Lecture 5 - Alterations In The Immune Response PDF

ALTERATIONS IN THE IMMUNE RESPONSE Dr. Carol Gardner [email protected]  Allergy & Hypersensitivity Immune responses in which the antigen is an environmental agent, food, or drug which is not intrinsically harmful.  Type I Hypersensitivity...

ALTERATIONS IN THE IMMUNE RESPONSE Dr. Carol Gardner [email protected]  Allergy & Hypersensitivity Immune responses in which the antigen is an environmental agent, food, or drug which is not intrinsically harmful.  Type I Hypersensitivity TYPE I Allergic Responses - Immediate, IgE mediated, causes release of histamine, leukotrienes and prostaglandins from mast cells and basophils, atopic (sustained, inappropriate IgE responses to common environmental antigens encountered at mucosal surfaces, usually familial association) Examples: Acute anaphylaxis, hay fever, food allergies Initiation of Type I Hypersensitivity Robbins, Basic Pathology, 10th edition Organ Effects of Mast Cell Degranulation  Acute Anaphylaxis Fla Assoc. EMS Educators Internet Pathology Laboratory for Medical Education, Mercer Univ. School of Medicine, GA  Type II Hypersensitivity TYPE II Cytotoxic Reactions - IgG OR IgM mediated, complement involved, reactions commonly effect cellular elements in intimate contact with circulating plasma. Can result in: Opsonization and phagocytosis Inflammation Antibody-mediated cellular dysfunction Examples: Hemolytic anemia, Transfusion reactions, Grave’s Disease Type II Hypersensitivity Reactions Robbins, Basic Pathology, 10th edition  Type III Hypersensitivity TYPE III Immune Complex Reactions – IgG OR IgM mediated, complement involved, formation of immune complexes, tissue damage Examples: 1) Serum Sickness – Disease caused by antibody produced to horse or bovine serum used in antitoxins. Aggregates of IgG activate complement 2) Arthus Reaction – Dermal inflammatory response, caused by reaction of antibody to antigen in skin Type III Hypersensitivity Reactions Arthus Reaction http://www.lookfordiagnosis.com/mesh_info.php?term=arthus+reaction&lang=1 Arthus Reaction Centers for Disease Control and Prevention  Type IV Hypersensitivity TYPE IV – Cell mediated or delayed hypersensitivity T-cell mediated, sensitized to locally deposited antigen. Reaction mediated by release of lymphokines and/or direct cytotoxicity. Examples: Contact sensitivity (poison ivy)  Type IV Hypersensitivity Reactions Pentadecacatechol molecules Pentadeca catechol molecules + skin proteins https://courses.lumenlearning.com/microbiology/chapter/hypersensitivities/ Contact Dermatitis Hypersensitivity Review phagocytosis http://voer.edu.vn/c/diseases-associated-with-depressed-or-overactive-immune-responses/948ed3b1/b33aa783  Autoimmunity A breakdown in tolerance in which the body’s immune system begins to Genetics + recognize self-antigens as foreign. Crohn’s Disease  Major Histocompatibility Complex (MHC) The major histocompatibility complex (MHC), also referred to as HLA (human leukocyte antigen) is a large genomic region or gene family found in most vertebrates, highly conserved. In humans, found on chromosome 6 It is the most gene-dense region of the mammalian genome and plays an important role in the immune system, autoimmunity, and reproductive success. Extreme polymorphism: millions of alleles or variants exist, individuals inherit haplotypes. Determination of “self” vs “non-self”, direct T cell responsiveness.  Major Histocompatibility Complex Class I MHC: expressed on all somatic cells; classic “transplantation antigens”, genes: A, B, C, interact only with T cytotoxic cells Class II MHC: expressed on immune cells (B,T, macrophages, dendritic cells, thymus epithelium); immune associated (IA) antigens; important in immune regulation, cell-cell communication, genes: DP, DQ, DR (and others), interact only with T helper cells Class III MHC: complement Prevalence of Autoimmune Diseases http://www.the-scientist.com/?articles.view/articleNo/24982/title/Supplement--The-Trials-of-Keeping-Track Mechanisms Leading to Autoimmune Disease A) Original Insult –Drug induced (hydralazine, a-methyldopa, procainamide) or virus-induced changes in cell surface antigens causes production of anti- idiotypic antibodies. B) Similarities between exogenous antigens and self-antigens (cross reactivity). C) Genetic factors – usually familial, products of the MHC locus (HLA-DR2 over represented in