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Hypersensitivity Reactions:

Chapter 13 Hypersensitivity Reactions

Objectives:

Objectives Define the terms hypersensitivity, allergy, & allergen. Compare the basic differences among the Types I, II, III, & IV hypersensitivity reactions. Give examples of each type of reaction. Describe the etiology of each type of reaction. Describe the symptoms in each type of reaction. List the laboratory tests used to determine each type of reaction.

Hypersensitivity:

Hypersensitivity Hypersensitivity – exaggerated immune response against normally harmless antigens that causes inflammation and/or tissue damage 4 Types Type I – Immediate (anaphylactic) Type II – Antibody-Dependent Cytotoxic Type III – Immune-Complex-Mediated Type IV – Delayed (cell-mediated)

Type I Hypersensitivity/ (Allergy or Atopy):

Type I Hypersensitivity/ (Allergy or Atopy ) Immediate – occurs rapidly (2-3 min.) after exposure to the allergen Antibody involved: IgE Cells involved: mast cells, basophils Allergens Pollen Food Insect venom Animal danger Many others

Type I Hypersensitivity, Cont.:

Type I Hypersensitivity, Cont.

Mediators Functions:

Mediators Functions Histamine : Increased vascular permeability Smooth muscle contraction in airway and intestinal tract Increased mucus secretion by goblet cells Eosinophil chemotactic factor: Attracts eosinophils to site of IR Neutrophil chemotactic factor: Attracts neutrophils to site of IR Cytokines released from mast cells and basophils IL-4, IL-5, IL-6, TNF- α Induce leukocyte migration and activation Induce inflammatory response that can last for 1-2 days post exposure

Clinical Manifestations of Type I Hypersensitivity:

Clinical Manifestations of Type I Hypersensitivity Allergic rhinitis Allergic asthma Atopic dermatitis Urticaria (Hives) Gastrointestinal symptoms Systemic Anaphylaxis

Systemic Anaphylaxis:

Systemic Anaphylaxis Potentially life-threatening; can involve multiple organ systems Commonly associated with food (shellfish, peanuts), drugs (penicillin), or venom (bee-sting) Symptoms: Hypotension, shock, airway obstruction Can be fatal without prompt treatment Injection with epinephrine

Allergic Rhinitis:

Allergic Rhinitis Most common atopic disorder in U.S. Common symptoms: Runny nose, sneezing, watery eyes Elicited by airborne allergens: Pollens, molds, animal dander, dust mites Can be seasonal or year-round

Allergic Asthma:

Allergic Asthma Often occurs with allergic rhinitis Caused by some of the same allergens that cause allergic rhinitis Often associated with environmental factors Pollution, cigarette smoke Symptoms: Exaggerated bronchial response, cough, wheezing, shortness of breath

Atopic Dermatitis:

Atopic Dermatitis Triggered by many factors: Contact with irritants such as soap or detergents, airborne allergens, foods Symptoms: Itchy, red skin rash Chronic lesions with thickened skin may develop Secondary bacterial infection may occur if lesion are not left clean and dry.

Urticaria/Hives:

Urticaria/Hives Commonly associated with allergies to latex, foods, and drugs Symptoms: Widespread, itchy white areas surrounded by redness (erythema) Called “wheal and flare” reaction May be localized or associated with anaphylaxis

Gastrointestinal Reactions:

Gastrointestinal Reactions Usually associated with food allergy or may cause systemic anaphylaxis Symptoms: Nausea Vomiting Abdominal pain Diarrhea

Type I Hypersensitivity Testing:

Type I Hypersensitivity Testing Skin testing method of choice Cutaneous or prick test Intradermal testing Quantitative tests for IgE by ELISA methodology ELISA noncompetitive – measures total IgE ELISA noncompetitive – measures antigen-specific IgE

CutaneousTest Panel (Prick Testing):

CutaneousTest Panel (Prick Testing) Drop of each allergen applied to skin ~2 cm apart on skin of arm or back Scratch with needle or lancet to deliver antigen into skin  Measure and record each response in 15-30 min.  POS NEG  Wheel and flare > control Small or no reaction Pos control – histamine; Neg control – diluent

Pros and Cons of Skin Testing:

Pros and Cons of Skin Testing Advantages: Increased sensitivity over in vitro tests Inexpensive Easy to perform Gives immediate results Disadvantages: Cannot be used if patient has dermatitis Antihistamine use must be discontinued May induce large local reaction or anaphylaxis

In Vitro Allergy Tests:

In Vitro Allergy Tests Noncompetitive ELISA for Total IgE Quantization of total IgE (IU/ml) May indicate atopy, but other diseases also have an increase Does not identify specific allergen Noncompetitive ELISA for antigen-specific IgE Detects allergen-specific IgE Has more clinical value

Usefulness of Invitro Testing:

Usefulness of Invitro Testing Advantages: Useful when skin testing cannot be performed Useful in testing infants or small children for food or inhalent allergies Can monitor IgE after therapy or avoidance Disadvantages: More expensive and less sensitive than skin tests

Type II Hypersensitivity/Antibody-Dependent Cytotoxic:

Type II Hypersensitivity/Antibody-Dependent Cytotoxic Immediate form of hypersensitivity Caused by IgG and IgM antibodies directed against cell surfaces or tissue antigens Damage or destruction of target cells by either phagocytosis or complement lysis.

Type II Antibody-Medicated Cytotoxic Hypersensitivity:

Type II Antibody-Medicated Cytotoxic Hypersensitivity

Clinical Manifestations of Type II Hypersensitivity:

Clinical Manifestations of Type II Hypersensitivity Transfusion reaction Graft rejection Hemolytic disease of the newborn (HDN) Drug-induced hypersensitivity Autoimmune diseases

Transfusion Reactions:

Transfusion Reactions Antibodies against red blood cell (RBC) antigens can result in intravascular or extravascular hemolysis of the transfused RBCs Intravascular caused by transfusion with donor blood incompatible for ABO or other blood group Extravascular caused by other blood group antigens Treatment – immediate termination of transfusion Prevented by performing compatibility testing (crossmatch) of donor and recipient prior to transfusion

Hemolytic Disease of the Newborn:

Hemolytic Disease of the Newborn Mother has antibody directed again fetal RBCs. The IgG antibody crosses the placenta and destroys the fetus’s RBCs. Most Severe Rh(D-) negative mother produces anti-D. If infant’s RBCs are Rh(D) positive, then hemolytic anemia occurs in the fetus. Prevented by administration of Rh Immune Globulins (D antibodies) within 48 hours of first delivery Least Severe ABO where mother is type O and infant is type A or B. The natural IgG antibodies cross the placenta and cause a mild form of HDN.

Autoimmune Diseases:

Autoimmune Diseases Autoantibodies form against patient RBCs spontaneously that cause an autoimmune hemolytic anemia. Autoantibodies can also be produced against platelets, that will cause thrombocytopenic purpura Autoantibodies can be produced against body tissues such as pancreas, thyroid, skin, etc and cause diseases such as diabetes, thyroiditis, etc.

Type III Hypersensitivity/ Immune-Complex-Mediated:

Type III Hypersensitivity/ Immune-Complex-Mediated IgG or IgM antibody involved Antigen/antibody form complexes with foreign protein, microorganism or self-antigen When ag/ab complexes are not cleared by body’s mononuclear phagocytic system, they are deposit in tissues and activate the complement cascade, yielding biologically active fragments that can damage tissues

Type III Hypersensitivity Immune-Complex-Mediated, Cont.:

Type III Hypersensitivity Immune-Complex-Mediated, Cont .

Clinical Manifestations of Type III:

Clinical Manifestations of Type III Arthus Reaction Serum Sickness Autoimmune diseases Systemic lupus erythematosus (SLE) Rheumatoid arthritis (RA)

Type IV Hypersensitivity/ Delayed or Cell-Mediated:

Type IV Hypersensitivity/ Delayed or Cell-Mediated No antibody involved Sensitized T cells react with antigen & reaction occurs ~24 hours Sensitization phase Occurs 1-2 weeks after initial antigen contact Antigen processed and presented to antigen-specific TH cells  TH cells activated and proliferate; these cells are called delayed-type hypersensitivity T cells (TDTH) Effector phase Begins after subsequent exposure to antigen Memory TDTH cells produce a variety of cytokines and chemokines that causes the inflammatory response.

