Micro Lecture Notes: Chap 20

BIOL 2421 Microbiology Lecture Notes: Immunological Diseases
Chapter 20
Dr. Weis

Immune system and organ transplants :: to prevent reaction, blood type , cross match so that MHC antigens determined. Mediated by helper and cytotoxic T cells. T-Helper cells are involved in the initial reaction, while cytoxic T cells accelerate the reaction. Treatment involves immunosuppression with corticosteroids, radiation, azathioprine, and cyclosporine to inhibit lymphokine production and suppressed helper T cells.

Immune Disorders :

1. Immunodeficiency --> abnormal production or function of immune cells, phagocytes, or complement.

Can be congenital or acquired.

Congenital -->most genetic errors occur on the X chromosome

thymic aplasia (born without a thymus)

Chediak-Higashi syndrome (affects neutrophil granules)

Agammaglobunlinemia (no antibody production)

C2 deficiency (missing C2 compliment protein)

Bare Lymphocyte Syndrome (no MHC class II proteins)

Selective IgA deficiency (B cells do not make Ig A)

Acquired Immunodeficiency-->

1. AIDS.......interferes with helper T cells due to destruction by the HIV virus. This RNA virus can fit the CD4 receptor and invade the helper T cell and therefore will decrease cell mediated immunity. (will be discussed in greater detail in another chapter)

2. Immunosuppressive drugs

3. Radiation treatments

2. Autoimmune disease -->

When the individual's immune system ceases to tolerate self-antigens and mounts a response to that antigen to cause actual tissue destruction. Four factors influence the development of autoimmune disesase: Genetic, Environmental, Endocrine, and Psychoneuroimmunological [the influence of stress and neurochemicals on the immune system].

Usually occurs after a microbial infection, bacterial or viral and most often in older patients due to a loss of self-tolerance

Causes ::

* The tissue that is damaged will expose antigens deep within the tissues

* Microbe antigen resembles self antigen and there is a cross reaction

* Neuroendocrine imbalances ( occurs in females due to sex hormones)

* Genetic background, especially changes that occur in MHC regions.

The immune system will now target normal cells and creates auto-antibodies.

Other mechanisms can also occur ::

Sensitization of cytotoxic T cells caused by altered body proteins from antibody damage or tissue antigen change due to disease. Also can involve antigens not previously exposed to the immune system such as the self antigens of the thyroid gland, lens of the eye, and sperm. Cross reactions can occur if antibodies made for foreign antigen react with self antigens

Autoimmune disease Examples :: glomerulonephritis, rheumatic fever, Grave's disease, lupus erythematosus, myasthenia gravis, rheumatoid arthritis, MS, DM (juvenile)

Type I Autoimmunity

Antibodies that were made in response to an infectious agent such as a virus, but these antibodies attack self due to similarities between viral and self proteins. Example: Hepatitis C causing autoimmune hepatitis

Type II Autoimmunity

Antibody reactions to cell surface antigen, with no cytotoxic destruction
Examples: Grave's Disease : antibodies attach to thyroid gland cells at the TSH receptor site. MG: antibodies attach to ACH nicotinic recptors of skeletal muscles

Type III Autoimmunity

Immune complexes deposited in tissues, resulting in inflammation and destruction.
Examples: SLE - antibodies for the basement membrane and DNA of own cells. RA - IgM binds to IgG at Fc receptors and immune complexes are deposited in the joints with inflammation leading to the destruction of bone and cartilage

Type IV Autoimmunity

T cells and macrophages attack normal tissue
Examples: MS- myelin sheath of nerve attacked. Hashimoto's Thyroiditis - destruction of thyroid glands. Insulin dependant DM - destruction of beta cells of pancreatic islets

3. HYPERSENSITIVIES :: allergies. Hypersensitivity is an exaggerated immune response that results in tissue damage and is manifested in the individual on second or subsequent contact with an antigen. Reactions can be classified as immediate or delayed. The antigen is termed the allergen. Different types of hypersensitivies depending on the amount of time and the cells involved.

I. Type I Hypersensativities

immediate, occurs within 2-30 minutes. Most common type is ANAPHYLAXIS

Upon initial exposure to soluble allergen, B cells are stimulated to differentiate into plasma cells and produce specific IgE with the help of T cells. Once synthesized, IgE binds to Fc receptors on mast cells (basophils and eosinophils can also be activated) which then senstitizes these cells and leaves the two antigen binding sites free. When a second exposure occurs, the allergen cross links IgE antibody attached to mast cells or basophils and causes a degranulation and release of mediators such as histamine due to a change in cAMP levels. These inflammatory mediators increase capillary permeability, vasodilation and contraction of smooth muscle. Other mediators that maybe synthesized by the antigen triggered cell are: leukotrienes, heparin, prostaglandins, platelet activating factor, eosinophilic chemotaxic factor, proteolytic enzymes.

