Week 4 Immunodeficiency and immunomodulation Flashcards
What are the General principles of immune response?
Main physiological function is to protect from infection
Multilayer defense
Network of pathogen recognition
Adaptive responses to changing pathogen
Multiple mechanisms of pathogen clearance
Effective inter-cellular communication
Limitation of host damage
Self-regulation
what is the importance of patern recognition receptor ?
structures on macrophages–> can differentiate between gram positive, negative bacteria, fungi and virus
tell you what type of pathogen the body is dealing
What are the Major Components of the Innate Immune System?
Pattern recognition receptors
(PRR
Antimicrobial peptides
Cells
Cytokins
Complement components
What is the function of B cells?
develop potential to secret antibodies: humoral immunity
what are the different types of T cells and there function?
Killer or cytotoxic T lymphocytes are able to kill. Cellular immunity
Helper T lymphocytes secrete growth factors (cytokines) which control immune response: Help B lymphocytes and T lymphocytes (Helper T cells are target of HIV)
Suppressor T lymphocytes may damp down immune response
What are the different ways antibodies inactivate the antigen?
Neutralization, Agglutination of microbes and precipitation of dissolved antigens –> enhances phagocytosis
Activation of complement cascade –> Cell lysis
How does cytotoxic T cells work?
Cytotoxic T cell bind to the infected cell
They release perforin which damages the infected cell membrane and enzyme enteres
The infected cell is destroyed
What is immunodeficiency?
Clinical situations where the immune system is not effective enough to protect the body against infection
What are the causes of primary and secondary immunodeficiency?
Usually secondary to the effects of external factors
Some are primary immunodeficiencies caused by genetic defects in individual components of the immune system –> seen in children
What are the causes of SECONDARY OR ACQUIRED IMMUNODEFICIENCIES?
Stress
Surgery/burns
Malnutrition
Cancer – especially lymphoproliferative disease
Immunosuppressive effect of drugs inc. cancer therapy
Lymphocytes
Neutrophils
What are the characterstics of primary IMMUNODEFICIENCIES?
Very rare
Often diagnosed in early childhood but can present in
adult life
Recurrent infection often suggests immunological problem
How do you identify the underining cause of immunodeficiency?
The type of infection is a guide to underlying cause.
Laboratory tests confirm.
Are secondary immunodeficiency permanent?
No they can be transient or long lasting
Why is family history important to consider when considering a diagnosis of primary immunodeficiency?
Caused by genetic defects
What do you test for when examining someone with reccurent infection and are suspect of immunodeficiency?
You test for the levels of immunoglobulins for B cells , lymphocytes ,
neutrophils
Test of CRP if current infection to see if actually mounting an inflammatory response
Why would normal levels of immunoglobulins, lymphocytes and neutrophils be a indication of a problem for someone with a infection?
Normally these levels will be raised because of the infection. The fact that they are not means that the immune systme is not working properly
What is the role of IRAK?
is formed as part of the intracellular signalling pathway of toll like receptors (a type of PRR) when they encounter a pathogen - forms NF-kbeta which is a transcriptional factor which leads to the release of inflammatory cytokines/chemokines which leads to inflammatory and adaptive immune response
Why does deficiency in IRAK cause immunodeficiency?
Irak deficiency causes immunodeficiency because IRAK is a key component in the pathway to release of inflammatory cytokines/chemokines from the cells of the innate immune system which plays a role in the development of an adaptive and inflammatory response
How do you test for neutrophils?
Nitroblue tetrazolium test (NBT
What is the mechanism of phagocytosis in neutrophils?
NADP transport H ion
H ion travels into the cell via a specific proton channel
THis reduces the Ph within the cell making it more acidic. Therefore this allows proteolytic enzymes to enter the phagasome and destroy the pathogens
What is the defect in CHRONIC GRANULOMATOUS DISEASE ?
It is a an inherited disorder of phagocytic cells resulting in an inability to phagocytose pathogenic material
What diseases can occur in CHRONIC GRANULOMATOUS DISEASE ?
Osteomyelitis Pneumonia Swollen lymph nodes Ginigivitis Non-malignant granulomas Inflammatory bowel disease
what type of infection can indicate the person has immunodeficiency?
meningococcal meningitis
What are the 3 activating pathways for the complement pathway?
Classical pathway
Alternative pathway
MB-lectin pathway
In CHRONIC GRANULOMATOUS DISEASE (CGD) what is the effect on neutrophils?
The number of neutrophils is not reduced however due to not being able to transfer Hydrogen atoms the material within the neutrophil cannot be digested.
Therefore the size of the neutrophils increase
What happens in CHRONIC GRANULOMATOUS DISEASE (CGD) when neutrophils are being produced?
