I6 Drivers of Inflammation and Immunodeficiency Flashcards Preview

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Flashcards in I6 Drivers of Inflammation and Immunodeficiency Deck (33):
1

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 

2

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)

3

What are the signs of inflammation?

What are the main drivers of inflammation?

  • Rubor
  • Tumor
  • Calor
  • Dolor
  • Functio Laesa

Cytokines

4

  1. What are Cytokines?
  2. Why are many cytokines known as interleukins?
  3. What do they play an important role in linking?

  1. Cytokines are potent chemical messengers produced by cells of the immune system. Small peptides that are usually secreted. (Lymphokines and monokines collectively called cytokines)

  2. Cytokines act as a messenger between leukocytes 

  3. linking innate and adaptive immunity 

5

Cytokines

  1. Give some properties
  2. Generally, how do they act?

  1. Low molecular weight proteins. Their production is carefully regulated
  2. 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 

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Cytokines

They can act in three different ways.

Name these ways, and outline how the cytokines act.

  1. Autocrine - Cytokine binds to receptor on cell that secreted it 
  2. Paracrine - Cytokine binds to receptors on nearby cells 
  3. Endocrine - Cytokine binds cells in distant parts of the body 

8

Cytokines

  1. How do they signal?

  1. 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)

9

  1. How are cytokines classified?
  2. How many interleukins have been identified to date?

  1. Into four families based on their structure
    1. Haematopoietin Family (eg: IL-2 and IL-4) 
    2. Interferon family (IFNs)

    3. Tumour necrosis factor family (eg:TNF-α) 

    4. Chemokine Family (eg: CCL-2) 

  2. 35 Interleukins

10

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 

 

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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

12

Role of Cytokines in Immune Response

  1. What is their primary function in the immune response?
  2. Give some speficic cell interactions that they guide

  1. 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

13

Interleukin-2

  1. ​When is it produced?
  2. How does it act?
  3. Outline its specific actions further

  1. following T cell activation by antigen presenting cells. 

  2. acts in an autocrine loop to induce T cell proliferation 

  3. 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 

14

Interleukin-4 

  1. What is it?
  2. What does it do?
  3. What is it produced by?
  4. What is it required for the production of?
  5. What does it induce?
  6. How does it interact with Mast cells?

  1. a Th2 derived cytokine 

  2. stimulates B cell proliferation. Exogenous IL-4 drives Th2 differentiation 

  3.  Activated Thelper2 cells

  4. gG1 and IgE 

  5. Thelper2 cell differentiation 

  6. It is a growth factor for mast cells

15

Interleukin-17

  1. What is it produced by?
  2. What does it do?
  3. What conditions is it associated with?
  4. What is it?

  1. Activated Thelper17 cells
  2. Induces neutrophil maturation and activation 

  3. autoimmune pathologies (rheumatoid arthritis, lupus, psoriasis) drives bone resorption in arthritis. a major role in many infectious diseases  

  4. major pro-inflammatory cytokine 

16

Inhibitory Cytokines

  1. What are the inhibitory Cytokines?
  2. Outline what each does and where they are produced

  1. 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 

17

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

18

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

19

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 

20

Tumour Necrosis Factor-α (TNF-α) 

  1. Generally, what does it do?
  2. What is it derived from?
  3. What does it induce?
  4. What can it induce long-term?
  5. What does it act on the hypothalamus to produce?

  1. Principle mediator of the anti-bacterial response

  2. macrophages and T cells  

  3. Induces neutrophil activation (inflammation)

    Activates endothelial cells (inflammation) 

  4. Long-term it can induce cachexia (muscle and fat wasting) 

  5. Fever

21

Chemokines

  1. ​What are these?
  2. What do they do?

  1. Chemotactic cytokines 

  2. 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 

22

What are the main chemokine families?

