Chapter 19: Disorders Associated with the Immune System

What do allergies and asthma have to do with the hygiene hypothesis?

• observation that tribal population and children growing up on farms have less prevalence of allergies than children in urban settings

• Possibly due to wider range of microbial exposures in farm setting; also led to lower asthma rates

What does inflammatory bowel diseases have to do with the hygiene hypothesis?

possible link of lack of normal microbiota metabolic products leading to chronic inflammatory state

What is dysbiosis?

imbalance that causes adverse effects in humans

What is antibiotic therapy?

kills normal gut microbiota, causing Clostridium difficile to proliferate

What are possible causes of IBDs?

ulcerative colitis and Crohn’s disease

How do scientists treat Crohn’s disease with worms?

Whipworm eggs suppress T helper cell pathways

How do fecal transplants help with C. difficile infections?

taking gut microbiota from a healthy indivigual and transplanting it into the patient

What is hypersensitivity?

antigenic response beyond normal

• occurs when sensitized by previous exposure to an antigen (allergen)

What are the four typer of hypersensitivity?

• anaphylactic

• cytotoxic

• immune complex

• delayed cell-mediated

What is Immunopathology?

The study of hypersensitivity

What does the hygiene hypothesis say?

limiting exposure to pathogens may lower immune tolerance and the ability to cope with harmless antigens

What is type I hypersensitivity?

(anaphylactic)

• <30 minutes

• IgE binds to mast cells or basophils; causes degranulation of mast cell or basophil and release of reactive substances such as histamine

• Anaphylactic shock from drug injections and insect venom; common allergic reactions such as hay fever, asthma

What do histamines do in type I hypersensitivity?

increase the permeability of blood capillaries

What does Leukotrienes do in type I hypersensitivity?

cause prolonged contraction of blood capillaries

What does Prostaglandins do in type I hypersensitivity?

affect smooth muscle and increase mucus secretion

What is type II hypersensitivity?

(Cytotoxic)

• 5-12 hours

• Activation of complement by the combination of IgG or IgM antibodies with an antigenic cell, causes cell lysis or damage by macrophages

• Transfusion reactions, serum sickness

• ABO blood group system

  • antibodies form against certain carbohydrate antigens on RBCs

    • A antigens, B antigens, or both

    • Type O RBCs have no antigens

What is the Rh blood group system in type II hypersensitivity?

• Rh factor antigen (Rh⁺) found on RBCs of 85% of the population

• Rh⁺ blood given to an Rh^- recipient will stimulate anti-Rh antibodies in the recipient

What is hemolytic disease of the newborn (HDNB)?

• Rh^- mother with an Rh⁺ fetus causes the mother to produce anti-Rh antibodies

• Second Rh⁺ fetus will receive anti-Rh antibodies, damaging fetal RBCs

What are drug-induced cytotoxic reactions?

• Thrombocytopenic purpura

  • platelets combine with drugs, forming a complex that is antigenic

  • antibody and complement destroy platelets

• Agranulocytosis

  • drug-induced immune destruction of granulocyts

• Hemolytic anemia

  • drug-induced immune destruction of RBCs

What is type III hypersensitivity?

(Immune complex)

• 3-8 hours

• Antibodies form against soluble antigens in the serum

• form immune complexes that lodge in the basement membranes beneath the cells

  • activate complement, causing inflammation

• Arthus reactions, serum sickness

What is Arthus reactions?

• Rare side-effect of toxoid-containing vaccines

• Occurs in glomeruli and other vessel walls due to complement activation in a patient with already circulating IgG to an injected antigen

What is serum sickness?

occur with swelling and inflammation due to injection of foreign serum

What is type IV hypersensitivity?

(Delayed cell-mediated, or delayed hypersensitivity)

• 24-48 hours

• Antigens are phagocytized and presented to receptors on T cells, causing sensitization

• Re-exposure to antigen causes memory cells to release destructive cytokines

What is allergic contact dermatitis?

• haptens combine with proteins in the skin, producing an immune response

• allergic response to poison ivy, cosmetics, metals, and latex

What is Systemic anaphylaxis?

(anaphylactic shock)

• results when an individual sensitized to an antigen is exposed to it again

• may result in circulatory collapse and death

• treated with epinephrine

What is localized anaphylaxis?