Chronic inflammation occurs because the rest of the immune system becomes fustrated and response by iinflammation.
How do you test for terminal complement pathway?
Take sheep RBC’s, incubate with patient serum -
2) If complement is functioning properly all the sheep RBCs should undergo haemolysis
During the testing of terminal complement pathway why does sheeps RBCs undergo haemolysis but human ones don’t?
Human RBCs have structures on the surface which inhibit our own complement system, sheep RBCs dont have this
What are the key steps in terminal complement pathway?
Activation of C3 convertase which cleaves C5 2) Cleaving of C5 to C5b allows the rest of the complement (C6-C9) to set on the surface of the bacteria and create pores which leads to the lysis of susceptible microorganisms
What is X-linked agammaglobulinaemia?
X linked mutation where there is a defect in B cells
What happens in X-linked agammaglobulinaemia and what type of infection is caused by this?
Lead to different degrees of loss of antibody secretion.
Usually leads to recurrent bacterial infection with pyogenic organisms.
When is X-linked agammaglobulinaemia diagnosed and why?
Usually diagnosed at around 1-2 years because maternal IgG protects until this point
How do you treat X-linked agammaglobulinaemia?
Treat with antibiotics then iv IgG
Keep things under control
Need a pool of donours
what are 6 PRIMARY B-CELL DEFICIENCIES?
Common Variable Immunodeficiency
X-linked agammaglobulinaemia
Autosomal recessive Hyper IgM syndrome
IgA Deficiency
IgG Subclass Deficiency
Transient Hypogammaglobulinaemia of infancy
Why if you were hospitalized with extensive oro-pharyngeal candida would this indicate a immunodeficiency?
Because candida does not usually cause a serious problem in healthy people
Compare the characteristic of the chicken pox in a healtyh and immmunodeficient person?
Healthy : Mild disease
Typical vesicles
Immundeficient: Fulminant ((severe and sudden onset) disease
Haemorrhagic lesions
Severe combined immunodeficiency syndromes (SCID) refers to defects in what 2 kinds of cells?
B and T cells
What are the symptoms of Severe combined immunodeficiency syndromes (SCID)?
Symptoms are recurrent infection with opportunistic infections, bacteria, viruses, Fungi (candida), protozoa (pneumocystis).
Treatment for SCID?
Bone Marrow Transplantation curative
Gene therapy
GIve 4 examples of PRIMARY T- CELL DEFICIENCIES?
Adenosine Deaminase Deficiency
Purine Nucleoside Phosphorylase Deficiency
MHC Class II Deficiency
Wiskott-Aldrich Syndrome
What type of syndrome is Primary T-Cell Deficiencies?
Severe Combined Immunodeficiency syndromes
The presence of Mycobacterium who indicate a defect in ?
Defects in cytokines
If there was a defect in complement what infection would this present?
Meningococcus
Presence of Pneumococcus and HSV would indicate the defect in what?
Defect in PRR
A defect in B cells would present with what infection?
Recurrent sino-pulmonary infections
A defect in T cells would present with what infection?
SCID, opportunistic infections
The presence of ) Staphylococcus 2) Aspergillus would indicate a defect in what part of the immune system?
Defects in neutrophils and macrophages
What is the defintion of immunodulation
The act of manipulating the immune system using immunomodulatory drugs to achieve
a desired immune response
What are the 3 different types of immunodulation caused by therapeutic effect?
immunopotentiation,
immunosuppression,
induction of immunological tolerance
What are the mechanisms of immunodulation?
Immunization Replacement therapy Immune stimulants Immune suppressants Anti-inflammatory agents Allergen immunotherapy (desentization) Adoptive immunotherapy
Define Biologics- Immunomodulators
Medicinal products produced using molecular biology techniques including recombinant DNA technology
What are the 3 classes of biological immunomodulator?
Substances that are (nearly) identical to the body’s own key signaling proteins
Monoclonal antibodies
Fusion proteins
What are fusion proteins?
attach proteins with different biological function –> to reach a certain site
What is Adalimumab?
Is a Human IgG anti-TNF monoclonal Antibody
What is the structure of Adalimumab?
Human Fc portion and Human Fab portion that binds to TNF
What is Etanercept?
Is a fusion protein anti-TNF monoclonal
What is TNF?
An important pro-inflammatory cytokine
What is the structure Etanercept?
The Human Fc portion bound to a human TNFR2 (TNF receptor) which in the body serves to mop up extra TNF)
What is Cetrolizumab?
Is a humanized monovalent Fab-PEG anti-TNF monoclonal
What is the structure of Cetrolizumab?
Human Fab region bound to a polyethylene glycol - this makes the Fab region more stable and less digestible
What is Infliximab?
Is a chimeric mouse-human anti-TNF monoclonal Ab
What is the structure of Infliximab?