patients with SLE) or the inappropriate immune function may involve histocompatability-complex-linked immune response genes (e.g. C4 & C2 genes), can be triggered by ultraviolet light. X-chromosome? D) Abnormal immunoregulation – B cell overactivity, presence of spontaneously activated T & B cells, decreased T cell function. E) Hidden antigen theory F) Long noncoding RNA Xist – silences 1 of 2 X chromosomes, makes ribonucleoprotein complex with unique binding proteins, some are autoantigens, activate TLR pathways on innate immune system cells  Classification of Autoimmune Diseases MHC Class II-Associated Organ specific (autoantibody directed against a single organ or closely related organs) Systemic (systemic lupus erythematosis – variety of autoantibodies to DNA, cytoplasmic antigens, etc.) MHC Class I-Associated HLA-B27-Related spondyloarthropathies (ankylosing spondylitis, Reiter’s syndrome) Psoriasis vulgaris (associated with HLA-B13, B16, B17)  Examples of Antibody-Mediated Autoimmune Diseases DISEASE ANTIGEN Autoimmune Cytopenias (Anemia, Erythrocyte, platelet, or neutrophil Thrombocytopenia, Neutropenia) cell surface determinant Goodpasture’s Syndrome Type IV Collagen Myasthenia Gravis Acetylcholine Receptor Hyperthyroidism Thyroid stimulating hormone receptor Insulin resistant diabetes Insulin receptor  Examples of T Cell Mediated Autoimmune Disease DISEASE SPECIFICITY OF T CELL CLONE Multiple Sclerosis Myelin basic protein Autoimmune thyroiditis Thyroid follicular epithelial cells Insulin dependent diabetes mellitius Pancreatic islet b cells, insulin, glutamic acid decarboxylase Viral myocarditis Coxsackie B virus  Human Proteins with Structural Homology to Human Pathogens DISEASE HUMAN PROTEIN PATHOGEN Ankylosing spondylitis, HLA-B27 Klebsiella pneumoniae Reiter’s Syndrome Rheumatoid arthritis HLA-DR4 Epstein-Barr virus Insulin dependent Insulin receptor, Papillomavirus, diabetes HLA-DR, glutamate cytomegalovirus, decarboxylase coxsackievirus P2-C enzyme Rheumatic heart Cardiac myosin Group A Streptococci disease  Systemic Lupus Erythematosus (SLE) Antibodies produced against: Nucleic Acids RBCs, WBCs, platelets Phospholipids Coagulation proteins Damage caused by immune complex deposition (Type III hypersensitivity). Imbalance between CD4+ T cell subtypes (Law, et al. Nature 631:857-866, 2024) Lupus Malar Rash https://web.archive.org/web/20170227205201/http://hardinmd.lib.uiowa.edu:80/dermnet/lupus4.html  Anti-Nuclear Antigen Test Internet Pathology Laboratory for Medical Education, Mercer Univ. School of Medicine, GA Sometimes when performing the ANA test, the substrate cells demonstrate particular patterns of staining. This is the so-called "rim" pattern that is more characteristic of systemic lupus erythematosus (SLE) than other autoimmune diseases.  Alloimmunity The immune system acts against antigens on tissues of other members of the same species. Fetal and Neonatal Diseases: 1) Graves Disease – Antibody against thyroid-stimulating hormone receptor, neonatal hyperthyroidism 2) Myasthenia Gravis – Antibody binds with receptors for nicotinic acetylcholine receptors on muscle cells, transient 3) Neonatal alloimmune thrombocytopenia – Antiplatelet antibody, destroys fetal platelets cells, against paternally derived antigens 4) Alloimmune neutropenia – Anti-neutrophil antibody destroys neutrophils in fetus 5) Systemic lupus erythmatosus (SLE) – Autoantibodies cause abnormalities in fetus 6) Rh & ABO Alloimmunization – Erythroblastosis fetalis B) Transplant Rejection – 1) Hyperacute - Immediate, usually occurs in the presence of pre-existing antibody to donor HLA antigens in the graft. 2) Accelerated – Occurs within days, reactivation of sensitized T cells (presence of memory T cells from previous transplant) 3) Acute – Occurs within 2 weeks after transplant, immune response is mounted against unmatched HLA antigens, primary activation of T cells, antibody and cell-mediated. 4) Chronic – May occur months or years after transplant, characterized by slow progressive organ failure, typically a Type IV cell-mediated reaction, alloreactive T cells, antibodies and immune complexes involved.  