PDN23_PP_Lec_07_-_Mechanisms_of_self-defense_(Final_version).pdf

Immune Response and related disorders PDN23 Pathophysiology and Pharmacology  Intended Learning Outcomes Upon completion of the lecture, students would be able to: differentiate the innate and adaptive immunity describe the inflammatory response describe the five classes...

Immune Response and related disorders PDN23 Pathophysiology and Pharmacology  Intended Learning Outcomes Upon completion of the lecture, students would be able to: differentiate the innate and adaptive immunity describe the inflammatory response describe the five classes of immunoglobulins compare the passive and active immunity state the humoral and cellular mediated immunity explain the immune response to allergen by the mechanisms of hypersensitivity identify the primary and secondary immunodeficiency describe the mechanisms and manifestations of Systemic Lupus Erythematosus (SLE) and Acquired immune deficiency syndrome (AIDS) 2  Introduction The human body is exposed to different conditions that result in damage (e.g. sunlight, pollutants, agents that cause physical trauma, infectious agents include viruses, bacteria, fungi and parasites) Damage maybe at the level of a single cell which can be repaired easily Damage maybe at the level of multiple cells, tissues or organs result in disease and death 3 Human Defense Mechanisms Human defense mechanisms include two types of immunity to protect our body: Innate immunity Includes 2 lines of defense: Innate barriers (the first line of defense ) Inflammatory response (the second line of defense) Adaptive immunity Third line of defense Induced through a slower and more specific process and targets particular invaders and diseased tissues 4  Innate Immunity First line : Natural barriers (Physical, Cell-derived chemicals, Normal microbiome) Second line : Inflammation First-line of defense 1. Natural barriers a. Physical and mechanical barriers: Epithelial cells of skin, sheets lining of gastrointestinal, genitourinary and respiratory tract Normal turnover of the cells in these sites may remove many infectious microorganisms Routine sloughing off and replacement of dead skin cells removes adherent bacteria 6 First-line of defense 1. Natural barriers a. Physical and mechanical barriers: Mechanical cleaning of surface includes vomiting and urination Goblet cells of upper respiratory tract produce mucus that coats the epithelial surface and trap microorganisms that are removed by hair- like cilia that mechanically move the mucus upward to be expelled by coughing or sneezing 7 First-line of defense (cont’d) 1. Natural barriers (cont’d) a. Physical and mechanical barriers: (cont’d) low temperature on skin, and low pH of skin and stomach inhibit microorganisms 8 First-line of defense b. Biochemical barriers: Epithelia surfaces synthesize and secrete substances (e.g. mucus, perspiration, saliva, tears and earwax) trap or destroy microorganisms Sebaceous glands in the skin secrete antibacterial and antifungal fatty acids and lactic acid Perspiration, tears and saliva contain lysozyme which attacks the cell walls of gram-positive bacteria Defensins produced by monocytes, macrophages and neutrophils defend bacteria by disrupt their cell membranes Collectins facilitate macrophages to recognize and kill microorganism 9  First-line of defense c. Normal microbiome Body’s surfaces are colonized with normal microbiome (normal flora) which do not normally cause disease Prolonged treatment with broad-spectrum antibiotics can decrease its protective activity lead to overgrowth of pathogenic microorganisms Produce enzymes which facilitate digestion of fatty acids Synthesizes essential metabolites (vitamin K and B) Release antibacterial substances (e.g. ammonia) to pathogenic microorganisms Competes with pathogens for nutrients and block attachment of pathogens to epithelium 10 Second line of defense: inflammation Inflammatory response is activated if cells and tissues are damaged Migration of leukocytes, plasma proteins and other biochemical mediators from circulation into nearby damaged tissue, where they destroy the invaders, limit tissue injury and promote healing a. occurs in tissues with blood supply (vascularized) b. activated rapidly (within seconds) c. depends on the activity of both cellular and chemical components, including plasma proteins d. nonspecific 11 Second line of defense: inflammation Benefits of inflammation: Prevent infection and further damage caused by