1	CLSC320 Principles of Immunology Fundamental Concepts in Immunology Program for Clinical Laboratory Science Unit - 07 Abnormal Immune Responses
2	Unit Guidelines Reading assignment: Pages 148 - 171 of textbook Learning objectives: Those listed on page 149 of textbook Key terms: Those listed on pages 149 & 150 of textbook
3	Summary of Abnormal Immune Responses Hypersensitivity Disorders p Autoimmune Disorders p Immunodeficiency Disorders p Hypergammaglobulinemia Disorders
4	Hypersensitivity Disorders Hypersensitivity Disorders
5	Definition & Types of Hypersensitivity Disorders Definition: a normal but exaggerated or uncontrolled immune response to a persistent antigen and results in inflammation and tissue damage. Four types of hypersensitivity disorders: Type I Type II Type III Type IV Immediate or allergic hypersensitivity Antibody-Dependent Cytotoxic hypersensitivity Immune Complex-Mediated hypersensitivity T-cell mediated hypersensitivity
6	Type I - Immediate or Allergic - 1 Description: an immune response (called an allergic reaction or allergy) that is mediated by IgE and occurs immediately after subsequent contact with same antigen (called allergen). Mechanism of tissue damage: Uduring 1st contact with allergen IgE production is initiated by T_H2 response to allergen. UIgE produced bind to mast cells via Fc receptors and mast cells are said to be sensitized. mast cell Fc receptors IgE Sensitized mast cell
7	Type I – Immediate or Allergic - 2 Mechanism of tissue damage: - cont=d Uin subsequent allergen exposure the allergen binds with IgE on sensitized mast cells allergen must bind to 2 or more IgE molecules before mast cell will secrete mediators: eosinophil chemotactic factor histamine
8	Types of allergic reactions in Type I ]localized reaction: -a cutaneous reaction with: La Awheal and flair@ reaction Llocal edema Litching at site of allergen introduction ]generalized reaction: -also known as Aanaphylaxis@ -vasodilation -bronchioconstriction -edema Miscellaneous information: Uthe allergic reaction may be induced by C3a and C5a Uthe level of free IgE can be measured by RAST to determine allergen responsible for reaction
9	Type II – Antibody-Dependent Cytotoxic Description: an immune response that occurs when antibody (IgM or IgG) binds with cell surface antigen and activate complement which lyse cells and the C3a and C5a attract macrophages, neutrophils, and basophils into area or NK cells lyse antibody-coated cells. Mechanism of tissue damage: Uantigen causes antibody to be produced Uantibody produced attached to antigen on target cell UAb-Ag complex may activate complement which lysis target cell via MAC attack and/or UAb-Ag complex activates NK cell or T_Cytotoxic cells which lysis target cell
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11	Mechanism of Type II Antibodies are formed that bind to specific target cell antigens and the antibody-coated target cells are destroyed by cytotoxic substances being released from effector cells which bind via Fc receptors to the antibody=s Fc portion.
12	Examples of Type II Blood Transfusion Reactions Š Hemolytic Disease of Newborn (HDN) Š Goodpasture=s Syndrome (Glomerulonephritis)
13	Type II – Blood Transfusion Reaction Uthe reaction occurs when: ]incompatible antigens on donor red blood cells are infused into recipient ]recipient=s immune system has produced antibodies against antigens from a previous exposure Uthe reaction=s features : ]previously produced antibodies form Ab/Ag complexes on RBC=s surface ]these complexes activate complement via classical pathway ]RBC=s destroyed via MAC intravascularly
14	Type II – Hemolytic Disease of Newborn Uthe reaction occurs when: ]IgG antibodies from mother cross placental barrier and attack red cells of fetus ]mother must have been exposed to red cell antigens prior to pregnancy (previous pregnancy or transfusion) ]the incompatible antigens on fetal red cells are inherited from father Uthe reaction=s features : ]Ab/Ag complexes are formed on fetal red cells ]fetal red cells are destroyed
15	Type II – Goodpasture’s Syndrome Uthe reaction occurs when: ]antigen/antibody complexes form along basement membranes of glomeruli and alveoli ]complement is activated via classical pathway by complexes and MAC is responsible for tissue damage ]neutrophils accumulate at site of injury and release enzymes adding to injury Uthe reaction=s features : ]autoantibodies formed against collagen of basement membranes ]lesions form in both lungs and kidneys
16	Examples of Type III – Immune Complex-Mediated Serum Sickness Š Systemic Lupus Erythematosus (SLE)
17	Mechanism for Type III Antigen/antibody complexes formed are not effectively removed by phagocytes and are deposited in various tissues and organs. Tissue damage occurs at the site of immune complex deposition.
