I6 Drivers of Inflammation and Immunodeficiency Flashcards
Learning Outcomes (for general perusal)
● Cytokines:-
proinflammatory
anti-viral
involved in haematopoiesis
involved chemotaxis
in suppression, tolerance and therapy
● Causes of primary and secondary Immunodeficiency
What is homeostasis?
Why is this important?
The property of a system, especially a living organism, to regulate its internal environment so as to maintain a stable, constant condition.
Ability of the immune system to self-reguate is critical. Inflammation underpins most chronic diseases.
- Hypersensitivity (viral infection)
- Chronic Inflammation (bacterial infection)
- Immunodeficiency (recovery)
- Immunosuppression (tissue repair)
What are the signs of inflammation?
What are the main drivers of inflammation?
- Rubor
- Tumor
- Calor
- Dolor
- Functio Laesa
Cytokines
- What are Cytokines?
- Why are many cytokines known as interleukins?
- What do they play an important role in linking?
- Cytokines are potent chemical messengers produced by cells of the immune system. Small peptides that are usually secreted. (Lymphokines and monokines collectively called cytokines)
- Cytokines act as a messenger between leukocytes
- linking innate and adaptive immunity
Cytokines
- Give some properties
- Generally, how do they act?
- Low molecular weight proteins. Their production is carefully regulated
- Bind to receptor on the cell which produced it or another cell
Receptor binding triggers a signal
Signal results in altered pattern of gene expression
Cytokines
They can act in three different ways.
Name these ways, and outline how the cytokines act.
- Autocrine - Cytokine binds to receptor on cell that secreted it
- Paracrine - Cytokine binds to receptors on nearby cells
- Endocrine - Cytokine binds cells in distant parts of the body
Cytokines
- How do they signal?
- Through cytokine receptors, TI and TII cytokines (JAK family tyrosine kinases, phosphorylation of R. STAT phosphorylation, STAT dimerisation, into nucleus and acts upon specific gene transcription)
- How are cytokines classified?
- How many interleukins have been identified to date?
- Into four families based on their structure
- Haematopoietin Family (eg: IL-2 and IL-4)
- Interferon family (IFNs)
- Tumour necrosis factor family (eg:TNF-α)
- Chemokine Family (eg: CCL-2)
- 35 Interleukins
How do Cytokines regulate hematopoiesis?
- Common lymphoid progenitor will give rise to NK cells and T and B lymphocytes under the action of IL-7
- Common myeloid progenitor will give rise to Erythroid Progenitor, Megakaryocyte, Basophil progenitor, Eosinophil projenitor and Granulocyte-monocyte projenitor under the actions of IL-3, GM-CSF, IL-6
- Eosinophil from eosinophil projenitor by IL-5
- Neutrophils (by GM-CSF) and Monocytes (by M-CSF) from granulocyte-monocyte projenitor
What are cytokines important in linking?
The innate and adaptive immune response. Secreted by Th cells
- Guides clonal expansion of Th cells and Tc cells
- Activates resting B cells into Active B cells then into Plasma Cells (IL-6)
- Guides differentiation of mast cells, Eosinophils, NK cells
Role of Cytokines in Immune Response
- What is their primary function in the immune response?
- Give some speficic cell interactions that they guide
- Linking the innate and the immune response (there is also an initial pro-inflammatory response)
2.
- Interaction between T cell and APC
- DC instruction to T cell
- T cell polarisation - Th1, Th2, Th17
- Anti-viral response
Interleukin-2
- When is it produced?
- How does it act?
- Outline its specific actions further
- following T cell activation by antigen presenting cells.
- acts in an autocrine loop to induce T cell proliferation
- The major autocrine growth factor for T cells.
IL-2 (and IL-15) stimulates NK cell cytolytic function.
Acts on B cells as a growth factor. Induces the death of activated T cells
IL-2 receptor has 3 chains IL-2Rαβγ. The α chain is the cytokine specific chain and the γ chain is shared by a number of cytokine receptors
Interleukin-4
- What is it?
- What does it do?
- What is it produced by?
- What is it required for the production of?