contaminating microorganisms Limit and control of inflammatory process from spreading to area of healthy tissue Interaction with components of the adaptive immune system to elicit a more specific response to contaminating pathogens Preparation of area of injury for healing and initiation of mechanisms of healing and repair 12 Pathogenesis of Acute Inflammation 1. Vascular response (the response of blood vessels ) 2. Cellular response (the response of cells) 13 Inflammation: Vascular response Inflammation is activated by virtually any injury to vascularized tissues Triggers include ischaemia, trauma, foreign bodies, physical / chemical injury Inflammatory changes that happen within seconds of the injury in the arterioles, capillaries and venules: a. Haemostasis b. Vasodilation c. Increased vascular permeability d. White blood cell adhesions The above vascular changes deliver leukocytes, plasma proteins and other biochemical mediators to the site of injury Chemical mediators activate pain fibers, produce characteristic of pain Tissue injury and swelling contribute to loss of function 14 Inflammation: Vascular response a. Haemostasis Injury to blood vessels initiates the clotting cascade and activates platelets Clotting slows blood flow, walls off injury and provide meshwork for healing b. Vasodilation Increased diameter of blood vessels that increases the volume of blood delivered to the injured site Result in erythema and warmth in area of injury 15  Inflammation: Vascular response c. Increased vascular permeability Blood vessels become porous, enlarging the spaces between these cells Result in exudation ( the leaking of fluid from vessel) and oedema (tissue swelling from fluid leakage) of the area surrounding injury Plasma moves outward, blood in the microcirculation becomes more viscous and flows more slowly, and the increased blood flow and increasing concentration of red cells at the site of inflammation cause locally increased redness  erythema, and warmth 16 Inflammation: Vascular response d. White blood cell adhesion White blood cells adhere to the inner walls of vessels into the surrounding tissue An influx of phagocytes (neutrophils and macrophages) to injured tissue to target the foreign microorganisms 17 An effective inflammatory response : Three key plasma protein systems 1. Complement system: Destroy pathogens directly or eradicate pathogens through enhancing the immune response Intensifies the capacity of antibodies and activate inflammation 2. Clotting system: A group of plasma proteins form a blood clot at injured or inflamed site A blood clot is a meshwork of fibrin that contains platelets (the primary cellular initiator of clotting), traps other cells such as erythrocytes, phagocytes, and microorganisms Clots serve to plug damaged vessels and stop bleeding, trap microorganisms, prevent their spread to adjacent tissues 18 An effective inflammatory response : Three key plasma protein systems 3. Kinin system: Interacts closely with the clotting system Bradykinin (primary product from kinin system) causes dilation of blood vessels to induce pain, trigger smooth muscle cell contraction and increase vascular permeability 19 Inflammation: Cellular response Vascular tissues and cells During inflammation, vascular endothelium becomes a principal coordinator of blood clotting and facilities passage of cells and fluids into surrounding tissue The tissues surrounding the vessels contain mast cells, macrophages and erythrocytes carry oxygen to tissues and platelets Cellular receptors Cells involved in initiating the innate immune response have evolved a set of receptors referred as pattern recognition receptors (PRRs) PRRs generally expressed on cells in tissues near the body’s surfaces where they monitor the environment for products of cellular damage and infectious microorganisms 20 Cellular components of inflammation Cellular meditators and products Chemokines are members of cytokines that are chemotactic (i.e. they attract leukocytes to the site of inflammation) Interleukins (ILs) produced by macrophages and lymphocytes which have the following effects: - Facilitate cells to bind with other cells - Attract leukocytes to a site of inflammation (chemotaxis) - Induction, proliferation and maturation of leukocytes in bone marrow 21 Cellular components of inflammation Immunoreactive cells Mast cells have abundant granules containing biochemical mediators histamine, which causes increased vascular permeability, secondary to the retraction