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Block F: Defence > W3P1 > Flashcards

W3P1 Flashcards

1
Q

What is the route of entry, mode of transmission and pathogen for the following diseases

Influenza
meningitis
Diarrhea
Syphilis
AIDS
A

Influenza: airway -> inhaled droplet -> influenza virus
meningitis: airway -> spores -> N. meningitidis
Diarrhea: GI tract -> contaminated water or food -> rotavirus
Syphilis: reproductive tract -> physical contact -> treponema pallidum
AIDS: reproductive tract -> physical contact -> HIV

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2
Q

What is the route of entry, mode of transmission and pathogen for the following diseases

Yellow Fever
Lyme disease 
Malaria 
Tetanus
Athlete's foot
A

Yellow Fever: insect bites -> mosquito -> flavivirus
Lyme disease: insect bites -> deer tick bites -> borrelia burgdorferi
Malaria: insect bites -> mosquito bites -> plasmodium
Tetanus: Wounds and abrasions -> puncture wounds -> clostridium tetnai
Athlete’s foot: external surface -> physcial contact -> trichophyton

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3
Q

Which four classes of pathogens does the immune system protect against?

A
  1. Extracellularbacteria, parasites, fungi
  2. intracellular bacteria, parasites
  3. viruses (intracellular)
  4. Parasitic worms (extracellular)

the way our immune system fights pathogens does depend on the type of pathogen as different parts of the immune system are selectively activated.

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4
Q

What are some mechanical barriers to infection?

A

epithelial cells joined by tight junctions (everywhere)
longitudinal flor of air or fluid
movement of mucus by cilia (lungs)

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5
Q

What are some chemical intrinsic barriers to infection?

A

skin; fatty acid
gut: low pH, enzymes (pepsin)
eyes/nose: salivary enzymes (lysozyme)
all have antibacterial peptides

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6
Q

What is the timeframe of innate immunity

A

immediate: 0-4 hours

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7
Q

What is the time frame of early induced response?

A

early: 4-96 hours/4 days

involves:
recognition of microbial-associated molecular patterns
- inflammation and recruitment and activation of effector cells

once the level of antigens passes a certain threshold, this adaptive immune response is activated^

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8
Q

What is the timeframe of adaptive immunity

A

late: greater than 96 hours/4 days
- involves transport of antigen to lymphoid organs
- recognition by naive B and T cells
- clonal expansion and differentiation to effector cells
- removal of infectious agents.

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9
Q

What are the receptors expressed by macrophages for bacterial components?

A 
Mannose receptor 
glucan receptor
LPS receptor (CD14) 
TLR-4 
Scavenger receptor
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10
Q

What are the 5 main cytokines secreted by macrophages and DCs?

A 
IL-1
IL-6
CXC8 (IL-8)
IL-12
TNFa
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11
Q

For IL-1 what are:

  • The main producer
  • Acts upon
  • Effect
A
  • The main producer: Macrophages, keratinocytes

Acts upon–>
endothelial cells: release IL 6 -> liver -> platelets and Induces acute-phase protein secretion (CRP)

bone marrow: increased secretion of granulocytes and platelelts

hypothalamus: increase temperature, FEVER

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12
Q

What are acute phase proteins

A

Acute-phase proteins (APPs) are a class of proteins whose plasma concentrations increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response is called the acute-phase reaction (also called acute-phase response).

they facilitate/ signal inflammation

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13
Q

IL-6 what are:

  • The main producer
  • Acts upon
  • Effect
A

producer: Macrophages, DCs

acts upon ->
lymphocytes –> Enhances responses
Liver –> Induces acute-phase protein secretion

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14
Q

CXCL8 (IL-8)

  • The main producer
  • Acts upon
  • Effect
A

Producer:
Macrophages, DCs

acts up -> effect
Phagocytes -> chemoattractant for neutrophils

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15
Q

IL-12

  • The main producer
  • Acts upon
  • Effect
A

producer: macrophage, dendritic cells

Acts on: Naive T cells
Effect: diverts immune response to type 1, proinflammatory, cytokine secretion

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16
Q

TNF a

  • The main producer
  • Acts upon
  • Effect
A

producers: macrophages and DCs
act upon: vascular endothelium
effect: induces changes in vascular endothelium (expression of cell-adhesion molecules (E - and P- selectin) changes in cell-cell junction with increased fluid loss.