- What does it induce?
- How does it interact with Mast cells?
- a Th2 derived cytokine
- stimulates B cell proliferation. Exogenous IL-4 drives Th2 differentiation
- Activated Thelper2 cells
- gG1 and IgE
- Thelper2 cell differentiation
- It is a growth factor for mast cells
Interleukin-17
- What is it produced by?
- What does it do?
- What conditions is it associated with?
- What is it?
- Activated Thelper17 cells
- Induces neutrophil maturation and activation
- autoimmune pathologies (rheumatoid arthritis, lupus, psoriasis) drives bone resorption in arthritis. a major role in many infectious diseases
- major pro-inflammatory cytokine
Inhibitory Cytokines
- What are the inhibitory Cytokines?
- Outline what each does and where they are produced
- TGF-B, IL-10
2.
TGF-B- generally suppresses lymphocyte function, produced by many cells of the immune system
- Suppresses the activation of macrophages
- Inhibits growth of many cell types especially lymphocytes
- Enhances wound repair
IL-10 - generally suppresses the immune system, produced by activated T Helper 2 cells and T regs
- Is required for suppression of macrophages, T cells, NK cells
- Inhibits TNF, IL-1, IL-12 and chemokine production The absence of IL-10 causes IBD
Outline T Cell subsets and defence against pathogens
TH2 - secretes IL-4 - defence against parasitic worms. Allergy, asthma.
TH1 - secretes IF-gamma - defence against intracellular pathogens
TH17 - secretes IL-17 - defence against extracellular bacteria, autoimmunity, cancer
Treg - secretes TGF-B1 - immunosuppression
Cytokines produced by Macrophages in response to bacterial challenge
Activated macrophages secrete a range of cytokines
What are these cytokines? What do they do?
- IL-1 - Activates vascular endothelium, lymphocytes, local tissue destruction, increases access of effector cells: fever IL-6
- TNH-a - Activates vascular endothelium, increases vascular permeability (increased entry of IgG, complement and cells to tissues and increased fluid drainage to lymph nodes): fever, mobilisation of metabolites, shock
- IL-6 - Lymphocytes activation, increased, increased antibody production: fever, induces acute-phase protein production
- IL-8 - Chemotactic factor results in neutrophils, basophils and T cells to site of infection
- IL-12 - activates NK cells, induces differentiation of CD4 cells to Th cells
Outline the anti-viral effects of interferon a/b
- Induce resistance to viral replication in all cells
- Increase MHC class 1 expression and antigen presentation in all cells
- Activate NK cells to kill virus infected cells
Tumour Necrosis Factor-α (TNF-α)
- Generally, what does it do?
- What is it derived from?
- What does it induce?
- What can it induce long-term?
- What does it act on the hypothalamus to produce?
- Principle mediator of the anti-bacterial response
- macrophages and T cells
- Induces neutrophil activation (inflammation)
Activates endothelial cells (inflammation)
- Long-term it can induce cachexia (muscle and fat wasting)
- Fever
Chemokines
- What are these?
- What do they do?
- Chemotactic cytokines
- Recruit leukocytes to sites of infection
Regulate traffic through peripheral lymphoid tissues
Organ development (morphogenesis) Lymph node organization Cell activation
structurally homologous 8-12 kDa
50 or more already described
What are the main chemokine families?
C (XCL1,2)
CC (CCL2,3,4)
CXC (CXCL1,8,9,10,12)
CX3C (CX3CL1)
Outline chemotaxis
Attracted leukocyte (macrophage) has Rs on surface, moves towards inflammatory site along the chemotactic gradient
Outline Chemokine signalling?
Transmembrane chemokine receptor coupled to G protein.
Cellular cascade results in
- Actin polymerisation
- Adhesion
- Cytoskeletal rearrangement
These all contribute to chemotaxis
- Differentiation, proliferation
Cytokine Dysregulation
Outline cytokine dysregulation in
- Asthma
- Allergy
- Autoimmunity
- Dysregulation of Th1/Th2 balance. Th2 cytokines overproduction
- Chronic inflammatory response: dysregulation of Th17 cells
Other cytokine related diseases
- Bacterial septic shock
- What are the symptoms?
