Lecture 7: Immunological disorders, antimicrobial drugs Flashcards
What is immunological hypersensitivity?
Antigenic response beyond normal such as allergy. Occurs when sensitized by previous exposure to an antigen.
What are the types of hypersensitivity?
Types of hypersensitivity:
Type I Anaphylactic
Type II Cytotoxic
Type III. Immune complex
Type IV. Delayed cell-mediated
Limited exposure to pathogens may lower immune tolerance and the ability to cope with harmless antigensType 1 (Anaphylactic) Reaction
Occurs minutes after a person sensitized to an antigen and reexposed to that antigen
- Antigens combine with IgE antibodies
- IgE attaches to mast cells and basophils
- Mast cells and basophils release mediators:
What are the mediators released by mast cells and basophils?
- Histamine: increases the permeability of blood capillaries
- Leukotrienes: cause prolonged contraction of smooth muscles
- Prostaglandins: affect smooth muscle and increase mucus secretion
What is systemic anaphylaxis?
This is anaphylactic shock where a individual is sensitized to an antigen and then re-exposed to it. It may result in circulatory collapse and death. it is treated with epinephrine.
What is localized anaphylaxis?
Usually associated with ingested or inhaled antigens. Symptoms depend on the route of entry. Hives, hay fever and asthma are examples.
How can anaphylactic reactions be prevented?
- Antigens are inoculated beneath the epidermis to test for rapid inflammatory reaction (wheal)
- Desensitization: increasing dosages of antigen injected beneath the skin. Produces IgG, which act as blocking antibodies to intercept and neutralize antigens
What are Type II (Cytotoxic) Reactions?
This involves activation of complement by the combination of IgG or IgM antibodies with an antigenic cell. Causes cell lysis or damage by macrophages.
How can the ABO blood types create Type II reactions?
- Antibodies in the blood form against certain carbohydrate antigens on red blood cells. A, B or both. Type O do not have any carbohydrate antigens attached.
How can Rh factor create a type II reaction?
Rh factor is found on the RBC’s of 85% of the population. Rh+ blood given to an Rh- recipient will stimulate anti-Rh antibodies.
What is hemolytic disease of the newborn?
An Rh- mother with an Rh+ fetus causes the mother to produce anti-Rh antibodies during birth. The second Rh+ fetus may be damaged by the anti-Rh antibodies because these can cross the placental barrier. This can cause hemolysis, jaundice, edema, and death. The cure is to give antibodies (Rhogam) to attach to the mother’s antibodies to bind them. Give this during the third trimester of the first birth.
What are three types of drug-induced
- Thrombocytopenic purpura
- Agranulocytosis
- Hemolytic anemia
Thrombocytopenic purpura
Platelets combine with drugs , forming a complex that is antigenic. Antibody and complement destroy platelets.
Agranulocytosis
Drug-induced immune destruction of granulocytes
Hemolytic anemia
Drug-induced immune destruction of RBC’s
What is a Type III (Immune Complex) reaction?
Antibodies form against soluble antigens in the serum. These form immune complexes that lodge in the basement membranes under the cells. They activate complement and attract neutrophils. These release enzymes that damage the endothelial cells of the basement membrane. This causes damage and inflammation.
What is glomerulonephritis?
Inflammatory damage to the kidney glomeruli due to immune complexes as a result of infection.
Type IV (Delayed Cell-Mediated) reactions
- These are cell mediated immune responses caused by T cells that do not appear for days.
- It takes time for T cells and macrophages to migrate and to accumulate near the foreign antigen.
- Antigens are phagocytized and presented to receptors on T cells, causing T cells to proliferate into mature differentiated T cells and memory cells.
- Reexposure to antigen causes memory cells to release destructive cytokines
What is different about Type IV from all of the other types of hypersensitivity reactions?
Type IV involves T cells while all of the others involve antibodies immediately.
Give an example of a type IV reaction.
Allergic contact dermatitis
- Haptens combine with proteins in the skin, producing an immune response
- Allergic response to poison ivy, cosmetics, metals, latex etc.
What is autoimmunity?
Autoimmunity is a loss of self-tolerance where the immune system does not discriminate self from non self. Type II, III or IV
What are some examples of autoimmune disorders?