Type IV Hypersensitivity:

Type IV Hypersensitivity

Clinical Manifestations of Type IV Hypersensitivity:

Clinical Manifestations of Type IV Hypersensitivity Chronic infection with intracellular pathogens Examples: M. tuberculosis, M. leprae, C. albicans, pneumocystis, HSV, measles, etc. Contact dermatitis Examples: detergents, cosmetics, poison ivy or oak, nickel in jewelry Hypersensitivity pneumonitis (extrinsic allergic alveolitis) Inhalation of allergen (spores, chemicals, animal or plant protein)

Clinical Diagnosis of Type IV Hypersensitivity Reactions:

Clinical Diagnosis of Type IV Hypersensitivity Reactions Skin tests to measure memory response of T DTH previously sensitized with antigen Intradermal injection – i.e., Mantoux TB test Look for induration (hardness) on skin around injection site in 48-72 hours Patch tests – used for allergic contact dermatitis

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Autoimmune Diseases:

Autoimmune Diseases Chapter 14

Objectives:

Objectives Define autoimmunity. Explain the effect of autoimmunity on tissues. Define tolerance, anergy, and apoptosis. Explain immunological tolerance. Compare and contract clonal deletion and anergy. Discuss the etiology, clinical manafestations and laboratory findings for Hashimoto’s, Graves’, Type 1 Diabetes,Multiple sclerosis, ITP, AIHA, RA and SLE. Explain the difference between primary and secondary immunodeficiencies. Discuss the etiology, clinical manafestations, modes of transmission and laboratory findings for HIV.

Autoimmunity:

Autoimmunity Immune system’s failure to recognize self-antigens followed by an immune response against those antigens. Does not necessarily cause disease Disease occurs when autoantibodies are formed and damage tissues/organs. Autoimmune diseases can be classified as systemic or organ specific.

Autoimmune Diseases:

Autoimmune Diseases Endocrine Glands Hashimoto’s thyroiditis Addison’s disease Type 1 diabetes mellitus Nervous System Multiple sclerosis Myanthenia gravis Hematologic Autoimmune hemolytic anemia ITP Pernicious anemia Systemic Rheumatoid arthritis SLE Sleroderma Sjogren’s syndrome Hepatobiliary Autoimmune chronic hepatitis Primary biliary cirrhosis Gastrointestinal Ulcerative colitis Crohn’s disease

Systemic Lupus Erythematosus:

Systemic Lupus Erythematosus Chronic system inflammatory disease Caused by autoantibodies to DNA, nucleoproteins, cytoplasmic proteins or cell surface antigens Genetics & environment play a role Inflammation due to circulating immune complexes activating complement and also the release of cytokines by cells. Major organs affected most often Joints, skin, kidney, brain, heart and lungs

Systemic Lupus Erythematosus:

Systemic Lupus Erythematosus Clinical Symptoms Alopecia, fatigue, fever, arthralgia, weight loss, joint swelling, arthritis, & myalgia Glomerulonephritis Neurological manifestions Clinical diagnosis 4 of 11 specific criteria must be present Malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neurological disorder, hematologic disorder, immunologic disorder, and presence of antinuclear antibodies.

Discoid Lupus:

Discoid Lupus Chronic inflammation of the skin; may be one of the first signs of disease Skin involvement shows a “butterfly rash” across bridge of nose. Therapy Corticosteroids Sunscreens Retinols

SLE Diagnostic Testing:

SLE Diagnostic Testing Positive ANA Screen Positive anti-Sm Antiphospholipid Antibody Decreased complement (C3) Increased immunoglobulins and cryoglobulins CBC Biopsy shows immune complexes by direct FA examination

Rheumatoid Arthritis:

Rheumatoid Arthritis Inflammation of joints and progressive destruction of articular structures IgM antibodies directed against the IgG Fc region of antibodies present in the joint capsule Immune complexes (rheumatoid factor) are deposited in the synovium of the joints Clinical Presentation Weight loss, low-grade fever, malaise, stiffness and tenderness of joints, deformed joints

Rheumatoid Arthritis:

Rheumatoid Arthritis

Rheumatoid Arthritis:

Rheumatoid Arthritis Laboratory Testing Elevated total protein Elevated ESR Positive CRP test Positive RF test Positive Anti-CCP test Sometimes a positive ANA test

Hashimoto’s Thyroiditis:

Hashimoto’s Thyroiditis Autoantibodies to the thyroid gland Anti-thyroglobulins Anti-thyroid peroxidase (anti-TPO) Anti-TSHreceptors Results in hypothyroidism through direct killing of thyroid cells Clinical Presentation Enlarged thyroid (goiter) Alopecia, dry, coarse, cold skin Tiredness, weight gain, mild depression Slow speech and movement Facial puffiness Testing Decreased T3, T4 & increased TSH Autoantibody Testing - positive

Graves Disease:

Graves Disease A type of hyper throidism Antibody called thyrotropin receptor antibody (TRAb) stimulates the thyroid to make excessive amounts of thyroid hormone. Clinical Presentation Thyrotoxicosis Nervousness, palpitations, increased perspiration, fatigue, sensitivity to heat, weight loss Exophthalmos or protruding eyeballs Goiter

Graves Disease:

Graves Disease Laboratory Tests Increased T3 & T4 & decreased TSH levels 50% have Anti-TPO antibodies Positive antibody titer to Anti-TSHr Treatment Antithyroid drugs Radioactive iodine Thyroidectomy

Type 1 Diabetes Mellitus:

Type 1 Diabetes Mellitus Also known as insulin dependent diabetes mellitus (IDDM) Antibodies to beta cells of pancreas (insulin-producing cells) Associated with HLA-DR genes & viral infections Clinical Presentation Extreme hunger, weight loss, tiredness, unusual thirst, nausea, frequent urination Laboratory Tests Elevated serum & urine glucose Elevated hemoglobin A1c Decreased plasma insulin levels Antibodies to insulin

Multiple Sclerosis:

Multiple Sclerosis Inflammatory condition affecting CNS Formation of plaques or lesions damages the myelin sheath surrounding the nerves Associated with viral agents (Epstein-Barr virus and human herpes virus type 6) but also has genetic predisposition Inflammatory response to myelin-reactive T cells & macrophages & influx of cytokines cause the damage or demyelination. Demyelination of nerves in brain & spinal cord interrupt the nerve impulses causing symptoms.

Multiple Sclerosis:

Multiple Sclerosis Clinical Presentation Sensory loss, weakness of limbs, clumbsiness, spasticity, tremors, fatigue, vertigo, cognitive impairment, memory loss Laboratory Testing History, neurological exam, & diagnostic tests – no one single test Appearance of lesions on MRI Increased levels of IgG showing oligoclonal bands in spinal fluid

Myasthenia Gravis:

Myasthenia Gravis Autoimmune disease - antibodies destroys acetylcholine (Ach) receptors sites in muscles Acetylcholine is a neurotransmitter to muscles

Myasthenia Gravis Symptoms:

Myasthenia Gravis Symptoms Weakness & fatigability Dropping eyelids and double vision Difficulty swallowing & bobbing head DX: Neurological exam Blood test for AChR-binding auto antibodies Positive Tensilon Test Nerve Conduction Studies & Single-Fiber Electromyography

Goodpasture’s Syndrome:

Goodpasture’s Syndrome Autoantibodies directed against glomerular, renal tubules, and alveolar basement membranes. (anti-GMB) Cause unknown Characterized by glomeronephritis and hemorrhaging in the lungs. Fatigue, nausea, difficulty breathing, or skin pallor. Hematuria, proteinuria findings in urine Diagnosis Positive anti-GBM titer Positive IF test on renal tissue biopsy

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Immunoproliferative Diseases:

Chapter 15 Immunoproliferative Diseases

Objectives :

Objectives Discuss why normal cells transform into malignant cells. Discuss the clonal hypothesis of malignancy. Discuss the difference between leukemia & lymphoma and how CD antigens are used to differentiate the hematopoietic cells Differentiate multiple myeloma from Waldenstrom’s macroglobulinemia. Discuss the laboratory tests used in diagnosis of leukemias, lymphomas, & plasma cell dyscrasias.

Malignant Transformation:

Malignant Transformation Malignancy is characterized by an excess accumulation of cells due to a failure of growth regulation or an arrest of maturation. Leukemia – malignant cells arising in the bone marrow Lymphoma – malignant cells arising in the lymphoid system Plasma cell dyscrasias – involve the bone marrow, lymphoid organs, and other non-lymphoid sites.