• usually associated with ingested or inhaled antigens

• symptoms depend on route of entry

• hives, hay fever, and asthma

How do you prevent anaphylactic reactions?

Antigens are inoculated beneath the epidermis to test for a rapid inflammatory reaction (wheal)

What is desensitization?

increasing dosages of antigen injected beneath the skin

• produces IgG, which act as blocking antibodies to intercept and neutralize antigens

What are autoimmune diseases?

• immune system responds to self antigens, causing damage to the organs

• Autoimmunity is loss of self-tolerance

  • ability to discriminate self from non-self

• Cytotoxic, immune complex, or cell-mediated

What are cytotoxic autoimmune reactions?

• Multiple sclerosis

  • autoantibodies, T cells, and macrophages attack myelin sheath of nerves

  • compromises nerve impulse transduction

  • symptoms range from fatigue and weakness to severe paralysis

  • Etiology unknown; may involve genetic susceptibility and/or infective agent(s)

What are immune complex autoimmune reactions?

• antibodies react with cell-surface antigens

  • graves’ disease

    • abnormal antibodies in the thyroid produce excessive amounts of hormones

  • Myasthenia gravis

    • antibodies coat acetylcholine receptors; muscles fail to receive nerve signals

• Immune complexes of antibodies and complement deposit in tissues

  • Systemic lupus erythematosus

    • immune complexes form in kidney glomeruli

  • Rheumatoid arthritis

    • immune complexes form in the joints

What are cell-mediated autoimmune reactions?

• mediated by T cells that attack tissues

  • insulin-dependant diabetes mellitus

    • T cell destruction of insulin-secreting cells

  • Psoriasis and psoriatic arthritis

    • autoimmune disorders of the skin

What are Histocompatibility antigens?

self antigens on cell surfaces

What is the major histocompatibility complex (MHC)?

genes encoding histocompatibility antigens

What is the HLA complex?

MHC genes in humans

What are certain HLAs related to?

increased susceptibility to specific diseases

What are the selected diseases related to specific human Leukocyte antigens?

• Multiple sclerosis

• Rheumatic fever

• Addison’s disease

• Graves’ disease

• Hodgkin’s lymphoma

What does HLA typing do?

identifies and compares HLAs

What has to happen in tissue surgery?

The donor and the recipient must be matched by tissue typing

• Uses standardized antisera or monoclonal antibodies specific for HLAs

What is a risk for transplants?

They may be attacked by T cells, macrophages, and complement-fixing antibodies

What is true about transplants and privileged sites?

transplants to privileged site and privilege tissue do not cause immune response

• cornea transplants. heart valve transplants

What are stem cells?

master cells capable of renewing themselves and differentiating into organ-specific specialized cells

What are embryonic stem cells (ESCs)?

• harvested from blastocysts; used to regenerate tissues and organs

• Pluripotent-can generate all types of cells

What are adult stem cells?

• stem cells in adult tissues that have differentiated

• can become induced pluripotent stem cells by introducing genes

What are hematopoietic stem cell transplants?

AKA bone marrow transplants

• goal is to enable the recipient to produce healthy blood cells

• graft-versus-host (GVH) disease can result from transplanted bone marrow that contain immunocompetent cells

What is an autograft?

use of one’s own tissue

What is an Isograft?

Use of identical twins tissue

What is an Allograft?

Use of tissue from another person

What is a Zenotransplantation product?

Use of nonhuman tissue

• must overcome hyperacute rejection: response to nonhuman antigens

What is Ummunosuppresion to prevent transplant rejection?

• Prevents a cell-mediated immune response to transplanted tissues

What do Cyclosporine and tacrolimus do?

suppress IL-2, disprupting cytotoxic T cells

What does Sirolimus do?

inhibits cellular and humoral immunity

What does Mycophenolate do?

inhibits the proliferation of T cells and B cells

What does Basiliximab do?

chimeric monoclonal antibody that blocks IL-2

How are cancer cells removed?

immune surveillance

What kind of antigens do Cancer cells have?

tumor-associated antigens that mark them as nonself

What do CTLs (activated T_c cell) and Macrophages do to cancer cells?

lyse them

What are the limitation to the immune system and cancer?

• no antigenic epitope for the immune system to target

• Tumor cells reproduce too rapidly

• Tumor becomes vascularized and invisible to the immune system

What do endotoxins do to cancer?

