Immune related illnesses/diseases and treatmentsdb.phm.utoronto.ca/Dojo Soeandy lecture 3.pdf ·...

Immune related illnesses/diseases and

treatmentsLecture 3- Dojo Soeandy’s section

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Topics to be covered:• Exaggerated immune responses:

• Complications of immune response• Hypersensitivity• Adverse reactions to treatments:

• Adverse drug/ idiosyncratic drug reactions• Transplantation and immunologic considerations

• Autoimmunity

• Inefficient immune responses:• Primary immunodeficiency- genetic disorders • Secondary immunodeficiency- e.g. HIV

• Immune-related drugs/treatments:• Vaccines • Immunosuppressants/anti-inflammatory drugs

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• Complications of immune response• Hypersensitivity • Adverse reactions to treatments:


• Autoimmunity



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Complications of immune response• Extensive tissue damage

• hemorrhage (redness)• frustrated phagocytosis

• If a stimulus is overwhelming or if a target is too large, the cell will spread as if trying to engulf it, but cannot close to form phagosomes.

• Instead cells will release materials normally released into phagosomes (e.g. ROS and degradative enzymes)

• release of cytotoxic molecules (e.g. cytotoxic T cells)

• Abscess formation• contains fibrin, viable and necrotic neutrophils/macrophages,

tissue debris, and dead & live pathogen; surrounded by fibrous capsule

• Progression to chronic inflammation• Can lead to various diseases like cardiovascular diseases,

cancer, diabetes, etc.4

Slide adapted from Latif 2018

saintlukeskc.org

Complications of immune response• Systemic involvement

• Fever - cause: pyrogens (e.g. bacterial components, interleukin-1 released from activated macrophages) that affect the hypothalamus; functions: increase host metabolic activity + inhibit pathogens

• In some instances, this immune response can be too strong, causing tissue and organ damage and, in severe cases, even death

5Slide adapted from Latif 2018courses.lumenlearning.com

prostaglandin E2 (PGE2)

Complications of immune response

• Sepsis• Sepsis is the body’s overwhelming and life-threatening

response to infection that can lead to tissue damage, organ failure (e.g. kidneys, heart and lungs), and death- i.e. it’s your body’s overactive/extreme and toxic response to an infection.

• The immune system stops fighting the “invaders,” and begins to turn on itself.

• Septic shock is the most severe level and is diagnosed when your blood pressure drops to dangerous levels.

• On average, approximately 30% of patients diagnosed with severe sepsis do not survive. It’s the #1 leading cause of death in hospitals.

• Early detection and treatment is essential for survival and limiting disability for survivors.

• At risk populations: 65+ yrs old, <1yr old, weakened immune system, chronic medical conditions

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Complications of immune response• Signs and symptoms of sepsis

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• Treatments• Antibiotics

• IV fluids- usually crystalloid like saline (sometimes colloids like albumin or dextran); help keep the blood pressure from dropping dangerously low

• Cortocosteroid- reduce inflammation in the body and depress the immune system

• Vasopressors- increase blood pressure

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• Autoimmunity (arthritis, type 1 diabetes)



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Hypersensitivity

• Hypersensitivity reactions (HR) are immune responses that are exaggerated or inappropriate against an antigen or allergen (usually a secondary response).

• 4 types: based on mechanism of action; type I, II, and III reactions are the result of antibody reactions, while type IV reactions involve T cell lymphocytes and cell-mediated immune responses.

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Hypersensitivity- ACID• Type I: Allergic

• IgE mediated • Fast response from mast cells and basophils after re-exposure

• Type II: Cytotoxic/ antibody-mediated• IgG/IgM mediated against antigens on cell surfaces (e.g. red blood cells) • Activate either the complement system or antibody-dependent cell-

mediated cytotoxicity (ADCC) - i.e. activate cytotoxic T cells (CTLs), natural killer cells, neutrophils, etc.

• E.g. ABO blood group incompatibility

• Type III: Immune complex/ IgG/IgM-mediated• IgG/IgM form antigen-antibody complexes that settle on tissues and organs

(contain greater antibody concentrations than antigen concentrations)• Activate complement system and recruit neutrophils and phagocytes

• Type IV: Delayed or cell-mediated• T-cell mediated (TH1 usually)• Delayed type (takes a few days to develop)• Activates natural killer cells, macrophages, CTLs, etc.

