Genetics, Altered Immune Response, Transplantation

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Genes

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basic units of heredity

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allele

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one of two or more alternative forms of a gene that occupy corresponding loci on homologous chromosomes

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dominant allele

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the allele that is fully expressed

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recessive allele

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the othe allele that lacks the ability to express in the presence of a dominant allele

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phenotype

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physical traits expressed by a person

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genotype

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the actual genetic makeup of the person

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chromosomes

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contained in the nucleus of the cell and occurs in pairs

23 pairs:
22 homologous/autosomes
sex chromosomes

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DNA

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stores genetic info and encodes instructions for synthesizing specific proteins needed to maintain life

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RNA

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rna lacks the base thymine and has uracil instead

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protein synthesis

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making of proteins, occurs in two steps:

transcription and translation

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transcription

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process by which mRNA is synthesized from single stranded DNA

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translation

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the mRNA becomes attaached to a ribosome, where translation occurs.

at this oint, transfer rna arranges the amino acids in the correct sequence to assemble the protein

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mitosis

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a type of cell division that results in the formation of genetically identical daughter cells that contain identical sets of chromosomes

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meiosis

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occurs only in sexual reproductive cells

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genetic disorders

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can be categorized into

autosomal dominant
autosomal recessive
sex-linked (x-linked)
recessive disorders

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autosomal dominant disorders

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caused by a mutation of a single gene pair (heterozygous) on a chromosome

a dominant allele prevails over a normal allele

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variable expression

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the symptoms expressed by the individuals with the utated gene vary from peson to person even though they have the same mutated gene

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autosomal recessive disorder

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caused by mutations of two gene paris (homozygous) on a chromosome

a peson who inherits one copy of the recessive cell does not develop the disease because the normal allele predominates (but such a person is a carrier)

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x-linked recessive disorders

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caused by a mutation on the X chromosome

usually only men are affected by the disorder vecause women who carry the mutated gene on one X chromososme have another X to compensate for the mutation

women who carry the mutated gene can transmit the mutated gene to their offspring

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multifactorial inherited conditions

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caused by combination of genetic and environmental factors

run in families but do not show the same inherited characteristis as the single-gene mutation conditions

include: DM, obesity, hypertension, cancer, CAD

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genetic testing

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any procedure done to analyze chromosomes, genes, or any gene product that can determine a mutation or a predisposition to a condition

include:
direct testing,linkage testing, biochemical testing and karyotpying

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linkage testing

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looks for gene markers that cause disease in family members from at least two generations

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Gene for breast cancer

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gentetic testing for BRCA-1 and 2 mutationss can be done in women believed to be at risk for breast cancer.

a genetic mutaion has been found in 5-10% of all breast cancer patients

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Gene testing and alzheimers

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many people who test postive for apolipprotien E-4 will never develop alzheimer's disease

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gene therapy

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an experimental technique that is used to replace or repair defective or missing genes with normal genes

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First approved gene therapy trials

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involved children with severe combined immunodeficiency disease caused by adenosine deaminase deficiency

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Methods of Gene Delivery

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Vector (carrier) is ued to deliver the gene

most common are attenuated or modified versions of viruses

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immunity

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a state of responsiveness to foreign substances such as microbes and tumor proteins

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immune responses - 3 functions

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defense
homeostasis
surveillance

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innate immunity

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exists in a person without prior contact with an antigen

involves a nonspecific response

neutrophils, and monocytes are primary WBCs

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Classification of immunity

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innate (natural) or acquired

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acquired immunity

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development of immunity, either activley or passively

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active acquired immunity

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results from the invasion of the body by foreign substances such as microbes and subsequent development of antibodies and senstized lyphocytes

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active natural immunity

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natural contact with antigen through clincal infection

recovery from chicken pox
measles, mumps

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active artificial immunity

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immunization with antigen

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passive acquired immunity

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implies that the host recieves the antibodies to an antigen rather than synthesizing them

the benefit is it's immediate effect but it is short lived

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passive natural immunity

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transplacental and colostrum transfer from mother to child

