Chapter 19 - Diseases of the Immune System

Hygiene hypothesis

The proposition that increasing allergies among children are the result of decreased exposure to microbes, such as those found in dirt.

Dysbiosis

Disturbed homeostasis or imbalance of the microbiota composition

Hypersensitivity

an exaggerated response by the immune system to a particular substance

Allergen

An antigenic substance that produces an allergic reaction in an individual

Immunopathology

The study of disease states associated with overreactivity or underreactivity of the immune response

Type I (Anaphylactic) Hypersensitivity

Antigens combine with IgE; IgE attaches to mast cells and basophils and triggers degranulation

Degranulation

The emptying of granules from the interior of a mast cell or granulocyte into the extracellular environment.

Histamine

Chemical stored in mast cells and basophils that triggers dilation and increased permeability of capillaries.

Leukotrienes

Chemical substances that contribute to anaphylaxis by causing prolonged contraction of smooth muscles, particularly in the lungs

Prostaglandins

Chemical signal that causes smooth muscle contraction and increases mucus secretion, especially in the lungs

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, oxygen, IV antihistamines, albuterol

Localized anaphylaxis

Usually associated with ingested or inhaled antigens

Symptoms depend on the route of entry

Hives, hay fever, and asthma

Wheals

Itchy red, raised rash, consistent with allergic reactions

Rapid inflammatory reaction (wheal) test

Procedure in which allergy-causing substances are placed on the skin and a reaction is noted

Desensitization

increasing dosages of antigen injected beneath the skin

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

Type II (Cytotoxic) Hypersensitivity

Antigen is present on cell membrane

May be normal body component or exogenous

IgG or IgM reacts with antigen

Destruction by phagocytosis or cytolytic enzymes

Example: Response to incompatible blood transfusion

ABO blood group system

A system used to classify human blood by proteins found on the surface of red blood cells; antibodies form against certain carbohydrate antigens on RBCs

A blood type

A antigens are present on the surface of RBCs; serum contains anti-B antibodies

B blood type

B antigens are present on the surface of RBCs; serum contains anti-A antibodies

AB blood type

A and B antigens are present on the surface of RBCs; serum contains neither anti-A nor anti-B antibodies; universal recipient

O blood type

Neither A nor B antigens present on the surface of RBCs; anti-A and anti-B antibodies in serum; universal donor

Rh blood group

Category of blood type related to an Rh factor

Rh+

Has the Rh antigen on the surface of RBCs (~85% of population)

Rh-

Does not have the Rh antigen on the surface of RBCs

anti-Rh antibodies

-Only in Rh- individuals; form after exposure to Rh+ blood

*First exposure does not cause a serious response*

*Subsequent exposures can be serious*

Hemolytic disease of the newborn

Rh incompatibility of maternal and fetal blood when the mother is Rh- and the fetus is Rh+; fetal and maternal blood do not usually mix; however, maternal antibodies can potentially cross the placenta, or blood can mix during delivery of first pregnancy with an Rh+ fetus; anti-Rh antibodies cross placenta during second pregnancy with an Rh+ fetus, damaging fetal RBCs

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 RBCs

Type III (immune complex) hypersensitivity

Type of hypersensitivity in which antigen-antibody complexes are deposited in tissues

Arthus reaction

Rare side-effect of toxoid vaccines; complement activation in a patient with already circulating IgG antibodies to an injected antigen leads to acute local inflammation, edema, and sometimes necrosis.

