04 04 06geneticsofimmunity

Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Human Genetics: concepts and applications

6th edition Ricki Lewis
Chapter 17
Genetics of Immunity
Immunity
Immune system protects organisms from foreign invaders. Transplanted tissue is recognized as foreign unless only shared cell surface molecules are present.
This father donated part of his liver for daughter with cystic fibrosis.
17-2
Foreign versus self

To protect the body from harmful organisms, the immune system identifies foreign molecules as nonself and destroys those cells.
Bacteria Yeast Viruses Tumor cells Transplanted cells
Molecules recognized by the immune system are called antigens. Antigens are usually protein fragments or carbohydrates. Immune response to ones own body is called autoimmunity.
17-3
Viral invaders Virus = ss or ds, RNA or DNA wrapped in protein coat

Must enter host cell & use host resources to reproduce
Viruses are simple, but can be deadly

Ebola virus has only 7 proteins SARS virus has only 9 proteins HIV and smallpox viruses are much more complex
Few drugs can treat viral infections

17-4
17-5
ABO blood group

ABO system discovered in 1910 by Karl Landsteiner The I gene encodes enzymes that attach cell surface molecules on the sugar chains of red blood cells. A allele attaches antigen A B allele attaches antigen B O allele no attachment performed Blood type incompatibility A person with type A blood who is transfused with type B blood will have antibodies that recognize and clump the red blood cells carrying type B.
17-6
ABO blood group
Type O is the universal donor. Type AB is the universal recipient.

17-7
Rh factor
Rh factor or rhesus factor is another blood group affecting cell surface molecules. Three genes affect this phenotype. Phenotypes: Rh+ Rh17-8
produces Rh antigen on RBC no Rh antigen on RBC
Rh incompatibility
Rh incompatibility occurs when an Rh- mother has an Rh+ child. First Rh incompatible pregnancy fetal cells are recognized as foreign. mothers immune system attacks fetal cells. mild reaction, few antibodies present. Second Rh incompatible pregnancy large response, plentiful antibodies destruction of fetal blood cells fetal heart, blood vessel and respiratory damage
17-9
Rh incompatibility
17-10
Major Histocompatibility Complex (MHC)

MHC 6 million bp cluster of 70 genes on HSA 6p
Class III MHC encode proteins in blood plasma Class I & II MHC encode HLA proteins
HLA proteins link sugars to form branched glycoproteins on cell surface of white blood cells. HLA glycoproteins can recognize bacterial and viral proteins, marking them for immune system to target = antigen processing. Antigen processing is first step in immune response.
17-11
Antigen Presenting Cells

Cells which bind antigens with HLA glycoproteins are called antigen presenting cells. Two types of antigen presenting cells are: Macrophages T-cells or T-Lymphocytes (type of white blood cell)
17-12
Antigen-presenting macrophage activates helper T cell
17-13
HLA diversity
Several genes with multiple alleles determine an HLA type. Genetic diversity at HLA genes is large.
Only 1 in 10,000 unrelated people will share an HLA type by chance at the six major HLA genes. Matching at least 4 major HLA genes is needed for most transplants to succeed.
HLA genes account for about 50% of the genetic impact on immunity.
17-14
HLA alleles are associated with diseases

Ankylosing spondylitis is a disease in which vertebrae are inflamed and deformed. The HLA allele B27 is associated with ankylosing spondylitis. Those with HLA-B27 are 100 times more likely to have this disease. 90% of cases have B27 allele versus 5% of general population. However, 10% of cases do NOT have B27. Not all with B27 allele get disease. => HLA-B27 is a significant factor but not the sole factor in ankylosing spondylitis.
17-15
Components of the immune system

Lymphatic system of ducts and nodes
delivers lymph to lymph nodes
Immune cell production/maturation by:

Spleen Thymus Bone marrow Skin Small intestine
Immune system cells

Lymphocytes (white blood cells)
B cells T cells
macrophages
17-16
Many cells types contribute to immune response
17-17
Types of immune cells

Cell type
Macrophage Mast cell B cell Helper T cell
Function
Presents antigens Performs phagocytosis Releases histamine in inflammation Releases allergy mediators Produces antibodies and memory cells Recognizes foreign antigens on macrophages Stimulates B cells to produce antibodies Secretes cytokines Activates cytotoxic T cells
Cytotoxic T cell Gamma-delta T cell

17-18
Attacks cancer and virally-infected cells Coordinates adaptive and innate immunity
Bacteria
Viruses Cytokines Macrophages Cilia Antimicrobial secretions
Innate immunity
Mucous membranes
Physical barriers
Adaptive immunity Cellular response
Macrophages present antigens
Humoral response
T cells
Cytokines
B cells Memory B cells
Cytotoxic T cells 17-19
Plasma cells
Antibodies
Levels of immune protection

