Pathogen 4.2 Immunity Student Notes PDF

Objectives 1. Compare and contrast natural immunity and acquired immunity. 2. Inventory the main organs, cells and proteins that participate in the immune response. 3. Interpret the basic features of immunoglobulins and their reaction with antigen. 4. Debate the role of major histoco...

Objectives 1. Compare and contrast natural immunity and acquired immunity. 2. Inventory the main organs, cells and proteins that participate in the immune response. 3. Interpret the basic features of immunoglobulins and their reaction with antigen. 4. Debate the role of major histocompatibility complex (MHC) in antigen presentation. 5. Relate the genetic basis of the ABO and Rf system of blood type classification. 6. Illustrate the human leukocyte antigen (HLA) alleles as it pertains to autoimmune disease. 7. Relate the association between certain diseases and specific HLA alleles and haplotypes. 8. Inventory four mechanisms of hypersensitivity reactions. 9. Apply the principal of blood transfusion. 10. Distinguish the pathogenesis of autoimmune diseases. 11. Inventory four examples of systemic autoimmune disease and four examples of organ-specific autoimmune disease. 12. Debate the pathogenesis and molecular basis of SLE 13. Debate the pathogenesis and molecular basis of rheumatoid arthritis. 14. Apply the pathogenesis of acquired immunodeficiency syndrome (AIDS) and list its most important complications. 15. Differentiate the three forms of amyloid and relate them to clinical presentations of amyloidosis. 16. Debate the pathologic cause of transplant rejection Adaptive and Innate Immunity Innate vs. Adaptive (IO:1) Innate: Cell Types (IO:2) Neutrophils: Phagocytes + granules (enzymes that kill pathogens) Elastase, lactoferrin Macrophages: Phagocytes, APCs Dendritic Cells: Phagocytes, APCs NK cells: Phagocytes  Innate: Complement (IO:2) 1. Chemotaxis Recruitment of leukocytes 2. Opsonization Painting a target on microbe 3. MAC Attack complex – creating a giant pore Innate: Cytokines (IO:2) Summary functions Induce inflammation Induce Vasodilation TNF, IL-1 (systemic response to infxn, including fever) Damage Don’t remember all microbes this stuff! Innate (IO:2) PRR + PAMP Phagocytosis Phagocytes have pattern recognition receptor on their surface (PRR) 100 of these in our body’s cells – recognize 1000 pieces of pathogens Allow innate immune system to latch on to foreign invaders Connect to PAMPs (Pathogen associated molecular pattern) Pieces of pathogens that are recognizable and essential to pathogen’s life cycle and infectivity This is the same type of system that connects to DAMPs when a cell is damaged Remember they are triggered by Urea, alterations in ATP, DNA (in the cytosol), etc PRR + PAMP PRR is the receptor, PAMP is a ligand that exists on “bad” organisms Initiates phagocytosis and cytokine release  here comes leukocyte backup and vaso dilation/permeability, inflammation (you’re getting familiar with the story...) Innate (IO:2) Antigen presentation This accounts for how the adaptive immune system is introduced to the foreign invader After phagocytosis, the vacuole becomes a phagosome The pathogen gets digested inside of the phagosome Bits of the pathogen are placed on the APC cell surface These components of the digested microbe encounter B and T cells These cells induce further phagocytosis of the invader, as well as a more targeted response B and T cells will amplify the immune response; more on this later... But this involvement of B and T cells is what creates the bridge from innate to adaptive immune response Phagocytosis and the beginning of adaptive involvement Phagocytosis: 3 ways to grab a pathogen 1. PRR + PAMP, “attachment” 2. C3b receptor + C3b complement, “opsonization” 3. Antibody + FC receptor, “opsonization”  The presence of antibody is dependent upon B cells Which starts the involvement of adaptive response Traits of the adaptive immune system Generates specific chemical and cellular responses to destroy invading pathogens Is more effective than nonspecific defenses Has a memory component that allows for a rapid and specific response to subsequent exposures to specific pathogens Is mediated by lymphocytes Deficiencies in immune defenses and inappropriate activation both cause disease Adaptive Cell types Adaptive (IO:2) B cell Mature in the bone marrow Produces antibodies Controls antibody-mediated (humoral) immunity T cell Matures in the thymus Develop from naive → effector cells with the help of antigen presenting cell They can also fight on their own and be cytotoxic Controls cell-mediated (cellular) immunity T Cells: MHC (IO:4) Major histocompatibility complex Type I All cells translate MHC I and “self antigen”  Golgi  cell surface CD8 T-Cells go with MHC I CD8 T cells patrol the