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passive artificial immunity

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injection of serum from immune human

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antigens

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a substance that elicits an immune response

most antigens are composed of protein

all of the body's cells have antigens on their surface that are unique to that person and enable the body to recognize itself.

the immune system becomes "tolerant" to the body's own molecules and therefore is nonresponsive to "self" antigens

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lyphoid organs

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central/primary and peripheral lymphoid organs

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central lympoid organs

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the thymus gland and bone marrow

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peripheral lympoid organs

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tonsils
gut, genital, bronchial, and skin-associated lymphoid tissues
lymph nodes
spleen

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Two important functions of the lymph nodes

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1) filtration of foreign material brought to the site

2) circulation of lymphocytes

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cells involved in the immune reponse

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mononuclear phagocytes
lymphocytes
dendric cells

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mononuclear phagocytte system

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includes monocytes in the blood and macrophages found thoughout the body

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lymphocytes

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produced in the bone marrow

differentiate into B and T lymphocytes

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B lymphocytes

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differentiate into plasma cells when activated

plasma cells produce antibodies (immunoglobulins)

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T lymphocytes

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migrate from the bone marrow to the thymus differentiate into T lymphocytes

compose 70-80% of the circulating lymphocytes and are primarily responsible for immunity to intracellular viruses, tumor cells and fungi

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T cytotoxic Cells

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CD8

involved in attacking antigens on the cell membrane of foreign pathogens and releaseing cytolytic substances that destroy the pathogen

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T helper cells

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CD4

involved in the regulation of cell-mediated immunity and the humoral antibody response

differentiate into subsets of cells that produce distinct types of cytokines

significant for those with HIV

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Natural Kille Cells

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do not requre prior sensitization for their generation

involved in recognition and killing of virus-infected cells, tumor cells, and transplanted grafts

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dentritic cells

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make up a system of cells that are important to the immune system, esp the cell-mediated response

found in many places in the body, including the skin, lining of the nose, lungs, stomach, and inttestine

in the immature state, found in the blood

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function of dentritic cells

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capture antigens at sites of contact with the external environement

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cytokines

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soluble factors secreted by WBCs and a variety of other cells in the body

act as messengers between the cell types

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humoral immunity

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antibody-mediated immunity

antibodies are produced by plasma cells (differentiated B cells) and found in plasma

production of antibodies is an essential component in a humoral immune response

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cell mediated immunity

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immune responses initiated though specific antigen recognition by T cells

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immunocompetence

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exists when the body's immune system can identify and inactivate or destroy foreign substances

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hypersensitivity reactions

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when the immune response is overreactive against foreign antigens or fails to maintain self-tolerance

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autoimmune diseases

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the diseases that occur as a result of immune responses against self-antigenss

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type 1: IgE-mediated reactions

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anaphylactic reations are type I reactions that occur only in susceptible persons who are highly sensitized to specific allergens

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Anaphylaxis

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can occur when mediators are released systemiclly

occurs within minute and can be life threatening

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atopic reactions

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an inherited tendency to beome sensitive to environmental allergens

ie allergic rhinitis, asthma, atopic dermatitis, uricaria and angioedema

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Type II: cytotoxic and cytolytic reations

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involve the direct binding of IgG or IgM antibodies to an antigen on the cell surface

cellular tissue destroyed in two ways

1) activation of the comlement cascade

2) enhanced phagocytosis

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Type II: oxytoxic and cytolytic reactions examples

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ABO incompatibility transfusion reaction

Rh incompatibility transfusion reaction

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Type III: immune-complex reaction

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may be local or sytemic and immiate or delayed

ie systemic lupus erythematosis (SLE)

acute glomerulonephritis

rheumatoid arthritis (RA)

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type IV: delayed hypersensitivity reactions

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cell-mediated immune response

ie contact dermatitis,
microbial hypersensitivity reactions

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contact dermatitis

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example of delayed hypersensitivity reaction involving the skin

occurs when the skin is exposed to substances that easily penetrate the skin to combine with epidermal proteins

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microbial hypersensitivity reactions

