Blood Types Organ Transplants and HIV Chapter 13

Blood Types, Organ Transplants, and HIV Chapter 13

Central Points (1) § Genetics plays a part in the development of the immune system § Immune system compatibility is an important consideration in organ transplantation § Human blood types are inherited § Problems with immune system can cause serious disorders.

Central Points (2) § Allergies are related to the immune system § Many people carry organ donor cards to make their wishes known

13. 1 What Does the Immune System Do? § Protects body from infection caused by bacteria, viruses, and other foreign invaders § Composed of chemicals and cells that attack and inactivate things that enter the body § First line of defense is the skin, blocks invaders § T cells and B cells: white blood cells, more specific forms of protection

Antigens (1) § Molecules are detected by immune system Trigger response usually involves several stages: 1. Detection of the antigen activates T 4 helper cell, which activate B cells 2. Activated B cells produce and secrete protein antibodies that bind to antigen 3. White blood cells attack bacteria marked by antibodies

Antigens (2) § May enter body via blood transfusion, cut, or transplanted organ § May be attached to disease-causing agent such as a virus, bacteria, or fungus § Activated B cells produce specific antibodies • Bind to an antigen • Mark it for destruction by other cells • Produce memory cells for rapid response on second exposure

Response to Infection

Animation: Immune responses

Vaccine § Memory cells basis of vaccination against infectious diseases § Contains an inactivated or weakened antigen from disease-causing agent § Does not cause an infection, stimulates immune system to produce antibodies and memory cells § Provides protection from disease

Several Gene Sets Control Immunity § Code for antibodies that attack antigens and antigens themselves Mutations can cause: § Diseases of immune system § Autoimmune disorders § Allergies

Animation: Immunologic memory

Animation: Inflammation

Animation: Understanding nonspecific defenses

13. 2 Transplantation of Organs or Tissues § Transplanted organ has different antigens, molecular identification tags § Coded by gene cluster, HLA complex § Haplotype: set of HLA alleles on each chromosome 6 § Many alleles, combinations nearly endless, difficult to find two people with same HLA haplotypes

HLA Complex on Chromosome 6

Successful Transplants § Successful organ transplants, skin grafts, and blood transfusions depend on matches between the HLA § Many allele combinations, rarely have a perfect HLA match, often takes long time to find § HLA markers of donor and recipient analyzed, if least a 75% match, usually successful

First Transplant from Twin Brother § Genetically identical

Organ Rejection (1) § Can occur because mismatch of cell surface antigens § Can test HLA haplotypes of potential donor and match with recipient § After surgery, recipient takes immunosuppressive drugs, reduces possibility of rejection

Organ Rejection (2) § Cells of recipient’s immune system attack and rapidly destroy the transplanted organ § Patient will need another organ or will die § Closely matching HLA haplotypes absolutely necessary to ensure successful transplants § 25% chance that sibling will match

Organ Waiting List § 74, 000 need kidney transplant § Only ~17, 000 kidney transplants performed/year § Hundreds on waiting list die each year before receiving transplant § Estimated several thousand lives saved/year if enough donor organs were available

Animal Transplants § Animal donors would increase supply of organs for transplants § Xenotransplants, attempted many times, with little success § Problems related to rejection currently prevent use of animal organs

Pig-Human Transplants (1) § Surface proteins (antigens) of pig cells trigger hyperacute rejection, an immediate and massive immune response § Destroys transplanted organ within hours § Research to create transgenic pigs with human antigens on their cells § Transplants from genetically engineered pigs to monkey successful

Pig-Human Transplants (2) § Even if hyperacute rejection can be suppressed, transplanted pig organs may cause other problems § Requires high levels of immunosuppressive drugs, with many side effects and may be toxic over lifelong use § Pig organs may carry viruses potentially dangerous to humans

Chimeric Immune System § Transplant bone marrow from a donor pig to human, make pig blood cells part of the human recipient’s immune system § Chimeric immune system: pig-human immune system § Recognize organ as “self” and still retain normal immunity to fight infectious diseases § Used in human-to-human heart transplants

Xenografts

13. 3 Blood Types § Also determined by antigens on cell’s surface § Humans > 30 different blood types § Defined by presence of specific antigens on surface of blood cells § Serve as markers that identify “self ” to immune system

Examples of Blood Types § ABO system, important in blood transfusions § Rh factor: plays role in hemolytic disease of newborns (HDN)

ABO Blood Types § Determined by gene I that encodes for cell surface proteins, or antigens § Three alleles: I A, I B, and I O § A, B, and O encode for A antigens, B antigens, or no antigen § Able to produce antibodies against antigens you do not carry

Summary of A, B, and O Blood Types

Inheritance of ABO § IOIO Blood type 0 § IAIA § IAIO Blood type A (O recessive to A) § IBIB § IB IO Blood type B (O recessive to B) § IAIB Blood type AB (A and B codominant)

Blood Types

Blood Transfusions § ABO antigens of donor and recipient must match § If mismatch, recipient’s immune system will make antibodies against antigens • Causes the blood cells from donor to clump § AB blood type: universal recipients § O blood type individuals: universal donors

Transfusion Reaction § Clumped blood cells block circulation § Reduce oxygen delivery, often fatal results § Clumped blood cells can break down, release large amounts of hemoglobin into blood § Hemoglobin forms deposits in kidneys, can cause kidney failure