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17
Q

What do DMARDs stand for?

A

Disease-modifying anti-rheumatic drugs

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18
Q

What diseases are Biologics used in the treatment of?

A

Asthma
Rheumatoid arthritis
Hypercholesterolemia and Cancer

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19
Q

What are Biologics?

  • what are they specially designed to treat?
A

The term “biologics” is used for a class of medications (either approved or in development) produced by means of biological processes involving recombinant DNA technology

  • Specially designed to treat inflammatory diseases such as RA and asthma.
  • Work by different mechanisms.
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20
Q

What are the three mechanisms through which Biologics work?

A

These medications are usually one of three types:

  • Substances that are (nearly) identical to the body’s own key signalling proteins
  • Monoclonal antibodies
  • Receptor constructs (fusion proteins), usually based on a naturally-occurring receptor linked to the immunoglobulin frame
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21
Q

What is the first Biologic drug?

A

INSULIN :)

mechansims: one that simulates body’s own key signalling proteins

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22
Q

What is inflammation

A

The body’s natural response to injury

Dilation (increase in diameter) & fenestration (increase in permeability) of the capillaries

Edema (swelling, redness)

Local rise in temperature

Pain, sensitivity to pain

Influx of leukocytes, esp. polymorphonuclear leukocytes (PMNs), and macrophages

Increased (~tenfold) drainage into lymphatic system

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23
Q

What leukocytes are most commonly drawn to sites of inflammation?

A

polymorphonuclear leukocytes (PMNs) and macrophages

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24
Q

Asthma’s main mechanism

A

This is an inflammatory disease
mediated specifically by the activation of antibody IgE (which goes to mast cells degranulates them and releases histamines- pro-inflammatory, and bronchoconstricting)

specifically:
DC uptake of antigen, presentation to T cell, proliferation of TH2 cells which release: IL25 and IL33 and chemokines

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25
Q

Asthma approved drugs include?

A

ICS: Inhaled Corticosteroids

these act as anti-inflammatory.

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26
Q

How has antibody technology evolved over the past decades?

A

1st gen: Fully mouse, highly immunogenic (e.g. abciximab)

2nd gen: Chimeric, still very immunogenic

3rd gen: Humanized, better but time consuming to create (bococizumab)

4th gen: Fully Human e.g. evolocumab and alirocumab

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27
Q

What is the mechanism of action of Omalizumab

A
  • Binds to free IgE, decreasing cell-bound IgE
  • decreases expression of high-affinity receptors (FcE)
  • decreases mediator release
  • decreases allergic inflammation
  • prevents exacerbation of asthma and reduces symptoms

details:

IgE binding releases IL 4, 5 and 13
IL4 and 13: released by AND trigger: CD4TH2 -> B cell, basophil
IL5: eosinophil

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28
Q

What and when is Omalizumab perscribed?

A

Omalizumab was approved for the treatment of moderate-to severe persistent asthma in patients 12 years of age and older whose disease is not adequately controlled with ICSs alone.

It has been under recent investigations for the treatment of perennial (consistent) and seasonal allergic rhinitis.

anti-IgE?

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29
Q

Mepolizumab and Reslizumab

  • what do they treat
  • their mechanism
  • their target?
A
  • Mepolizumab and Reslizumab are humanized mAbs directed against IL-5.
  • Given that IL-5 induces the maturation, activation, and recruitment of eosinophils, it is a logical target for the treatment of asthma.
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30
Q

Dupilumab

  • what does it treat
  • mechanism
  • target
A

Dupilumab is a fully human mAb to the IL-4 receptor α subunit, which is shared by both the IL-4 and IL-13 receptors.