18	Initiating Factors of Type III Autoimmune disorders Persistent infection Repeated inhalation of antigens rhematoid arthritis viral hepatitis moldy hay Farmer=s lung
19	Factors Promoting Immune-complex deposition Uincreased vascular permeability histamine Uhigh blood pressure and turbulence in glomerular capillaries Usize of antigen larger antigens form larger complexes Uaffinity of antigen for tissue basement membranes & synovial linings Uclass of antibody involved IgG and anti-IgG
20	Mechanism of Tissue Injury in Type III Ucomplement is activated releasing anaphylotoxins (C3a & C5a) Uanaphylotoxins stimulate mast cells and basophils to release chemotactic factors & amines (histamine) Ueffector cells are called into area which release their lysosomal enzymes Ua local inflammatory reaction occurs Ubegins when Ag/Ab immune complexes are deposited onto tissue
21	Lab Indicators of Immune Complex Disorders Udecreased serum complement levels Udetection of immune complexes
22	Type III – Serum Sickness Uself-limiting systemic immune complex disease affecting: lymph nodes joints UCaused by passive immunization administration of pre-formed antibodies (gammaglobulin shots) formed in horses UMechanism: proteins from horse serum causes host to produce antibodies that complexed with horse proteins forming immune complexes
23	Type III – Systemic Lupus Erythematosus (SLE) Uan autoimmune disease characterized by: presence of autoantibodies immune complexes UImmune complexes are deposited within kidney glomeruli results in inflammation of blood vessels within the glomeruli
24	Examples of Type IV – Delayed Examples: Allergic contact dermatitis Š Tuberculin & Other skin tests Other Name: T cell-mediated hypersensitivity
25	Mechanism of type IV Mediated by T lymphocytes which had previous exposure with a stimulating antigen and release cytokines which induce an inflammatory reaction, activate and attract macrophages into area. Inflammation and swelling of infected area results.
26	Phases of Type IV Sensitization phase Š Effector phase
27	Sensitization Phase of type IV U lasts for 1 - 2 weeks following initial contact with antigen UT-helper cells are activated and proliferate when antigen is presented by APC=s in conjunction with MHC -II UT-helper cells are activated and proliferate when antigen is presented by APC=s in conjunction with MHC -II UT-cells that are activated are designated as T_DTH
28	Effector Phase of type IV - 1 U does not show clinical symptoms until 24 hours following subsequent contact with antigen Upeak response occurs between 48 - 72 hours UT-_DTH cells secrete a variety of cytokines that are responsible for : erecruitment & activation of macrophages erecruitment & activation of other non- specific inflammatory cells UGenerally the antigen is cleared with little tissue damage UIf the antigen is not cleared easily, a granuloma may develop
29	Effector Phase of Type IV - 2 UT-_DTH cells secrete a variety of cytokines that include the following: eIL-3 eGM-CSF eINF-( eTNF-$ eMIF chemotactic for macrophages hematopoietic stimulus for monocytes & neutrophils affects permeability of endothelial cells and activates macrophages migration-inhibition factor inhibits macrophages from leaving area of DTH reaction
30	Type IV – Contact Sensitivity - 1 Ualso called allergic contact dermatitis Ucharacterized by: eskin eruptions elesions of skin eblistering escaling eedema Udiagnosis confirmed by Apatch testing@ Umay persist for years or even a lifetime
31	Type IV – Contact Sensitivity - 2 Usome causative agents include: epoison ivy or poison oak ehair dyes eformaldehyde enickel eturpentine evarious cosmetics