Physical barriers Lymphocytes Macrophages Innate immunity Adaptive immunity
17-20
First line of defense: Physical barriers Unbroken skin Mucous membranes and secretions Infection-fighting chemicals in tears and saliva Flushing effect of tears, saliva, urination, and diarrhea
17-21
Second line of defense: Nonspecific, innate immunity

Nonspecific response to general pathogens Response time in minutes Phagocytosis (e.g. neutrophils & macrophages) Antimicrobial proteins
Complement system Collectins Cytokines
Interferon (IFN-gamma) Interleukins (IL12, IL8) tumor necrosis factor (TNF-alpha)
Inflammatory response Fever

17-22
Third line of defense: Specific, Adaptive Immunity

Requires stimulation highly specific & directed Response time in days. Major features: Diversity many different pathogens recognized Specificity distinguishes particular molecules Memory responds faster with subsequent exposure Primary immune response is reaction to first exposure. Secondary immune response is reaction to exposure using memory of first response.
17-23
Specific, Adaptive Immunity

Two types of response: Humoral immune response
B cells, antibodies, memory cells B cells produce antibodies in response to activation by T cells
Cellular immune response

T cells, cytokines, memory cells T cells produce cytokines & activate other cells
17-24
Humoral Immune Response

1. Antigen presenting macrophage activates a helper T cell. 2. Helper T cell activates a B cell with matching cell surface receptors. 3. B cells divide to produce plasma cells and memory cells. 4. Plasma cells secrete antibodies into blood that will recognize the antigen presented (primary) 5. Memory cells remain dormant until second exposure when they respond faster and more effectively (secondary)
17-25
Humoral immune response:

Antigens activate B cells directly and indirectly
17-26
Activated B cells produce antibodies and memory cells
Humoral immune response
17-27
Antibody structure
Antibodies minimally consist of four proteins connected by disulfide bonds in a Y shape
Two long proteins = heavy chains Two shorter proteins = light chains
Constant region of each protein is similar in all antibodies. Variable region of each protein is diverse. Antigen binding sites are pockets where antigen is held (at end of variable region) Idiotypes are sites in direct contact with antigen. The portion of the antigen contacting the antibody is called the epitope. Large antibody complexes may include 3-5 Y shaped basic antibody structures
17-28
The structure of antibodies
17-29
Function of Antibodies
When antibodies bind pathogen protein or toxin, protein function is inhibited. Pathogens bound with antibodies clump and macrophages identify them for destruction. Antibodies can activate the complement system boosting the innate immune response.
17-30 Humoral immune response
Types of antibodies or immunoglobins (Ig)

Type IgA IgD IgE Location Secreted fluids B cells in blood Secretions with IgA, mast cells Blood plasma and tissue fluid, passed to fetus Blood plasma Functions Protects points of entry Stimulates B cells to make other types of antibodies, in infants. Acts as receptor for antigens causing mast cell to secrete allergy mediators Protects against bacteria, viruses and toxins, especially in secondary response Fights bacteria in primary response; includes anti-A and anti-B antibodies of ABO blood groups
Humoral immune reponse
IgG
IgM
17-31
Diverse antibodies recognize multiple foreign antigens
17-32
Creation of antibody diversity

There are numerous but limited antibody genes in the human genome.
Due to different combinations of genes
During early development of B cells, sections of the antibody genes are rearranged along their chromosome Rearrangement of Ig genes creates new versions of the antibody proteins. By shuffling 200 genes, over 100 trillion different antibodies can be produced. A single stimulated B cell produces the same antibody combinations.
17-33
17-34
Cellular Immune response

T (thymus) cells can migrate in the body to site of infection.
Two major types of T cells Helper T cells express CD4 antigens Cytotoxic T cells express CD8 antigens
17-35
Maturation of T cells
To function effectively, T cells must recognize foreign antigens and not recognize self antigens.
Immature T cells, called thymocytes, travel to the thymus (from bone marrow) and display their cell surface receptors. The lining of the thymus displays self antigens. T cells which bind these self antigens are targeted to die by apoptosis. This process is called clonal deletion. T cells which do not bind the self antigens survive and mature. This process is called positive selection.
17-36
Role of helper T cells