IL4 seems to be involved in the TH2/Bcell stimulation of IgE -> mast cells, basophil

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31
Q

Lebrikizumab

  • what is it used to treat
  • mechanism
  • target?
A

For the treatment of asthma
- is a humanized anti–IL-13 IgG4 mAb

IL13: Involved in TH2-> bcell production of IgE -> mast cells and basophils

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32
Q

What are the components involved in the immunology of the inflammatory response in rheumatoid arthritis

A 
Macrophages
TNF a and IL-1
TH1
B cells
Osteoclasts
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33
Q

Role of Macrophages, TNFa/IL-1 in RA

A

Macrophages:

  • Produce cytokines
  • Cytokines (TNFα) cause systemic features
  • Release chemokines -> recruit PMNs into synovial fluid/membrane

TNFα & IL-1:

  • Proliferation of T cells
  • Activation of B cells
  • Initiates proinflammatory/joint-damaging processes
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34
Q

Rheumatoid Arthritis

  • pathophys
  • target
A

A disease of inflammation and autoimmunity
Rheumatoid factor complexes trigger complement activation
-> tissue damage

Attract PMNs & macrophages

Affects the joints - localized to synovial membrane

Initiating event - unknown - genetic predisposition

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35
Q

What is a rheumatoid factor

A
  • An IgM antibody against IgG
  • Present in most rheumatoid patients
  • Produced by B-cells in synovial fluid
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36
Q

What is a pannus

A

PMNs + macrophages + fibroblasts form scarlike tissue that accumulates in the joint

present in chronic stages of RA. formation of the pannus stimulates the release of IL1, platelet derived growth factor, prostaglandins

which all ultimately cause cartilage destruction and bone erosion.

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37
Q

What is the rationale to take a more aggressive treatment approach to RA?

A

Paradigm shift in the treatment of inflammatory arthritis
Rationale for Treatment
- Large body of evidence which shows joint damage is an early phenomenon of rheumatoid arthritis
- Joint erosions occur in up to 93% of patients with less than 2 years of disease activity
- The rate of radiographic progression is greatest in the first two years
- Disability occurs early – 50% of patients with RA will be work disabled at 10 years
- Severe disease is associated with increased mortality

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38
Q

What is the role of glucocorticoids in the treatment of Inflammatory arthritis?

A

They treat the symptoms but not the cause so really only useful for short term flaire ups.

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39
Q

What are the newer therapeutic strategies for RA?

A
  • Use of early DMARDs
  • Combinations of Conventional DMARDs
  • Three studies have confirmed the use of “triple therapy” in early RA is more effective than a single agent.
  • Combinations of Methotrexate plus Biologic agents

DMARD: disease modifying anti rheumatic drugs

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40
Q

What affect do DMARDs have

A

Disease Modifying Anti-Rheumatic Drugs (DMARDs)

Symptom Control
- Control current inflammatory features

Modify the course of disease

  • Reduce joint damage and deformity
  • Reduce radiographic progression
  • Reduce long-term disability
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41
Q

Function of DMARDs as RA treatment?

1st vs 2nd generation

A

DMARDs can actually arrest or slow RA progression (i.e., joint erosion as seen on X-rays)
More toxic than NSAIDS

1st generation: gold compounds, e.g., aurothioglucose

  • Accumulate in monocytes & macrophages
  • Interfere with migration and phagocytosis
  • Toxicity: colitis, immune dysfunctions
  • Weekly IM injections

2nd generation: cytotoxic B/T cell inhibitors e.g., methotrexate, leflunomide

  • Block synthesis of pyrimidines (used to make DNA)
  • Prevent B and T cell proliferation -> rheumatoid factor not produced
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42
Q

Examples of available DMARDs?

A 
Methotrexate
Sulfasalazine (Salazopyrin)
Hydroxychloroquine (Plaquenil)
Leflunomide (Arava)
Gold (Myochrisine)
Others:
- Cyclosporine
- Azathioprine
- Cyclophosphamide
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43
Q

What are some common DMARD combinations?

A

Triple Therapy
Methotrexate, Sulfasalazine, Hydroxychloroquine

Double Therapy
Methotrexate & Leflunomide
Methotrexate & Sulfasalazine
Methotrexate & Hydroxychloroquine
Methotrexate & Gold
Sulfasalazine & Plaquenil

Monotherapy (not done anymore)

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44
Q

Methotrexate

- mechanism of action

A

Tetrahydrofolate is an important cofactor in the production of purines transferring a carbon atom.