of endothelial cells lining the capillaries, increased leukocyte adherence to endothelial walls Endothelial cells regulate circulation through the microvessels and control the movement of water and solutes between blood and tissues Maintain normal blood flow in preventing spontaneous activation of platelets and other members of the clotting system 22 Cellular components of inflammation Phagocytes a cell that engulfs and digests debris and invading microorganisms including neutrophils, eosinophils, basophils and monocytes/macrophage and dendritic cell 23 https://pathologytestsexplained.org.au/ptests.php?q=White+Blood+Cell+Count Cellular components of inflammation Phagocytosis Ingestion of microbes, foreign particles, cell fragments by the following 4 steps: Recognition and adherence of the phagocyte to is target through PRRs and opsonization Engulfment and formation of phagosomesFusion of phagosome with lysosomal granules within the phagocyte Destruction of the target 24 Cellular components of inflammation Natural Killer Cells (NK cells) A heterogeneous population of lymphocytes that mediate spontaneous cytotoxicity against infected cells Binds to target cell and produces several cytokines and toxic molecules that can kill the target 25 Acute inflammation Self-limiting: continue until threat to the host is eliminated Usually takes 8 – 10 days to heal Local Manifestations - Redness and warmth due to increased blood flow into the damaged area - Swelling or edema due to the shift of protein and fluid into the interstitial space - Pain results from the increased pressure of fluid on the nerves and by the local irritation of nerves by chemical mediators such as bradykinins - Loss of function may develop if the cells lack nutrients or swelling interferes mechanically with function, as happens in restricted joint movement. 26 Acute inflammation Local Manifestations of acute Inflammation Inflammatory exudates result from increased vascular permeability and the leakage of fluid into tissues Serous exudate In early or mild inflammation Watery with very few plasma proteins or leukocytes Fibrinous exudate In more severe or advanced inflammation Thick and clotted Purulent exudate Accumulation of a large number of leukocytes, as (pus) occurs in persistent bacterial infections 27 Systemic Manifestations of acute Inflammation 1. Fever Endogenous pyrogens released by inflammatory cells act on hypothalamus Maybe beneficial as many microorganisms are sensitive to small increases in body temperature 2. Leukocytosis increased circulating leukocytes, primarily neutrophils 28 Systemic Manifestations of acute Inflammation 3. Increased synthesis of plasma proteins (e.g. fibrinogen) related to inflammation by liver Fibrinogen is associated with increased adhesiveness of erythrocytes Erythrocytes adhere to one another under these circumstances, forming large clumps that are buoyant and slow to settle to the bottom of a test tube of blood, this result in an increased value of a laboratory test, ⇑ erythrocyte sedimentation rate (ESR) 29 Chronic inflammation Lasts 2 weeks or longer Sometimes preceded by an unsuccessful acute inflammatory response or without a previous episode of acute inflammation Characterized by pus formation, suppuration (purulent discharge) and incomplete wound healing Characterized by dense infiltration of lymphocytes and macrophage; if macrophages are unable to limit tissue damage or infection, body attempt to wall off and isolate the infected area to granuloma formation 30 Adaptive (acquired) Immunity Third –line defense 31 Third –line defense Often called the immune response or immunity. Consists of lymphocytes and antibodies Once the external barriers (1st line) have been compromised and inflammation (2nd line) has been activated, the adaptive response is mobilized Inflammation is the “first responder” that contains initial injury and slows the spread of infection, adaptive immunity slowly augments the initial defense against infection and provides long-term security against reinfection 32 Adaptive (acquired) Immunity Inducible: the effectors of immune response, lymphocytes and antibody, do not pre-exist in large numbers but are produced in response to infection Specific: lymphocytes and antibodies induced in response to infection specific to infecting microbe Long-lived: provide long-term protection against specific invaders Memory: if infected with same microbe, protective lymphocytes and antibody are produced immediately Generation of clonal