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Hypersensitivity- Type I

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courses.lumenlearning.com

Hypersensitivity- Type II

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courses.lumenlearning.comCould also induce antibody-dependent cell-mediated cytotoxicity (ADCC) in other examples

Example of alloimmune hemolytic anemia

Hypersensitivity- Type III

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Hypersensitivity- Type IV

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Hypersensitivity- summary

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Ag = antigenAb = antibodyADCC = antibody-dependent cell-mediated cytotoxicity

Mast cell


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• Autoimmunity



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Adverse drug reactions

• Adverse drug reaction (ADR) is an unwanted, undesirable effect of a medication that occurs during typical clinical use.

• Type A (intrinsic)• reactions are predictable from known pharmacology of a drug

• high morbidity and low mortality

• dose-dependent

• Type B (idiosyncratic)• reactions are idiosyncratic and cannot be predicted from the

known pharmacology or therapeutic effect of a drug

• low morbidity and high mortality.

• not easily explained by dose

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Idiosyncratic drug reactions (IDR)

• Thought to be immune-mediated and caused by chemically-reactive species

• Major targets: skin, liver, bone marrow (blood cells)

• Each drug has spectrum of IDRs• eg halothane IDRs limited to the liver vs carbamazepine

IDRs include liver injury, skin rash, agranulocytosis, aplastic anemia, autoimmunity

• Delayed onset; more rapid onset upon second exposure

• Genetic component - MHC genes, slightly higher risk in women

22Slide adapted from Latif 2018

Idiosyncratic drug reactions- skin

1. Maculopapular Rash

• most common type of IDR skin rash

• onset: 1-2 weeks of treatment

• resolves even with continuation of drug

• mediated by cytotoxic CD4 cells that bind MHC Class II




2. Urticaria (Hives)

• second most common type of IDR skin rash

• IgE-mediated allergic reaction

• usually responsive to cyclosporine



3. Fixed Drug Eruption

• rash occurs at the same site (hyperpigmentation)

• onset is approx. 2 hours upon rechallenge

• mediated by CD8+ T cells

4. Drug-Induced Hypersensitivity Syndrome

• acute onset of rash, fever and hepatitis/nephritis/ pneumonitis/etc.

• onset is 2-6 weeks; mortality rate up to 10%

• treatment: corticosteroids



5. Acute Generalized Exanthematous Pustulosis• pustules on the face, neck and groin; fever; neutrophilia• onset as short as one day• largely associated with antibiotics

6. Toxic Epidermal Necrolysis• sudden onset of fever and malaise followed by painful

rash and blisters – gentle pressure results in sloughing off of the epidermis due to keratinocyte apoptosis

• mortality rate ~30% - the most severe type of skin rash• involves mucus membranes of the mouth, genitals,

intestine, and eyes (sometimes blindness)• onset is 7-21 days

Idiosyncratic drug reactions- liver


1. Hepatocellular Liver Injury• most common idiosyncratic liver injury• involves death of hepatocytes• onset usually 1-3 months; can be days to one year• damage is often greater in the regions of the liver

containing high levels of cytochrome p450

2. Cholestatic Liver Injury• characterized by a greater increase in alkaline

phosphatase (ALP) and bilirubin compared to alanine transaminase (ALT)

• associated with phenothiazines, amoxicillin/ clavulanic acid, and flucloxacillin

Idiosyncratic drug reactions- blood


1. Agranulocytosis

• Low granulocyte WBC count (usually involves severe neutropenia-peripheral neutrophil count <500 cells/microliter, normal= ~3,000-7,000/µL)

• onset is 1-3 months

2. Thrombocytopenia

• Low platelet count

• classically associated with heparin – antibodies directed to complexes containing heparin and an endogenous platelet protein, platelet factor 4 (PF4); no memory

3. Anemia

• due to hemolysis or decreased production of RBCs

• aplastic anemia: lack of hematopoietic cells in the bone marrow

IDR mechanism

• The Hapten Hypothesis: chemically reactive drug/ metabolite binds protein →drug-modified protein adduct recognized as “foreign” →results in immune response or tolerance

