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Immune system - protects us against foreign material proteins, viruses, bacterial infections Immune system has two major divisions. Non-Specific Response - block entry of foreign agents into the body - block the spread of foreign agents if they get into the body
Specific Responses - antibody-mediated immunity - humoral response - cell-mediated immunity cellular response
1. Physical barriers - skin, mucous membranes and their secretions - infection fighting chemicals,in tears, saliva, other body fluids
2. Nonspecific - Innate defenses - phagocytosis - (engulfing cells) - inflammatory response - fever - anti-microbial proteins complement, collectins, cytokines
3. Specific response - Acquired Immunity - Humoral immune response - B cells, antibodies, memory cells - Cellular immune response - T cells, cytokines, memory cells
Bacteria
Innate response
Mucous membranes
Physical barriers
Macrophages
Macrophages present antigens
Humoral response
T cells
Cytokines
Cytotoxic T cells
Plasma cells
Antibodies
Histamine - dilates local blood vessels - increases capillary permeability Result is redness, heat and swelling
heat - unfavorable to microorganisms - mobilizes white blood cells (monocytes) - raises metabolic rate of surrounding cells
Complement - chemotaxsis agent - recruits in WBC to injury site The Inflammatory Response - starts with release of histamine and other chemicals - ends with WBC cleaning up the debris
Complement System
- chemical defense system that kills microorganisms - named the complement system because of the way it works together with the immune system - are a series of proteins, C1, C2 , etc
- C5-C9 - form a large multi-protein complex - MAC - membrane-attack complex MAC - inserts itself into the membrane of invading microorganisms - creates a pore - disrupts control of ion balance - cells burst
Specific, Adaptive Immunity - Acquired Response Invoked when the inflammatory response and complement systems fails - Requires stimulation. - Response time is in days. Major features: Diversity - many different pathogens recognized Specificity - distinguishes particular molecules Memory - responds faster with subsequent exposure
Antibodies
- antibodies are proteins that bind to antigens - antigens - a protein or other molecule that causes antibody production antibody generators - antibodies are produced by B cell
B-cells - type of lymphocyte - matures in the bone marrow - circulates in the blood and lymph system - encounters an antigen - makes a specific antibody - each B-cell produces only one antibody - clonal
B- cells are the lymphocytes that mediate the Humoral response (antibody-directed immunity).
T cell lymphocytes. - target and destroy infected body cells - develop in the bone marrow - differentiate into mature T cells in the Thymus gland - T cells move in the circulation and the lymphatic system - are responsible for the Cellular Response (cellmediated immunity).
Antigens activate B cells directly and indirectly HOWEVER - indirect is the major pathway.
Antibodies - several different classes - known as immunoglobulins, IgG, IgM, IgE, etc
Antibody structure
Antibodies minimally consist of four proteins 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. Idiotypes are sites in direct contact with antigen.
The portion of the antigen contacting the antibody is called the epitope.
Problem
- humans produce billions of different types of antibodies - Where are the genes?
Simplest antibody
2 H (heavy) and 2 L (light) chains
30,000 x 3600 = 108 million combinations - other processes generate more than 100 trillion
- a particular B cells produces only one antibody - as it divides - its daughter cells produce the same antibody - it is these mature daughter cells that are circulating
Cell-mediated immunity
- helper T cells - recruit and activate B cells to make antibodies - suppressor T cell - inhibit immune reaction - are off switches
- killer T cells - destroy infected body cells - cytotoxic T cells - a subset of killer T cells - memory T cells - T cells ready to respond to make other cells when antigen is reintroduced
Vaccines
- work by triggering a primary immune response - with development of secondary immunity - boosters - increase the number of memory cells present - vaccines present an antigen that is derived from, or is highly related to that of, potential bacterial and viral invaders
Blood types
- are determined by cell surface antigens
Blood type incompatibility A person with type A blood who is transfused with type B blood will have antibodies that recognize and destroy the red blood cells carrying type B.
Rh factor
Rh factor or rhesus factor is another blood group affecting cell surface molecules.
Phenotypes:
Rh+ Rh-
Rh incompatibility occurs when an Rh- mother has an Rh+ child. - hemolytic disease of the newborn - HDN - HDN occurs with the second pregnancy - preventable through screening and anti-Rh+ therapy
Organ transplants
- need to match histocompatibility antigens between donor and recipient -only 1 in 10,000 unrelated people will share a HLA type by chance at the six major HLA genes. (twins 100%, siblings 25%) - 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.
HLA gene complex - consists of several gene clusters - class I HLA-A, HLA-B, HLA-C - class II HLA-SR, HLA-DQ, HLA-DP - each gene in each class has multiple alleles - haplotype - this is a set of alleles at a specific location - each of us has an specific array of HLA alleles on a given copy of chromosome 6 - since we have two copies of chromosome 6 - each have two HLA haplotypes - population has millions of haplotypes (allele combinations)
therapeutic cloning
Xenografts
- Those with HLA-B27 are 100 times more likely to have this disease. - 90% of those afflicted carry HLA-B27 (versus 5% of general pop) - maybe triggered by a bacterial infection Klebsiella 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.
Autoimmune Diseases
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.
Autoimmune disorder
Glomerulonephritis
Target of Antibodies
Symptoms
Lower back pain Kidney cell antigen that resembles Streptococcus antigen
Graves disease
Restlessness, weight loss, irritability, Thyroid gland antigen increased heart rate and blood pressure
Muscle weakness Nerve message receptors on skeletal muscle cells
Myasthenia gravis
Pernicious anemia
Rheumatoid arthritis Systemic lupus erythematosus Type I diabetes Ulcerative colitis
Chronic granulomatous disease: mutation of oxidase enzyme results in neutrophils that cannot kill bacteria.
Severe combined immune deficiency (SCID) impacts both humoral and cellular immunity due to lack of mature B cells and/or T cells.
X-linked agammaglobulinemia (XLA) - usually boys - characterized by having multiple serious bacterial infection during childhood (20 or more in 5 years). - have normal T cells - patients dont have any mature B cell - can't make antibodies - protected for the first 6 months by maternal antibodies
AIDS Acquired immunodeficiency syndrome - collection of disorders that develop as a result of infection with HIV - HIV , human immunodeficiency virus (retrovirus). - virus infects macrophages and T4 helper cell Problem - T cell activation also activates viral replication - with time, the helper T cells are killed off - eventually loose ability to activate the antibody-mediated immune response result - increased susceptibility to infection and certain forms of cancer - early death
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.
HIV envelope proteins gp41 and gp120 bind to CD4 and CCR5 receptors on the helper T cell.
Final note on AIDS: its not that the immune system cant fight the HIV infection, it just cant keep up - early HIV infections - produce 2 billion new B and T cell per day - virus does two things - produces millions to billions of new virus per day - it mutates very rapidly - antibodies useful today no effect tomorrow
The protease inhibitor limits the processing of several viral proteins required for new particle formation.
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.
Asthma
- 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.
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 cytokines. Severe allergic reaction throughout the body is called anaphylatic shock and can be life-threatening.