body’s tissues looking for the self antigen to be expressed in MHC I receptor checking for “ID” If cell encounters a CD8 T cell, it will need to present the “self antigen” The body cell will survive its encounter with a CD8 T cell, as long as the self antigen is present If the self antigen is missing, the cell will be destroyed by the CD8T cell – thus, CD8 is called a “cytotoxic T cell” The CD8 releases its cytokines that lead to apoptosis or it destroys the cell The main reasons for this to occur: cancer and viral infection, or a cell that is not our own, as in the case of transplant T-Cell Weapons How do cytotoxic cells “attack” Perforins – poke holes in membranes Fas ligand – activates apoptosis Cytokines - activate apoptosis T Cells: MHC (IO:4) Major histocompatibility complex Type II This protein only exists on phagocytic APCs This is where APCs present the bit of ingested pathogen on their surface The foreign antigen “sits” in the MHC II protein Here it can be recognized by a CD4 T cell This CD4 “helper T cell” will go on to activate B cells, causing them to proliferate B cell antibodies will further induce phagocytosis of the invading microbes This is our primary way of dealing with bacteria and fungi (Drawing  ) Receptors: Innate PAMP, & T cells MHC I, MHC II Term alert MHC = HLA (Major histocompatibility complex = human leukocyte antigen) HLA (IO:6, 7) (MHC = HLA) Gene complex responsible for coding MHC in human cells Located on chromosome 6 HLA genes are polymorphic and there are alternative forms or alleles. Inheritance of particular alleles can form harmful immunologic responses (HLA B27 causing JRA or ankylosing spondylitis just to name a few) Presence of HLA mutation can cause your body to attack healthy cells. Transition We’ve now covered the way in which adaptive immunity becomes involved in immune response We will now cover in more detail the details of adaptive immunity, how it evolved, and the function of its key machinery Immunoglobulin (IO:3) Immunoglobulin Y shaped proteins that can either be an antibody or a receptor Has an Fc portion (the stem) Fab portion (antigen binding tips of the Y) Has a variable portion Has a hyper variable region as well VDJ Antibody B-Cells and their antigens Binding Top portion of the Y is the “idiotype” Region Bottom portion of the Y, the stem, is called the “isotype” IgM, IgD, IgG, IgA, IgE As you learn about antibodies, pay attention to the evolution from IgM to the other antibody types Immunoglobulin (IO:3) B-Cell Antibody Isotypes IgM – always first, released as pentamer and it’s “weak” IgD – “this cell doesn’t work” IgG – comes second, released as a monomer and it’s “strong” IgA – mucosa IgE – mast cells How do these help you? Neutralization: antibodies coat the virus so it can’t get into the cell Opsonization: paint a target on the bacteria so it’s eaten Activation of complement: Opsonization, chemotaxis, MAC attack complex B Cell Maturation and Activation (IO:3) 1. B cells start in the bone marrow It’s a numbers game: (10^12) number of cells trying to make a receptor for every “possible” antigen Variation happens via DNA changes over the VDJ region (the variable end region) of the Ig Achieved through “somatic recombination” The DNA is “scrambling itself,” making as many combinations as possible, and some will match to foreign pathogens 2. The cell is then tested for self-tolerance As it makes its new IgM the body must make sure that the cells won’t attack you If it is tolerant to self, it is given IgD and allowed to leave the bone marrow 3. If it finds an antigen, it must be tested again to see if it’s “right” If approved by a T cell it can then proliferate B cell in the bone marrow  Leaves as a Mature Naive B cell  Activated B cell (Drawing) B Cell Maturation and Activation B Cell Specialization (IO:3) A mature naïve B cell receives an antigen It asks T cell for permission to react If no  silenced If yes  It releases begins to divide and releases IgM pentamer into plasma IgM response is fast and short-lived, and not that specific Then the cell’s antibodies undergo clonal expansion  affinity maturation through  somatic mutation  leads to hyper specific binding IgG is developed which is hyper specific, and it then gets stored in “memory cells” This is what will be used in a second wave! B-cell IgM  IgG  specialized cells Isotype switching occurs here B cells go from IgM to IgG Mature naïve B cells start with IgM on cell surface  activated plasma cell: IgM released as a pentamer Memory B cells have IgG on cell surface  Activated memory cell: IgG released as a monomer (Drawing) B Cell Specialization T and B Cell Recap B cells are genetically programmed to produce large quantities of unique antibodies: Helper T cells (CD4+) “Plasma cells” Stimulate proliferation of B cells Can also