• Hapten (definition): a low molecular weight chemical that binds irreversibly to protein through formation of a covalent bond

29Cho & Uetrecht, Chem. Res. Toxicol. 2017

IDR mechanism• The Danger Hypothesis : 2

signals• Signal 1- recognition of

MHC-complexed antigen (hapten) on an APC by TCR

• Signal 2- stressed or damaged cells produce danger signals (DAMPs) that lead to the activation of APCs and upregulation of costimulatory interactions such as B7 on APCs that bind to CD28 on T cells

30Cho & Uetrecht, Chem. Res. Toxicol. 2017




• Autoimmunity



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Transplantation and immune consideration

• Definition: replacement of a patient’s non-functional tissue or cells from a donor.

• Types of transplantations:• Autologous graft/autograft–Transplantation

of cells, tissues or organs between sites within the same individual e.g. skin graft.

• Isograft – Transplantation of tissue between genetically identical individuals (e.g. identical twins).

• Allograft – Transplantation of organs or tissues from a donor to a non-genetically identical individual of the same species. The most common type of transplant.

• Xenograft – Transplantation of an organ or tissue between two different species. ‘Pig valves’, for example, are commonly used to repair or replace a defective heart valve in humans.

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Roitt, Brostoff, Male, et al: Immunology, ed 7, Philadelphia, 2006

Transplantation and immune consideration• Graft/transplant rejection is caused by recognition

of allelic differences in major histocompatibility complex (MHC) loci between donor and recipient. For humans, we refer specifically to HLA (human leukocyte antigen complex = human MHC)

• Allorecognition= recipient immune response mounted against donor MHC

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Leukocyte infiltration

heartpathology.com

Transplantation and immune consideration• Allorecognition includes:

• Alloantibody production by B cells against the allo-MHC/HLA

• Direct allorecognition by T cells: donor antigen-presenting cells (APCs) interact and activated recipient T cells directly

• Indirect allorecognition by T cells: recipient APCs present processed donor allogeneic peptides to recipient T cells, similar to more typical immune responses

• Semidirect allorecognition by T cells: recipient APCs acquire donor HLA molecules that present peptides directly to recipient T cells

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DeWolf and Sykes, 2017

“cross-dressing”= transfer of preformed peptide–MHC/HLA complexes from donor cells to recipient cells


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• Types of graft rejection

This includes ABO blood group

(i.e. direct allorecognition)

Sometimes called acute humoral rejection (AHR)

Transplantation and immune consideration• Minimizing graft rejection:

• HLA typing- to ensure the closest possible match between MHC alleles of recipient and donor

• Alloantibody analysis- to make sure there aren’t already existing antibodies against donor (e.g. ABO blood groups)

• Immunosuppressive drugs- to reduce immune function generally

• Induction of graft tolerance- still currently researched; include things like inhibiting only recipient T cells that will attack graft

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• Autoimmunity



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Autoimmunity

• Occur when immune system does not appropriately differentiate self from non-self

• Healthy individuals exhibit limited autoimmunity (low-levels of anti-self antibodies)

• Autoimmune disease: • Arise when autoimmunity cause clinical damage to

tissue or disrupt its normal function

• Generally considered to be disorder of adaptive immune system

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Autoimmunity

• Examples of autoimmune diseases:• Multiple sclerosis- autoimmune attack against myelin

sheath of nerve axons

• Rheumatoid arthritis- autoimmune attack on antigens expressed in the synovial tissue and cartilage of the joints

• Systemic lupus erythematosus- autoimmune disease that affects the skin, joints, kidney, lung, heart and brain

• Type 1 diabetes mellitus- autoimmune attack against pancreas (β-islet cells)

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Autoimmunity

• Autoimmune disease determinants:• Genetic

• External triggers • Chemicals (hair dyes, smoking,

silica dust, etc.)