Mouse Fab portion Human Fc portion Mice
What is the function of Infliximab?
Produce a human Fc portion and are given TNF so produce an Ab against TNF with a mouse Fab portion and a human Fc portion
What are the different ways of Immunopotentiation?
Immunization –> Passive and Active
Replacement therapies
Immune stimulants
what is the definition of Passive immunization? What type of protection does it provide
transfer of specific, high-concentration antibody from donor to recipient.
Provides immediate but transient protection –> short lived
What are the problems of Passive immunization?
Risk of transmission of viruses –> as it is blood products
Serum sickness
What are the types of passive immunization and the uses of it?
Types
Pooled specific human immunoglobulin from human plasma
Animal sera (antitoxins and antivenins)
Uses
Hep B prophylaxis and treatment
Botulism, VZV (pregnancy), diphtheria, snake bites
What is active immunization?
To stimulate the development of a protective immune response and immunological memory
What immunological material is used in active immunization?
Weakened forms of pathogens
Killed inactivated pathogens
Purified materials (proteins, DNA)
Adjuvants
What are the problems with active immmunization?
Allergy to any vaccine component
Limited usefulness in immunocompromised
Delay in achieving protection
What are the different Replacement therapies and immune stimulation and what are they used for?
Pooled human immunoglobulin (IV or SC) –> Used in Rx of antibody deficiency states
G-CSF/GM-CSF –> Act on bone marrow to increase production of mature neutrophils
IL-2 (Stimulates T cell activation- rarely used)
α-interferon (Main use in treatment of Hep C)
β-interferon (Used in therapy of MS)
γ-interferon –>Can be useful in treatment of certain intracellular infections (atypical mycobacteria), also used in chronic granulomatous disease and IL-12 def
what are the 5 ways of Immunosuppression?
Cortocosteroids
Cytotoxic/ agents
Anti-proliferative/activation agents
DMARD’s
Biologic DMARD’s
What are the actions of Corticosteroids?
Decreased neutrophil margination to the tissue
Reduced production of inflammatory cytokines
Inhibition phospholipase A2 (reduced arachidonic acid
metabolites production)
Lymphopenia
Decreased T cells proliferation at high doses as they are
toxic
Reduced immunoglobulins production
What are the side effects of corticosteroids?
Carbohydrate and lipid metabolism
Diabetes
Hyperlipidaemia
Reduced protein synthesis–> Poor wound healing
Osteoporosis
Glaucoma and cataracts
Psychiatric complications
What are the uses of corticosteroids?
Autoimmune diseases –> Connective tissue disease,
vasculitis, RA
Inflammatory diseases–> Crohn’s, sarcoid, GCA/polymyalgia rheumatica
Malignancies –> Lymphoma
Allograft rejection –> used in transplant
What are the 4 types of drugs that target lymphocytes
Antimetabolites
Calcineurin inhibitors
M-TOR inhibitors
IL-2 receptor mABs
Give example of Antimetabolites?
Azathioprine (AZA) Mycophenolate mofetil (MMF)
what is the action of Antimetabolites? What effect does this have on B and T cells?
Inhibit nucleotide (purine) synthesis
T and B cells effects
Impaired DNA production
Prevents early stages of activated cells proliferation
What is the action of Azathioprine (AZA) ?
Guanine anti-metabolite
Rapidly converted into 6-mercaptopurine
What is the action of Mycophenolate mofetil (MMF)?
Non-competitive inhibitor of IMPDH
Prevents production of guanosine triphosphate
Give two examples of Calcineurin inhibitors?
Ciclosporin A (CyA) Tacrolimus (FK506)
What is the mode of action of Calcineurin inhibitors? What effect does this have on T cells?
Mode of action
Prevents activation of NFAT
Factors which stimulate cytokines (i.e IL-2 and INFγ) gene transcription
T cell effects
Reversible inhibition of T-cell activation, proliferation and clonal expansion
What does Ciclosporin A bind to?
Binds to intracellular protein cyclophilin
What does Tacrolimus (FK506) bind to?
Binds to intracellular protein FKBP-12
Give me a example of M-TOR inhibitors?
Sirolimus (rapamycin)
What does Sirolimus (rapamycin) bind to and therefore what does it inhibit?
Also binds to FKBP12 but different effects
Inhibits mammalian target of rapamycin (mTOR)
What is the mode of action of Sirolimus and therefore its effect on T cells ?
Inhibits response to IL-2 by the MTOR pathway.
This causes the T cell to arrest at G1-S phase which prevents it from proliferating
What are the side effect of Calcineurin/Sirolimus side-effects
Hypertension Hirsutism Nephrotoxicity Hepatotoxicity Lymphomas Opportunistic infections Neurotoxicity Multiple drug interactions (induce P450
What is the Calcineurin/mTOR inhibition clinical use?