Methotrexate inhibits dihydrofolate reductase which inhibits the production of tetrahydrofolate

it ALSO inhibits AICAR

inhibits T and B cells so you don’t get production of rhematoid factor (IgM against IgG)

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45
Q

how do glucocorticoids work?

A

Inflammation is your immune system’s response to an injury or infection. It makes your body produce more white blood cells and chemicals to help you heal. Sometimes, though, that response is too strong and can even be dangerous. Asthma, for example, is inflammation in your airways that can keep you from breathing.

If you have an autoimmune disease, your body triggers inflammation by mistake. That means your immune system attacks healthy cells and tissue as if they were viruses or bacteria.

Glucocorticoids keep your body from pumping out so many of the chemicals involved in inflammation. They can also dial back your immune system’s response by changing the way white blood cells work.

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46
Q

What is Allogeneic Tissue Transplant

A

Recipient (host) receives tissue (graft) from non-self donor

Recipient and graft are fully or partially HLA matched

Recipient is immunosuppressed to prevent graft rejection and a graft-vs-host reaction using immune-ablative chemo- and/or radiotherapy

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47
Q

What is Graft vs Host Disease

A

Complication following an allogeneic tissue transplant

GVHD results from a donor-driven immune attack against the recipient

Donor T lymphocytes attack the immune suppressed recipient’s tissues: respond to genetically determined proteins on recipient cells
These proteins are human class I and class II leukocyte antigen (HLA)
expressing peptides

*Result is a multisystem clinical syndrome

Graft attacks the host = GVHD

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48
Q

GVHD vs Rejection

A

Graft attacks the host = GVHD

Host attacks graft = rejection

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49
Q

What are the three types of GVHD

A
  1. Following an allogeneic stem cell transplant
  2. Following solid organ transplant
  3. Following a blood transfusion: transfusion-associated GVHD
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50
Q

What are Billingham’s Criteria

A

3 Conditions for GVHD

  1. Graft must contain immunologically competent donor cells (Tolerant to donor self, intolerant to foreign)
  2. Host must be unable to reject/eliminate the donor cells of the graft (immunosuppressed or genetically similar to donor)
  3. Host and graft must be antigenically different from each other (MHC differences)
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51
Q

What is HLA

A

Human Leukocyte Antigens = MHC

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52
Q

GVHD after solid organ transplant

  • common in which organs
  • mechanism
  • Clinical manifestations
A

More common in small intestine and liver transplants: Large number of immune competent cells in the organ (graft) are transplanted into the pharmacologically immunosuppressed recipient (host)

Clinical manifestations
Skin rash
Fever 
Diarrhea and gut dysfunction
Pancytopenia (from GVHD of the Bone Marrow: marrow aplasia leading to pancytopenia)
53
Q

Diagnosis, Prognosis and Treatment of GVHD after SOT?

A

Diagnosis is clinical

Mortality rate is high
Adult deaths > pediatric deaths
Causes of death include infections and bone marrow failure leading to severe cytopenias

Treatment
Systemic steroids

54
Q

Why is GVHD so rare in the setting of solid organ transplant

A

the host is LARGER (more immune cells) than the small graft (less immune cells)

graft unlikely to overpower host in organ transplants.

rejection is more likely

55
Q

Transfusion-Associated GVHD

  • Prognosis
  • Mechanism
A

Scope
Rare (< 0.2%), almost always lethal

Mechanism
Results from an attack on recipient tissues by T lymphocytes in the transfused product

Requirements
Viable T lymphocytes in the blood product
Donor and recipient are not HLA identical
Recipient cannot neutralize the T lymphocyte attack – recipient is immunocompromised or genetically similar to the donor

56
Q

What are the Normal Transfusion conditions vs Immunosuppressed conditions

A

Normal transfusion conditions
Recipient T lymphs
attack and destroy the
donor lymphocytes

Transfusion of blood into
Immunosuppressed host
Donor T lymphocytes
attack host tissues, unchecked,
no recipient counterattack
57
Q

Transfusion-Associated GVHD clinical manifestations

  • How do you prevent this?
A 
Clinical manifestations start 7-10 days post transfusion:
fever
rash
pancytopenia
hepatitis
diarrhea

Prevention
irradiation of fresh blood products to inactivate T lymphs

58
Q

What is the most common type of GVHD?

