
Which interleukin discussed is prototypical of both autocrine and paracrine signaling?
IL-2
Which interleukin is *produced by Th1 cells*, and primarily *promotes T and B cell proliferation*?
IL-13
Which interleukin is *produced by Th2 cells*, and primarily *promotes B cell differentiation*?
IL-4
Which interleukin is *produced by Th2 cells*, and primarily *promotes Th2 cell differentiation and class switches B cells to IgE production*?
IL-10
Which interleukin is *produced by Treg cells*, and is primarily an *anti-inflammatory* cytokine?
IL-1
Which interleukin is *produced by macrophages and dendritic cells*, and is primarily a *pro-inflammatory* cytokine?
IL-12
Which interleukin is *produced by macrophages and dendritic cells*, and primarily *promotes Th1 cell differentiation*?
IL-4
Which interleukin promotes activation of B cells?
IL-2, IL-4, IL-5
Which interleukins act on proliferation of B cells?
IL-4, IL-5, IL-6
Which interleukins act on terminal differentiation of B cells into plasma cells?
Th1, Th2
Which two populations of CD4+ αβ T-cells are *mutually antagonistic* towards each other (at least to some extent)?
GM-CSF (granulocyte macrophage colony stimulating factor)
Which type of colony stimulating factor *acts early in myeloid development*?
G-CSF (granulocyte colony stimulating factor)
Which type of colony stimulating factor *induces granulocyte differentiation*?
M-CSF (macrophage colony stimulating factor)
Which type of colony stimulating factor *induces monocyte differentiation*?
neutrophils, monocytes
______________ and ______________ migrate to extravascular sites of infection or tissue damage by binding to *venular endothelial adhesion molecules* and in response to chemoattractants produced by tissue cells reacting to infection or injury.
humoral immunity
________________ is immunity provided by *antibodies* as well as *complement factors* present in bodily fluid. It is the major function of the B-cell component of the adaptive immune response, in contrast to cell-mediated immunity which results from the activity of T-cells.
cell-mediated immunity
___________________ is immunity that is provided by *cytotoxic T-cells and by T-helper cell-mediated activation of macrophages*. It is required to defeat *intracellular pathogens* which are hidden from the effects of antibody and complement. This type of immunity is mainly against *protein antigens* because presentation of antigen to T cells is mainly via MHCs. *Not present in serum*.
NK Cells, Macrophages, Neutrophils, Eosinophils
*Antigen non-specific* cells include ____________, ____________, ____________, and ___________.
innate immunity
*IL-1, TNF-a, IL-6, IFN-a/b, IFN-g*, etc. are functionally classified as *mediators and regulators of ____________*. They act on endothelial cells and leukocytes to stimulate early innate responses.
adaptive immunity
*IL-2, IL-4, IL-5, TGF-b*, etc. are functionally classified as *mediators and regulators of ____________*. They act on lymphocytes to stimulate and regulate adaptive responses to specific things.
Th1, Th2, macrophages
*Interferon gamma (IFNγ)* is produced by NK cells, Th1 cells, and Tc1 cells. It promotes production of _____ cells, inhibits production of _____ cells, activates ______________, and *increases MHC class I and class II expression*.
NK, Th1, Tc1
*Interferon gamma (IFNγ)* is produced by ______ cells, ______ cells, and ______ cells. It promotes production of Th1 cells, inhibits production of Th2 cells, activates macrophages, and increases MHC class I and class II expression.
IL-2
*Pleiotropism* is where a single cytokine has multiple effects (and this is probably true for all cytokines). For example, the cytokine ________ can cause: - T cell proliferation - B cell proliferation - NK cell activation
IL-5, IL-4
*Redundancy* is a property of some cytokine networks by which different cytokines may have the same effect on one type of cell. For example, the cytokines ________ and ________ both cause *B cell proliferation*.
hematopoiesis
*Stem cell factor, IL-3, IL-7, GM-CSF*, etc. are functionally classified as *stimulators of ____________*. They act on bone marrow to stimulate growth and differentiation of leukocytes and lymphocytes.
IL-21, ICOS
*Tfh* cells are CD4+ αβ T-cells that express the transcription factor *Bcl-6*; they produce a variety of different *cytokines* including ______ and ______.
cross-presentation (cross-priming)
*Th1 activation of Tc cells:* Th1 cells and Tc cells can both be sitting on the surface of the dendritic cell (because dendritic cells express both MHC Class I and MHC Class II). This is referred to as _______________ (by the dendritic cells). Following activation, the *Th1 cell will secrete cytokines (such as IL-2)*, which will be detected by *receptors on the Tc cell*. This activates the Tc cell. This cell can then leave the environment where it's been activated (for example in a lymph node), seek out where the infected cells are, and then subsequently kill them.