Serum sickness

Swelling and inflammation due to injection with foreign serum

Type IV (delayed cell-mediated) hypersensitivity

Cell mediated reaction in which the signs appear 12-72 hours after exposure; APCs in lymph nodes display antigens to helper T cells and these T cells secrete cytokines that activate CTLs and macrophages

Allergic contact dermatitis

Haptens combine with proteins in the skin, producing an immune response

Allergic response to poison ivy, cosmetics, metals, and latex

Autoimmune disease

A condition in which the immune system mistakenly attacks itself, targeting the cells, tissues, and organs of a person's own body

Autoimmunity

Loss of immune tolerance through the survival of "forbidden clones"

Forbidden clones

The immune system of a fetus develops tolerating by eradicating all self-reacting lymphocytes; some of these forbidden clones may survive and B or T cells can inappropriately attack tissues with self antigens

Cytotoxic Autoimmune Reactions

Antibodies (IgG, IgM) react with cell surface antigens and induce lysis via complement

Multiple sclerosis

Multiple sclerosis

Autoimmune disorder that attacks the proteins in the myelin sheath causing a disruption in nerve impuls transduction resulting in person being unable to control muscle movement.

Immune complex autoimmune reactions

Immune complexes of antibodies, self-antigens, and complement deposit in tissues; graves' disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis

Graves' disease

Abnormal antibodies in the thyroid mimic thyroid-stimulating hormone (TSH) and cause the thyroid to produce excessive amounts of hormones

Myasthenia gravis

Antibodies coat acetylcholine receptors; muscles fail to receive nerve signals

Systemic lupus erythematosus

Immune complexes form in the kidney glomeruli; can result in chronic inflammatory disease of collagen in skin, joints, and internal organs

Rheumatoid arthritis

A chronic autoimmune disorder in which immune complexes form in the joints

Cell-Mediated Autoimmune Reactions

Autoimmune disorder mediated by T cells that attack tissues; insulin-dependent diabetes mellitus, psoriasis, psoriatic arthritis

Insulin-dependent diabetes mellitus

T cell destruction of insulin-secreting cells

Psoriasis and psoriatic arthritis

Autoimmune disorders of the skin

Histocompatibility antigens

Self antigens on cell surfaces

Major Histocompatibility Complex (MHC)

A family of genes that encode a large set of cell surface proteins that are self antigens

Human Leukocyte Antigen (HLA)

Molecules found on all nucleated cells in the body that help the immune system to recognize whether or not a cell is foreign to the body; used to determine the compatibility of tissues and organs for transplantation from one individual to another

HLA Typing

A process used to identify and compare HLA; involves standardized antisera or monoclonal antibodies for specific HLAs

Privileged sites

Sites of transplantation that do not reject allografts; cornea, heart valves

Privileged tissue

Tissue that does not stimulate an immune rejection

Stem cells

Master cells in the body that can generate specialized cells

Embryonic stem cells

An undifferentiated cell, taken from an embryo that has potential to give rise to various other cell or tissue types

Adult stem cells

stem cells that are found in adults that can differentiate and form a limited number of cells

Induced pluripotent stem cells

A pluripotent stem cell that was generated by manipulation of a differentiated somatic cell

Hematopoietic stem cell transplantation

Bone marrow transplant

Graft-versus-host disease (GVHD)

Complication that occurs following a stem cell or bone marrow transplant in which the transplant produces antibodies against recipient's organs that can be severe enough to cause death

Autograft

Transplantation of healthy tissue from one site to another site in the same individual

Isograft

Transplant between identical twins

Allograft

Transplantation of healthy tissue from one person to another person

Xenograft

transplantation from a foreign donor (usually a pig) transferred to a human; also called xenotransplantation product

Hyperacute rejection

Response to nonhuman antigens that occurs immediately after transplantation with a xenograft

Immunosuppression

Prevents a cell-mediated immune response to transplanted tissues

Cyclosporine and Tacrolimus

Immunosuppressants that suppress IL-2, disrupting cytotoxic T cells

Mycophenolate

Immunosuppressant that inhibits proliferation of lymphocytes

Sirolimus

Immunosuppressant that inhibits cellular and humoral immunity

Basiliximab

Immunosuppressant monoclonal antibody that blocks IL-2

Immune surveillance

The body's immune response to cancer.

Tumor-associated antigens

Cancer cells may display altered cell surface antigens as a result of malignant transformation. Immune surveillance is the response of the immune system to these antigens.