A

Allogenic SCT

59
Q

GVHD after allogenic SCT

A

Allogeneic SCT is the most common clinical scenario in which GVHD develops

Unlike GVHD after SOT or TA-GVHD it affects 20-80% of all SCT recipients

Can account for up 20% of deaths

60
Q

What is a stem cell transplant

A

A procedure that infuses healthy hematopoietic cells, including stem cells, into the blood stream of an individual who has received immune suppressive chemotherapy and/or radiation therapy

SCT replaces in part or in whole, host bone marrow cells with donor stem cells

SCT can replace an unhealthy immune system with a healthy one (i.e. aplastic anemia), restore normal hematopoiesis and prevent cancer relapse (i.e. acute leukemia)

61
Q

Aplastic Anemia

A

Aplastic anemia is a form of bone marrow failure. Marrow, the soft, fatty tissue inside bones, is the place where new blood cells are formed. In aplastic anemia, the bone marrow does not produce new cells, leaving the body susceptible to bleeding and infection.

62
Q

What are the three types of stem cell transplant donors?

A

Syngeneic - identical twin transplant
Allogenic Transplant: donnor
Autologous Transplant: self

63
Q

What are the three Stem Cell Sources

A

Bone Marrow
Peripheral Blood
Umbilical Cord Blood

64
Q

What are the 3 stem cell sources

A

Bone Marrow
Peripheral Blood
Umbilical cord blood

65
Q

What are the common conditions for which Autologous SCT are used

A
  1. Lymphomas: makes sense the problem is in the lymph nodes, nothing wrong with hosts bone marrow
  2. plasma cell dyscrasia: a monoclonal proliferation of plasma cells that produce a clonal immunoglobulin protein (i.e., monoclonal gammopathies or paraproteinemias). They are derived from malignant B lymphocytes
66
Q

For what conditions are Allogeneic SCT used ?

A

Leukemia’s: because these problems arise in the bone marrow so you can’t use your own bone marrow

Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia

67
Q

Key points in the ALLOGENIC SCT timeline

A
  1. select HLA well matched donor
  2. Recipient conditioned with chemotherapy and radiation to prepare for stem cells: TO PREVENT REJECTION
  3. infuse donor stem cells
  4. Immune Suppression up to 90 days after transplant: TO PREVENT GVDH
68
Q

What is the mechanism of GVHD after allogenic SCT

A
  • Immune-mediated
  • Primarily a T cell mediated disease
    • Immune attack by donor T cells
    • Primary antigenic targets are genetically different host tissues and proteins (major or minor histocompatibility antigens) of the immunosuppressed recipient
69
Q

What are the determinants of the GVH and its strength

A

T cells

  • Types of T cells in the graft (naïve, memory)
  • T cell trafficking to organs in the recipient
  • Interactions between T cells and endothelium

HLA match between donor and recipient

Amount and type of cytokines released during GVH reaction

Signaling between different immune cells

B cell function and activation

Activation of innate immune system

70
Q

What are the three phases of ACUTE GVHD pathophysiology

A

phase 1: Conditioning
mediated Tissue damage:
Inflammatory
Activation: increased TLR, cytokines prime T cells, increase MHC expression

phase 2: Cytokine Storm: donor T cell
Activation:
Antigen-Directed
T cell attack

phase 3: Phase III: Tissue Death: Effector phase:
Cell injury due to cytotoxic T cells and TNFa causing lysis or apoptosis of HOST cells

71
Q

Manifestations of Acute GVHD

- how to diagnose it

A

Rash on skin
Primarily a clinical diagnosis*

Tissue biopsy for confirmation is encouraged
Important to rule-out other causes

72
Q

What is the treatment for Acute GVHD

A

Treatment
Topical therapy only: grade I (skin stage < 2)
Systemic steroids: > grade 2

73
Q

Chronic GVHD

- pathophys

A

Occurs in 30-70% of all Allo SCT recipients

Major cause of morbidity and non-relapse death after allo SCT

similar to acute pathophysiology: Initiated by naïve T cells, involves inflammatory T helper cells (Th17), loss of Treg, thymic damage, aberrant T and B cell activation, allo- and autoreactive T cells, macrophage stimulation and TGFb overproduction with resultant downstream tissue fibrosis
May exist in a clinical continuum with aGHVD