stimulate phagocytes Antibodies Cytotoxic “Killer” T cells (CD8+) Proteins produced by B cells that bind to specific foreign molecules (antigens) and Secrete enzymes to destroy inactivate them infected body cells - some circulate in blood and lymph; Directly attack viruses, bacteria, others remain attached to the surface of cancer cells, and transplanted B cells organs Antigens Memory T cells Molecules that initiate antibody Activate the immune response if production, carried or produced by the same antigen is reintroduced microbes Antibodies recap IgG Antibodies coat (opsonization) microbes for phagocytosis Actively transported across placenta to provide passive immunity until newborns immunity is mature IgM and IgG Represent the first and second waves of immune response IgA Secreted in mucosal tissue to bind microbes in GI and respiratory tracts IgE Asthma and allergies (They also coat helminthic parasites and functions with mast cells and eosinophils to kill them) Blood Typing Blood Types Are Determined by Cell-Surface Antigens (IO:5) Blood type Two blood groups are of major significance: the ABO system and the Rh blood group It is important to remember that the surface antigens that are absent lead to antibodies in the blood This is because self-tolerance was never developed for them  Blood Types (IO: 5, 9) Recipient AB A B O AB Donor A B O  Rh Factor and Pregnancy (IO:5) In some cases, mother-fetus incompatibility in the Rh system can cause maternal antibodies to destroy red blood cells of the fetus, resulting in hemolytic disease of the newborn Hemolytic disease of the newborn (HDN) A condition of immunological incompatibility between mother and fetus that occurs when the mother is Rh – and the fetus is Rh+ So, mamma doesn’t have Rh+ - express Rh D antigen on their blood cells the antigen, but baby Rh– - do not express Rh D antigen does! But, interestingly, there are no naturally occurring antibodies to Rh. So, mother will not have any antibodies until her immune system interacts with baby’s blood for the first time The Rh Factor and pregnancy (IO:5) The Rh Factor and pregnancy (IO:5) The Rh Factor and pregnancy (IO:5) Rh Factor and Pregnancy Hypersensitivity Hypersensitivity (IO:8) Type I Under normal circumstances this happens when CD4 cell encounters something too big for phagocytes to eat  helminth/parasites But can occur with an allergen B and T cells activated CD4 cell excretes: IL-4  IgE IL-5  activates mast cells IL-13  allergy sx (body trying to flush out parasite) On first exposure mast cells become coated with IgE On second exposure, the mast cells burst open (degranulate) and release lots of Histamine Your body also upregulates prostaglandins and leukotrienes and eosinophils THIS MUCH histamine causes vasodilation and bronchospasm i.e. anaphylaxis Give epinephrine!  Hypersensitivity (IO:8) Type II (cytotoxic) Antibodies develop against the self Dependent upon the FC portion of antibody The “stick” Ig attaches to self cell Opsonizes cell for phagocytosis Compliment further opsonizes cell, initiates MAC attack, draws leukocytes Examples Hemolytic anemia – immune destruction or RBC Thrombocytopenia – platelets targeted Type II (receptor) Ig lands on a receptor and either turns it off or turns it up Ig shuts off Ach receptors in neuromuscular junction in MG Ig activates TSH receptors in Graves disease Hypersensitivity (IO:8) Type III Immune deposition Circulating antigen is bound to antibodies that get stuck in small vessels Will occur in systemic disease Lupus FC portion initiates response Opsonization +/- complement This destroys good tissue Vasculitis, arthritis, kidney dz Hypersensitivity (IO:8) Type IV T cells activated and attack the body Can use their cytokines Can use perforins Autoimmune Disease Autoimmune Disease (IO:10) The immune system normally recognizes and Autoimmune tolerates self-antigens on body cells and destroys only Reactions what it perceives as non-self Cause the antigens Immune System to In autoimmune diseases, the Attack the immune system attacks self- antigens and kills cells and Body tissues of the body Examples of Autoimmune Diseases Systemic Diseases Systemic lupus erythematosus Rheumatic fever Rheumatoid arthritis Systemic sclerosis Polyarteritis nodosa Examples of Autoimmune Diseases System/organ-Specific Diseases CNS: Multiple sclerosis Thyroid: Hashimoto thyroiditis Blood: Autoimmune hemolytic anemia Kidney: Membranoproliferative glomerulonephritis Liver: Primary biliary cirrhosis Skin: Pemphigus vulgaris Peripheral Nervous/Muscle: Myasthenia gravis Rheumatoid Arthritis IO:13 Rheumatoid Arthritis Chronic, systemic, inflammatory, autoimmune disease that affects mainly the joints Proliferation of synovial membranes with destruction of articular cartilage and bone causes disabling arthritis