• Pathogens (inflammation, molecular mimicry)

• Drugs, toxins

• Hormone (e.g. lupus is more common in women, whereas graves’ disease is more common in men)

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Mak, Saunders & Jett, 2008

Autoimmunity

• Autoimmune disease general treatments:• Conventional therapies include

• Anti-inflammatory drugs

• Immunosuppressive drugs

• Plasmapheresis (mechanical removal of all antibodies from blood)

• Immunotherapies include• Targeting of leukocyte extravasation

• Targeting of T-lymphocyte receptors

• Cytokine blockade/administration

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• Autoimmunity



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Immunodeficiency

• Immunodeficiency results from a failure or absence of elements of the immune system. • Primary immunodeficiency (PIDs): individual is

born with a genetic mutation that results in an immune defect

• Secondary immunodeficiency: individual is born with normal immune responses, but later experience an event that damages the immune system• E.g. acquired immunodeficiency syndrome (AIDS)

caused by human immunodeficiency virus (HIV)

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Primary immunodeficiencyDefects in innate immunity:

1. Leukocyte adhesion deficiency• Leukocytes cannot extravasate into areas of injury • Patients suffer from severe infections and compromised

wound healing • Clinical sign e.g. absence of pus at sites of infection• Autosomal recessive mutations in integrin components (e.g.

CD18, CD15 or kindlin-3)

2. Congenital neutropenia• mild (ANC 1000-15000 cells/μL); moderate (ANC 500-1000

cells/μL); severe (ANC<500 cells/μL)• Causes recurrent bacterial and fungal infections• Many autosomal dominant and autosomal recessive causes

• E.g. autosomal dominant mutation of CXCR4 chemokine receptor-mature neutrophils can’t leave bone marrow and enter circulation

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Primary immunodeficiency

3. Chronic granulomatous disease• Characterized by failure in phagosomal killing

• Patients suffer from recurrent and sometimes life-threatening bacterial and fungal infections; persistent infections result in excessive granuloma formation

• Caused by mutation in any of the subunits that make up the NADPH oxidase that generates ROS in phagosomes• X-linked mutation in gp91 (most common and severe)

• Autosomal recessive mutations in p22

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Primary immunodeficiencyDefects in adaptive immunity:

1. Severe combined immunodeficiency (SCID) and combined immunodeficiency (CID)• Account for 20% of primary

immunodeficiency, with a prevalence of ~1 in 50,000 live births

• Multiple different types, but in all cases, T cell development is impeded, and may also affect B cells and natural killer (NK) cell development

• “Boy in the bubble” David Vetter suffered from X-linked SCID, which accounts for ~40% of all SCID cases 47

Gaspar, Gilmore & Jones, 2001

Immunology.org

Primary immunodeficiency2. Common variable immunodeficiency

(CVID)• Most frequently diagnosed primary

immunodeficiency (~50%)

• Family of diverse diseases characterized by general impairment of humoral response

• Present in patients who are in their 20s or 30s

• All patients demonstrate significantly decreased IgA and IgG, and about 50% lack IgM.

• Circulating B cells are present, but differentiation into plasma cells are inhibited, and memory B cells may be absent.

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Primary immunodeficiency

• Treatments:• Immunoglobulin/enzyme replacement

• Hematopoietic stem cell transplantation

• Gene therapy

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• Autoimmunity



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Secondary immunodeficiency- HIV• UNAIDS: approximately 37.9 million people living with

HIV, ~1.7 million people became newly infected globally in 2018; as many as 43.8 million people have died from AIDS-related illnesses since the beginning of the epidemic.

• HIV (human immunodeficiency virus): an enveloped single-strand RNA virus• mechanisms of transmission: sexual transmission,

transmission via injection drug use, exposure of blood and blood products during transfusion, and exposure of fetus/infant to HIV from an infected mother

• AIDS (Acquired Immunodeficiency Syndrome): disease caused by HIV mediated destruction of CD4+ T lymphocytes• diagnosis: CD4+ T cell count below 200 cells per microlitre

(normal range is 500-1500); antibodies against virus51


Secondary immunodeficiency- HIV

• Evasion from host immune system (esp. humoral immunity) via:

1. Glycoproteins- carbohydrate “cloak” conserved protein regions underneath

2. Variable loops

3. Error-prone reverse transcription • HIV genome: 10 thousand nucleotides

• on avg.: 1-10 nucleotides mutated/replication

• 10 billion virions/day


Wilen, Tilton, Doms, 2011

Secondary immunodeficiency- HIV• Molecular mechanisms of HIV entry: three steps for

infecting CD4+ T cells1. Attachment and CD4 Binding

2. Coreceptor binding

3. Membrane Fusion

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Wilen, Tilton, Doms, 2011


54

aidsinfo.nih.gov

For more info, please watch: https://www.youtube.com/watch?v=PlSvywlLuNw

https://www.youtube.com/watch?v=PlSvywlLuNw


• Treatments:• Antiretroviral Therapy

• To date there are 24 FDA-approved drugs available for HIV treatment

• Works by suppressing HIV replication and so reduce viral load to undetectable levels → increase in circulating T lymphocytes

• Can’t cure HIV per se, but can help people with HIV live longer, healthier lives and help reduce HIV transmission





• Autoimmunity



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Vaccines• Vaccines:

• Modified form of a natural immunogen; can be either the whole pathogen, one of its components, or a toxin

• Does not induce disease per se, but does activate host primary response to generate large numbers of memory B and T cells

• Usually a form of active immunization: because host lymphocytes are being actively induced to form antibodies.

• Passive immunization: protective antibodies are directly transferred from immune individual to unimmunized.

• Helps promote herd immunity: the probability of infection in the population decreases if a sufficiently high proportion of individuals are immuned to the disease 57


VaccinesRequirements of vaccine design:• Efficacy

• The immune response that the vaccine induce must be appropriate forthe elimination of the pathogen of interest.

• Refers specifically to an ideal situation, such as a tightly controlled clinical trial where it is compared to a placebo or other intervention

• Usually expressed as coverage- i.e. percentage of individuals that do not experience disease after exposure to the pathogen.

• No vaccine is 100% effective because of human genetic variations, but generally 80-95% effective.

• Safety• Have very few detrimental side effects or adverse events

• Effectiveness• Describes how the drug works in a real-world situation• Includes interactions with other medications or health conditions of the

patient• Protection must be long-lasting and help induce herd immunity• Low cost (<$1, WHO); genetic stability; storage considerations; delivery

(oral vs. needle)58

Vaccines

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Types of vaccines

toxoid

VaccinesType Description Advantages Disadvantages Examples

Live, attenuated

Weakened strain of whole pathogen

- Low number of doses, usually very effective

- Minimal need for adjuvant

- Cellular and humoral immunity

- ”Cold chain” required for storage and transport

- Chance of reversion of attenuating mutation

Chickenpox, measles, mumps, tuberculosis, typhoid fever

Killed or inactivated

Whole pathogen killed or inactivated with heat, chemicals, or radiation

- No possibility of reversion

- No cold chain required

- Require boosters and adjuvants

- Limited longevity- Weaker immunity

(primarily humoral)

Cholera, hepatitis A, influenza, plague, rabies

ToxoidChemically inactivated toxin of pathogen

- Avoids use of whole organism

- Effective only if disease caused solely by toxin (not prevent infection)

Botulism, diphtheria, pertussis, tetanus

Subunit, recombinant, polysaccharide, and conjugate

Pathogen protein and/or polysaccharide (antigen) purified directly from natural sources or synthesized using recombinant DNA methods

- Avoids use of whole organism

- Can be manipulated to increase immunogenicity

- Lower risk of side effects

- Can be costly to produce

- May not be as immunogenic as natural pathogen

- Identifying specific antigen takes time

Anthrax, hepatitis B, influenza,meningitis, pneumococcal pneumonia

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VaccinesType Description Advantages Disadvantages Examples

Recombinant DNA vector

Virus-based vector containing recombinant DNA of pathogen antigen. Vacinee is infected with the viral vector and the pathogen DNA is transcribed and translated within the vacinee’s cells like a viral protein

- Avoids use of natural pathogen

- Replicates like a pathogen to produce large amounts of immunogen

- Minimal need for boosters and adjuvant

- Possible side effects due to vector components

- Anti-vector antibodies raised during priming may necessitate boosting with a different vector

- Experimental

HIV, rabies, measles

Naked DNA

Small plasmid-containing recombinant pathogen DNA. Plasmid is injected into a vacinee, and the pathogen DNA is taken up by the vacinee’s cells and transcribed and translated