32	Type IV – Tuberculin & Other Skin Tests Uperformed by injecting of test antigens intradermally Umost common allergins injected include: ePPD - purified protein derivative from M. tuberculosis is used eCandida albicans Utests read between 48 - 72 hours after injection Udevelopment of a red, slightly swollen firm lesion indicates a positive reaction
33	Autoimmune Disorders - Index Autoimmune Disorders
34	Definition of Autoimmune Disorders When the immune regulatory mechanism becomes responsive to Aself-antigens@ giving rise to an uncontrolled and exaggerated immune response The autoimmune response is an antigen- specific immune response that may be either cell-mediated or humoral
35	Mechanism of Self-Tolerance Uinvolves the T lymphocyte populations UPre-T lymphocytes with a potential to react with self-antigens are eliminated in the thymus gland Examples of Self-antigens involved in autoimmune disorders include: Ucell-surface receptors UErythrocyte surface proteins UBasement membranes of glomeruli UHormone receptors UNucleoproteins
36	Factors Associated with Autoimmune Disorders Alterations in lymphocytes \| Local tissue alterations \| Genetic factors \| Environmental factors
37	Alterations in Lymphocytes & Local Tissue Uinvolves the T and/or B lymphocyte populations Umay invlove the following alterations or changes: eabnormal selection of lymphocytes eCross-reactions with Ashared antigens@ eIncreased production of cytokines ePolyclonal stimulation of lymphocytes Local tissue alterations Uinvolves the T and/or B lymphocyte populations Umay invlove the following alterations or changes: eRelease of previously Ahidden@ self-antigens eAlterations in structure of self-antigens
38	Genetic Factors Uno direct evidence in humans Uthose that inherit certain MHC alleles have higher probability of developing diseases HLA allele Disease Relative risk NOTE: Relative risk is the Atimes higher@ the risk compared to normal population DR4 B27 DR2 DR3 DR3/DQW8 pemphigus vulgaris - blistering skin disorder 5 Ankylosing spondylitis 90 Goodpasture=s syndrome 16 Myasthenia gravis 10 Diabetes mellitus 100
39	Environmental Factors Usome factors that may cause alterations in self- antigen eDrugs eToxins ËPenicillin - autoimmune Hemolytic anemia ËProcainamide - SLE ËMercuric chloride - antinuclear antibodies ËPolyvinyl chloride - scleroderma ËSilicon - scleroderma & Rheumatoid arthritis eUltraviolet radiation Ëcorrelated to increased risk for skin cancers but not with autoimmune disorders
40	Categories of Autoimmune Disorders Organ-Specific Š Organ-Non-Specific
41	Organ-Specific Autoimmune Disorders The immune response is directed primarily against antigens in or on a specific organ Organ involved Antigen targeted Disease Clinical features Adrenal gland Adrenal cortex Addison=s Hypoadrenalism Thyroid gland TSH receptors Grave=s Hyperthyroidism Thyroid cells Hashimoto=s Hypothyroidism Skeletal or heart Muscle Acetylcholine receptors Myasthenia gravis Muscle weakness Kidney Glomerular basement membrane Goodpasture=s Glomerulonephritis Pancreas Islets of Langerhan Diabetes mellitus type I Insulin-dependent hyperglycemia CNS myelin Multiple sclerosis (MS) neurologic dysfunction
42	Organ-Non-Specific Autoimmune Disorders The immune response is directed against specific antigens but the immune complexes involve many other organs or tissues of the body Examples of these types of diseases include: Systemic Lupus Erythematosus (SLE) Š Rheumatoid Arthritis (RA)
43	Tissue Injury – Autoimmune Diseases Mechanism responsible for tissue injury include: UAntibody-mediated cytotoxicity eIgG or IgM type antibodies eAttach to antigen and causes cytolysis as in type II hypersensitivity reactions UImmune complex deposition eAntibody-Antigen complex forms eNormally removed by phagocytes eIf not removed they are deposited on various tissues as in Type III hypersensitivity reactions UCell-mediated cytotoxicity eWhen T cells fail to recognize self-antigens they can begin destroying host cells via type IV hypersensitivity reactions
