Genetics of Immunity Sunne Woo and Naoko Charity Table of Contents 1. THE IMPORTANCE OF CELL SURFACES • Pathogens • Genetic Control of Immunity • Blood Groups • The Human Leukocyte Antigens(HLA) THE HUMAN IMMUNE SYSTEM • Physical Barriers And The Innate Immune Response • The Adaptive Immune Response ABNORMAL IMMUNITY • Inherited Immune Deficiencies • Acquired Immune Deficiency Syndrome (HIV) • Autoimmunity • Allergies ALTERING IMMUNE FUNCTION • Vaccines • Immunotherapy • Transplants A GENOMIC VIEW OF IMMUNITY- THE PATHOGENS PERSPECIVE • Crowd diseases • Bioweapons 2. 3. 4. 5. Introduction The Immune System is more than just cells attacking foreign bodies to prevent getting sick. The Immune System is a powerful tool that consists of about 2 trillion cells and biochemicals. Click here It’s attacking actions are highly coordinated And multipronged with both general and specific responses. Basic logic of the immune system = Recognize ―foreign‖ or ―non-self‖ surfaces. When the Immune system shuts down (death), the body starts decomposition. Overview of the Immune System Immune response and cell signaling by amino acid sequence (LTL): 1. 2. 3. 4. Diapedesis occurs. Cell membrane begins to surround its target Two calcium waves begin to circulate around the cell. When the target is completely surrounded, one wave splits in two, with the second wave encircling the phagosome (sac). This second wave allows the digestive enzymes to enter the phagosome and destroy the target. 5. Diapedesis The Importance of Cell Surface Pathogens Bacteria Non-membrane bonded prokaryotic cell treated by antibiotics Virus Single and Double stranded DNA or RNA. Reproduce by entering and using the host cell. Can not be treated by antibiotics Attacked by Immune system. Prions Infectious Proteins. Not recognized by the Immune System. Not treatable. (e.g.. Mad cow disease) Genetic Control of Immunity Genes oversee immunity by encoding Antibodies, Cytokins, and Antigen. Antibodies (protein) – respond to antigen Antigen (protein or carbohydrates molecule) -mark the cell surface as ―self‖ Cytokines (protein) - released by immune cells to act as intercellular mediators in an immune response. Mutation of gene = impair immune function •Immune deficiencies - Inherited or not inherited. Missing or defective Immune System (e.g. Severe Combined Immune Deficiency (boy-in-thebubble disease)). •Autoimmune disorders - Attack of own tissue. The genes contribute to the susceptibility for developing an autoimmune disease. Maybe triggered by outer factor (e.g. Systemic Lupus Erythematosus). •Allergies •Cancer Inheritance of abnormal genes X - linked recessive (sex chromosome. No disease are inherited through Y). Female (XX) = carrier or affected. Male (XY) = affected. Autosomal (non-sex chromosomes). Recessive = abnormal chromosomes from both parents are required to cause disease. Dominant = only one abnormal chromosome is required to cause disease. Blood Groups (ABO Group) I gene alleles encode enzymes to place antigens A, B, Both or Neither on red blood cells. Clumping-agglutination Blood Type A B AB A AB B A AB O No A/B Antigens AB RH factor (another blood group antigen) • RH+ produces RH-antibodies • RH- produces RH+ antibodies Antibody against A, B AB AB OK to donate to B A, B AB O, AB • ABO group is one of the major 26 Blood groups Human Leukocyte Antigens (HLA) Cell surfaces have proteins that are encoded by genes that are part of Chromosome 6, called Major Histocompatibility Complex (MHC). Class I & II genes encode Human Leukocyte Antigens (HLA). MHC 3 classes Class III genes encode proteins in blood plasma. Phagocytosis (eating of an invader) by Macrophage cell (HLA) 1. The Antigen attaches to MHC. 2. MHC proteins and Antigens are displayed on the macrophage surface. 3. Helper T cells recognize both and bind to the macrophage to initiate the immune events. Macrophage The Human Immune System The immune system consists of 2 defensive barriers that block pathogens. They are the innate barrier which is generally immediate to phagocytes, collectins, and cytokines. Inflammation is part of the innate immune response. This process engulfs and destroys certain pathogens around the injury. ―Inflammaton at the site of an injury can prevent infection‖ (Lewis, 2007). The adaptive immune response has to be stimulated into action. The immune response has 3 characteristics that are: diverse because it defeats many different types of pathogens. It is specific because it can distinguish the certain cells and molecules that are dangerous to cause diseases from the harmless ones. And it remembers so it can respond faster than the first time with a foreign antigen. • The humoral immune response is part of the Adaptive Immune Response. It is where the B-cells are stimulated and then divided into plasma and memory cells. The Humoral Immune Response– B-cells & Antibodies • Plasma cells secrete a bunch of antibodies of a single type. • Antibodies are of Y-shaped polypeptides, that consist of 2 heavy chains and 2 light chains. ―Each of these chains consists of a constant and a variable region, and the tips of the Y form and antigen binding site with a specific idiotype‖ (Lewis, 2007). The T-cells give cellular immune response because the cells travel to where they need to act. T-cells are unlike B-cells because they don’t secrete antibodies in the blood stream. The bone marrow lets the T-cells descend from each stem cell to travel to the thymus gland. In the picture below, it shows a death of a cancer cell… the cytotoxic T-cells binds to the cancer to inject perforin.