Limitations of immune surveillance

-no antigenic epitope for the immune system to target

-tumor cells reproduce too rapidly

-tumor becomes vascularized and invisible to the immune system

Immunotherapy for cancer

Bacterial endotoxins stimulate TNF that interferes with blood supply of cancers

Vaccines prophylaxis: cervical, anal, and throat cancer (HPV vaccine); liver cancer (hepatitis B)

Monoclonal antibodies: Herceptin for breast cancer; Immunotoxin: Mab combined with toxic agent to target and kill tumor without damage to healthy cells

Congenital immunodeficiencies

Immunodeficiency due to defective or missing genes

Acquired immunodeficiencies

Immunodeficiencies that develop during an individual's life due to drugs, cancers, and infections

Origin of HIV/AIDS

SIV crossed over into the human population in west and central Africa from chimpanzees (around 1908, from bushmeat)

Spread throughout Africa as a result of urbanization and increased sexual contact

Patient who died in 1959 in the Congo is the oldest known case

Norwegian sailor who died in 1976 is the first known case in Western world

HIV structure

ss + stranded RNA retrovirus in genus Lentivirus; two identical + strand RNA molecules, integrase, and reverse transcriptase in capsid; enveloped with gp-120 and gp-41 glycoprotein spike

GP120

Protein on the HIV viral envelope that attaches to the CD4 cell

GP41

Transmembrane glycoprotein on HIV envelope that promotes fusion of the viral envelope to target cell

HIV receptors and co-receptors

CD4 receptor - Helper T cells, macrophages, dendritic cells

CCR5 or CXCR co-receptors

HIV integration

After entry into cell, RNA genome is reverse transcribed into cDNA; viral integrase enzyme integrates the HIV cDNA into the host cell genome

Active HIV Infection in CD4+ T Cells

The provirus is activated, allowing it to control the

synthesis of new viruses in the cytoplasm. Final assembly takes place at the cell membrane, taking up the viral envelope proteins as the virus buds from the cell

Active HIV infection in macrophages

New viruses are produced from provirus. Completed virions are either released or persist in the macrophage within vacuoles.

Latent HIV infection

Viral DNA is integrated into cellular DNA as a provirus that can later be activated to produce infective viruses; some memory T cells can become a reservoir for HIV

HIV-1

Related to viruses that infect chimpanzees and gorillas; Most prevalent and pathogenic type of HIV virus

HIV-2

Not often encountered outside of Africa; Less pathogenic than HIV-1; lower viral load and mortality rate relative to HIV-1

Group M HIV

The cause of more than 90% of global HIV infections

Phase 1 of HIV infection

Asymptomatic or chronic lymphadenopathy caused by HIV infection of many CD4+ T cells; highest level of HIV in blood prior to seroconversion

Seroconversion

A change in serologic tests from negative to positive as antibodies develop in reaction to an infection or vaccine

Seroconversion of HIV

When HIV-specific antibodies develop; 3 weeks to 6 months after initial infection

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)

Phase 3 of HIV infection

AIDS develops; the CD4+ is count below 200 cells/μl; indicator conditions

Variations in response to HIV

Older adults and younger children with less developed immune system are more susceptible; CCR5 mutation can inhibit infection; Long-term survivors have low viral load and effective CTLs

HIV diagnostic tests

HIV antibodies detected by ELISA; viruses detected by Western blotting or RNA testing (APTIMA)

Plasma viral load (PVL)

Amount of virus in blood plasma; determined by PCR or nucleic acid hybridization

HIV transmission routes

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

AIDS worldwise

36 million infected (70% in Africa); heterosexual intercourse most common mode of transmission; injected drugs are common mode of transmission in Eastern Europe and Central and Southeast Asia

Biomedical interventions for HIV

Condoms; health services/HIV testing; needle programs

Behavioral interventions for HIV

Sex education; safe infant feeding programs; counseling

Structural interventions for HIV

Changes in social, economic, political, and environmental factors to reduce vulnerability to H I V