Immunology II Lecture 13 PDF

Immunology II BMS44210A Dr. Afsheen Raza [email protected] Fall Semester 2024-2025 1  Hypersensitivity Reactions (CLO4) At the end of this session you will be able to understand: Mechanisms of Type III and Type IV hypersensitivity reactions...

Immunology II BMS44210A Dr. Afsheen Raza [email protected] Fall Semester 2024-2025 1  Hypersensitivity Reactions (CLO4) At the end of this session you will be able to understand: Mechanisms of Type III and Type IV hypersensitivity reactions 2 Immune complex-mediated (type III) Hypersensitivity Reactions 3  Immune complex-mediated (type III) Hypersensitivity Reactions The reaction of antibody with antigen generates immune complexes Generally. this complexing of antigen with antibody facilitates the clearance of antigen by phagocytic cells 4  Immune complex-mediated (type III) Hypersensitivity Reactions The body may be exposed to an excess of antigens in many conditions such as: persistent infection with a microbial organism auto-immunity to self components repeated contact with environmental agents In some cases, large amounts of immune complexes can lead to tissue- damaging type III hypersensitive reactions 5  Immune complex-mediated (type III) Hypersensitivity Reactions These immune complexes can deposit in various tissues such as blood vessel walls synovial membrane of joints glomerular basement membrane of the kidney choroids plexus of the brain When the complexes are deposited in tissue very near the site of antigen entry, a localized reaction develops 6  Immune complex-mediated (type III) Hypersensitivity Reactions When the complexes are formed in the blood, a reaction can develop wherever the complexes are deposit These deposited immune complexes, in certain cases, cannot be cleared by phagocytic cells The deposition of these complexes initiates a reaction that results in the recruitment of neutrophils to the site. The tissue is injured as a consequence of granular release from the neutrophil 7  Immune complex-mediated (type III) Hypersensitivity Reactions Type III hypersensitive reactions develop when immune complexes activate complement system and its components: C3a, C4a, and C5a that cause localized mast-cell degranulation and increase in local vascular permeability C3a, C5a, and C5b67 serve as chemotactic factors for neutrophils, which accumulate in large numbers at the site of immune-complex deposition 8  Immune complex-mediated (type III) Hypersensitivity Reactions Unsuccessful attempts of the neutrophil to ingest the deposited immune complex activates the membrane-attack mechanism of the complement system leading to destruction of tissue Activation of complement can also induce aggregation of platelets, and release of clotting factors can lead tissue damage 9 Immune complex-mediated (type III) Hypersensitivity Reactions 10 Clinical Manifestations of Type III Hypersensitivity Reactions 11  Clinical Manifestations of Type III Hypersensitivity Reactions (Arthus Reaction) A localized immune reaction usually occurs within 4-8 hours This is known as Arthus reaction Neutrophils adhere to the vascular endothelium and then migrate into the tissues at the site of immune complex deposition As the reaction develops, localized tissue and vascular damage results in : accumulation of fluid (edema) and red blood cells (erythema) at the site pronounced erythema and edema after 4-8 hours If occurring in lungs, Intrapulmonary Arthus-type reaction cause pneumonitis or alveolitis For example “pigeon fancier’s disease” results from inhalation of a serum protein in dust derived from dried pigeon feces 12 Clinical Manifestations of Type III Hypersensitivity Reactions (Arthus reaction) 13  Clinical Manifestations of Type III Hypersensitivity Reactions (Serum Sickness) Serum sickness results from passive immunization with anti-toxins using animal serum, usually horse or bovine, used to treat such infections as diphtheria, tetanus, and gangrene Vaccines and bee stings may also trigger this type of reaction 14  Clinical Manifestations of Type III Hypersensitivity Reactions (Serum Sickness) When foreign antiserum is given, the recipient develops specific antibodies against the foreign serum proteins (which act as antigens) These antibodies form circulating immune complexes and within days or weeks after exposure an individual begins to manifest a combination of symptoms called serum sickness 15  Clinical Manifestations of Type III Hypersensitivity Reactions (Serum Sickness) Symptoms include: fever, weakness generalized vasculitis (rashes) with edema and erythema lymphadenopathy, arthritis, and sometimes glomerulonephritis The precise manifestations of serum sickness depend on quantity of immune complexes formed overall size of the complexes 16 Clinical Manifestations of Type III Hypersensitivity Reactions (Serum Sickness) 17  Clinical Manifestations of Type III Hypersensitivity Reactions Type III hypersensitivity reactions are also involved in: Autoimmune Diseases Systemic lupus erythematosus Rheumatoid arthritis Drug Reactions Allergies to penicillin and sulfonamides Infectious Diseases Meningitis Hepatitis Malaria 18  Recall-Systemic lupus erythematous (SLE) Systemic autoimmune disorder in which multiple autoantibodies are generated against cell nuclear constituents (DNA, histones, and ribonucleoproteins). This leads to deposition of immune complexes in several organs, mainly kidney, skin, and joints, causes rashes, inflammation and tissue damage Due to deficiency of the complement system to clear these immune complexes from the tissues, clinical symptoms are triggered: Kidney damage, and kidney failure: causes of death among people with lupus Brain and central nervous system damage: cause headaches, dizziness, behavior changes, vision problems, and even strokes or seizures. Many people with lupus experience memory problems and may have difficulty expressing their thoughts Blood and blood vessels damage: inflammation of the blood vessels Lung damage: inflammation of the chest cavity lining, bleeding into lungs and pneumonia Heart damage: inflammation of heart muscle, arteries or heart membrane with increased risk of cardiovascular disease and heart attacks 19 9/1/2024  20 9/1/2024  Diagnostic tests for Type III Hypersensitivity Reactions Fluorescent staining of tissue biopsy specimens can be used to observe the deposition of immune complexes in tissues Measurement of complement component levels by nephelometric or turbidimetric approaches Both nephelometric and turbidimetric measurements utilize the formation of antibody–antigen immune-complexes to determine protein concentrations. 