Transfusion Reaction

Rh Factor § Rh blood group (discovered in rhesus monkey) has complex organization • Rh positive (Rh+) carries Rh antigen • Rh negative (Rh-) does not carry antigen § Rh+ allele dominant to Rh- allele § Rh positive blood type: Rh+Rh+ or Rh+Rh§ Rh negative blood type: Rh-Rh-

Rh Factor and Problems in Newborns (1) § During pregnancy or childbirth, small number of fetal cells may cross placenta, enter mother’s bloodstream § If mother is Rh- and fetus is Rh+, fetal cells placenta stimulate production of antibodies against Rh+ antigen § If first pregnancy, usually not harm either the fetus or mother

Rh Factor and Problems in Newborns (2) § During second Rh+ pregnancy, mother’s antibodies cross placenta and destroy the fetus’ red blood cells § Hemolytic disease of newborns § To prevent HDN, Rh- women given Rho. GAM (Rh+ antibodies) during pregnancy § Must be given before mother produces antibodies against Rh+ antigen

Animation: Rh and pregnancy

HDN

13. 4 HIV, AIDS, and Immune System § Acquired immunodeficiency syndrome (AIDS): a clinical disease § Develops after infected with human immunodeficiency virus (HIV) § HIV infects and kills T 4 helper cells § T 4 important for the onset of immune reaction and body’s ability to recognize foreign bacteria or viruses

T 4 Helper Cell Attacked by HIV (1) § T 4 recognizes antigen and activates production of antibodies by B cells § HIV, once inside cell, copies its genetic information and inserts it into a chromosome in infected cell § Viral genetic information can remain inactive for months or years

T 4 Helper Cell Attacked by HIV (2) § When infected, T 4 cell called upon to participate in an immune response • Viral genes become active • New viral particles formed in the cell • Bud off the surface, rupturing, and killing it § Over the course of an HIV infection: • Number of T 4 helper cells gradually decreases • Body loses its ability to fight infection

Photomicrograph of HIV RNA Drawing of HIV, showing its RNA genome and the proteins it carries. Protein Nucleus Viral DNA After HIV injects its RNA into the T cell, the RNA is copied into DNA which is then integrated into the T cell’s DNA. The viral DNA makes new viral RNA and proteins, creating new virus particles that bud off the surface of the infected cell. New virus particles Stepped Art p. 213

AIDS § Body loses its ability to fight infection § HIV infection disables immune system, AIDS causes death from infectious diseases § HIV transmitted through body fluids, including blood, semen, vaginal secretions, and breast milk § Not transmitted by food, water, or casual contact

Natural Resistance to HIV § Some individuals with high-risk behaviors, did not become infected with HIV § Homozygous for mutant allele of CC-CKR 5 gene, encodes a protein that signals infection present § HIV uses CC-CKR 5 to infect T 4 helper cells § Mutation has small deletion (32 base pairs), protein shorter, HIV cannot use this protein to infect

Frequency of CC-CKR 5 in Populations § Mutant allele present only in Europeans and those of European ancestry § Highest frequency in northern Europe, lowest frequency in Greece and Sardinia § In past, may have offered resistance to an unknown but deadly infectious disease § Carriers of mutant CC-CKR 5 allele lived to pass on gene to offspring

Drugs to Treat HIV § Current drugs prevent the virus from replicating once it is inside T 4 helper cells § Other drugs block HIV at other stages of its infection and reproduction cycle § Combinations of these drugs successful in slowing or stopping progress of HIV § Serious side effects, drug-resistant strains of HIV developed

AZT

Drugs to Prevent HIV from Entering Cell § Studying the way HIV enters cells leading to new generation of drugs § Prevent entry of virus into its target cells § Enfuvirtide: approved by FDA for clinical trials § Other drugs under development

Animation: Proteins - as described through HIV

Animation: HIV replication

13. 5 Allergies and Immune System § Allergies: immune system overreacts to antigens § Allergens: carried by dust, pollen, and certain foods and medicines § Serious food sensitivity: allergy to peanuts § Reactions to peanuts, bee stings, or others may cause anaphylactic shock

Anaphylactic Shock § Bronchial tubes constrict, restricting air flow in the lungs, making breathing difficult § Heart arrhythmias and cardiac shock can develop, death 1 -2 minutes § Treat with injectable epinephrine, counters molecular events in immune response § 80% of cases due to peanut allergies

Peanut Allergy

Peanut Allergies Increasing in U. S. (1) § 1988– 1994, 2 X as prevalent as 1980– 1984 § Why? Unclear, but environmental factors appear to play major role § Extremely rare in China, but Chinese immigrant children about same frequency of peanut allergies as native-born American children • Suggests involvement of environmental factors

Peanut Allergies Increasing in U. S. (2) § Peanuts now a major part of the diet in U. S. § Exposure of newborns and young children to peanuts more common, possibly breast milk § Immune system of newborns immature, exposure to some antigens may cause food allergies § More study needed, some recommend that pregnant and young children avoid nuts

13. 6 Legal and Ethical Issues Associated with Organ Donation § Siblings are best donors, but they cannot always consent, most require 18 years of age to consent § If declared incompetent, next of kin may give consent, extended to comatose or unconscious § Important to inform family of wish to donate § Laws make organ donation easier, organ donor stickers or cards, some considering assumed consent