* The cell then dies and leaves debris that microphages come to clear away. “T” in Tcells refer to the thymus!! *Perforin is a protein that punctures the cancer cell’s plasma membrane. Altering Immune Functions This sections contains different areas of possible cures to bacteria and viruses. They are vaccines, immunotherapy, and transplants. Vaccines are drugs that ―trick the immune system into acting early‖ (Lewis, 2007). Immunotherapy increases and redirects the immune response. This is done by monoclonal antibody technology (MAb), and cytokines that boost cellular immunity. Transplants are done after suppressing the immune system in order to accept the organs from another person, self, or animal. The Abnormal Immunity There are more than 20 types of inherited immune deficiencies. Possible causes • Abnormal Phagocyte cells • No thymus or natural killer cells • Deficiencies of T cells, B cells, and Neutrophils Neutrophils Thymus gland Acquired Immune Deficiency HIV enters Macrophages Aids Virus Encountering HIV virus Immune cells being attacked by HIV virus HIV sticks to the primary receptor "CD4 HIV sticks to a second receptor ”CCR5” CCR5 ensures HIV to dock at a helper T cell for infection to occur. CCR5 CD4 The lack of CCR5 receptor by gene defect prevents HIV infection. Quick replication + Fast mutation + Able to hide = No Cure Human Immunodeficiency Virus From RNA to DNA (Reverse transcriptase) Transcription of the viral DNA begins with the activation of lymphocyte, resulting in the multiple copies of viral RNA(codes) to produce new proteins and to be packaged later as new viruses. Enzyme"integrase" incorporates the viral DNA into the host cells DNA. The integrated DNA is called a provirus. HIV enzyme "reverse transcriptase" transcribes the sequence into a complementary DNA sequence. Viral RNA is translated into chain of proteins with polypeptide sequence (reverse transcriptase, protease, integrase). Later, Viral protease cuts the chain into its individual enzyme components to facilitate the production of new viruses. Finally, viral RNA and proteins are packaged and released from the lymphocyte surface with a membrane containing viral surface proteins. These proteins will bind to the receptors on other immune cells and infect other cells. Is there a cure for But, You can slow the disease by AIDS? combining drugs with different actions, “ NO ” such as inhibiting reverse transcritase, stopping the cutting action of viral proteins that assemble to make new viral particles, and blocking the virus’s ability to bind and fuse with the plasma membrane. HIV + since 1991 1. Inhibiting reverse transcritase (Recoding of RNA to DNA). 2. Stopping the cutting action Of Protease. I am on HAART or Highly Active Anti-Retroviral Therapy that targets multiple HIV life cycles. 3. Blocking the entry. New Therapy for the future: Structured treatment interruption (STI) = the practice of alternating time spent on antiretroviral drugs with time spent off drugs. Vaccines • • • Vaccines technology was first started in China back in the 11th century. Vaccines are a pathogen that stimulate the B-cells in the immune system to produce antibodies against the disease. Vaccines against several different illnesses can be combined into only one injection– so you don’t need more than one shot per vaccine!! • A popular vaccine was made for the smallpox disease. When people in China observed the recovery of smallpox, and that the person never had it again… people started crushing scabs into a powder to inhale or rub onto the blistered skin. Vaccines are still dispensed through injections, but with new technology, patients can use nasal sprays and eat genetically modified fruits and vegetables. • •To the left, a collection of pictures of smallpox. The black & white picture shows Edward Jenner, the creator of the smallpox vaccine. This boy was the last known victim of smallpox. The bottom-left pictures shows the vaccine in 1798. •The picture on the right show the difference between smallpox and chickenpox. When someone has smallpox, the blisters are more on the extremities– the feet, hands, and face. Chickenpox is prominent on the abdomen with a few blisters on the arms and legs. It is important for the vaccinations to be dispensed within the whole population because of ―herd immunity.