74
Q

Clinical presentations of Chronic GVHD

A 
Usually occurs within the first year but may manifest years after SCT
Resemble autoimmune disease(s)
Scleroderma
Sjogren’s
Primary biliary cirrhosis
Bronchiolitis obliterans
Immune cytopenias
Chronic immunodeficiency
May target one or many organs
May linger for years and impact quality of life
75
Q

Diagnostic clinical findings for chronic GVHD

A

Lichen-planus type features
papulosquamous skin
nail dystophy

76
Q

What increases the risk for acute GVHD

  • Match vs unmatches
  • related vs unrelated
A

Risk from lowest to highest

  1. Matched UNRELATED donor
  2. MISMATCHED related donor
  3. MISmatched UNrelated donor
77
Q

Treatment of cGVHD

A

Prevention: Best strategy

Treatment

  • Systemic therapy initiated based on number of organs involved and severity of organ involvement: i.e. 3 or more organs; severity score > moderate
  • Systemic steroids are first-line
  • Combine with aggressive local care (eyes, skin…)
78
Q

Take home point:

*****GVHD is the result of an immune reaction following _________

A

allogeneic tissue transplant

79
Q

***GVHD is mediated by ________

A

immunologically competent T cells in the donor graft

80
Q

*****GVHD is most frequently see after____ and least frequently seen after____

A

GVHD is a multisystem disease most frequently seen after allogeneic SCT, and less frequently after SOT and blood transfusions

81
Q

*****Treatment for GVHD is ________

A

Treatment is immune suppression: systemic steroids

82
Q

Small Pox

A

Disease caused by the variola virus

83
Q

How to vaccines work to fight infectious disease?

A
  1. Stimlulate immunity, trained immunity
  2. Stimulate memory
  3. Herd Immunity
84
Q

What you need to know inorder to stimulate appropriate immunity

A
  1. Need to figure out the TYPE of immune response that induces protection
    a. Active vs Passive Immunity
    b. Live vs Killed vaccines
  2. Need to understand the immune-infection interface
    Conjugated vs multiple vaccines
  3. Safety
    - Particulate vaccines: avoiding severe side effects
85
Q

Difference between Active and Passive immunity

A

Active: Produced inside of the body
Passive: Introduced from outside of the body

86
Q

Are vaccinations an example of active or passive immunity?

A

Active! because it stimulates your body to produce the antibodies/cytotoxis cells on your own*

87
Q

What are examples of passive immunity?

A
  • Maternal antibodies when you’re an infant : through placenta, then through breast milk
  • injection of antibodies (IVIg), monoclonal treatments
88
Q

What are examples of live vs dead vaccines?

A

Live virus vaccines use the weakened (attenuated) form of the virus. The measles, mumps, and rubella (MMR) vaccine and the varicella (chickenpox) vaccine are examples.

Killed (inactivated) vaccines are made from a protein or other small pieces taken from a virus or bacteria.
(RNA/DNA) i.e. COVID

89
Q

What disease is routinely prevented in Canada today thanks to vaccines

A

prior to vaccination resulted in complications including paralysis and death in 3% of those infected

90
Q

Whooping cough

A

Associated with Pertussis

  • vaccine-preventable deaths
91
Q

Who do you vaccinate?

A

Those at risk
Family contacts
Health professionals

Children under the age of 1 and elderly are particularly vulnerable
Adults facing chemotherapy or transplant also vulnerable
Patients with immunodeficiencies
Travelers

92
Q

how do COVID vaccines work

A

Lipid nanoparticles surround mRNA encoding spike protein

  • upon injection, host cells produce Spike proteins
    they get presented by APCs and activated adaptive immune system
93
Q

Guillain-Barre Syndrome

A

side effect of vaccination in some people: causes immune system to attack nerve cells :(

94
Q

Why are RNA vaccines predicted to have high safety?

