Cytokine Messengers - Bowden Flashcards
What is the role of IL-7? 6
Pluripotent stem cells differentiation into lymphoid progenitors (T, B, and NK cells)
Important for T cell survival
Where is IL-7 produced? 6
Secreted from bone marrow and thymic stromal cells
What produces TNF? 7
TNF - tumor necrosis factor
Macrophages
T cells
Mast Cells
What are the main and secondary roles of TNF? 7
Activation of endothelial cells (inflammation/coagulation)
Neutrophil activation
Induces fever in hypothalamus
Induces apoptosis in many cell types
What is the role of TGF-β? 7
Inhibits inflammatory T cells
Th17 differentiation
Treg differentiation
What is the principal source of IL-15? What is the role of IL-15? 7
Source - macrophages
Induces proliferation of NK cells
Induces proliferation of T cells
What secretes IL-18? What is its role? 7
IL-18 secreted by macrophages
Induces NK cells and T cells to synthesize IFN-γ
What are the type 1 interferons? 7
IFN-α
IFN-β
What are the main roles of Type 1 IFNs? 7
Induces an antiviral state meaning:
increased HLA Class I expression on all cells
NK cell activation
What is the main role of IFN-γ?
Activation of macrophages
What type 1 IFN is produced by leukocytes
IFN-α
What type 1 IFN is produced by Fibroblasts? 8
IFN-β
How do Type I IFNs inhibit viral replication? 8
Degrade viral mRNA
Shuts down human protein synthesis
Secreted from viral infected cells to neighboring cells
What is the role of Endogenous pyrogens on bone-marrow epithelium and DCs? 9
Pyrogens - IL-1/IL-6/TNF-α
Bone Marrow - Neutrophil mobilization for phagocytosis
Dendritic Cells - TNF-α stimulates DC migration to lymph nodes and maturation (start of adaptive response)
Before it’s a macrophage it’s a _______? 10
Monocyte (in circulation)
What are the 2 major functions of macrophages? 10
M1 Classical Macrophage Function
M2 Alternative Macrophage Function
What induces the M1 Macrophage function? 10
M1 - classical function
A monocyte that receives:
- ) TLR ligand binding
- ) Induction via IFN-γ
What induces the M2 Macrophages? 10
M2 - alternative function
A Monocyte that receives:
- ) IL-13
- ) IL-4
What is the main summary role of M1 Macrophages? 10
Induced by innate immunity and involved in inflammation
What is the main summary role of M2 Macrophages? 10
Play a role in tissue repair and inflammation control
What is the combined role of TGF and IL-10? 11
Contraction of the immune response (anti-inflammatory properties)
What secretes IL-10? 11
Macrophages
Dendritic Cells
Tregs
What is unique about the repair process induced by TGF-β? 11
Induces repair without regulatory immune cells having to be in the vicinity
What are all the cytokines produced by CD4+ T helper cells and what is the function of each? 12
IL-2 –> full development of TCR, α subunit
IL-4 –> B cell class switching IgM to IgE
IL-5 –> Act. Eosinophils
IFN-γ –> macrophage activation
TGF-β –> T cell act. Inhibition + induction of Treg cells
What are all the cytokines produced by CD8+ Cytotoxic T cells and what is their function? 12
IL-2 –> allows for addition of α subunit to finish TCR (autocrine signal)
IFN-γ –> activates macrophages
At the site of infection what would induce Th1 development? 13
Coming from a Ag-presented CD4+ T Helper Cell:
IFN-γ
IL-12
Transcription Factor: T-bet
At the site of infection what would induce TH2 development? 13
Coming from a Ag-presented CD4+ T Helper Cell:
IL-4
Transcription Factor: GATA-3
At the site of infection what would induce TH17 development? 13
Coming from a Ag-presented CD4+ T Helper Cell:
TGF-β
IL-6
IL-23
IL-1
Transcription Factor: RORγT
What are the target cells of Th1, Th2, and Th17 and what do these targets cells defend the host against? 14
Th1 –> Macrophages, defense against IC pathogens
Th2 –> Eosinophils, defense against Parasites (helminths)
Th17 –> Neutrophils, defense against EC pathogens
What part of the immune response do we consider IFN’s to be? 8
Part of the innate system because they shut down human protein synthesis
What do M1 Macrophages produce and do? 10
ROS + NO + lysosomal enzymes –> phagocytosis and bacteria killing
IL-1,12, and 23 –> inflammation
What do M2 Macrophages produce and do? 10
IL-10, TGF-β:
Wound repair
Antiinflammatory effects
Fibrosis
What cytokines are produced by Mast Cells? 12
IL-4 –> B cell class switching IgM to IgE
IL-5 –> activation of eosinophils
What role do Macrophages and Th1 play in disease? 14
Autoimmunity and chronic inflammation
What role do Eospinophils and Th2 play in disease? 14
