Soluble mediators of the immune system Flashcards
4 main sources of BRMs by (mononuclear leukocytes)
Biological response mediators (BRMs)
-B lymphocytes: secrete specific Abs
-T lymphocytes: secrete soluble mediators (IL-2, other-ILs, GM-CSF, TNF-β, IFY-γ)
-Monocytes and macrophages: secrete (IL-1, other ILs, GM-CSF, TNF-α, M-CSF, IFN-α)
–NK lymphocytes: secrete IFN-α
^modulate individual’s own immune response
Classes of BRM immunotherapy
-Active— use of microbial or chemical immunomodulators (adjuvants) in a specific or non-specific form
-Adoptive— use of soluble mediators, such as ILs, to regulate components of the immune systems
-Passive— Transfer of preformed antibodies to tumorous recipients, such as monoclonal antibodies
-Restorative— application of soluble substances, such as interferons, for a wide range of diseases
What are Cytokines, what do they do?
-A polypeptide product of activated cells (lymphocytes or macrophages) that control a variety of cellular responses & thereby regulates the immune system
-Most cytokines have multiple activities & act on numerous cell types
-synthesized and secreted by cells of the innate/adoptive immunity in response to microbial & other Ag exposures (variety of host defense)
-Very potent; act on neighboring cells by binding to their surface cytokine receptors
-effect limited to local area; BUT CAN HAVE systemic effects
What are Lymphokines vs Interleukins
(separate?)
-Lymphokines— cytokines produced by activated lymphocytes
-Interleukins— cytokines produced by leukocytes that act on other leukocytes
Describe the role of cytokines in innate immunity
-mediate early inflammatory reactions to microbial products
-stimulate adaptive immune response
Cytokines in adaptive immunity
-stimulate proliferation/ differentiation of Ag-stimulated lymphocytes
-activate specialized effector cells (e.g macrophages)
What actions do the different cytokines share?
They differ in molecular structure but share the following
-secrete cytokines in rapid bursts (keep? in response to cellular activation)
-bind to specific receptors on target cells
-regulate receptor expression in T/B cells, for positive amplification or negative feedback
-excite the same functional effects w/ multiple cytokine (redundancy)
-act close to site of synthesis/ same cell or (different) neighboring cell
-influence the synthesis & actions of other cytokines
What’s a Cytokine storm
-Severe immune reaction characterized by
the rapid release of a high concentration
of cytokines into peripheral blood
circulation
-biological concepts not completely understood
-associated w/ covid-19
-termed in 2005 w/ h1n1 bird flu
-important factor— the kinetics of cytokines & chemokine gene expression
What chemokines make the cytokine storm? Think broad categories. Not asking for specifics like IL-1 or TNF-alpha
-ILs, CSFs, TNFs, IFNs, chemokines
-severe damage can occur b/c body attacks own cells/tissues rather than fighting virus (acute lung injury is common)
-SARS chemokines => strong pro-inflammatory response => pulmonary fibrosis
Interleukins (ILs)
-cytokines produced by leukocytes that affect the inflammatory process thru increase in soluble factors (or cells)
-modulate inflammation (IL-1)
-Modulate immunity by regulating growth, mobility, & differentiation of lymphoid cells
-many different individual families/superfamilies of ILs have been identified w/ overlapping functions
Interferons (IFNs)
-cytokines produced by T lymphocytes & other cells that inhibit viral synthesis or act as immunes suppressors
-natural defensive responses to foreign components (microbes, tumors, Ags)
Type I IFNs
-mediate in early innate immune response to viral infections
-consist of IFN-α and IFN-β
^structurally different; bind to same cell surface receptor; similar biological functions
IFN-γ
-Principal macrophage-activating cytokine
-critical for innate immunity & specific cell-mediated immunity
-Stimulates expression of MHC class I and MHC II
-costimulates APCs
-Promotes the differentiation of naïve CD4+ T cells to the TH1 subset
-Inhibits the proliferation of TH2 cells
Tumor necrosis factor (TNF)
- Principal physiologic functions is to stimulate the recruitment of neutrophils & monocytes to sites of infection (to eradicate microbes)
- principal mediator of acute inflammatory response to gram negative bacteria (other microbes)
- responsible for many systemic complications of severe infections
- TNF receptor family stimulate gene transcription or induces apoptosis in a variety of cells
Stem cell factor (c-kit ligand)
-Cytokine interacts w/ tyrosine kinase membrane receptor (the protein product of the cellular oncogene c-kit)
-Acts on immature stem cells
-Needed to make bone marrow stem cells responsive to other CSFs (Does not cause colony formation itself)
-May play role in sustaining, viability & proliferative capacity of immature T cells in the thymus & mast cells in mucosal tissues
Colony stimulating factors (CSF)
-Variety of CSFs (like G-CSF and GM-CSF) are made by T cells -Provide a link between lymphoid and hematopoietic systems
-G-CSF and GM-CSF regulate the production of granulocytes and monocytes—allows T cell system to promote inflammatory response
-necessary for survival, proliferation, & differentiation in precursor cells of the immune system
-Increases circulating leukocytes in patients w/ AIDS, chemo patients, bone marrow transplants (important in treatment of disease)
Transforming growth factors (TGFs)
-products of virally transformed cells
-induce phenotypic transformation in nonneoplastic cells
TGF-β
-group of 5 cytokines released by cells (Macrophages & platelets)
-potent inhibitor of IL-1-induced T cell proliferation/ differentiation
-inhibits proliferation/activation of lymphocytes (T-cell p/d) & leukocytes (activation of macrophages)
Chemokines
Large family of structurally homologous
cytokines that:
-Move leukocyte from the blood to site of infection
-Regulate/maintain migration of PMNs & mononuclear (immune cells) to lymphoid organs/ specialized cells
3 families Largest, second, third families
other functions:
-increase the affinity of leukocyte integrins to their endothelial ligands
-regulate traffic of lymphocytes (& other leukocytes) thru peripheral lymphoid tissues
CC chemokine
Part of large family - attract mononuclear cells to sites of chronic inflammation
CXC chemokine
Part of second family - attracts PMNs to acute inflammation; activates monocytes; direct WBC to vascular lesions
CXC3 chemokine
Part of third family - forms a cell adhesion receptor capable of arresting cells under physiologic flow conditions (WBC slowing down & crossing blood vessel)
what are Acute phase proteins / reactants?
