Module 5 Flashcards
cytokines
low molecular weight regulatory proteins or glycoproteins secreted by leukocytes and various other cells in the body in response to stimuli
- cytokines are mainly produced by helper T cells, dendritic cells, and macrophages
- function to act as local messengers of the immune system, but can exert effects systemically
cytokine types
if cytokines are secreted by lymphocytes, they are called lymphokines, whereas if they are secreted by monocytes, they are called monokines
common cytokine classes
interleukins (IL): IL-1 to IL-33
tumor necrosis factor (TNF)
interferon (IFN)
chemokines
cytokine effect exertion
cytokines can either be autocrine (exert their effects by binding to receptors on the same cell), paracrine (exerting effects on nearby target cells), or endocrine (exerting effects on distance cells)
cytokine properties
cytokines exhibit a very high affinity for their receptors and are able to exert their effects with a very small amount of active cytokine
roles of cytokines
- cellular and humoral immune response: cytokines are the messengers between the innate and adaptive immune systems
- inflammation: pro-inflammatory cytokines are produced by activated macrophages
- hematopoiesis: cytokine IL-7 is integral for B-cell development
- cellular proliferation and differentiation
- wound healing
cytokines in the immune system
cytokines provide the link mediating the transition from innate to adaptive immunity
- suggested that T cell derived cytokines play a role in limiting the innate response and promote the initiation of the antigen-specific adaptive response
cytokines and the immune response
cytokines regulate the magnitude and nature of the immune response by influencing the growth and differentiation of lymphocytes and other cells of the immune system
four attributes of cytokines
pleiotropy
redundancy
synergy
antagonism
pleiotropy
a single cytokine can produce multiple effects either by acting on a single cell type of on multiple cell types
- ex: IL-4 can stimulate multiple effects in B cells, and can stimulate additional effects in thymocytes and mast cells
redundancy
many cytokines are redundant in nature
- they can target the same cell and elicit the same effect
- this is advantageous if there is a deregulation in one of the cytokines, as the ‘redundant’ cytokines can continue to exert the effects and maintain the immune response
syngergy
the combined effects of some cytokines is greater than the added effect of each of them separately
antagonism
cytokines can act on other cytokines to impact their effects
pro-inflammatory cytokines
IL-1 beta
IL-6
TNF-alpha
inflammatory cytokines play a crucial role in immune cell activation
anti-inflammatory cytokines
IL-10
TGF-beta
cytokine storm
the release of large concentrations of inflammatory cytokines after infection or injury
- prolonged inflammation can lead to complications like tissue damage
- highlights the importance of having a balance of pro- and anti-inflammatory cyoktines
T-cell cytokines
these support T-cell proliferation and activation
- IL-2: made by T-cells
- IL-4: made by helper T-cells
- IL-12: made by macrophages and dendritic cells
B-cell cytokines
these support B-cell proliferation and differentiation
- IL-4 and IL-5: made by helper T cells
- IL-7: made by stromal cells
interferon cytokines
IFN alpha and IFN beta: produced by macrophages and dendritic cells to fight viruses
IFN-gamma: produced by NK and T-cells to enhance immune responses
cytokines in an anti-inflammatory state
if there is an anti-inflammatory state, no immune cells would be called to the site, thus no foreign antigens would be killed, and there would be no response to infection, resulting in an increased susceptibility of serious infection
cytokine receptors
facilitate cellular activation and signalling
divided into 5 classes based on structure and function:
1. Class I cytokine receptors
2. Class II cytokine receptor
3. TNF receptor family
4. chemokine receptor family
5. immunoglobulin superfamily receptors
immunoglobulin superfamily receptors
this class of cytokine receptors has the same Ig domain structure that is found in MHC and Ig’s
Class I cytokine receptors
these receptors share the Trp-Ser-X-Trp-Ser (WSXWS) amino acid motif, where X is any amino acid
Class II cytokine receptors
similar in structure to Class I, but do not have the WSXWS motif
- this class is characterized by the presence of cysteine disulfide bonds
TNF receptor family
these receptors have cysteine rich domains
chemokine receptor family