44	Immunodeficiencies - Index Immunodeficiencies
45	Definition of Immunodeficiency A defect or deficiency in any one or more of the main components of the immune system which results in an abnormally low immune response. The components of the immune system include: B lymphocytes Š T lymphocytes Š Phagocytes Š Complement
46	Categories of Immunodeficiencies Primary immunodeficiencies Šalso called congenital or hereditary immunodeficiencies Šimmunodeficiencies that are the result of genetic defects Šbecome evident at birth or early childhood Secondary immunodeficiencies Šalso called acquired immunodeficiencies Šimmunodeficiencies that develop subsequent to infection, cancer, or therapy Šbecome evident later in life
47	Congenital Immunodeficiencies Name of Disorder Origin of Defect Specific Defect Bruton=s agammaglobulinemia mutated gene on X chromosome blocked B cell maturation IgG subclass deficiency defect in Ig isotype switching blocked B cell differentiation Common variable immunodeficiency intrinsic B cell defect B cell differentiation to plasma cells abnormal DiGeorge=s syndrome abnormal thymus gland defect in T cell maturation SCID (autosomal rec.) PNP enzyme deficiency abnormal T & B cell development SCID (X-linked) IL-2 receptor gene mutation abnormal T cell growth & development Chronic granulomatous disease intracellular H₂O₂ not produced defective phagocytosis
48	Acquired Immunodeficiencies Name of Disorder Origin of Defect Specific Defect Acquired Immunodeficiency Syndrome (AIDS) HIV-induced loss of CD4+ cells lysis of CD4+ cells by viral budding Acquired Immunodeficiencies - secondary to Malignancy or R_x Hodgkin=s disease T cell abnormality impaired T cell function Immunosuppressive drug therapy destruction of lymphs, PMN, & monocytes cytotoxic effects Name of Disorder Origin of Defect Specific Defect
49	Congenital Defects in Complement Characteristics of deficiency: Šincreased susceptibility to infection by pyogenic and intracellular bacteria Šincreased tendancy to develop immune complex diseases Examples of some component deficiencies: ŠC3 - lack of opsonization results in decreased phagocytic function Šfactor H may be fatal due to pyogenic bacteria ŠC5 - results in lack of MAC - susceptible to intracellar infections by Neisseria species ŠC1, C4, or C2 - lack of clearing of immune complexes Šfactor I
50	Hypergammaglobulinemias - Index Hypergammaglobulinemias
51	Definition & Types of Hypergammaglobulinemia An increased proliferation of antibody- producing plasma cells that leads to increased immunoglobulin production Types of gammopathies: Monoclonal gammopathies Š Polyclonal gammopathies
52	Monoclonal Gammopathies Ualso called plasma cell dyscrasias Ucharacterized by an uncontrolled proliferation of a single clone of plasma cells at the expense of other clones Uin Multiple Myeloma the monoclonal antibodies produced in 52% of patients is of the IgG class Uin Waldenstrom=s macroglobulinemia the antibodies produced are of the IgM class
53	Polyclonal Gammopathies Ucharacterized by an uncontrolled proliferation of several clones of plasma cells which results in the production of more than one class of immunoglobulin being produced UExamples of diseases associated with polyclonal gammopathies include: Šacute infections Šchronic infections Šrheumatoid arthritis Šliver disease
54	Lab Diagnosis of Gammopathies Uprotein electrophoresis is most common method Normal Electrophoretic mobility - + ( $ "₂ "₁ globulins albumin IgG IgA IgD IgM
55	Monoclonal Gammopathy Electrophoretic mobility - + Concentration º ( $ "₂ "₁ albumin
56	Polyclonal Gammopathy Electrophoretic mobility - + Concentration º ( $ "₂ "₁ albumin
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