(APPs)
what triggers them?
-a group of glycoproteins associated w/ acute phase response
-various protein rise to various rate/ lvls in response to injury
-increased synthesis starts shortly after trauma (initiated/sustained by pro-inflamm-cytokines)
- >20 APPs have role in inflammation
clinically useful acute phase proteins (APPs)
-CRP binds to membranes of microbes & activates complement
-Inflammatory mediators C3/C4 of complement
-fibrinogen
-transport protein => haptoglobin
-inhibitors => α1- antitrypsin
-α1-acid glycoprotein
synthesis and catabolism of acute phase proteins (APPs)
-acute phase proteins have different kinetics & various degrees of increase
-rate of change & peak concentrations vary w/ component & clinical situation
—acute inflammation: CRP & α1-antichymotrypsin increase w/ 12hrs
—C3, C4 & ceruloplasmin don’t rise for several days
-Acute phase proteins don’t always change in parallel
Increase
-tissue injury/ damage rapidly produces APP
-strenuous exercise triggers inflammation response similar to sepsis
-indices; Leukocytosis, release of inflammtory mediators & acute phase reactants, priming of WBCs, production of free radicals, complement activation, coagulation & fibrinolytic cascades
Decrease
-Negative acute phase proteins (fibrinogen /DIC)
—most have half-life of 2-4 days, CRP 5-7hrs (CRP falls more rapidly back to normal)
C-reactive protein (CRP)
-used for monitoring infections, autoimmune disorders, healing after heart attack
-lvls of CRP are parallel with inflammatory course
-lvls rise with tissue injury or surgery (CRP peak at 2 days post surgery. Back to normal in 7-10 days —uncomplicated Sx)
-fastest/most sensitive indicator of inflammation
-increase faster w/ ESR
-CRP can signal infection hrs before culture (useful when WBCs counts don’t shoot up)
What diseases can CRPs be elevated in?
-meningitis in neonates
-Myocardial infractions (MIs)
-burns complicated by infections
-malignant tumors
-Serious post-op infections
-infections in immunosuppressed patients
-septicemia
-Rheumatic diseases
True or False
CRP can help differentiate b/w bacterial & viral infections
TRUE - CRPs will be extremely high in bacterial infections compared to viral infections
True or False
CRP can be used as a definitive diagnostic tool
FALSE - CRP lack specificity
True or False
CRP can be used in serial measurements
TRUE - can monitor; effect of treatment, post-op complications, or recurrent infections
True or False
CRP can be used as a reliable indicator for SLE, ulcerative colitis, & dermatomyositis
TRUE
True or False
CRP can used to evaluate risk of cardiovascular disease
TRUE - used with low density lipoprotein (LDL) to evaluate cardio disease
True or False
Procalcitonin (PCT) is NOT a good marker for sepsis
False - PCT has greater specificity than other proinflammatory markers
True or False
Procalcitonin (PCT) can be used to diagnose bacterial infections
TRUE
True or False
α1-Antitrypsin decreases with acute inflammatory reactions
False - it increases with acute inflammatory reactions
True or False
α1-Antitrypsin decreases with generalized vasculitis
TRUE
True or False
Ceruloplasmin is measured as serum copper
TRUE
True or False
Ceruloplasmin is NOT used for Hodgkin disease
FALSE - it can indicate relapse
True or False
C3, C4 components decrease with immune complex diseases & gram-negative bacteremia
True - components decrease with complement activation because they get used up
True or False
C3, C4 components are slightly elevated with acute inflammation
True
True or False
Inflammation does not follow acute tissue damage
False - Damage->inflammation
Lab tests for early acute inflammation
-total WBC count (segs/bands/ neutrophils)
-Acute-phase proteins
-ESR (erythrocyte sedimentation rate)
-CRPs
Erythrocyte sedimentation rate (ESR)
-most common ordered lab test
-non-specific indicator of disease
-increase in acute & chronic inflammation, malignancies
Diagnostic categories for APP include
-bacterial causes
-non-bacterial causes: trauma, chronic inflammation, viral disease