‖ This is where the unvaccinated population is rare, and that the pathogens may resurface; when it does, the disease won’t spread because the people will have been exposed to it and be protected. But, when there are pockets of people that haven’t been vaccinated, and the diseases resurfaces… the pathogen will have its way and be spread throughout. MAbs The process was mentioned on the previous page. Today MAbs are used in research, veterinary health and human health care. It can also be used in agriculture, forestry, and the forensics fields. It can be used to diagnose everything spanning from strep throat to turf grass disease. MAbs can actually be used in home pregnancy tests also! It binds with the pregnancy hormone hCG on the paper strip of the home pregnancy applicator. You will know you are pregnant when the color changes from the MAb hits the target. Cytokines Boost Cellular Immunity Cytokines can be used to treat different conditions. These cells have short periods of activity. If they don’t go to where they are needed right away, then overdose or side effects can happen. They can kill cancer cells! Timeline of Transplantation 1899- the 1st allograft transplant, a kidney from dog to dog 1905- the 1st corneal allograft transplant, an eye from a boy to man 1906- the 1st kidney transplant in a human body fails 1954- success of the 1st isograft transplant… kidney from a monozygotic twin 1967- the 1st heart transplant leaves patient living for an extra 14 days 1984- a xenograft heart transplant from a baboon was transferred into ―Baby Fae‖ whom was born with ½ a heart. She lived for 20 days before her body rejected the xenograft. 1998- scientists start transplanting hands and forearms 2003- DNA gene expression microarrays are likely to tell doctors which patients will have rejection toward kidney transplants Future- using stem cells from patients, embryos, or animals may replace transplantation Baboons and Pigs can transplant different organs into the human body 4 Different types of transplants These are the different parts of the body that can have transplants done. Some of the most well known parts of the body that can be transplanted are the heart, cornea of the eye, kidney, liver, blood, bone marrow, and skin. Rejection Reactions– Or Acceptance In allograft transplants, the tissue in the recipients body can reject the newly transplanted part of the body. Xenograft transplants can cause hyperacute rejection. In hyperacute rejection, the blood vessels blacken and cut off the blood supply within minutes of the transplantation. In bone marrow transplants, the recipient can reject to the new bone marrow tissue. This can be deadly. According to Lewis, ―Graft versus Host Disease develops sometimes when bone marrow transplants are used to correct certain blood deficienceies and cancers‖ (2007). According to Merriam-Webster dictionary, ―the bodily condition results when cells from a tissue or organ transplant mount an immunological attack against the cells or tissues of the host .‖ Rejection Reactions – Or Acceptance cont. When the recipient is in need of a transplant, the doctors need to match the HLA as closely as they can. If this doesn’t happen, then the recipient will reject the donor’s tissue. But, if the HLA is matched too closely, there could be a chance that the disease will come back again because the same cell surfaces that it had earlier will be equally unable to fight the cancer. ―The donor bone marrow should be different enough to control the cancer, but no so different that rejection occors‖ (Lewis, 2007). Side effects of GVHD Bone Marrow Transplants Bone marrow transplants are for patients that have a deficiency of blood because the bone marrow doesn’t produces enough blood cells. These cells are the red and white blood cells, and platelets. Some examples of the diseases affected by the lack of the bone marrow working are: Leukemia, Anemia (along with some forms of anemia, for example– Aplastic Anemia), Hemophilia, etc. Allogenic transplants are only available to a minority of patients because 70% lack a suitablity of a sibling donor. Survival rates for transplantation is as high as 90% from a single experienced institution performing the procedure. For people who are not candidates, immunosuppression drugs are used. One of the most common immunosuppression drug is ATG (antithymocyte globulin), which consists of horse protein. But this can have toxic effects, this could lead to serum sickness after 11 days after treatment. Biopsy specimen of bone marrow. Magnetic resonance imaging scan of the spine shows uniform replacement of bone marrow with fat. Long-term bone marrow culture-initiating cell number as a surrogate of stem cell number. Horizontal bars indicate mean values. Bone Marrow Transplants cont. 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