(corey’s toxins) stimulate TNF that interferes with the blood supply of cancers

What are vaccines used for prophylaxis?

cervical, anal, and throat cancer (HPV), liver cancer (hepatitis B)

What are monoclonal antibodies?

• Herceptin for breast cancer

• Immunotoxin combines a Mab with a toxic agent

  • Targets and kills a tumor without damage to healthy cells

What are immunodeficiencies?

absense of a sufficient immune response

What are congenital immunodeficiencies?

due to defective or missing genes

What are acquired immunodeficiencies?

develop during an individuals life

• due to drugs, cancers, or infections

What are acquired immunodeficiency syndrome?

virus causing the loss of immune function (HIV), selectively infects helper T cells

What is the structure of HIV?

Genus Lentivirus

• Retrovirus

• Two identical + stranded RNA genome molecules, reverse transcriptase enzyme, phospholipid envelope

• gp120 glycoprotein spikes

How is HIV spread?

dendric cells and carried to the lymphoid organs; contacts activated T cells

What does HIV do inside the cell?

viral RNA is transcribed into DNA using reverse transcriptase

What happens to DNA when HIV gets into the cell?

integrated into the host’s DNA

What is Active infection?

new viruses bud from the host cell

What is latent infection?

DNA is hidden in the chromosome as a provirus

• some become memory T cells that serve as the reservoir for HIV

What does the virus undergo inside the cell?

rapid antigenic changes and a high rate of mutation

What is HIV-1?

• related to viruses that infect chimpanzees and gorillas

• 99% of cases

• Group M (majority) accounts for 90%

What is HIV-2?

• not often encountered outside of west Africa

• Less pathogenic than HIV-1

• Longer asymptomatic period with lower viral load and morality rate than HIV-1

What is Phase 1 of HIV infeciton?

Asymptomatic or lymphadenopathy

What is phase 2 of HIV infection?

CD4+ T cells decline steadily; only a few infected cells release the virus; few serious disease symptoms (persistent infections, fever, and oral leukoplakia).

What is phase 3 of HIV infection?

AIDS develops; the CD4+ is count below 200 cells/μl; indicator conditions [healthy 500 to 1500 CD4+ T cells/μl]

What happens once the HIV establishes the pool of latenly infected CD4⁺ T cells?

it is impossible to clear the infection

What is the impact of age of survival with HIV infection?

Older adults and young children do not a have fully developed immune system, making them more susceptible

What is the Seroconverion?

Period of time between infection and the appearance of antibodies

How are HIV antibodies detected?

ELISA

How are viruses detected

Western blotting or APTIMA (RNA testing)

How are plasma viral load (PVL) determined?

by PCR or nucleic acid hybridization

How long does HIV survive outside the cell

6 horus

How long does HIV survive inside the cell?

1.5 days

What are the routes of transmission of HIV?

sexual contact, breast milk, transplacental infection of a fetus, blood-contaminated needles, organ transplant, artificial insemination, and blood transfusion

• anal intercourse is the worst

What are biomedical intervesiton on preventing HIV?

use of condoms, health services/HIV testing, needle programs

What are the behavioral intervention of preventing HIV?

sex education, safe infant feeding programs, counseling

What are structural interventions?

making changes in social, economic, political, and environmental factors to reduce vulnerability to HIV

What is highly active antiretroviral therapy (HAART)?

use of combinations of drugs to minimize survival of resistant strains.

What are fusion/entry inhibitors?

• Targets the gp41 region of the viral envelope that prevents fusion of the virus with the cell

• Enfuvirtide and maraviroc

What are reverse transcriptase inhibitors?

• nucleoside reverse transcriptase inhibitors (NRTIs)

  • Tenofovir and emtricitabrine

• Non-nucleoside reverse transcriptase inhibitors (NRTIs)

  • Efavirenz

What are Integrase inhibitors?

• inhibit HIV integrase that integrates cDNA into the host chromosome

  • Raltegravir, dolutegravir, elvitegravir

What are protease inhibitors

• inhibit proteases that cleave viral precursor proteins into structural and functional proteins

  • Atazanacvir, indinavir, and saquinavir

What are Tetherins?

Tether viruses to the cells, preventing their release and spread