Allergies
What role do neutrophils and Th17 play in disease? 14
Autoimmunity
What do Th2 cells secrete? 14
IL-4 –> M2 macrophage activation, peristalsis, B cell Class switch IgM to IgE
IL-5 –> Eosinophil activation
IL-13 –> peristalsis, M2 activation
What do Th17 cells secrete? 14
IL-17,22
Who secretes IL-2 and what type of signal is it? 15
T cells secrete IL-2 and it’s an autocrine signal
What binds IL-2? 15
IL-2R or CD25 of Tcell
How are T cells induced to proliferate? 15
IL-2 binds CD25 (IL-2R) in a low affinity state
α subunit of CD25 receptor expressed
CD25 now able to bind IL-2 in a high affinity state
T cell proliferates
What is the role of IFN-γ released by Th1? 16
M1 Macrophage activation
Act. B cells to stimulate complement binding
Stimulates Class II HLA and CD80
What is the relationship between Th1 and Th2? 16, 18
Th1 cytokines are inhibitors of Th2 responses
Th2 cytokines are inhibitors of Th1 responses
What is Th1 activation dependent on firstly? 17
Dependent on Ag recognition (by a macrophage)
In a naive B cell Ig Chain what happens if you induce with IL-4? 19
IgG4 production
IgE production
In a naive B cell Ig Chain what happens if you induce with TGF-β? 19
IgA production
IgG production
What cytokines do Th17 produce? 21
Look at diagram, make sure you have all the detail!
IL-17 –> inflammation, neutrophil response, antimicrobial peptides
IL-22 –> increased barrier function, antimicrobial peptides
What is the main function of Th17? What disease are Th17 involved in? 21
Proinflammatory T cell
Multiple sclerosis
IBD
Rheumatoid arthritis
What’s the Dx and treatment: Gradual loss of sensation on back of hand, hypo-pigmented lesions on elbows, wrists, and hands. Lesion expansion. No eyelashes or eye brows. Varying response to pinprick test.
Elevated Neutrophils everything else normal
IgG elevated everything else normal
Biopsy: Multiple acid-fast bacilli in clumps, foam cells
22, 23, 24, 25, 26, 27
Dx - lepromatous leprosy (M. Leprae)
Tx - dapsone, clozapine, rifampin
How does Leprosy cause infection? 28
M. Leprae colonized macrophages and host cells multiplying within them
Can only be killed by IC killing of activated macrophages
What type of infection does M. Leprae result in? 28
Intracellular infection
What transcription factor induces Th1? What transcription factor induces Th2? 29
Th1 - NFAT-c
Th2 - GATA-3 | c-MAF | NIP-45
What are two types of infection as a result of M. Leprae? 30
Tuberculoid leprosy
Lepromatous leprosy
What’s the difference between Tuberculod leprosy and Lepromatous leprosy? 30
Lepromatus:
Highly infective, disseminated. Neuropathological infection (schwann cells) major deformity. Low T cell response and hypergammaglobulinemia
Tuberculoid:
Organisms present at low levels with localized inflammation. Normal T cell response and serum Ig levels
Which cytokine might be beneficial to a patient with lepromatous leprosy? 32
IL-12 and IFN-γ to push the shift towards Th1 (from the leaning Th2 state)
What causes Leishmania Major? What causes Mycobacterium leprae? 29
Leishmania major - protozoal parasite
Mycobacterium Leprae - Bacterium
What is the dx and tx:
Male with healthy sister
3 months: dry cough and runny nose,
4 months: ottis media (ear infection), oral polio and DPT vaccination given
5 months: dry cough, recurrent otitis media, re-immunized chest X-ray - bilateral pneumonia (treated with clarithromycin)
6 months: thrush (yeast), diaper rash, not gaining weight, tachypnea
WBCs - low Lymphocyte count - low Differential of periphery - 99% B cells Ig titers are all very low No recall of immunizations RBCs - normal \+ pseudomonas aeruginosa \+ respiratory syncytial virus (RSV)
34, 35, 36, 37, 38, 39, 40
Dx: X-linked SCID (IL-2Rγ chain defect)
Tx: IV-Ig, Bone Marrow Transplant
What are the two main issues associated with SCID? What cells are present in Severe Combined Immunodeficiency (SCID)? 41
Severe B and T cell dysfunction
- T cells always absent
- B cells MAY be absent (B cell pos or neg)
- NK cells MAY be absent
Persistent opportunistic infections
IL-2 look at 43!
Heterodimer that becomes a trimer when α subunit gets added
What is the classification of SCID based on? 42
Whether or not the pt is B cell + or B cell -
What are the clinical presentations of SCID and what are they caused by? 44
Caused by opportunistic infections
Failure to thrive
Dehydration
Fever
No lymphadenopathy (increased secondary lymphatic tissues)
Diagram slide 45
(Will be helpful)
