Immunopathology I PDF

Immune System & Hypersensitivity DR. HASSAN OTIFI Path 333 _1st semester_1442- 2020  Objectives…  Understanding the basics of Immune Response (IR)  Highlighting the most common types of IR  Explanation the cellular involvement in IR  Outlining the defense mechanis...

Immune System & Hypersensitivity DR. HASSAN OTIFI Path 333 _1st semester_1442- 2020  Objectives…  Understanding the basics of Immune Response (IR)  Highlighting the most common types of IR  Explanation the cellular involvement in IR  Outlining the defense mechanisms of IR Clarification the concepts of Auto-Immune processes  Explanation the major types of Hypersensitivity Rxns  The Immune System  A functional system – NOT an organ system we i.at is in  A complex system – includes: molecule tissue » Skin – physical barrier » Lining of mucus membranes – physical barrier like » Secretions – tears, mucus etc. - antimicrobial » Blood cells and vasculature – WBCs » Bone marrow Production of immune cells » Liver – makes complement proteins » Lymphatic system and lymphoid organs » Most tissues – have resident immune cells  IMMUNITY  Immunity: is body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells.  It consists of the following activities: » Defense against invading pathogens (viruses & bacteria) no longer ingoodconditions » Removal of 'worn-out' cells (e.g., old RBCs) & tissue debris (e.g., from injury or disease) » Identification & destruction of abnormal or mutant cells (primary defense against cancer) » Rejection of 'foreign' cells (e.g., organ transplant) » Inappropriate responses: overreaction – Allergies - response to normally harmless substances – Autoimmune diseases. Overview of the Immune System Immune System from motherafterdelivery fromourbody orwithvaccine or Infection Innate Adaptive (Non-specific) (Specific) 1o line of defense 2o line of defense Interactions between the two systems  A Typical Immune Response atural killersare rt of innate Why INNATE IMMUNITY ACQUIRED IMMUNITY patent.ruPe fificinffeftion Rapid responses to a Slower responses to broad range of microbes specific microbes whichmake it Skin is the first strong lineofexternaldefence 20 186 External defenses Internal defenses gjw.si Thin c.ttiahinPaf is IT Skin Phagocytic Yes she ph cells Humoral response Mucous membranes Antimicrobial proteins (antibodies) egcytokines B lymphocyte Secretions STIcids Inflammatory response Invading microbes 85 shifietumers Natural killer cells Complement Cell-mediated response (pathogens) I chistical s proteins 22innumber (cytotoxic lymphocytes) Tlymphocyte 3 alternative formed intheLiver activated 3 mechanisms Helper Tcytotoxic Innate immunity vs Adaptive Immunity Innate Immunity Adaptive Immunity (first line of defense) (second line of defense) Delay No time lag A lag period 9 eks Not antigen specific Antigen specific I T.IT No memory Development of memory Thisinvaccite  CELLS OF IMMUNE SYSTEM  Hematopoiesis Bic.PTduction of » Immune cells originate in the bone marrow » Hematopoietic Stem Cell (HSC) – pluripotent-self regulating ftp.p – give rise to progenitors of more limited potential rentTg Lymphoid progenitor lymphoid  titikid » B cells » T cells » NK cells  Myeloid progenitor  Polymorphonuclear leukocytes, monocytes, dendritic cells  Erythroid progenitor …. antibody » Parasitic pathogens Type of T helpercell – stimulate Th2 cells --> activate eosinophils- phagocytosis  Intracellular » intracellular bacteriaEg Tb – stimulate Th1 cells ----> cytokines - phagocytosis » viruses – stimulate CD8 CTL ----> cytolytic molecules CTL: Cytotoxic T lymphocytes  Regulation of Immune Response  Immune responses need to be turned off When whent.tt genis removed  If not: » Autoimmunity » Hypersensitivity reactions » Tissue damage - necrosis  Disorders of Immunity MD w Ii A- Hypersensitivity Reactions higher than needed reaction MI I B- Autoimmune DiseasesAgainst body C- Immunodeficiency Diseases less in needed reaction D- Amyloidosis Deposition