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classic example is tuberculosis

results from invasion of lung tissue by tubercle bacillus

organism itself doesn't damage the lung tissue. antigenic material released from the tubercle bacilli reacts with the T lymphocytes, initiating a cell-mediated immune response

the response causes extensive caseous necrosis of the lung

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Allergy assessment and family history

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including info about atopic reactions in relatives, is esp important in identifying at-risk patients

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Allergic disorders - assessment

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health history
physical exam

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Radioallergosorbent test
(RAST)

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an in vitro diagnostic test for IgE antibodies to specific allergens

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skin tests

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used to confirm specific sensitivity in pts with atopic disease

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skin tests - procedure

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two methodsL:

1) a cutaneous scratch or prick

2) an intracutaneous injection

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skin tests results

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if the perrson is hypersensitive to the allergen, a positive reactin will occur within minutes and may last 8-12 hours

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anaphylaxis

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occur suddenly in hypersensitive pts after exposure to the offending allergen

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anaphylaxis - management

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cardinal principles:

1) recognition of s/s
2) maintenance of patent airway
3) prevention of spread of the allergen by using a tourniquet
4) admin of drugs
5) treatment for shock

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anaphylaxis - management of mild symptoms

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such as pruritus and urticaria can be controlled by admin of 0.2 to 0.5 mL of epinephrine, diluted 1:1000

given subQ or IM every 10-15 min

IV infusion 0.5mL of epi diluted 1:10,000 at 5-10 min intervals

volume expanders and vasopressor agents such as dopamine (Intropin)

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anaphylaxis - management of more severe symptoms

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hypovolemic shock may occur

peripheral vasoconstriction and stimulation of the sympathetic nervous system occur to compensate for fluid shift

must be timely

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allergen recognition and control

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pt will never be desensitized or completely symptom free

preventative measures can help control the allergic symptoms

most important to identify the allergen

many allergic reactions can be aggravated by fatigue and emotional stress

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chronic allergies - drug therapy

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antihistamines
sympathomimetic/decongestants
corticosteroids
antip;ruritic drugs
mast cell stabilizing drugs
leukotriene receptor antagonists

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antihistamines

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the best drugs for treatment of allegic rhinitis and urticaria

less effective for severe allergic reactions

best results achieved if they are taken as soon as allergy s/s appear

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sympathomimetic/decongestants

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epinephrine (adrenalin)

drug of choice to treat an anaphylactic reaction

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corticosterioids

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nasal sprays are very effectivce in relieving symptoms of allergic rhinitis

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antipruritics

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topically applied are most effective when the skin is not broken

calamine lotion
coal tar solutions
camphor

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mast cell-stabilizing drugs

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cromolyn
nedocromil

inhibit the release of histamines, leukotrienes and other agents form the mast cell after antigen IgE interaction

available as inhalant or nasal spray

used for asthma and rhinitis

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leukotriene receptor antagonits (LTRAs)

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block leukotriene, one of the major mediators of the allergic inflammatory process

can be taken orally
for asthma and rhinitis

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immunotherapy

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recommended treatment for control of allergic symptoms when the allergen cannot be avoided and drug therapy is not effective

indicated only in individuals with anaphylactic reactions to insect venom

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immunotherapy mechanism of action

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immunotherapy involves injecting allergen extracts that will stimulate increased IgG levels

the binding of IgG to allergen-reactive sites interferes with allergen binding to mast cell-bount IgG,

goal is to keep blocking IgG high

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immunotherapy - administration

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subcutaneous injection of titrated amounts of allergen extracts weekly or biweekly

in most patients a decrease in symptoms is sustained after discontinuation but sometimes treatment is continued indefinitely

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immunotherapy - admin and nursing consideations

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admin allergen extract in an extremity away from a joint

use tourniquet
rotate sites
aspirate for blood

wait 20 minutes to potentiate response, but can occur up to 24 hours later

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latex allergies

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type IV contact dermatitis is caused by latex

delayed reaction 6-48 hours

dryness, pruritus, fissuring, cracking of the skin followed by
redness, swelling, crusting at 24-48 hours