diversity: production of large population of B cells and T cells before birth and throughout life that have the capacity to recognise any foreign antigen 33 Adaptive (acquired) Immunity - Third –line defense Antigens: found on surface of microbes In the fetus, some lymphoid stem cells enter the thymus and differentiate into T lymphocytes , others enter specific regions of bone marrow and differentiate into B lymphocytes Each type of cell develops cell surface proteins that identify them as T or B cells Both B and T cells develop cell surface antigen receptors Receptors are remarkable because an individual lymphocyte is programmed to recognize one specific antigen Clonal selection : initiated when exposure to antigen occur - Differentiation of T and B cells into memory cells , activation of memory cells if second exposure occurs with same antigen 34 Adaptive (acquired) Immunity 1. Humoral immunity Antibodies circulate in blood and defend against extracellular antigens (e.g. microbes and microbial toxins) 2. Cell-mediated immunity Effector T cells are found in blood and tissues and defend against intracellular pathogens (e.g. viruses) and abnormal cells (e.g. cancer cells) 35 Antibody-mediated immune response (Humoral immune response) Antigen-antibody binding (specific) 36 Antibody-mediated immune response (Humoral immune response) When B cell matures in response to antigen exposure, it becomes a plasma cell capable of producing antibodies Classes of antibodies 80 – 85% of antibodies in blood IgG Account for most of the protective activity against infection Transport across placenta and protect newborn child during first 6 months of life Largest antibody and first antibody produced during initial response IgM to antigens Maybe Synthesized early in neonatal life but ay be increased as a response to infection in utero 37 Antibody-mediated immune response (Humoral immune response) Classes of antibodies Found in blood and bodily secretions as secretory IgA IgA Attached to dimeric IgA during transportation through mucosal epithelial cells to protect against degradation by enzymes also found in secretions IgD Functions as part of the B cell receptor antigen receptor on surface by early B cells Normally at low concentrations in circulation IgE Very specialized functions as a mediator of many common allergic responses and as a defense against parasitic infections 38 Antibody-mediated immune response (Humoral immune response) Large multicellular parasites usually invade mucosal tissues IgG, IgM, IgA bind to surface of parasites, activate complement, generate chemotactic factors for neutrophils and macrophages The only inflammatory cell that can damage parasite is eosinophil because of the special contents of its granules IgE is designed to specifically initiate an inflammatory reaction that preferentially attracts eosinophils to site of parasitic infection 39 Antibody-mediated immune response (Humoral immune response) Function of antibodies Affect infectious agents or their toxic products by neutralization (inactivating or blocking the binding of antigens to receptors Antibodies may protect the host by covering sites on microorganism that are needed for attachment By agglutination (clumping insoluble particles that are in suspension) Activate components of innate immunity, including complement and phagocytes 40 Cell-mediated Immune Response T-cells mature in thymus and resident in lymph nodes It detects pathogens inside the cells where they cannot be recognized by antibodies The specificity of T lymphocyte recognition of foreign antigens involve: – Cell surface markers on Antigen-presenting cells (APCs) – Infected body cells (Major Histocompatibility Complex, MHC) 41 T-lymphocytes Major Histocompatibility Complex (MHC) Proteins Primary role: antigen presentation Found on surface of all human cells except red blood cells 42 Primary Response of Adaptive Immunity On initial exposure to antigens, there is a latent period, during which B cell differentiation and proliferation occur Around 5 – 7 days, IgM antibody specific for the antigen can be detected in circulation The latent period is a result of time necessary for clonal selection, including processing and presentation of antigens, induction of Th cells, interactions between immunocompetent B cells and Th cells, maturation and proliferation of B cells into plasma cells and memory cells 43 Primary Response of Adaptive Immunity IgM will be produced first, followed by IgG against same antigen If no