Cytokine Messenger Systems Flashcards
What is the most important cytokine in induction of the lymphoid cell lineage?
IL-7
IL-7 causes differentiation of pluripotent stem cells into _________ progenitors, as well as proliferation of all cells in this lineage.
It is important for T cell ___________.
Lymphoid
Survival
Where is IL-7 secreted from?
Bone marrow
Thymic stromal cells
What is the primary purpose of type I interferons?
Type I interferons = IFN-alpha and IFN-beta
Directly inhibit viral replication by degrading mRNA, thus nonspecifically inhibiting protein synthesis
Where are type I interferons produced?
IFN-alpha: produced by leukocytes
IFN-beta: produced by fibroblasts
What is the major function of M1 macrophages?
M1 = classical macrophages
Induced by innate immunity
Play a role in inflammation
What induces M2 macrophages, and what is their major function?
M2 = alternative macrophages
Induced by IL-4 and IL-13
Tissue repair and control of inflammation
What are the 2 regulatory cytokines and what are their primary functions?
IL-10 and TGF-beta
Contraction of immune responses and anti-inflammatory properties
What secretes TGF-beta and what does it do?
TGF-beta is secreted by many types of cells
Allows for repair without regulatory immune cells in the vicinity
What secretes IL-10?
Macrophages
Dendritic cells
Treg cels
What secretes IL-2?
CD4+ and CD8+ T cells
What are the principle actions of IL-2?
Survival, proliferation, and differentiation of effector and regulatory T cells
What secretes IL-4?
CD4+ T cells
Mast cells
What is the principle action of IL-4?
B cell switching to IgE
What cells secrete IL-5?
CD4+ T cells
Mast cells
What is the principle action of IL-5?
Activation of eosinophils
What secretes IFN-y?
CD4+ and CD8+ T cells
Natural Killer cells
What is the principle action of IFN-y?
Activation of macrophages
What is the cellular source of TGF-beta?
CD4+ regulatory T cells
Many other cell types
What is the principle action of TGF-beta?
Inhibition of T cell activation; differentiation of regulatory T cells
What transcription factor is associated with Th1 cells?
T-bet
What transcription factor is associated with Th2 cells?
GATA-3
What transcription factor is associated with Th17 cells?
RORyT
What cytokines are required to differentiate a naive CD4+ T cell into a Th1?
IFN-y and IL-12 –> T-bet expression
What cytokines are required to differentiate a naive CD4+ T cell into a Th2?
IL-4 –> GATA-3 expression
What cytokines are required to differentiate a naive CD4+ T cell into a Th17?
TGF-beta, IL-6, IL-23 –> RORyT expression
What are the defining cytokines and target cells associated with Th1 cells?
IFN-y
Target cell: macrophages
What are the defining cytokines and target cell of Th2 cells?
IL-4
IL-5
IL-13
Target cell: eosinophils
What are the defining cytokines and target cell of Th17 cells?
IL-17
IL-22
Target cell: Neutrophils
Which specific T helper cell plays a role in host defense against intracellular pathogens?
Th1
Which specific T helper cell plays a role in host defense against extracellular pathogens?
Th17
Which specific T helper cell plays a role in host defense against parasites?
Th2
What is the overall role of Th1 in disease?
Autoimmunity; chronic inflammation
What is the overall role of Th2 cells in disease?
Allergy
What is the overall role of Th17 in disease?
Autoimmunity
IL-2 is an ___________ signal that binds _______, which is constitutively expressed as a low affinity receptor
Autocrine
CD25
What is the result of IL-2 ligation at the CD25 receptor?
Ligation induces expression of the alpha chain of the receptor, which increases its affinity
Binding of IL-2 to the now high affinity CD25 receptor promotes T cell proliferation and differentiation
Other than activation of macrophages, what role does IFN-y play in the immune response?
Activates B cells to stimulate complement binding
Stimulates class II HLA and CD80
What effect do Th1 cytokines have on Th2 responses?
Th1 cytokines are inhibitory of Th2 responses
Th1 cells activate macrophages via IFN-y. What is this dependent on?
Antigen recognition
Macrophage activation by Th1 cells is the basis for what type of reaction?
Delayed-type hypersenstivitiy (DTH)
What is the macrophage’s response to activation by IFN-y?
Production of ROS, NO, and lysosomal enzymes
Secretion of inflammatory cytokines (TNF, IL-1, IL-12, chemokines)
Increased expression of B7 costimulators and MHC molecules
What effect do Th2 cytokines have on Th1 responses?
Th2 cytokines are inhibitory of Th1 responses
Th cells promot Ab _______ _________ by providing cytokine help
Class switching
If a naive B cells is exposed to a nonspecific polyactivator (mitogen) like LPS, what will its isotype be?
IgM
If a naive B cells is exposed to a nonspecific polyactivator (mitogen) like LPS in addition to IL-4, what will its isotype be?
IgE
If a naive B cells is exposed to a nonspecific polyactivator (mitogen) like LPS and TGF-beta, what will its isotype be?