these receptors belong to the family of GPC receptors (GPCRs) and contain 7 transmembrane domains
- also called hepta-helical or serpentine receptors
cytokine receptor chain characteristics: redundancy
cytokine receptors are often composed of one or more chains
- different combinations of chains for a given receptor will bind the same cytokine to induce cellular signals, but will bind with different affinities
cytokine receptor characteristics: pleiotroy
cytokine receptors may exhibit a common chain that allows the receptor to bind unique cytokines depending on their additional cytokine specific subunits
cytokines in T cell differentiation
cytokines serve as a link between the innate and adaptive immune responses, which is relevant in the differentiation of Th1 and Th2 cells
differentiated helper T-cell subsets
CD4+ helper T cells may differentiate into subsets of effector cells that secrete distinct sets of cytokines in response to processed antigens presented by APCs
- when APC-MHC complex interacts with CD4 co-receptor on the helper T cell, it will signal in an autocrine fashion by secreting IL-2 to induce cell proliferation
induction of Th1 cells
activated APCs secrete IL-12 which promotes T cell differentiation to Th1+ cells through STAT4 activation
STAT4
- a transcription factor required for the development of Th1 cells from naive CD4+ T cells
- activates transcription 4
induction of Th2
basophils and mast cells secrete IL-4 to promote T cell differentiation into Th2+ cells through activation of STAT6
STAT6
a protein that plays a central role in exerting IL-4 mediated responses
- activator of transcription 6
JAK-STAT pathway
the main pathway associated with cytokine signalling inside of the cell that results in T-cell commitment
JAK-STAT pathway steps
- cytokine binds to cytokine receptor, causing it to dimerize
- activation of JAK family tyrosine kinases resulting in phosphorylation of receptor
- tyrosine phosphorylation of STAT by JAK kinase
- dimerization of STAT
- translocation of STAT into the nucleus and binding to DNA
- specific gene transcription committing the T cell to Th1 or Th2 lineage
cross-regulation
newly differentiated Th1 and Th2 cells can secrete cytokines that can either:
- inhibit proliferation of the other subset
- enhance proliferation of its own subset through positive feedback
this cross regulation effect of cytokines is a way to control the population of a specific T cell subset during infection
effector functions of Th1
secretes IFN-y
promotes further Th1 differentiation and inhibits Th2 proliferation
plays a role in cell mediated immune response
effector functions of Th2 cells
primarily secrete IL-4 and IL-5, and sometimes IL-10, which collectively promotes Th2 differentiation and inhibits Th1 activation
plays a role in the humoral immune response
cytokine related diseases
bacterial septic shock
bacterial toxic shock
disease association
bacterial septic shock
in bacterial induced sepsis, patients experience fever, weakness, and rapid heart and breathing rates
- when patients get dangerously low blood pressure, it is termed as septic shock
process of bacterial septic shock
gram negative cell wall endotoxins stimulate the patient’s macrophages to overproduce IL-1 and TNF-alpha, causing a shock state
- pro-inflammatory cytokines amplify inflammatory cascades in an autocrine and paracrine manner, activating macrophages to also secrete pro-inflammatory cytokines (IL-6 and IL-8)
- this results in symptoms like fever, organ dysfunction, and clotting
bacterial toxic shock
infectious bacteria release SAGs, which are a class of antigens that cause non-specific activation of T cells, resulting in polyclonal T cell activation, creating a cytokine storm within the body
- characteristics of the cytokine storm is high levels of IL-1 and TNF-a
disease association
in lymphoid and myeloid cancers, overproduction of IL-6 leads to exaggerated cell proliferation
- chronic IL-6 signalling results in plasmacytosis, which can cause lymphoid cancers and bone marrow cancers
- IL-6 can also deactivate the tumour suppressor gene p53
Chagas disease
caused by the transmission of the tropical protozoan parasite T. cruzi by the triatomine bug
- bugs hide in the crevices of mud and straw houses in Latin and South America during the day, and emerge at night to feed on the faces of people, and defecate after biting
- an individual can become infected with T. cruzi if the infected bug feces enters the body through mucous membranes or if the skin is broken