further exposure to the antigen occurs, the circulating antibody is broken down 44 Secondary Response of Adaptive Immunity Subsequent exposures to the same antigen Memory B-lymphocytes generated after first infection rapidly divide and antibody production begins immediately Faster and more powerful immune response IgM may be transiently produced and quantity may be about the same as in primary response IgG production is increased considerably and may remain elevated for an extended period of time 45 Classification of Adaptive Immunity (BYJU’S Biology, 2018) 46 Classification of Adaptive Immunity 1. Natural immunity is a normal biological experiences Active: acquired upon infection and recovery Passive: acquired by a child through placenta and breast milk 2. Artificial immunity is acquired through medical procedures such as immunization Active (vaccination): acquired through inoculation with a selected antigen Passive: administration of immune serum or globulin (BYJU’S Biology, 2018) 47 Alterations in Immunity and Inflammation 48 Alterations in Immunity and Inflammation Inappropriate immune responses may be: Exaggerated against noninfectious environmental substances (allergy), e.g. pollen allergies Misdirected against the host’s own cells (autoimmunity), e.g. SLE Directed against beneficial foreign tissues (alloimmunity), e.g. transfusions or transplants Insufficient to protect the host against pathogens and abnormal or foreign cell (immune deficiency), e.g. AIDS 49 Hypersensitivity 50 Hypersensitivity Definition An altered immunologic response to an antigen that results in disease or damage to the host Hypersensitivity reaction can be classified by: a) Source of the antigen that the immune system is attacking (Allergy, autoimmunity, alloimmunity) b) Mechanism that causes disease (types I, II, III and IV) 51 Hypersensitivity 1. Allergy The deleterious effects of hypersensitivity to environmental antigens 2. Autoimmunity Disturbance in immunologic tolerance of self-antigens Immune system reacts against self-antigens 3. Alloimmunity Occurs when immune system of an individual produces an immunologic reaction against tissues of another individual (e.g. transfusion, transplanted tissue or fetus during pregnancy) 52 Mechanisms of Hypersensitivity Diseases caused by hypersensitivity reactions can be characterized by the particular immune mechanism that results in the disease Can be divided into four distinct types: 1. Type I: IgE mediated hypersensitivity reactions 2. Type II: Tissue – specific hypersensitivity reactions 3. Type III: Immune Complex – mediated hypersensitivity 4. Type IV: Cell-mediated hypersensitivity reactions 53 Type I: IgE Mediated Hypersensitivity Mediated by the binding of antigen-specific IgE and the products of tissue mast cells Most type I reactions occur against environmental antigens e.g. allergic rhinitis, asthma 54 Type I: IgE Mediated Hypersensitivity Mechanism: IgE has a relatively short life span in blood because it rapidly binds to antibody receptor on mast cells After a large amount of IgE has bound to the mast cells, an individual is considered sensitized, when there is a re-exposure of a sensitized individual to the allergen, IgE antibodies signal mast cells to release mediators Histamine is the most potent mediator which acts within 15 – 30 minutes and affects several key target cells 55 Type I: IgE Mediated Hypersensitivity Mechanism: Acting through histamine 1 (H1) receptors, histamine contracts bronchial smooth muscles (bronchial constriction), increases vascular permeability (oedema) and causes vasodilation (increased blood flow) The interaction of histamine with H2 receptors result in increased gastric acid secretion 56 Type I: IgE Mediated Hypersensitivity histamine Mast cell degranulation 57 Type I: IgE Mediated Hypersensitivity Mechanism: Urticaria / hives occurs due to localized release of histamine and increased vascular permeability with limited area of oedema Urticaria is characterized by white fluid-filled blisters (wheals) surrounded by areas of redness (flares), usually accompanied by pruritus Effects of allergens on mucosa of eyes, nose and respiratory tract include conjunctivitis, rhinitis, and asthma Symptoms are caused by vasodilation, hypersecretion of mucus, oedema and swelling of respiratory mucosa 58 Type II: Tissue-Specific Hypersensitivity Reactions Immune reactions against a specific cell or tissue Cells express a variety of antigens on their surface with tissue-specific antigens