21 Type IV or Delayed-Type (Cell mediated) Hypersensitivity (DTH) 22  Type IV or Delayed-Type (Cell mediated) Hypersensitivity (DTH) When some subpopulations of activated T helper cells (CD4) cells encounter certain types of antigens, they secrete cytokines that induce a localized inflammatory reaction called delayed-type hypersensitivity (DTH) It differs from the other types of hypersensitivity reactions because it is mediated through cell-mediated immunity In this type of reaction, macrophages are involved 23  Type IV or Delayed-Type (Cell mediated) Hypersensitivity (DTH) Type IV hypersensitivity reaction is called delayed-type hypersensitivity (DTH) because the response is delayed It starts hours or days after primary contact with the antigen and often lasts for days The reaction is characterized by large number of nonspecific inflammatory cells, in particular, macrophages This reaction occurs due to the activation of specifically sensitized T lymphocytes rather than the antibodies Antibody and complement are not directly involved 24 Phases of Delayed-Type Hypersensitivity (DTH) 25  Phases of Delayed-Type Hypersensitivity (DTH) Sensitization Phase: occurs 1-2 weeks after primary contact with Ag CD4 are the cells activated during the sensitization phase and antigen- presenting cells (APCs) such as dendritic cells and macrophages will be activated 26  Phases of Delayed-Type Hypersensitivity (DTH) Effector Phase: After second exposure to the same antigen, CD4 T cells secrete a number of cytokines that recruit and activate macrophages and other nonspecific inflammatory cells A DTH response generally peaks 48–72 h after second exposure to antigen The delayed onset of this response is due to the accumulation of cytokines to induce localized secretion of macrophages 27  Phases of Delayed-Type Hypersensitivity (DTH) Effector Phase: Once a DTH response begins, a complex interplay of nonspecific cells and mediators results in amplification of the immune response By the time the DTH response is fully developed, only about 5% of the participating cells are antigen-specific CD4 T cells; the remainder are macrophages and other nonspecific cells 28 Phases of Delayed-Type Hypersensitivity (DTH) 29 Delayed-Type Hypersensitivity (DTH) 30  Delayed-Type Hypersensitivity (DTH) Among the cytokines produced by CD4 T cells, the most commonly involved in activating macrophages are : IL-3 and GM-CSF IFN-γ and TNF-β (together with macrophage-derived TNF-α and IL-1) These cytokines act on nearby endothelial cells, inducing a number of changes that facilitate extravasation of monocytes and other nonspecific inflammatory cells 31  Delayed-Type Hypersensitivity (DTH) As the monocytes enter the tissues to become macrophages, they accumulate at the site of DTH response by chemokines monocyte chemotactic and activating factor (MCAF) Magrophage migration-inhibition factor (MIF) inhibits macrophages from migrating beyond the site of a DTH reaction 32  Delayed-Type Hypersensitivity (DTH) As macrophages accumulate at the site of a DTH reaction, they are activated by cytokines: IFN-γ membrane bound TNF-β produced by CD 4 T cells The activated macrophages efficiently mediate activation of more T cells, which in turn secrete more cytokines that recruit and activate even more macrophages making a vicious cycle Extensive accumulation of immune cells leads to a detrimental response characterized by extensive tissue damage 33 Delayed-Type Hypersensitivity (DTH) related Diseases 34  Delayed-Type Hypersensitivity (DTH) related Diseases Tuberculosis (TB) infection M. tuberculosis (MTB)cells are engulfed by macrophages after being identified as foreign However, the MTB cells block the fusion of the phagosome with lysosomes within the macrophages, the MTB cells escape the immune response of macrophages and is able to replicate within macrophages After several weeks, the immune system is activated and, on stimulation with IFN-γ, the macrophages become capable of killing M. tuberculosis by forming phagolysosomes and nitric oxide radicals The hyper-activated macrophages secrete TNF-α which recruits multiple monocytes to the site of infection These cells differentiate into epithelioid cells. which wall off the infected cells, but results in significant inflammation and local damage 35 Effects of Delayed-Type Hypersensitivity (DTH) 36 Testing of Delayed-Type Hypersensitivity (DTH) In Mycobacterium tuberculosis 37  Testing of Delayed-Type Hypersensitivity (DTH) In Mycobacterium tuberculosis To determine whether an individual has been exposed to M. tuberculosis, PPD, a protein derived from the cell wall of this mycobacterium, is injected intradermally Development of a red, slightly swollen, firm lesion at the site between 48 and 72 h later indicates previous exposure The skin lesion results from intense infiltration of cells to the site of injection during a DTH reaction; 80%–90% of these cells are macrophages Note, however, that a positive test does not allow one to conclude whether the exposure was to a pathogenic form of M. tuberculosis or to a vaccine form received through immunization 38 Testing of Delayed-Type Hypersensitivity (DTH) In Mycobacterium tuberculosis 39 40