IL-2, IFN-gamma
*Th1 cells* typically secrete a variety of cytokines: - ______ promotes *activation of cytotoxic T cells* and *activation of B cells* - ______ helps to *activate macrophages* and *down-regulate activity of Th2 cells*
IFN-gamma, IL-2, TNF-beta
*Th1* cells are CD4+ αβ T-cells that express the transcription factors *T-bet and STAT4*; they produce a variety of different *cytokines* including ______, ______, and ______.
IL-4
Th0 cells will differentiate into *Th2 cells* if specific PRRs on the dendritic cells are stimulated by ______ *cytokines*.
C
Gamma delta (γδ) T cells have been shown to recognize all EXCEPT which of the following? A. Major histocompatibility complex class I polypeptide-related sequence B. Cluster of differentiation 1 C. B-cell lymphoma 6 protein D. Mycobacterium Tuberculosis E. Plasmodium species
IL-1, IL-6
In addition to TNF, which *two interleukins* typically cause *fever*?
E-selectin
In response to *TNF and IL-1*, HEVs express _______________. Other stimuli cause translocation of *P-selectin* to the endothelial surface. The term 'selectin' refers to the *carbohydrate-binding property* of these molecules. Circulating neutrophils and monocytes express surface carbohydrates that bind to these selectins. The neutrophils become tethered to the endothelium, flowing blood disrupts this binding and bonds reform downstream, and the repetitive process results in the *rolling of the leukocytes* along the endothelial surface.
cell adhesion molecules (CAMs)
Leukocyte *homing* is regulated by receptor-ligand interactions between members of the different families of surface proteins, including _____________________ - families of these molecules include: - Selectins - Addressins - Integrins
colony stimulating factors
Reversing cellular defects (Cytokine Therapy): Use of __________________ to increase the number of immune cells is helpful for patients with low numbers of these cells *(i.e. from chemotherapy)*. Neulasta is used to treat neutropenia which occurs as a result of chemotherapy
cytokines
Small (~8-80 kDa) secreted proteins that act as *messengers* between cells. They have multiple functions, including control of hematopoiesis and immune responses, and they bind to specific receptors that initiates intracellular signaling - this signaling leads to *increased or decreased expression of genes*.
T-independent antigens
Some antigens are ___________________ with respect to the B-cell response. These are antigens that tend to have *repeating structures* which extensively *cross-link the B-cell receptor* or *cross-link Pattern Recognition Receptors (PRRs)* and the B-cell receptor together. Because T-cells do not participate in the response to these antigens, there is *no class switching and only IgM is produced* - *CD40 ligand* is required on the surface of the *T-cell* to interact with CD40 on the surface of the B-cell in order to get class switching. Examples of these antigens include *bacterial lipopolysaccharide*, capsular polysaccharides of bacteria and polymeric proteins.
TNF-alpha, IFN-gamma
Some cytokines act *synergistically*, in other words they work together in a much stronger way than you would imagine just from the summative effect. For example, the cytokines ________ and ________ act synergistically in the *inhibition of viral replication*.
IL-4, IFN-gamma
Some cytokines act as *antagonists* to the activity of others. For example ________ will cause *B-cells to class switch to IgE* production, but ________ will prevent that happening.
therapeutic cytokines
Sometimes in a pathological situation, there may be either underproduction of a cytokine, or it may be that one can beneficially stimulate responses using cytokines. These therapeutic agents are collectively called _______________.
plasma cells
T cells and B cells work together: - B cells function as professional *antigen-presenting cells* using MHC class II to present pMHC to CD4+ T cells. - Also, helper T cells help B cell to *class switch* and differentiate into antibody-secreting _______________.
true
T/F: Cytokines are potentially very dangerous molecules if they are produced in excessive quantities.
true
T/F: Cytokines are rarely stored in a cell.
CD28, B7 (CD80/86)
Th cells are initially naive, meaning that they have not seen antigen. After encountering an antigen, the T cells get *primed* and become *effector T cells*. Priming needs two signals: 1. Antigen presentation on MHC that binds to TCR. 2. Co-stimulation via _______ (on the T cell) binds to ______ (on the antigen presenting cell).
IL-12, IFN-gamma
Th0 cells will differentiate into *Th1 cells* if specific PRRs on the dendritic cells are stimulated by ______ or ______ *cytokines*.
IL-6, IL-23, TGF-beta
Th0 cells will differentiate into *Th17 cells* if specific PRRs on the dendritic cells are stimulated by ______, ______, or ______ *cytokines*.