because they are expressed on the plasma membranes of only certain cells 59 Type II: Tissue-Specific Hypersensitivity Reactions Five mechanisms by which it affect cells: 1. The cell can be destroyed by antibody; formation of membrane attack complex damages the membrane may result in lysis of the cell 2. Antibody may cause cell destruction through phagocytosis by macrophages 3. Toxic products produced by neutrophils may cause tissue damage 4. Antibody-dependent cell-mediated cytotoxicity - Antibody release toxic substances that destroy the target cell 5. The antibody are directed against specific cell surface receptors, they change the function of the receptor by blocking, appropriately stimulating or destroying the receptor 60 Type II: Tissue-Specific Hypersensitivity Reactions Type II mechanisms cause other conditions, e.g. Autoimmune haemolytic anaemia Autoimmune thrombocytopenic purpura Graves disease (autoantibodies bind to and activate receptors for thyroid stimulating hormone stimulates the thyroid cells to abnormally produce thyroxine) 61 Type III: Immune Complex Mediated Hypersensitivity Caused by the formation of antigen-antibody (immune) complexes in the circulation and are deposited in vessel walls and other tissues Difference between type II and type III mechanism : - Type II hypersensitivity: antibody binds to antigen on the cell surface - Type III hypersensitivity: antibody binds to soluble antigen that was released into blood or body fluids Type III reactions are not organ specific Most commonly result in a vasculitis in skin, kidneys or lungs 62 Type III: Immune Complex Mediated Hypersensitivity Mechanism: Harmful effects of immune complex deposition are caused by complement activation and by neutrophils attempting to phagocytose the immune complex During the attempted phagocytosis, large quantities of lysosomal enzymes are released into inflammatory site With attraction of to cause tissue damage 63 Type III: Immune Complex Mediated Hypersensitivity Mechanism: Intermediate sized immune complexes are the most likely to be deposited in certain tissues, where they have severe pathologic consequences such as glomerulonephritis, vasculitis, arthritis etc. The damage can be localized or systemic: – localized: Arthus reaction (vasculitis caused by repeated local exposure to an antigen that reacts with antibody and form complexes in local blood vessel walls) – systemic: serum sickness, systemic lupus erythematosus (SLE) 64 Type III: Immune Complex Mediated Hypersensitivity 65  Type IV: Cell-Mediated Hypersensitivity Mediated by T lymphocytes and do not involve antibodies Delayed response: 24 to 72 hours Mechanism: Response is delayed as it takes time for sensitized T cells to travel to the site of antigen reexposure and the time needed to produce cytokines that activate macrophages e.g. graft rejection, rheumatoid arthritis, poison ivy allergy, tuberculin reaction 66  Comparison of Different Types of Hypersensitivity Characteristics Type-I Type-II Type-III Type-IV antibody IgE IgG, IgM IgG, IgM None antigen exogenous cell surface soluble tissues & organs response time immediate immediate immediate delayed principal effector macrophages and mast cells macrophages in tissues neutrophils cells involved lymphocytes transferred with antibody antibody antibody T-cells allergic asthma, transfusion reactions, poison ivy allergy, examples SLE conjunctivitis MG graft rejection 67 Allergy Refer to hypersensitivity to environmental antigens (include medicines, pollen, bee stings Majority of allergies are type I reactions lead to rhinitis, sneezing, these reactions can be life-threatening (anaphylaxis) Antigens that cause allergic responses by allergens 68 Allergy Allergic disease: Bee Sting allergy Bee venoms contain mixture of enzymes and other proteins that serve as allergens Within minutes, they may develop excessive swelling at the bee sting site causing generalized hives, pruritus and swelling in areas distal form the sting (e.g. eye, lips) Other systemic symptoms include flushing, sweating, dizziness and headache Severe symptoms include tightness in the throat, wheezing, difficulty breathing, shock 69 Systemic Lupus Erythematous (SLE) 70 Systemic Lupus Erythematosus A chronic, multisystem, inflammatory, autoimmune disease of connective tissue Idiopathic, as a result of disturbed immune regulation The disease process develops slowly, characterized by frequent remissions and exacerbations 71 Systemic Lupus Erythematosus Epidemiology More