C (XCL1,2)

CC (CCL2,3,4)

 CXC (CXCL1,8,9,10,12)

CX3C (CX3CL1)

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Outline chemotaxis

Attracted leukocyte (macrophage) has Rs on surface, moves towards inflammatory site along the chemotactic gradient

24

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

25

Cytokine Dysregulation

Outline cytokine dysregulation in 

  1. Asthma 
  2. Allergy
  3. Autoimmunity

  1. Dysregulation of Th1/Th2 balance. Th2 cytokines overproduction 

  2. Chronic inflammatory response: dysregulation of Th17 cells 

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Other cytokine related diseases

  1. Bacterial septic shock 
    1. What are the symptoms?
    2. What is the pathological process?
  2. Lymphoid and myeloid cancer

    1. Why does this come about?

  3. Chagas’ disease 

    1. What is this?

  1. Bacterial septic shock
    1. Blood pressure drops, clots form, hypoglycemia ensues, patient dies

    2. LPS(lipopolysaccharide) triggers results in TNF release

      TNF induces IL-1 which induces IL-6 and IL-8

  2. Some cancer cells secrete cytokines  
  3.  Trypanosoma cruzii infection results in severe immune suppression

    ◦Depression of IL-2 receptor production 

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Cytokine Receptors in Disease

  1. What do mutations in R shared by IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cause?
  2. What can EPO ( Erythoropoietin) receptor mutations cause?
  3. What does TNF receptor mutations cause?

  4. What is consitutive activation of cytokine signalling pathways associated with?

  1. X-SCID (X- linked severe combined immunodeficiency) 

  2. benign erythrocytosis 

  3. tumour necrosis factor receptor associated periodic syndrome (TRAPS

  4.  many leukaemias. 

28

Cytokines in Therapy

  1. What has been used to treat cancer?
  2. What is the main therapy in viral hepatitis?
  3. What is the main therapy for MS?
  4. What is IFN-g used to treat?
  5. What is IL-10 under investigation for treating?
  6. What is EPO used for?
  7. What can be used following bone marrow transplantation?
  8. What is used to treat rheumatoid arthiritis?
  9. What is under investigation to treat IBD?

  1. IL-2
  2. IFN- a is the main therapy viral hepatitis also Leukemia
  3. IFN- b is the main therapy for Multiple Sclerosis
  4. IFN-g used to treat chronic granulomatous disease
  5.  autoimmune diseases
  6. to treat patients prior to transplantation as it stimulates erythrocyte proliferation; has neuroprotective effects (stroke).
  7. G-CSF
  8. Antibodies to TNF (anti-TNF) 
  9. Antibodies to IL-12 (anti-IL-12) 

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Primary Immunodeficiency Diseases

  1. What are the clinical features?
  2. What are examples?
  3. What is the main characterisitic?
    1. What are the adaptive immune defects?
    2. What are the innate immune defects?

  1. Clinical feature variable. Recurrent and often overwhelming infection in very young children

  2. Allergy, autoimmunity, cancer, lymphocyte abnormal proliferation 

  3. Inherited mutations 

    1. T cells, B cells, antibodies 

    2. Complement components Phagocytes
      TLRs signalling 

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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 

31

Primary Immunodeficiency Diseases

T-Lymphocyte Deficiencies 

  1. What do defects in T-cell development result in?
  2. What is DiGeorge Syndrome?
  3. What  gives rise to Deficiency of Cytokine Receptor chains?

  4. What is Wiskott-Aldrich Syndrome (WAS)?

  5. Give examples of a metabolic defect

  1. severe combined immunodeficiencies ( SCID) 

  2. Intra-uterine damage to 3rd and 4th Pharangeal pouches 

  3. ◦ X-linked SCID: mutation in the gene IL2RG on the X chromosome ◦ common gamma chain
    ◦ IL-7 receptor α & IL-2 receptor α 

  4. membrane defects of T cells and platelets

  5. -Adenosine Deaminase Deficiency
    -Purine Nucleoside Phosphorylase Deficiency 

     

32

Secondary Immunodeficiency Diseases

  1. What are these a result of?
  2. Give an example

  1. A consequence of other diseases Environmental factors

    An adverse consequence of medical interventions such as chemotherapy

  2. Acquired immune deficiency disease (AIDS) 

33

Acquired immune deficiency disease (AIDS)

  1. What is it a result of?
  2. What are the actions of this virus?
  3. What does it leave the sufferer prone to?

  1. Human immunodeficiency virus (HIV) 

  2. HIV infects CD4 T cells, macrophages and

    dendritic cells.􏰁 A massive reduction in the number of CD4 T cells.

  3. Severe infections by pathogens