IgA
What is the principle effector function of IgM?
Complement activation
What are the principle effector functions of IgG1 and IgG3?
Opsonization and phagocytosis
Complement activation
Neonatal immunity (placental transfer)
What are the principle effector functions of IgE and IgG4?
Immunity against helminths
Mast cell degranulation (immediate hypersensitivity)
What cytokines associated with mucosal tissues contribute to IgA class-switching?
TGF-beta
APRIL
BAFF
What is the principle effector function of IgA?
Mucosal immunity (transport of IgA through epithelia)
True or false: Th17 cells are anti-inflammatory
FALSE, they are highly pro-inflammatory
_______ cells were first described in animal models of diseases like MS, IBS, and RA
Th17
What are the 2 primary functions of Th17 cells?
Inflammation
Barrier function
Neutrophil activation
Anti-microbial peptide production
A patient presenting with progressive neurological symptoms in the setting of skin rash as well as numerous acid-fast bacilli clumps and foam cells in the skin biopsy would indicate what diagnosis?
Lepromatous leprosy
Leprosy is characterized by cutaneous lesions, neuropathic changes, and deformities.
It is a __________ bacteria (which are relatively rare) that colonizes _____________ and other host cells and multiplies within them.
Intracellular
Macrophages
M. leprae can only be eliminated by intracellular killing by activated ______________
It grows best at 86 degrees F, hence predominant growth of lesions occurs on ____________
Clinical symptoms vary, depending on type of immune response to the mycobacterium
Macrophages
Extremities
The balance between a Th1 and a Th2 response to M. leprae can influence the outcome of infection.
What is the outcome in those that exhibit a Th1 response?
Tuberculoid leprosy
The balance between a Th1 and a Th2 response to M. leprae can influence the outcome of infection.
What is the outcome in those that exhibit a Th2 response?
Lepromatous leprosy (high bacterial count)
[note that this may be due to defective Th1 response, or just a dominant Th2 response]
The balance between a Th1 and a Th2 response to Leishmania major (protozoal parasite) can influence the outcome of infection in mice.
What is the outcome in those that exhibit a Th1 response?
Recovery
The balance between a Th1 and a Th2 response to Leishmania major (protozoal parasite) can influence the outcome of infection in mice.
What is the outcome in those that exhibit a Th2 response?
Disseminated infection
Tuberculoid leprosy results from a dominant Th1 response, characterized by organisms present at low to undetectable levels
It has _____ infectivity
Produces ___________ and local inflammation as well as peripheral _______ damage.
_____ serum Ig levels
______ T-cell responsiveness and a specific response to M. leprae antigens.
Low
Granulomas; nerve
Normal
Normal
Lepromatous leprosy results from a dominant Th2 immune response characterized by florid growth of organisms in macrophages.
It has _____ infectivity and results in __________ infection in bone, cartilage, and diffuse nerve damage.
In terms of Ig levels, patients exhibit ________________.
Low or absent _____ cell responsiveness, and No response to M. leprae antigens
High; disseminated
Hypergammaglobulinemia
T
Why would someone with lepromatous leprosy be prone to asthma?
Their default to the Th2 response results in high levels of IL-4 production –> IgG and mast cell degranulation/activation
Also IL-5 –> eosinophils
Both IL-4 and IL-5 are big in atopic disease, increasing the risk of asthma
Which cytokine might be beneficial to a patient with lepromatous leprosy?
IFN-y or IL-12
Goal is hyperactivation of macrophages in order to kill M. leprae pathogen
What is the downside to infusing someone with IFN-y for Lepromatous leprosy?
Nonspecific systemic hyperactivation of macrophages will lead to constant state of fever, malaise, body aches, etc.
If genetic testing reveals random inactivation of the mother’s X chromosome, as well as mutational analysis revealing a defect in the IL2RG gene with deletion of a single nucleotide, what is a possible diagnosis?
X-linked SCID, IL-2Rgamma chain defect
What is typical treatment for SCID?
IVIG, bone marrow transplant
How effective is a bone marrow transplant for someone with X-linked SCID + IL-2Ry chain defect?
For case presented in class: 3 months post BMT showed that T cells were positive to activation by recall Ags. Patient remained unable to produce IgG, so IVIG will continue throughout life
Why do B cell defects manifest later than T cell defects in SCID?
Passive Ab transfer from mom via placenta and breastfeeding provide temporary protection
What immune function is ALWAYS impaired in SCID?
T cell function
Patients with SCID present with recurrent persistent infection by ________ organisms
Opportunistic
Since T cell function is always impaired in SCID, what is classification of SCID based on?
Based on if B cell function is directly impaired by molecular defect
[B cell positive or B cell negative]
Most patients with SCID present around 3 months of age with life-threatening, recurrent opportunistic infections.
What are some of the other abnormal clinical findings associated with SCID, noting that these are due to infection, not the immunodeficiency itself?
Failure to thrive
Dehydration
Fever
No lymphadenopathy (increased secondary lymphatic tissues)