A

RNA is not inserted into our gene
we have enzymes that break down the mRNA
there are no viruses involved to cause illness or mutations in our genes

95
Q

Local Vs Systemic infection pathways

A

Macrophage activation to secrete TNFa in the TISSUES: keeps it localized with ultimate outcome -> removal of infection or adaptive immunity

with systemic:

Macrophage activated in the liver and spleen secrete TNFa into the BLOODSTREAM

  • systemic edema causing decreased BV, hypoproeinemia! neutropenia/neutrophilia.
    low BV leads to collapse of vessels, coagulation leading to wasting and multiple organ failure and DEATH
96
Q

What makes us FEEL sick?

A

The cytokines released by macrophages

IL1B
IL6
TNFa 
* these three specifically cause fever
IL8 (attract neutrophils0
IL12 (promote TH1 differentiation)
97
Q

Liver involvement in innate immunity

A

IL6 released by macrophages act on hepatocytes to produce acute phase proteins like

a. CRP: act like opsonin to increase phagocytosis and complement activation
b. Mannose binding lectin to also act as opsonin on bacteria and activate compliment

98
Q

What does your body do in response to when you are infected with a virus?

A

Virus infected host cell use THREE mechanisms

  1. releases cytokines to enhance anti viral defence/ resistance to viral replication
  2. up-regulate MHC1 to increase CD8 killing
  3. Activating NK killing
    notice: ***NO antibodies are used in the fighting of VIRUSES because they are INTERCELLULAR

You use covid ab count in serology as a SURROGATE meausure of responsiveness to covid. you assume if antibodies are up, so are CD8

99
Q

Time line of NK vs T cell vs Virus proliferation/plateau

A

NK cells are activated like right away. you notice the level of virus titre kind of plateaus with NK cells alone UNTIL the T cells start to rise, THEN you see a fall in virus load.

without T cell activation, the virus load stays plateau, does not go down, you’ll thus end up with chronic inflammation!!

100
Q

How do we “clear” infection?

A

CD8 killing of infected cell
and NKs

we want implosions through apoptosis.
NOT explosions

101
Q

How can you tell the difference, visibly between an activated an an inactivated macrophage

A

inactivated: lysosomes are individual and small
activated: lysosomes fuse with bacteria filled granules, create larger darker areas

102
Q

What are the three functions of antibodies?

A
  1. neutralization: gets ingested, can’t enter cells and infect more host cells
  2. opsonization: flagged for ingestion by macrophages
  3. Compliment activation: lysis and ingestion
103
Q

Arm of defence elicited for Extracellular vs Intracellular pathogens?

A

Intracellular: CD8, NK, macrophage activation

Extracellular: Antibodies, compliement, phagocytosis, neutralization (IgA especially for epithelial surfaces)

104
Q

Examples of Direct vs Indirect mechanisms of tissue damage by pathogens

A

Direct: released by pathogens themselves

  • exotoxin production
  • endotoxins

Indirect; damage caused by activation of our defence system:

  • immune complexes
  • Anti-host antibodies (cross reactivity)
  • cell mediated immunity (?)
105
Q

What are some ways pathogens evade the immune system

A

Inhibition of humoral immunity
Inhibition of inflammatory response
Blocking of antigen presenting cells
Immunosuppression of host

106
Q

Mechanism of HIV

A

HIV specifically depleted CD4 T cells!!

you get symptoms whenever the infected T cells gets activated aka when you get an infection/sick

in small group, someone who has latent TB who then gets HIV now risks promoting active TB with inappropriate immune response

HIV becomes AIDS-> death

107
Q

What causes severe COVID? the virus or our defense mechanisms?

A

US. we produce cytokine storm and that is what is dangerous

Severe COVID-19 results from excessive activation of innate immune cells especially macrophages/dendritic cells resulting in uncontrolled cytokine release and pulmonary inflammation.

T cells play a key role in elimination of the virus and control of inflammation

B cells produce antibodies which may help to prevent subsequent infection. B cells are a source of inflammatory cytokine which may worsen disease

108
Q

Patient with IBD is taking anti TNF-R inhibitor
- reduces actions of TNF

would you advise her to continue taking an immunosupressing drug during a PANDEMIC?