In humoral immune response: Recognize antigens presented by macrophages Stimulate B cells to produce antibodies In cellular immune response: Secrete cytokines Activate cytotoxic T cell (killer T cell)
17-37
Types of cytokines
Colony stimulating factors stimulate lymphocyte production in bone marrow. Interferons block viral replication, stimulate macrophages to engulf bacteria, stimulate B cells to produce antibodies, attack cancer cells. Interleukins control lymphocyte development, cause fever with bacterial infection. Tumor necrosis factor stops tumor growth, releases growth factors, stimulates lymphocyte differentiation, dismantles bacterial toxins.
17-38
Cytotoxic T cells can destroy cancer cells
Join T cell surface receptors to bind antigen
17-39
Release perforin protein Cell transport is disrupted and cell which drills holes in dies membrane of attacked cell Cytotoxic T cells also attract body cells with viruses on the surface to destroy them prior to infection.
Coordinating immune response: gamma-delta T cells

Damaged epithelium activates gamma-delta T cells. Functions: Recognize molecules released by cells under stress Release growth factors to stimulate epithelial growth important for wound healing Produce chemicals for inflammatory response Secrete cytokines that coordinate the innate and adaptive immune response linking the two branches of the immune system
17-40
17-41
Quick review Lines of immune defense

Physical barriers Innate immunity Adaptive immunity
Cellular response (T cells, cytotoxic T cells) Humoral response (macrophages, helper T cells, B cells, plasma cells/antibodies, memory B cells)
17-42
When things go wrong: Abnormal Immunity
17-43
Inherited immune deficiencies Mutations in genes encoding proteins involved in immunity result in impaired immune response. 20 types of inherited immune deficiency Chronic granulomatous disease
mutation of oxidase enzyme results in neutrophils that cannot kill bacteria 4 polypeptide chains make up oxidase 4 genes, all X-linked
17-44
Inherited immune deficiencies
Severe Combined Immunodeficiency disease Loss of both antibody-mediated (humoral) and cellmediated (cellular) immune response
17-45
AIDS
(Acquired Immune Deficiency Syndrome)
Results from HIV (human immunodeficiency virus) infection. The term AIDS implies that the immune system impact of HIV infection has progressed to impairment of immune function.
17-46
Human Immunodeficiency Virus (HIV)

HIV enters the body with direct contact of bodily fluids (blood, saliva, semen). Virus infects macrophages and later helper T cells. Virus replicates and bursts out of the helper T cell, killing it. Loss of helper T cells prevents B cell activation. Infections occur because the immune system cannot respond.
17-47
Viruses
Viruses are DNA or RNA molecules enclosed in a protein coat called a capsid. Viruses enter a cell by binding to cell surface receptors. Viruses insert their DNA genome into the DNA of the host cells (RNA viruses make a DNA version of their genome first). Viruses use enzymes of the host cell to replicate their DNA.
17-48
17-49
Structure of HIV
HIV is an RNA virus (a retrovirus). The RNA molecule encodes a reverse transcriptase enzyme which synthesizes a DNA copy of the RNA virus. The virus is enclosed within a capsid within a coating of envelope protein studded with glycoproteins that can bind cell surface molecules on the host cell.
17-50
17-51
HIV envelope proteins gp41 and gp120 bind to CD4 and CCR5 coreceptors on the helper T cell.
Early HIV infection
1. HIV binds CD4 and CCR5 receptors of helper T cell 2. The capsid with the HIV RNA enters helper T cell. 3. Viral reverse transcriptase creates a DNA copy of the virus which integrates into the host genome. 4. Viral proteins are made from the viral DNA, new virus is produced and packaged for release. 5. Released HIV particles can infect new cells.
17-52
Late HIV infection
17-53
1. HIV mutates rapidly due to errors of reverse transcriptase (~ 1 in 5,000 bases). 2. HIV variants occur which can bind CXCR4 receptor in cytotoxic T cells, inducing apoptosis. 3. Lack of cytotoxic T cells severely impairs response to infections and cancer.
Treatment of HIV infection

Drug therapies have cut the mortality rate from AIDS in half since 1996. Two reverse transcriptase inhibitors and a protease inhibitor are commonly used. Reverse transcriptase inhibitors block conversion of the viral RNA into DNA. The protease inhibitor limits the processing of several viral proteins required for new particle formation.
17-54
HOWEVER.. HIV replicates quickly HIV changes quickly (mutation)