Immunodeficiency Diseases Inhibition of normal immune responsiveness, deficiency may be “primary” (hereditary) or “secondary” (occurs after birth). There are over 50 different primary immunodeficiency diseases. Types of Deficiencies 1) B Cell 2) T Cell 3) Complement 4) Phagocytosis 1. Reticular Dysgenesis 4. Bruton Agammaglobulinemia 2. Severe Combined Immunodeficiency 5. Chronic Mucocutaneous Candidiasis 3. DiGeorge Syndrome 6. Selective IgA Deficiency  B Cell Deficiencies I. Primary - A. Transient Hypogammaglobulinemia – Delay in antibody production until age 2-3, makes child susceptible to bacterial and respiratory infection, self limiting, reduced expression of co-receptor CD19. B. X-Linked Hypogammaglobulinemia - MALES ONLY, called Bruton’s Disease –Low Ig levels, low or absent B cells and plasma cells, pre-B cells develop but do not mature, mutation of Btk gene on X chromosome, no antibody light chain production. C. Selective IgA Deficiency - MOST COMMON – lack of both serum and secretory IgA, failure of terminal differentiation of IgA-secreting B cells, occasionally familial, 2 genes identified. II. Secondary - A. Decreased synthesis of immunoglobulins – Occurs with lymphomas B. Increased loss of immunoglobulins - Nephrotic syndrome C. Production of defective antibodies - Multiple myeloma - Production of Bence Jones proteins, only monoclonal antibody light chains  T Cell Deficiencies I. Primary – A. DiGeorge’s Syndrome – Deletion in chromosome 22 at q11 region. Failure of thymus gland development – deficient T cell maturation, T cells absent from lymph nodes, spleen, peripheral blood Underactive parathyroid Heart defects Cleft lip and/or palate B. Chronic mucocutaneous candidiasis – Autosomal dominant or recessive, some association with chromosome 2, onset may be in infancy or adulthood, persistent Candida infections, alterations in cytokine production by TH1 cells. DiGeorge’s Syndrome (Velocardiofacial syndrome) Normal Thymus  Candidiasis http://medical-dictionary.thefreedictionary.com/candidiasis Carboni, et al. Acta Derm Venereol 82: 68-69, 2002 II. Secondary - A. Malignant Disease – Some Non-Hodgkin’s Lymphomas, Anergy – Failure to respond to skin antigens B. Transient suppression of T-cell production & function due to acute viral infection C. AIDS – Acquired immunodeficiency syndrome HTLV III (Human T-Cell lymphotropic virus; HIV-Human immunodeficiency virus). Attacks T helper cells, macrophages act as a reservoir of virus. Combined Antibody and Cellular Immunodeficiencies I. Primary – 1:58,000 newborns A. Complete lack of immune response (Severe Combined Immunodeficiency) – “David – The Bubble Boy”, sex-linked or autosomal recessive, caused by mutations in any of more than 15 known genes, commonly nonfunctioning interleukin receptors, atropic thymus, defective expression of MHC II, defective lymphocyte signaling B. Wiskott-Aldrich Syndrome – X-linked (WASp mutation), progressive age- related T cell depletion, no affective antibody production against polysaccharide antigens, accompanied by thrombocytopenia & eczema, defective neutrophils C. Ataxia Telangiectasia – Autosomal recessive, associated with mutation on chromosome 11, mutation of ATM protein (lack of DNA repair), loss of muscle coordination, blood vessel dilation combined with deficits in Ig production & low T cell numbers II. Secondary – A. X-irradiation B. Immune suppressant and cytotoxic drugs C. Aging  Complement Abnormalities Comprise between 1-10% of all primary immunodeficiencies I. Primary A. Hereditary angioedema – Congenital deficiency of complement 1 inhibitor B. Atypical hemolytic uremic syndrome – deficiency of Factor I or Factor H; gain of function mutation Factor B C. Selective deficiency of 1 or more complement components Most common – C2 and C3 deficiencies, C5 familial dysfunction II. Secondary – Primarily acquired disorders where complement is utilized – decreases in complement  Disorders of Innate Immunity I. Primary – Usually caused by enzyme deficiencies in leukocyte metabolic pathways A. Chronic granulomatous disease - X-linked disorder, metabolic pathways of both neutrophils & monocytes abnormal, no oxidative burst B. Myeloperoxidase deficiency – neutrophils unable to convert H2O2 to HOCl, mild predisposition to infection. C. Leukocyte adhesion deficiency - autosomal recessive, failure to bind to adhesion molecules (ICAMs or selectins) & complement opsonized particles, results in diminished Type IV hypersensitivity, necrotic skin lesions, cellulitis, pneumonia, sepsis. II. Secondary – A. Decrease in opsonins (antibody or complement) B. Immunosuppressive or corticosteroid drugs C. Diabetes