Clonal Hypothesis of Malignancy:

Clonal Hypothesis of Malignancy Malignancies arise from a single genetically identical line Arise from a single mutant parent cell Proto-oncogenes vs oncogenes Proto-oncogenes are normal genes Oncogenes are mutated genes caused by viruses, microbes, and/or environmental pollutants. Tetragen – anything that will cause a mutation in a gene that causes the development of cancer.

Lymphomas:

Lymphomas REAL Classification Based on clinicopathologic and immunogenetic features Divides malignancy into neoplasms of precursor T or B cell cells and/or neoplasms of mature T, B or NK cell lineage. Hodgkin’s Lymphoma Very treatable (95-% cure-rate) Characterized by Reed-Sternberg Cell typically large with a bilobed nucleus and two prominent nucleoli. Are of B-cell lineage Associated with Epstein-Barr Virus infections.

Non-Hodgkin’s Lymphoma:

Non-Hodgkin’s Lymphoma See Table 15-2 of text on page 261. B-cell neoplasms Precursor B-cell Lymphoblastic leukemia and lymphomas Mature B-cell neoplasms T-cell & NK neoplasms Precursor T-cell neoplasms Lymphoblastic leukemia and lymphomas Mature T-cell and NK neoplasmas

Leukemias:

Leukemias Classified as either acute or chronic. Chronic leukemias show more mature cells & progresses slowly Acute leukemias are generally much more rapidly progressive but have a higher response rate to therapy compared to the chronic leukemias. Diagnosis bone marrow morphology and immunophenotyping by flowcytometry looking at the CD numbers. See Table 15-3 & 15-4 of your text.

Plasma Cell Dyscrasias:

Plasma Cell Dyscrasias Characterized by an overproduction of an immunoglobulin by a malignant clone of plasma cells. Classification Multiple myeloma IgG, IgA, IgE, IgD or Kappa or Lambda chains Lytic Lesions formed in bone causing fractures & pain Waldenstrom’s Macroglobulinemia IgM 10-20% are cryoglobulins Diagnosed by SPE, IEP/IFP & Bone Marrow Biopsy

Immunodeficiency Diseases:

Immunodeficiency Diseases Chapter 16

Objectives:

Objectives Recall the organization & development of the immune system. Explain how a defect in the B-cell, T-cell, myeloid, or complement system can lead to clinical manifestations. Discuss how laboratory tests can be used to diagnose and monitor the different types of congenital immunodeficiency syndromes. List the common deficiencies explaining which component is deficient.

Immunodeficiency Disorders:

Immunodeficiency Disorders Primary Immunodeficiency Disorders Present at birth but may not manifest itself until later in life Genetic/inherited Subdivided on basis of cell type affected or the point at which maturation of the cell lineage is blocked Rare except for IgA deficiency Secondary Immunodeficiency Disorders Due to exogenous agent or severe nutritional defect other than a genetic mutation present at birth. Nutritional defects, tumors, immunosupression

Deficiencies of B-cell System:

Deficiencies of B-cell System IgA deficiency Deficient in IgA Loss of IgA B cell differentiation Most common deficiency Usually asymptomatic unless patient produces and antibody against IgA; then have sever anaphylactic reactions when receiving blood products. X-linked agammaglobulinemia Also known as Bruton’s agammaglobulinemia Deficient in all immunoglobulins Pre-B cell differentiation defect

Deficiencies of Cellular Immunity:

Deficiencies of Cellular Immunity DiGeorge Anomaly Developmental abnormality in thymic development Varies as to severity but some have severe decrease in T-cell numbers Have recurrent viral, fungal & parasitic infections. SCID Affects both T-cell and B-cell functions Different defects but present with infections from any type of organism

Deficiencies of Cellular Immunity:

Deficiencies of Cellular Immunity Wiskott-Aldrich Syndrome X-linked recessive syndrome Presents with thrombocytopenia and bleeding tendencies, eczema and recurrent bacterial infections

Laboratory Evaluation of Immune Dysfunction:

Laboratory Evaluation of Immune Dysfunction Screening Tests Humoral Immunity Serum immunoglobulin levels Cell-mediated Immunity Skin tests Complement Ch50 & C3 assays Specialized tests T & B cell assays to determine #s T & B cell functional cultural assays

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