A

well, this drug is specifically targetting the INNATE immune system. which is GOOD because overactivation of the innate system is what leads to severe COVID. this would actually be beneficial to take

it is not targeting the arm of our defence that is more useful in fighting covid (T cells)

109
Q

What are the 4 uses of immunosuppressive agents

A

1 . Autoimmune disease

  1. Isoimmune disease (Rh hemolytic disease of the newborn)
  2. Organ Transplantation
  3. Prevention of cell proliferation (e.g. coronary stents)
110
Q

What is an example of an isoimmune disease, describe it

A

Rh Hemolytic disease of the newborn

if baby has diff Rh value (from father) after first delivery, mother is exposed and sensitized. if second baby also has diff Rh, maternal antibodies will attack baby blood :(

111
Q

What are the targets for immunosuppressive drugs from least to most selective

A
  1. Cell proliferation
  2. T cell function
  3. Antibody/antigen recognition
112
Q

Immunosuppressive drugs that target Cell Proliferation

A

Glucocorticoid receptor agonists

e.g. Prednisone, dexamethasone

113
Q

ASthma alarmins

A

these are released by epithelial cells from environmental stimuli
IL25 ,IL33, TSLP

114
Q

Mechanism of Glucocorticoids?

A

Glucocorticoids:
↓ transcription of pro- inflammatory genes

Decrease: IL1, IL6, IL2

↑ expression of anti- inflammatory genes

The net result is a decrease in immune cell signaling and proliferation.

115
Q

Dexamethasone use?

A

glucoccorticoid, immunosuppressent, works to inhibit cell prloiferation

Dexamethasone use may be recommended for patients who require supplemental oxygen.

116
Q

What are examples of Cytotoxic Drugs

A

Methotrexate
MMF
azathioprine

117
Q

Azathioprine

A

cytotoxic cell
- blocks DNA and RNA synthesis

an immunosuppressant

118
Q

Mycophenolate mofetil (MMF)

A

blocks de novo purine synthesis

INHIBITS B AND T CELL proliferation and functions

119
Q

Methotrexate

A

immunosuppresion drug that is cytotoxic: starves cells of thymidine

120
Q

Examples of immunosuppressors that target T cells

A

Calcineurin inhibitors
cyclosporine, tacrolimus
sirolimus

121
Q

Polyclonal Antibodies

- an example, how it works

A

This is a type of immunosuppressor that targets antibodies

e.g. Anti Thymocyte globulin ATG

Rapid depletion of peripheral lymphocytes: prevent initial graft rejection

122
Q

Monoclonal Anitbodies

A

Type of immunosuppressor that targets antibodies

MUROMONAB
BASILIXIMAB
INFLIXIMAB

123
Q

Muromonab

A

Monoclonal antibodies
- binds to TCR:CD3

  • used to reverse acute allograft rejection
124
Q

Whats a monoclonal ab used for Chron’s disease and RA?

A

Infliximab:

anti TNFa

125
Q

What immunosuppressive agents should be used fo autoimmune diseases?

A

Steroids: prednisone. dexamethasone

Cytotoxic drugs: azathioprine,
mycophenolate mofetil, methotrexate, etc. •

Biologics: Anti-IL-1,Anti-IL-6,Anti-TNF,etc.

126
Q

What is used to treat isoimmune disease: Rh hemolytic disease of the new born?

A

Initial response is blocked if specific Ab (RhD IgG, with a high Ab titer to RhD Ag) is administered to the mother at 28 weeks gestation and/or within 72 hrs of birth of 1st baby.

127
Q

What immunosuppressive agent is used for organ transplant

A
  1. Carefully prepare the patient and select the best available ABO blood type–compatible HLA match for organ donation.
  2. Employ immunosuppressive therapy; simultaneously use several agents, each of which is directed at a DIFFERENT MOLECULAR TARGET

For example: Kidney Transplant Recipients • Tacrolimus
• Mycophenolate mofetil
• Prednisone

128
Q

Sirolimus

A

Drug-eluting coronary stents, prevention of cell proliferation using these medicated coronary stents

129
Q

What are unwanted effects of immunosuppressive agents

A
  1. Increased risk of infections

2. Lymphomas and secondary malignancies

Block F: Defence (9 decks)

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