often 20 to 40- year-old in women (~9:1) Blacks are affected more often than whites (~an eightfold increased risk) Increased incidence in twins & existence of autoimmune disease in families with SLE Risk Factors Idiopathic Both genetic and environmental factors; Tends to run in families Environmental factors, e.g. ultraviolet light, infection(viral), chemicals (hair dyes) Drugs, e.g. Hydralazine, Procainamide 72 Pathophysiology of SLE Deposition of circulating immune complexes containing antibody against DNA produces tissue The Immune complexes are deposited in connective tissues anywhere in the body, activating complement and causing inflammation and necrosis They have a high affinity for glomerular basement membranes & selectively deposited in glomerulus The presence of DNA in circulation increases from cellular damage in response to trauma, drugs or infections and is usually removed in the liver 73 Pathophysiology of SLE Removal of circulating DNA is slowed in the presence of immune complexes, thereby increasing the potential for deposition in kidney Vasculitis, or inflammation of the blood vessels, develops in many organs, impairing blood supply to the tissue. The resulting ischemia (inadequate oxygen for the cells) leads to further inflammation and destruction of the tissue. Deposition of immune complexes composed of DNA and antibody also causes inflammatory lesions in the renal tubular basement membranes, brain, heart, spleen, lung, gastrointestinal tract, skin and peritoneum 74 Systemic Lupus Erythematosus Clinical manifestations Arthralgias or arthritis (90% of individuals) Vasculitis and rash (70 – 80 % of individuals) Renal disease: Glomerulonephritis with antigen–antibody deposit in glomerulus, causing inflammation with marked proteinuria and progressive renal damage Haematologic abnormalities (50% individuals, with anemia being the most common) Cardiovascular diseases: Carditis (inflammation of any layer of the heart, commonly pericarditis) 75 Immunodeficiency 76 Immunodeficiency The failure of immune mechanisms of self-defense to function at their normal capacity, resulting in increased susceptibility to infections (opportunistic infections) Classification − Primary (before birth) − Secondary (acquired in later life) 77 Primary Immune Deficiency Mostly the result of a single gene defect The mutations are sporadic and not inherited Sporadic mutations occur before birth 78 Secondary Immune Deficiency Not related to genetic defects Far more common than primary deficiencies Acquired in later life as the result of another disease 79 Secondary Immune Deficiency Complications of other physiologic or pathophysiologic conditions: 1. Psychological stress, e.g. emotional trauma, eating disorders 2. Dietary insufficiencies, e.g. malnutrition 3. Malignancies, e.g. Hodgkin disease, sarcomas 4. Physical trauma, e.g. Burns 5. Medical treatments, e.g.. Splenectomy, Immunosuppressive treatment with corticosteroids, Cancer treatment with cytotoxic drugs or ionizing radiation 6. Congenital Infections, e.g. rubella, cytomegalovirus, hepatitis B 7. Acquired infections ,e.g. Acquired immunodeficiency syndrome (AIDS) 80 Acquired Immune Deficiency Syndrome (AIDS) 81 AIDS Secondary immune deficiency that develops in response to viral infection Human immunodeficiency virus (HIV) infects and destroys CD4-positive (CD4+) Th cells, which are necessary for the development of both B cells (humoral immunity) and cytotoxic T cells (cellular immunity) HIV suppresses the immune response against itself and secondarily creates a generalized immune deficiency by suppressing the development of immune responses against other pathogens and opportunistic microorganisms Acquired immunodeficiency syndrome (AIDS) is the most advanced stage of HIV infection 82 AIDS HIV infection is a blood borne infection Typical routes of transmission: - Blood or blood products (There is a slight risk that blood donated by newly infected persons will not test positive for antibodies during the “window” period that blood products are now tested for the virus and treated when possible) - intravenous drug abuse - Unprotected sex - Maternal-child transmission before or during birth 83 Pathophysiology of AIDS HIV is a retrovirus which primarily infects the CD4 T-helper lymphocytes, leading to a decrease in function and number of these cells, which play an essential role in both humoral and cell-mediated immune responses. HIV attacks macrophages and central nervous system cells. At an early stage, the virus invades and multiplies in lymphoid tissue, the lymph nodes, tonsils, and spleen, using these tissues as a reservoir for continued infection. 