Transplantation -> Allograft rejection
Autoimmune diseases
What is the action of Methotrexate (MTX)?
Folate antagonists
What is the action of Cyclophosphamide
Cross-link DNA
What is the two step process of once a T cell is presented with a antigen by a APC?
1) Activation occurs by autocrine cytokine IL-2
2) Proliferation - IL2 stimulates signalling pathway involving mTOR which allows cells to go into the cell cycle and proliferate
Give 2 examples of IL-2 receptor mABs
Basiliximab
Daclizumab
What are the side effect of all cytotoxic drugs?
Bone marrow suppression
Gastric upset
Hepatitis
Susceptibility to infections
What is the specific side effect of Cylophosphamide?
Cystitis
What is the specific side effect of Methotrexate ?
pneumonitis –> inflammation of the walls of the alveoli (air sacs) in the lungs
What is the clinical use of methotrexate?
RA, Psoriatic Arthritis, Polymyositis, vasculitis
Graft-versus-host disease in bone marrow transplant
What is the clinical use of Cyclophosphamide?
Vasculitis (Wagner’s, CSS)
SLE
What is the clinical use of Azathioprine, Mycophenolate mofetil ?
Autoimmune diseases (SLE, vasulitis, IBD) Allograft rejection
What are Disease-modifying antirheumatic drugs (DMARDs)?
Disease-modifying antirheumatic drugs (DMARDs) are a group of medications commonly used in patients with rheumatoid arthritis.
What catogerios do Biologic DMARD’s fall into?
Anti-cytokines (TNF, IL-6 and IL-1) Anti-B cell therapies Anti-T cell activation Anti-adhesion molecules Complement inhibitors
What are the three types of Anti-cytokines?
Anti-IL-1
Anti-IL-6 (Tocilizumab
Anti-TNF
What is Anti TNF used for?
First biologics to be successfully used in therapy of RA (5 different agents now licensed)
Used in a number of other inflammatory conditions (Crohn’s, psoriasis, ankylosing spondylitis)
What does Anti TNF increae the risk of?
TB
What is Anti-IL-6 (Tocilizumab) used for?
Blocks IL-6 receptor
Used in therapy of RA and Adult-onset Still’s disease (AOSD) –> rare form of arthritis
What problems can be caused by the use of Anti-IL-6
May cause problems with control of serum lipids
What are the 3 different agents of Anti-IL-1?
anakinra, rilonacept and canakinumab
What is Anti-IL-1 used for?
Used in treatment of AOSD and autoinflammatory syndromes
What is the action of Rituximab?
Chimeric mAb against CD20- B cell surface
What was the initial use of Rituximab?
For treatment of chemotherapy resistant DLCL
What is the current use of Rituximab?
Lymphomas, leukaemias
Transplant rejection
Autoimmune disorders
What are the two forms of adoptive immunity?
Bone marrow transplant (BMT)
Stem cell transplant (SCT)
What are the uses of adoptive immunity?
Immunodeficiencies (SCID)
Lymphomas and leukemias
Inherited metabolic disorders (osteopetrosis)
Autoimmune diseases
What are the different types of Immunomodulators against allergy?
Immune suppressants
Allergen specific immunotherapy
Anti-IgE monoclonal therapy
Anti-IL-5 monoclonal treatment
What is Allergen specific immunotherapy?
People are given doses of an allergen in a controlled manner to inducer tolerance to that allergen, may be give subcutaneously or sublingually
What is the mechanisms of allergen specific immunotherapy?
Switching of immune response from Th2 (allergic) to Th1 (non-allergic)
Development of T reg cells and tolerance
What are the routes of allergen specific immunotherpay?
Subcutaneous injection or sublingual for aero-allergens
What are the side effects of allergen specific immunotherapy?
Localised and systemic allergic reactions
Give 2 uses of allergen specific immunotherpay?
Allergic rhinoconjutivitis not controlled on maximum medical therapy
Anaphylaxis to insect venom
What is monclonal antibodies?
Are monospecific antibodies that are made by identical immune cells that are all clones of a unique parent cell, in contrast to polyclonal antibodies which are made from several different immune cells.
What is Omalizumab? What does it act against?
It is a mAb against IgE
What is the use of Omalizumab?
Used in Rx of asthma
Also useful in Rx of chronic urticaria and angioedema
What is a side affect of omalizumab?
May cause severe systemic anaphylaxis
What is Mepolizumab? What does it act against?
It is a mAb against IL-5
What is the use of Mepolizumab?
Prevents eosinophil recruitment and activation
What syndromes does Mepolizumab have little or no effect against?
Limited effect on asthma
No clinical efficacy in hypereosinophilic syndrome