- Graves disease
- Myasthenia gravis
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Multiple Sclerosis
- Insulin dependent diabetes mellitus
- Psoriasis
Graves’ disease
Antibodies react with cell-surface antigens. Abnormal antibodies are produced that mimic TSH, produce excessive amounts of hormones. Increase heart rate, metabolism, cause bulging of eyes.
Myasthenia gravis
Antibodies coat acetylcholine receptors; muscles fail to receive nerve signals. Action potentials cannot be produced. If it affects respiratory muscles death may result.
SLE
Immune complexes of antibodies and complement deposit in tissues. Immune complexes form in kidney glomeruli.
Rheumatoid arthritis
Immune complexes form in joints. Also a tendency to deposit on heart valves.
MS
T cells and macrophages attack the myelin sheath of nerves. Causes include genetic susceptibility and epstein-barr virus
IDDM
Insulin-dependent diabetes mellitus; T cell destruction of insulin-secreting cells. This is Type 1 where insulin is not produced.
Psoriasis
Autoimmune disorder of the skin
What are reactions related to Human Leukocyte Antigen (HLA) complex?
- Histocompatibility antigens: self antigens present on cell surfaces
- Major histocompatibility complex (MHC): genes encoding histocompatiblity antigens on the surface of leukocytes.
HLA typing must be done prior to transplant because…
the donor and recipient must have matching antisera or monoclonal antibodies specific for HLA.
What are some examples of privileged tissue?
Cornea, heart valve, brain
What are stem cells?
Master cells capable of generating many different types of cells.
Embryonic stem cells
Harvested from blastocysts, used to regenerate tissues and organs. Pluripotent - can generate all types of cells.
Adult stem cells
Stem cells that have already differentiated. Can become induced pluripotent stem cells by introducing genes.
Autograft
use of one’s own tissue
Isograft
use of identical twin’s tissue
Allograft
use of tissue from another person
Xenotransplantation product
Use of nonhuman tissue (must overcome hyper acute rejection)
Graft-vs-host disease
can result from transplanted bone marrow that contains immunocompetent cells
Immunosuppression
- prevents a cell-mediated immune response to transplanted tissue
Cyclosporine and tacrolimus
suprress IL-2, disrupting cytotoxic T cells
Sirolimus
inhibits cellular and humoral immunity
Mycophenolate
inhibits proliferation of T cells and B cell
Basiliximab
chimeric monoclonal antibody that blocks IL-2
How does immune surveillance remove cancer?
Cancer cells have tumour associated antigens that mark them as non self. Activated Tc cells and macrophages lyse cancer cells.
What are immune limitations that allow cancer to spread?
No antigenic epitope for the immune system to target
Tumor cells reproduce too rapidly
Tumor becomes vascularized and invisible to the immune system
What are some possible immunotherapies for cancer?
- Endotoxins from bacteria (Coley’s toxins) stimulate TNF that interferes with the blood supply of cancers.
- Vaccines can be used as prophylaxis (eg. Gardasil)
- Monoclonal antibodies such as herceptin for breast cancer.
Acquired Immunodeficiency Syndrome
This is the final stage of HIV infection. HIV is a retrovirus with a single stranded RNA. HIV attaches with CD4+ (receptors on Th cells, macrophages and dendritic cells)
- HIV is a retrovirus such that viral RNA is transcribed into DNA and integrated into the host chromosome
What are the phases of HIV infection?
Phase 1: asymptomatic or lymphadenopathy
Phase 2: CD4+ T cells decline steadily; only a few infected cells release the virus; few serious disease symptoms (persistent infections, fever, and oral leukoplakia)
Phase 3: AIDS develops. the CD4+ is count below 200 cells/μl. indicator conditions
How is HIV spread?
- Spread by dendritic cells and carried to the lymphoid organs, contacts activated T cells
- gp120 combines with CD4+ receptor and CCR5 or CXCR4 coreceptors
- Virus fuses and enters the cell
Where are CD4 molecules found?
Carried on T helper cells, macrophages and dendritic cells
Talk about resistance to HIV infection.
Initial strong and effective immune response
CTLs suppress viral numbers
Once HIV establishes a pool of latently infected CD4+ T cells, it is impossible to clear the infection
Challenge to make a vaccine because virus stay inside the host cell
Talk about the impact of age on survival of HIV
Older adults and young children do not a have fully developed immune system, making them more susceptible
Exposed, but not infected population (CCR5 mutation)
Long-term survivors:
- Low viral load
- Effective CTLs
What is seroconversion?