1/5,000 bases mutated due to sloppy RT No repair mechanism
HIV can hide (go dormant) so, it is easy for HIV to get the upper hand, despite recent advances in antiviral drugs
17-55
Resistance to AIDS?
Are some individuals less susceptible to AIDS than others? People at high risk for HIV infections (individuals with multiple partners or hemophilia) who are not infected more often have a CCR5 receptor gene with a 32-base deletion. This deletion truncates the protein and prevents localization to the cell surface. Long term nonprogressors are infected but healthy. Correlated with heterozygous carriers of CCR5 deletion. Correlated with milder inflammation response.
17-56
Autoimmunity
When the immune system attacks the tissues of an individuals own body it is called autoimmunity. Autoantibodies recognize self proteins. Some mechanisms include: Viruses use host proteins on the viral cell surface. These host proteins become the target of the immune system which responds as if they are viral proteins. Thymocytes which recognize self antigens survive instead of apoptosing. Nonself antigen may coincidentally resemble self antigens.
17-57
Autoimmune disorder
Glomerulonephritis
Target of Antibodies Symptoms

Lower back pain Kidney cell antigen that resembles Streptococcus antigen Thyroid gland antigen
Graves disease
Restlessness, weight loss, irritability, increased heart rate and blood pressure Muscle weakness Fatigue and weakness Joint pain and deformity Red rash on face, fever, weakness and kidney damage Thirst, hunger, weakness, emaciation Lower abdominal pain
Myasthenia gravis Pernicious anemia Rheumatoid arthritis Systemic lupus erythematosus Type I diabetes Ulcerative colitis
Nerve message receptors on skeletal muscle cells Binding site for vitamin B on cells lining stomach Cells lining joints DNA, neurons, blood cells Pancreatic beta cells Colon cells
17-58
Fetal cell persistence Fetal cells can persist in womans circulation even decades after delivery Fetal cells effectively hide Some event (unknown) triggers fetal cells to emerge & stimulate antibody production Explains higher prevalence of autoimmune disorders in women?
17-59
An autoimmune disease?
Scleroderma is thought to be an autoimmune disorder.
Fatigue, swollen joints, stiff fingers, hardening of skin, masklike appearance.
17-60
Allergy
Is an immune system response to a non-threatening foreign substance called an allergen. Size of allergens may determine type of allergic response: Larger particles (e.g. grass pollen) -> hay fever Smaller particles (e.g. cat dander, dust mites) -> asthma
Asthma is a chronic disease involving contraction of the respiratory airways, inflammation and mucus production in the lungs. Breathing becomes difficult during an asthma attack. Some asthma attacks are triggered by allergic reactions.
17-61
Allergic response
Humoral and cellular arms respond. IgE class antibodies are made and bind mast cells. Mast cells release allergy mediators like histamine and heparin that cause inflammation, runny eyes and nose, rashes and asthma. Allergens activate a class of helper T cells which release particular cytokines from genes clustered on HSA 5q. Severe allergic reaction throughout the body is called anaphylatic shock and can be life-threatening.
17-62
Allergic response: environment vs. heredity

Higher incidence of allergies in recent decades indicates environmental component
Do we live in a dirtier environment? Hygiene Hypothesis
Increase coincident with antibiotic use Highest prevalence of allergies in developed countries Are you germaphobic?
Also controlled by genetics

75% concordance in twin studies Isolated populations with inbreeding have high prevalence of certain allergies
17-63
Treatment of allergies
Corticosteroids enter nuclei of affected cells and suppress activity of cytokine and allergy mediator genes. Antihistamines block receptors on mast cells that bind IgE antibodies preventing the release of histamine. Antibodies produced in the laboratory bind IgE, blocking contact with mast cells. Sensitization is the gradual exposure to small amounts of allergens to prevent allergy attacks. Mechanism is unknown.
17-64
Altering Immune Function
17-65
Vaccination
A vaccine uses antigens from a pathogen to invoke immunity before an individual has been exposed to the pathogen. Antigens are chosen to be harmless alone. Ability to respond rapidly to subsequent exposure prevents infection to a degree that would cause disease. Vaccination has been performed from the 11th century China.
17-66
Vaccine type
Entire weakened (attenuated) pathogen Inactivated toxin Part of pathogen surface Recombinant vaccine (part of pathogen gene in harmless bacteria or yeast) Naked DNA from pathogen Plant based: potato Plant based: tomato
17-67
Disease prevented
Polio Tetanus Hepatitis B Lyme disease
Influenza, hepatitis B Travelers diarrhea Hepatitis B, rabies
Establishing immunity via digestion

Foreign antigens entering the digestive tract enter specialized cells called M cells. Dendritic cells capture and present antigens to T cells. T cells stimulate B cells to produce plasma cells making IgA antibodies. IgA antibodies coat the small intestine and protect against food-borne pathogens.
17-68
Immunotherapy
Medical treatment used to amplify or redirect the immune response.
Cytokines enhance cellular immunity. Production of cytokines has been developed for drug treatments. Monoclonal antibodies (MAb) are useful for detecting and targeting one particular antigen. Single B cells recognize a single antigen and make a single or monoclonal antibody.
17-69
Uses of monoclonal antibodies