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multiple chemicl sensitivities (MCS)

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an acquired disorder in which certain people exposed to various foods and chemicals in the environment have many symptoms related to multiple body systems

odor seems to be a principal trigger

symptoms occur at levels below the established guidelines of toxic levels

no established diagnostic

most effective treatment is to avoid trigger

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human leukocyte antigen (HLA)

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system consists of a series of linked genes that occur together on the 6th chromosome in humans

major histocompatibility complex

they are highly polymorphic

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principal factors of autoimmunity are:

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the inheritance of susceptibility genes, which may contribute to the failure of self-tolerance

initiation of autoreactivity by triggers, such as infections, which may activate self-reactive lymphocytes

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Systemic lupus erythematosus (SLE)

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systemic autoimmune disease

damage to muliple organs

most frequently in women 20-40

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immunodeficiency disorders involve an impairment of one ore more immune mechanisms, including

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1) phagocytosis
2) humoral response
3) cell-mediated response
4) complement
5) combined humoral and cell-mediated immunity

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primary immunodeficiency disorders

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1) phagocytic defects
2) b-cell deficiency
3) T-Cell deficiency
4) Combined B and T cell deficiency

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Causes of secondary immunodeficiency

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drug-induced (chemo, corticosteroids)
age (infants, older adults)
malnutrition
diseases/disorders
therapies (radiation, surgery, anesthesia)
stress (chronic stress, emotional trauma)

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Diseases/disorders that contribute to secondary immunodeficiency

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Aids
cirrhosis
chhronic kidney disease
DM
malignancies
SLE
burns
trauma
severe infection

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graft-versus-host (GVH) disease

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occurs when an immunoincompetent (immunodeficient) patient is transfused or transplanted with immunocompetent cells

may have an onset of 7-30 days

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organ transplantation

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histocompatibility studies to identify the HLAs for both donors and potential recipients

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transplant rejection

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occurs if the donor organ does not perfectly match the recipient's HLAs

can be prevented by closely matching ABO, Rh, and HLAs

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hyperacute rejection

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(antibody-mediated, humoral) occurs minutes to hours after transplantation

no treatment
organ is removed

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acute rejection

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most commonly occurs days or months after transplation

mediated by reciptient's T cytotoxic lymphocytes

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chronic rejection

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process that occurs over months or years and is irreversible

transplanted organ is infiltrated with large numbers of T and B cells characteristic of an ongoing, low-grade immune-mediate injury

no therapy for this rejection

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immunosuppressive therapy

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goal is to adequately suppress the immune resonse to prevent rejection of the transplanted organ while maintaining sufficient immunity to prevent overwhelming infection

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immunosuppressive therapy ADEs

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increased risk of infection

increased risk of malignancies

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calcineurin inhibitors (cyclosporine)

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MOA: acts on T helper cells to prvent production and release of IL-2 and y-interferon;
inhibits production of T cytoxic lymphocytes and B cells

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calcineurin inhibitors (cyclospoine) ADEs

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nephrotoxicity
increased risk for infection
hepatotoxicity
lymphoma
hypertension
tremors
hirsutism
leukopenia
gingival hyperplasia

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Sirolimus

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immunosuppressive agent for use in renal transplant recipients

in combo with corticosteroids and cyclosporine

also in combo with tacrolimus

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Mycophenolate Mofetil (Cell-Cept)

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a lymphocyte-specific inhibitor of purine synthesis with suppressive effects on both T and B lymphocytes

effects addicitive
decreases late graft loss

ADEs GI toxicities inc nausea, vomiting and diarrhea

lowering dose or giving smaller doses more frequently might help

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polyclonal antibody

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prepaired by immunizing horse with human T cells

polyclonal antibodies directed against T cells, thus depleting them

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polyclonal antibody ADes

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serum sickness
fever, chills, muscle pain
tachycardia
back pain
SOB
hypotension
anaphylaxis
leukopenia
thrombocytopenia
rash
increased risk for infection

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monoclonal antibodies

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used for preventing and treating acute rejection episodes