The period of time between infection and the appearance of antibodies (takes up to 3 months).
How is plasma viral load (PVL) determined?
PCR or nucleic acid hybridization
How long can HIV survive outside a cell?
6 hours
How long can HIV survive inside cell?
1.5 days
What are routes of transmission of HIV?
Intimate sexual contact, breast milk, transplacental infection, contaminated needles, organ transplants, and blood transfusion
What are some ways to treat HIV?
- Reverse transcriptase inhibitors
- Highly active antiretroviral therapy (HAART) which is a combination of drugs
- Integrase inhibitors
- Protease inhibitors
- Maturation inhibitors
- Teherins which tether viruses to cells preventing their release and spread
Examples of RTI’s
- Nucleoside reverse transcriptase inhibitors (NRTI’s) like tenofovir and emtricitabrine
- Non-nucleoside reverse transcripatse inhibitors (NNRTI’s) like Efavirenz
Integrase inhibitors
- Inhibit HIV integrate that integrates cDNA into the host chromosome eg. Raltegravir
Protease inhibitors
Inhibit proteases that cleave viral precursor proteins into structural and functional proteins (eg. atazanavir, indinavir and saquinavir)
Selective toxicity
selectively finding and destroying pathogens without damaging the host
Chemotherapy
the use of chemicals to treat a disease
Antibiotic
a substance produced by a microbe that, in small amounts, inhibits another microbe
Antimicrobial drug
synthetic substances that interfere with the growth of microbes.
Who discovered penicillin?
Alexander Fleming in 1928
When were the first clinical trials of penicillin?
1940
Narrow spectrum of microbial activity
Drugs that affect a narrow range of microbial types. (eg. penicillin affects gram-positive bacteria)
Broad-spectrum antibiotics
Affect a broad range of gram-positive or gram-negative bacteria
Super infection
Drugs destroy many normal microbiota of the host which compete with pathogens. This can result in overgrowth of those micro-organisms which are resistant to the given antibiotic. Example Candida albicans (not sensitive to bacterial antibiotics)
Drugs that inhibit the synthesis of folic acid… how do they affect bacteria but not humans?
Humans can still ingest folic acid, while bacteria must create it.
Bactericidal
kill microbes directly
Bacteriostatic
prevent microbes from growing
Inhibiting cell wall synthesis
penicillin prevents the synthesis of peptidoglycan (cell wall) Cell wall is weakened and cell undergoes lysis
Inhibiting protein synthesis
- Target bacterial 70S ribosomes
- Chloramphenicol, erythromycin, streptomycin, tetracyclines
Injuring the plasma membrane
Polypeptide antibiotics change membrane permeability. Antifungal drugs combine with membrane sterols
Inhibiting nucleic acid synthesis
Interfere with DNA replication and transcription
Inhibiting the synthesis of essential metabolites
Antimetablites compete with normal substrates for an enzyme
- sulfanilamide competes with para-aminobenzoic acid (PABA) stopping the syntheses of folic acid
Inhibitors of Cell wall synthesis
Don’t know look up
Penicillin
Contain a β-lactam ring
Types are differentiated by the chemical side chains attached to the ring
Prevent the cross-linking of peptidoglycans, interfering with cell wall construction (especially gram-positives)
Natural penicillins
Extracted from Penicillium cultures
Penicillin G (injected) and Penicillin V (oral)
Narrow spectrum of activity
Susceptible to penicillinases (β-lactamases)
Semisynthetic penicillins
Contain chemically added side chains, making them resistant to penicillinases (eg. methicillin and oxacillin)
Extended spectrum penicillins
Effective against gram-negatives as well as gram-positives (aminopenicillins, ampicillin, amoxicillin)
Penicillins plus Beta lactamase inhibitors
Contain clavulanic acid, a noncompetitive inhibitor of penicillinase
Carbapenems
Substitute a C for an S and add a double bond to the penicillin nucleus
Broad spectrum
Primaxin, doripenem
Monobactam
synthetic, low toxicity works against only certain gram-negatives like aztreonam