- What is the pathological process?
- Lymphoid and myeloid cancer
- Why does this come about?
- Chagas’ disease
- What is this?
- Bacterial septic shock
- Blood pressure drops, clots form, hypoglycemia ensues, patient dies
- LPS(lipopolysaccharide) triggers results in TNF release
TNF induces IL-1 which induces IL-6 and IL-8
- Some cancer cells secrete cytokines
- Trypanosoma cruzii infection results in severe immune suppression
◦Depression of IL-2 receptor production
Cytokine Receptors in Disease
- What do mutations in R shared by IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cause?
- What can EPO ( Erythoropoietin) receptor mutations cause?
- What does TNF receptor mutations cause?
- What is consitutive activation of cytokine signalling pathways associated with?
- X-SCID (X- linked severe combined immunodeficiency)
- benign erythrocytosis
- tumour necrosis factor receptor associated periodic syndrome (TRAPS)
- many leukaemias.
Cytokines in Therapy
- What has been used to treat cancer?
- What is the main therapy in viral hepatitis?
- What is the main therapy for MS?
- What is IFN-g used to treat?
- What is IL-10 under investigation for treating?
- What is EPO used for?
- What can be used following bone marrow transplantation?
- What is used to treat rheumatoid arthiritis?
- What is under investigation to treat IBD?
- IL-2
- IFN- a is the main therapy viral hepatitis also Leukemia
- IFN- b is the main therapy for Multiple Sclerosis
- IFN-g used to treat chronic granulomatous disease
- autoimmune diseases
- to treat patients prior to transplantation as it stimulates erythrocyte proliferation; has neuroprotective effects (stroke).
- G-CSF
- Antibodies to TNF (anti-TNF)
- Antibodies to IL-12 (anti-IL-12)
Primary Immunodeficiency Diseases
- What are the clinical features?
- What are examples?
- What is the main characterisitic?
- What are the adaptive immune defects?
- What are the innate immune defects?
- Clinical feature variable. Recurrent and often overwhelming infection in very young children
- Allergy, autoimmunity, cancer, lymphocyte abnormal proliferation
- Inherited mutations
- T cells, B cells, antibodies
- Complement components Phagocytes
TLRs signalling
Primary Immunodeficiency Diseases
T-Lymphocyte Deficiencies
What can cause these?
- Deficiency of Signalling Molecules
- Jak3, Lck, Zap70 , CD45
- RAG-1 & RAG-2 deficiency
- combination activating genes
- Ataxia Telangiectasia
- MHC Class I & Class II deficiency
- (Bare lymphocyte syndrome)
- X-linked lymphoproliferative disease
Primary Immunodeficiency Diseases
T-Lymphocyte Deficiencies
- What do defects in T-cell development result in?
- What is DiGeorge Syndrome?
- What gives rise to Deficiency of Cytokine Receptor chains?
- What is Wiskott-Aldrich Syndrome (WAS)?
- Give examples of a metabolic defect
- severe combined immunodeficiencies ( SCID)
- Intra-uterine damage to 3rd and 4th Pharangeal pouches
- ◦ X-linked SCID: mutation in the gene IL2RG on the X chromosome ◦ common gamma chain
◦ IL-7 receptor α & IL-2 receptor α - membrane defects of T cells and platelets
- -Adenosine Deaminase Deficiency
- Purine Nucleoside Phosphorylase Deficiency
Secondary Immunodeficiency Diseases
- What are these a result of?
- Give an example
- A consequence of other diseases Environmental factors
An adverse consequence of medical interventions such as chemotherapy
- Acquired immune deficiency disease (AIDS)
Acquired immune deficiency disease (AIDS)
- What is it a result of?
- What are the actions of this virus?
- What does it leave the sufferer prone to?
- Human immunodeficiency virus (HIV)
- HIV infects CD4 T cells, macrophages and
dendritic cells. A massive reduction in the number of CD4 T cells.
- Severe infections by pathogens