- Easy and inexpensive to manipulate

- Cellular and humoral immunity activation

- Plasmid sequences may act as adjuvant

- Not as immunogenic as protein vaccines in humans

- Integration of plasmid into host cell genome may induce tumorigenesis

Influenza, Herpes, HIV

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• Autoimmunity



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Immunosuppressants /anti-inflammatory drugs:

• Numerous immunosuppressive/anti-inflammatory agents available:• Calcineurin inhibitors

• mTOR inhibitors

• Corticosteroids

• NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)

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Calcineurin inhibitors Calcineurin

• Activated upon TCR binding of MHC-antigen complex, resulting in Ca2+ increase

• A subunit: Phosphotase activity, dephosphorylation of NF-AT

• B subunit: Calcium binding• Results in: Upreg. of cytokines & costimulatory

molecules important in T cell activation (eg IL-2,4,6; Interferon; CD40)

Calcineurin inhibitors:ligand/receptor complex bind to and inhibit calcineurin

1. Cyclosporine (immunophilin: cyclophilin A)• Side effects: High blood pressure, swollen or

inflamed gums, numbness or tingling of the hands or feet, nephrotoxicity, etc.

2. FK506 (immunophilin: FKBP12)• Also known as Tacrolimus• Side effects: hypertension, tremor, neurologic

toxicity, anemia, etc. 64Slide adapted from Latif 2018

Snyder, Sabatini, etc. 1998

mTOR InhibitorsmTOR (mammalian target of rapamycin)

• Ser/Thr kinase involved in PI3K/Akt signaling pathway• transcriptional regulation of T cell glycolytic enzymes• regulates the cell cycle of proliferating cells (including

lymphocytes)

mTOR inhibitors

1. Rapamycin• used alone or in combination with calcineurin inhibitors• similar structure to FK506 - also binds FKBP12 immunophilin• rapamycin-FKBP12 complex binds and inhibits mTOR• immunosuppressant and antiproliferative properties (blocks T

cell proliferation and others)• side effects: nephrotoxicity, myelotoxicity, etc.


CorticosteroidsPrednisone + Methylprednisolone

• Mechanism: 1. Passive diffusion into the cell2. Bind glucocorticoid receptors in the

cytoplasm3. Translocates to nucleus4. Reduces transcription of inflammatory

cytokines and increase anti-inflammatory cytokines

• Glucocorticoid also inhibit Phospholipase A2 in the prostaglandin pathway

• Effects: stabilize lysosomal membranes, suppress prostaglandin synthesis, reduce histamine release, reduce capillary permeability, impair macrophage function, reduce number of CD4+ T cells.

• Side effects: diabetogenesis, protein loss from skeletal muscle, fluid retention + hypertension, adrenal suppression + atrophy, psychosis, etc. 66


Kino, 2017

NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)

• Group of drugs that reduce inflammation and relieve pain and fever

• Work by inhibiting cyclo-oxygenase enzymes (COX-1 and/or COX-2), which are responsible for the production of prostaglandins.

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68Slide adapted from Girnita, 2014

Phospholipase A2Membrane phospholipid

corticosteroids


69Slide adapted from Dutta, 2017


• Side effects of COX-1 inhibitors: stomach bleeding and risk GI ulcer formation• inhibits cox-1 activity thereby increasing tissue

unsaturated fatty acid levels and causing acidosis

• decreases PGE2 levels that protect stomach membrane

• inhibits thromboxane formation and platelet aggregation

• Side effects of COX-2 inhibitors: increased risk of cardiovascular disease

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Drug examples:• Aspirin (e.g. Bayer)- irreversibly

acetylate Ser530 of COX-1 and COX-2 (slight selectivity for COX-1)

• Ibuprofen (e.g. Advil & Motrin), Naproxen (e.g. Aleve)- reversibly bind to COX-1 and COX-2

• Celecoxib (Celebrex)- COX-2 inhibitor

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Midterm

Wednesday, October 9 from 3:30 to 6:30 p.m. in EX 200

•Make sure to bring your T-card•Write with pen if potentially want a

regrade

GOOD LUCK!72

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