Monoclonal antibodies (MAb) are useful for detecting and targeting one particular antigen. Home pregnancy test strips contain a monoclonal antibody. If urine contains hCG protein (present only during pregnancy), it binds the MAb and changes the color of the test strip. Herceptin is a monoclonal antibody-based drug used to target breast cancer cells by preventing them from receiving signal to divide.
17-70
Transplantation
when organs are moved from one individual to another. Types of transplantation are defined by the relationship between the donor and recipient: Autograft from one person to self Isograft from identical twin Allograft from member of same species Xenograft from another species
17-71
Graft rejection
The immune system reacts to grafted tissue recognized as foreign by trying to destroy it
positive correlation with amount of difference between donor & recipient cell surfaces
Hyperacute rejection reaction is a severe form of graft reaction in which the blood supply to the graft tissue is cut off. Graft versus host disease occurs in bone marrow transplants. The immune cells of the grafted bone marrow recognizes the host body as foreign and attacks it. The transplant rejects the host.
17-72
History of organ transplantation

1905 first successful human transplant (corneal) 1940s first successful kidney transplants on young people with end-stage kidney failure 1950s blood typing used to predict success of organ transplants 1960s first effective immunosuppressive drugs 1967 first human heart transplant (lives 18 days) 1970s most hospitals ban transplants 1980s improved immunosuppressive drugs, surgical techniques, & tissue matching lead to resurgence of interest
17-73
New horizons in organ transplantation

Modern technologies allow for various types of successful organ transplants to extend quality and duration of life.. However, there is currently a serious shortage of organ donors Xenotransplantation controversial & hopeful 1997 living liver removed from 15-week old pig & used to keep 19-year-old boy alive as he waited human liver transplant
Pig cells displayed human protein controlling the complementmediated hyperacute rejection reaction
17-74
Xenografts
pigs and baboons have been tissue and organ donors for human transplants
17-75
Xenotransplants & ethics Intentionally raising animals to use their organs as transplants requires killing donors Different from using tissues as food source? What are consequences of genetic modifications of tissues? Can latent viruses in organ donors cross species?
17-76

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Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Human Genetics: concepts and applications

Foreign versus self

Viral invaders Virus = ss or ds, RNA or DNA wrapped in protein coat

Viruses are simple, but can be deadly

Few drugs can treat viral infections

ABO blood group

ABO blood group

Type O is the universal donor. Type AB is the universal recipient.

produces Rh antigen on RBC no Rh antigen on RBC

Major Histocompatibility Complex (MHC)

Antigen Presenting Cells

Antigen-presenting macrophage activates helper T cell

HLA alleles are associated with diseases

Components of the immune system

Immune cell production/maturation by:

Immune system cells

Many cells types contribute to immune response

Types of immune cells

Cytotoxic T cell Gamma-delta T cell

Viruses Cytokines Macrophages Cilia Antimicrobial secretions

Adaptive immunity Cellular response

Macrophages present antigens

B cells Memory B cells

Cytotoxic T cells 17-19

Levels of immune protection

Second line of defense: Nonspecific, innate immunity

Inflammatory response Fever

Third line of defense: Specific, Adaptive Immunity

Specific, Adaptive Immunity

Cellular immune response

Humoral Immune Response

Humoral immune response:

Activated B cells produce antibodies and memory cells

Humoral immune response

The structure of antibodies

Humoral immune response

Types of antibodies or immunoglobins (Ig)

Humoral immune reponse

Diverse antibodies recognize multiple foreign antigens

Humoral immune reponse

Creation of antibody diversity

Humoral immune reponse

Cellular Immune response

Role of helper T cells

Cytotoxic T cells can destroy cancer cells

Join T cell surface receptors to bind antigen

Coordinating immune response: gamma-delta T cells

Quick review Lines of immune defense

When things go wrong: Abnormal Immunity

Inherited immune deficiencies

Human Immunodeficiency Virus (HIV)

Early HIV infection

Late HIV infection

Treatment of HIV infection

HOWEVER.. HIV replicates quickly HIV changes quickly (mutation)

Target of Antibodies Symptoms

Fatigue, swollen joints, stiff fingers, hardening of skin, masklike appearance.

Allergic response: environment vs. heredity

Also controlled by genetics

Altering Immune Function

Influenza, hepatitis B Travelers diarrhea Hepatitis B, rabies