Local reactions in skin --> hives, urticaria

respiratory --> asthma, hayfever

gi--> vomiting/diarrhea (food allergy)

Systemic --> Anaphylactic shock, impairs smooth muscle of bronchioles and blood vessels which effect air exchange and blood pressure

Atopy --> allergies to environmental antigens due to genetic causes of large amounts of IgE

2. Subacute Hypersensitivity 1-3 hours ::

a. Type II Hypersensitivites --> AgAb reaction (Ig M, Ig G) as those seen in blood transfusion reactions (RBCs), platelets, drug reactions
Also called cytolytic or cytotoxic reactions because it results in the destruction of host cells. Stimulation of complement pathways with exposure of C-1 binding sites on IgG or IgM.

.Examples of Diseases: Hemolytic anemia, Thromobcytopenic purpura [drug related], MG, pemphigus, Grave's disease, Hemolytic disease of the Newborn

b. Type III Hypersensitivities --> AgAb (Ig G) immune complex that is not able to be removed by macrophages due to overaccumulation. Complement pathways activated and a variety of inflammatory processes are initiated and damage is caused, primarily in blood vessels [vasculitis], kidneys [glomerularnephritis], joints [arthritis] and skin.

Diseases resulting from Type III hypersentitivity reactions can be placed into three categories

Chronic Immune complex: persistant infection [viral, bacterial, protozoal] result in a weak antibody response and complex accumulates in host tissue
Prolonged Immune complex: autoimmune disease continues production of autoantibodies to self antigen and complexes are deposited in host tissue
Local Immune complex: immune complexes form at body surfaces [lungs] due to repeated exposure to allergen.
Examples of diseases: Systemic Lupus

3. Delayed Type IV Hypersensitivities

1-3 days, involves activated delayed hypersenitivity T cells (cytotoxic & helper)

examples of this hypersensitivity are contact dermatitis, poison ivy / oak, jewelry, cosmetics, herpes simplex, TB, leprosy, leishmaniasis, candidiasis, Type I DM, MS

Clinical usage involves TB (tuberculosis testing), coccidioidomycosis, leprosy, brucellosis, histoplasmosis

Specific MOA (mechanisms of action): Macrophages present antigen to dhTcells, which causes them to release cytokines. Cytokines then attrack more lymphocytes, macrophages, and basophils to the area. Specific actions of cells are as follows:

T-h1 -> MO --> TB

T-h2 -> Eosinophils --> chronic allergies, asthma

T-c DH cells ->contact dermatitis

Superantigens: are bacterial proteins that stimulate the immune system much more extensively than do normal antigens by interacting nonspecifically to T cell Class II MHC proteins as well as the beta chain of the TCR. Overstimulation of the cell mediated immunity cause symptoms due to the massive release of immune cytokines.
Examples of superantigens are:

Streptococcal scarlet fever toxins [serotypes A, B, C]
Staphylococcal toxic shock syndrome toxin-1
Staphylococcal enterotoxin serotypes A, B, C, D, E, and G
Streptococcal M protein
Streptococcal Group B, C, F, and G pyogenic toxins

Transplantation [Tissue] Rejection

Some transplants and grafts do not stimulate an immune response and rea therefore considered to be privileged sites. Examples: cornea, brain, heart valves, pregnancy, stem cells

Allografts: transplants between genetically different individuals within a species
Autograft: transplants taken from one part of the body and transplanted to another part of the body in the same individual
Isograft: transplants from one identical twin to another identical twin
Xenograft: transplants between different species

Tissue rejection: recipient cell recognize donor cell as foreign which triggers the recipient's immune mechanisms to destroy the donated tissue. Two mechanisms:

Foreign MHC Class II molecules on graft sitmulate host Th cells to aid Tc cells in graft destruction by recognizing changes in class I MHC regions
Th cells react to graft by releasing cytokines, which in turn stimulate macrophages to enter graft and destroy it

Graft vs.Host Disease

immunocompetent cells in graft recognize host cells and attack host. Seen in transplanted bone marrow because post thymic T cells are present in donated bone marrow.
Current use of umblical cord blood and placental blood due to stem cells

Drugs used to help prevent transplant rejection

Azathioprine and Cyclophosphamide => attack T cells
Cyclosporin => immunosuppressive
Corticosteroids => anti-inflammatory

Cancer

One cause is a failure of immunological surveillance or else due to immunosuppression by artificial or natural means.
A cell becomes cancerous when it undergoes transformation and begins to proliferated out of control
Surface of tumor is marked with tumor-associated antigens that mark them as non-self, but may not stimulate Tc cells
Tumors can also actively suppress the immune system if they produce factors that decrease the effectiveness of Tc or induce immune cells to undergo apoptosis
Tumors may also aggressively divide that they exceed the capacity of the immune system
Causes:

Mutations due to exposure to chemicals or radiation
Viruses
Genetic predisposition