of misfolded protein Causing tissue damage  Hypersensitivity Hypersensitivity: refers to undesirable reactions produced by the normal immune system. normal immune system give abnormal reaction It is classified into 4 types based on the immune mechanisms of tissue injury:  Type I (immediate or anaphylactic) hypersensitivity  Type II (cytotoxic) hypersensitivity  Type III (Immune complex) hypersensitivity  Type IV (Delayed-type) hypersensitivity  Type I Hypersensitivity Known as immediate or anaphylactic hypersensitivity. Commonly called allergy Mediated by IgE antibodies produced by plasma cells in response to stimulation of Th2 cells by an antigens. The antigens that stimulate it are called allergens (i.e. House dust, Pollens, Cosmetics, e Insects, Clothing and Drug). Exposure may be ingested, inhalation, injection or direct contact. in no Type I hypersensitivity reactions can be systemic (e.g., systemic anaphylaxis) or localized to a specific target tissue or organ (e.g., allergic rhinitis, asthma).  Type I Hypersensitivity ECF = eosinophil chemotactic factor NCF = neutrophil chemotactic factor Anaphylaxis; Anaphylactic Reaction PAF = platelet-activating factor  Mast cell proliferation and IgE production by plasma cells  IgE bound mast cells  Recurrent exposure: fistmin -- Mast cell degranulation -- Vasodilation -- Bronchoconstriction, etc. I in amine 9 EF  Phases of Type I Hypersensitivity -Initial (rapid) response: within 5-30 min after re- exposure with resolution within 30 min, mediated by primary mast cell mediators. - Second (delayed) phase: 2-8 hours later, lasts for days and characterized by an intense infiltration by inflammatory cells and tissue damage. It is mediated by secondary mast cell mediators.  Phases of Type I Hypersensitivity Primary mast cell mediators include: no Biogenic amines (histamine): bronchial smooth muscle contraction, increased vascular permeability and increase mucous gland secretions. chemotactic mediators (eosinophil chemotactic factors and neutrophil chemotactic factors. enzymes contained in granule matrix (tryptase,chymase) which lead to generation of kinins and activated complement by acting on precursor proteins. Proteoglycans (heparin) prostaglandin Secondary mediators: Lipid mediators and cytokines Type I Hypersensitivity A sequence of Events Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7th ed., Saunders, Philadelphia, 2003.  Type I Hypersensitivity Reaction Clinical Manifestations  Systemic anaphylaxis: -- Acute asthma -- Laryngeal edema May Cause airway obstruction anddeath -- Diarrhea -- Urticaria Skin disease -- Shock (Anaphylactic shock) Typically follows oral administration of allergen as:  E.g.: penicillin allergy  E.g.: bee sting allergy urticaria  Antisera, Drugs, Hormones Antibodies in Serum  Type I Hypersensitivity Reaction Clinical Manifestations  Local anaphylaxis (Atopy):  Food allergies: -- Urticaria or Hives -- Asthma -- Hay fever/ allergic rhinitis (Ragweed pollen)  Wheal reaction: Local area Eosinophil of erythema and edema due to intradermal injection of antigen in sensitized individual.  Type II Hypersensitivity Type II hypersensitivity is also known as cytotoxic hypersensitivity and may affect a variety of organs and tissues. Type II hypersensitivity involves IgG or IgM antibody- mediated. IgM or IgG immunoglobulin react with cell-surface antigens to activate the complements system and produce direct damage of the cell surface. Through Classical pathway  Type II Hypersensitivity 1- Complement Dependent Reaction:  Antibody is directed against a tissue antigen -- e.g. RBC or basement membrane o  Ag-Ab complexes activate complement leading to cell lysis or extracellular tissue damage s Two mechanisms: A- Direct Lysis CS Ca F B- Opsonization Examples: (Enhanced phagocytosis). sC3b -Transfusion reactions -Haemolytic anemias -Goodpasture’s disease of the kidney autoimmune disease  Type II Hypersensitivity 2- Antibody- Dependent Cell- Mediated Cytotoxicity (ADCC) parasite  Targets are lysed by non- sensitized cells with Fc receptors.  