84 Pathophysiology of AIDS The core of HIV contains two strands of RNA and the enzyme reverse transcriptase, and the coat is covered with a lipid envelope studded with “spikes” of glycoproteins that the virus uses to attach to human cells. Once inside the human host cell, the viral RNA must be converted by the viral enzyme into viral DNA, which is then integrated with the human DNA. The virus then controls the human cell and uses its resources to produce more virus particles, and subsequently the host cell dies. 85 Pathophysiology of AIDS There is a delay or “eclipse” before the antibodies to the virus appear in the blood; the delay may be from 2 weeks to 6 months but averages 3 to 7 weeks. Antibodies form more rapidly following direct transmission into blood and more slowly from sexual transmission. The viral RNA or DNA can be identified in the blood and lymphocytes in about 5 days using polymerase chain reaction (PCR) technology to rapidly replicate the genetic material in the laboratory. 86 Pathophysiology of AIDS Early in the infection, large numbers of viruses are produced, followed by a reduction as the antibody level rises. The failure of the antibodies to destroy all the viruses is not totally understood, but the factors include the following: - The virus is hidden safely inside host cells in the lymphoid tissue during the latent phase - There appear to be frequent slight mutations in the viral envelope, making the antibodies less effective - Progressive destruction of the T-helper cells and macrophages gradually cripples the entire immune system 87 3 Stages of HIV According to CDC, when people get HIV and don’t receive treatment, they will typically progress through three stages of disease. Stage I : Acute HIV infection Stage II : Clinical latency Stage III : Acquired immunodeficiency syndrome (CDC, 2018) 88 Stage I – Acute HIV infection Within 2 to 4 weeks after infection with HIV, this is the body’s natural response to infection Large amount of virus in their blood and are very contagious; viral replication is rapid There may be mild, generalized flulike symptoms such as low fever, fatigue, arthralgia, and sore throat. These symptoms disappear without treatment (CDC, 2018) 89 Stage II: Clinical latency (HIV inactivity or dormancy) HIV is still active but reproduces at very low levels Symptoms may not occur, whereas some have a generalized lymphadenopathy or enlarged lymph nodes. Viral replication is reduced during this time. This period can last a decade or longer if not taking medication. If people takes medication, can last long for several decades. (CDC, 2018) 90 Stage II: Clinical latency (HIV inactivity or dormancy) Still be transmitted to others even though taking ART (antiretroviral therapy ) People with ART, has less chance to transmit HIV to others. At the end of this phase, viral load starts to go up and the CD4 cell count begins to go down. Symptoms may occur and moves into stage III. Increasing number of severe illnesses, called opportunistic illnesses Without treatment, survive about 3 years (CDC, 2018) 91 Stage III: Acquired Immunodeficiency Syndrome Most severe phase Immune system is badly damaged People are diagnosed with AIDS when their CD4 cell count drops below 200 cells/mm or if they develop certain opportunistic illnesses Have a high viral load and be very infectious in this stage Increasing number of severe illnesses, called opportunistic illnesses Without treatment, survive about 3 years (CDC, 2018) 92 Reference American College of Rheumatology (2018). ACR-endorsed Criteria for Rheumatic Diseases. Retrieved from https://www.rheumatology.org/Practice-Quality/Clinical-Support/Criteria/ACR-Endorsed-Criteria BYJU’S Biology (2018). Immune System – Active and passive immunity. Retrieved from https://byjus.com/biology/immune-system-active-and-passive Centers for Disease Control and Prevention (CDC) (2018). What are the stages of HIV? Retrieved from https://www.cdc.gov/hiv/basics/whatishiv.html Hubert, R. J., & VanMeter, K. C. (2018). Gould's pathophysiology for the health professions (6th ed.). Elsevier Mosby. McCance, K. L., & Huether, S. E., & Brashers, V. L. (2020). Understanding Pathophysiology (7th ed.). Elsevier. McCance, K. L., & Huether, S. E. (2019). Pathophysiology : The biologic basis for disease in adults and children. (8th ed.). Elsevier Mosby. 93