Prevalence of 1% (3-5X more common in women) Any age, usually in second to fourth decades Genetic predisposition Proposed environmental trigger is activation of helper T cells by self-antigen or microbial antigen Type IV hypersensitivity Rheumatoid Arthritis Systemic Lupus Erythematous IO:12 Systemic Lupus Erythematosus  Systemic autoimmune disease caused by autoantibodies against self-antigens (mainly nuclear antigens) and formation of immune complexes  Fatigue, fever, malaise, nephritis, skin lesions, arthritis, but highly variable  More common in female and black populations  Can occur at any age, usually young adults over 30  Inherited susceptibility in Class II MHC and complement genes  Type III Hypersensitivity Systemic Lupus Erythematosus A chronic, inflammatory, connective tissue disease that can affect many organs AIDS IO:14  Acquired Immunodeficiency Syndrome (AIDS) A collection of disorders that develop as a result of infection by human immunodeficiency virus (HIV) HIV is a retrovirus that selectively infects and kills the helper T cells Transmission of blood or body fluids that contain HIV Sexual contact (75%) Parenteral inoculation – IV drug users, blood transfusions Vertical transmission: Infected mothers to newborns HIV Infection and Replication Progression of HIV Infection Acute phase Infection of memory T cells in mucosal lymphoid tissues High levels of virus production, viremia Signs of systemic infection Seroconversion: immune system responds and antibodies against HIV appear (1-6 months) Viremia abates and helper T cell numbers return to nearly normal Virus continues to replicate in CD4+ T cells and macrophages Progression of HIV Infection Chronic phase (clinical latency) Virus is continuing to replicate Immune system still largely intact Minor opportunistic infections Number of CD4+ cells begin to decline Greater numbers of surviving CD4+ cells are infected Immune defenses diminish May last 7-10 years  Pathologic Findings in AIDS AIDS (Acquired Immune Deficiency Syndrome) Catastrophic breakdown of immune defenses Marked increase in viremia CD4+ cell count reduced below 200 cells/L Even in the absence of AIDS-defining conditions, if patients have CD4+ cell counts below 200 cells/L, they are considered to have AIDS AIDS-defining conditions - Serious opportunistic infections - Secondary neoplasms - Neurologic manifestations Misc. Transplant rejection and Amyloid Rejection of Transplants (IO:16) Rejection of solid organ transplants is initiated mainly by host T cells that recognize the foreign HLA antigens of the graft, either directly (on APCs in the graft) or indirectly (after uptake and presentation by host APCs). Types and mechanisms of rejection of solid organ grafts are as follows: Hyperacute rejection: Preformed anti-donor antibodies bind to graft endothelium immediately after transplantation, leading to thrombosis, ischemic damage, and rapid graft failure. Acute cellular rejection: T cells destroy graft parenchyma (and vessels) by cytotoxicity and inflammatory reactions. Acute antibody-mediated (humoral) rejection: Antibodies damage graft vasculature. Chronic rejection: Dominated by arteriosclerosis, this type is caused by T cell activation and antibodies. The T cells may secrete cytokines that induce proliferation of vascular smooth muscle cells, and the antibodies cause endothelial injury. The vascular lesions and T cell reactions cause parenchymal fibrosis. Treatment of graft rejection relies on immunosuppressive drugs, which inhibit immune responses against the graft. Transplantation of hematopoietic stem cells (HSCs) requires careful matching of donor and recipient and is often complicated by graft-vs- host disease (GVHD) and immune deficiency. Amyloidosis (IO:15) Amyloidosis is a group of conditions in which extracellular deposits of fibrillar proteins are responsible for tissue damage and functional compromise Amyloid is defined based on the physical properties of the of the fibers: Abnormal folding of proteins Arranged in beta-pleated sheets Aggregate and deposit as fibrils in extracellular tissues Definitive diagnosis of amyloidosis is made only by demonstrating amyloid in tissue, which requires biopsy Amyloid Protein Primary Amyloidosis Usually of the AL type Caused by clonal proliferations of Clinical plasma cells Presentatio i.e. multiple myeloma n of Reactive Systemic Systemic Occurs secondary to an associated Amyloidosi inflammatory condition s Usually of the AA type i.e. chronic inflammation Other forms Hereditary Localized Thank you! Nussbaum, R. L., McInnes, R. R., Williard, H. F., Thompson, J. S., & Thompson, M. W. (2007). Genetics in medicine. Estados Unidos: Saunders. Robbins, S. L., Aster, J. C., Perkins, J. A., Abbas, A. K., & Kumar, V. (2018). Robbins basic pathology. Philadelphia: Elsevier.