NK cells, monocytes, and granulocytes then bind to the immunoglobulin Fc receptors and causes damage. 4h25 antibody iv 21 parasite I antigen is 21 ten IgE I Ige 11 cellesnophilmacrophages mast 261 is a parasite I w̅ granules 21 the gig  Type II Hypersensitivity Reaction 3- Antibody- mediated cellular dysfunction Antibodies directed against cell surface receptors impairs me or dysregulate function without causing cell injury.  Examples:  Myasthenia gravis: Antibodies against acetylcholine receptors in motor end plate of skeletal muscles impair neuromuscular transmission & result in muscle weakness.  Grave's disease (thyrotoxicosis): Anti-TSH receptor antibody stimulate thyroid and result in hyperthyroidism.  Type II Hypersensitivity Antibody-Mediated Injury Myasthenia gravis (Acetylcholine receptor antibody)  Type II Hypersensitivity Reaction Clinical Manifestations  Transfusion and transplant reactions Bilirubin staining  Rhesus incompatibility between Rh-negative mother and Rh-positive fetus (erythroblastosis fetalis) Erythroblastosis fetalis  Elevated Rh antibody titers thebaby's bloo   3in Many immature RBCs in blood Excess bilirubin from RBC breakdown  Progressive anemia, ischemia, death  Brain damage from bilirubin: kernicterus  Prevention: Rh- mother gets anti-D o immunoglobulin after birth (covers antigenic sites on baby’s RBCs in mother’s blood  Rx: phototherapy of baby (breaks bilirubin) Immune hydrops from Rh hemolysis Treatment  Type II Hypersensitivity Reaction 7 I c Clinical Manifestations Aanemia z.ie RBCs 6 24 68  Autoimmune hemolytic anemia  Agranulocytosis is neutrophil granulocyteswhich iiitiiifiit.nl platelet  Thrombocytopenia pat pa.ge ttii c Pemphigoid  Pemphigus vulgarist.si siiiiiii i  Pemphigoid (Cicatricial pemphigoid) Is Pemphigoid  Type III Hypersensitivity Same astype2 butthe differant that e type3 in theblood notinthe surface Type III hypersensitivity is also known as immune complex hypersensitivity (ICH). The reaction may take 3 - 10 hours after exposure to the antigen (as in Arthus reaction). The reaction may be general (e.g., serum sickness) or may involve individual organs B Antigens causing immune complex mediated injury are: Exogenous forshort timebecause Endogenous nata i.it Life longdisease i i Et se  Type III Hypersensitivity Immune Complex Mediated  Ag-Ab complexes is formed either in circulation or extravascular.  Tissue damage primarily through complement activation  Exogenous antigen: i.e. bacterial, viral  Endogenous antigen: i.e. DNA antigens  C3b acts as an opsonin  C5a acts as a chemoattractant for neutrophils -- Acute Necrotizing Vasculitis  Type III Hypersensitivity Immune Complex Mediated 5 Immune complexes can be deposited:  I- Systemically (Serum sickness type) due to administration of large amount of foreign serum  II- Locally (Arthus reaction type) in one organ Usually in joints Common clinical findings: Fever UrticariaSkin rash ArthralgiaPain in joints Enlargeof Lymphadenopathylymph node Proteinuria or hematuria I. Systemic Immune Complex Disease  Immune Complex Mediated Damage  Acute (single large dose of Ag exposure):  Acute serum sickness  Post-Streptococcal glomerulonephritis  Chronic (persistent/repeated Ag exposure): Life persisting conditions  Systemic lupus erythematosus SLE  Rheumatoid arthritis  Membranous glomerulonephritis Immune Complex Deposition in Glomerulus Type III Hypersensitivity  II- Local Immune Complex Disease (Arthus Rx) Only one organ affected A localized area of tissue necrosis resulting from acute immune complex vasculitis. Local formation and deposition of immune complexes. on Planting of antigen within a particular tissue (e.g., renal glomeruli) with subsequent formation of immune complexes. Produced experimentally by intracutaneous antigen injection in a sensitized host carrying antibody Large immune complexes deposition = complement and coagulation cascades activation and platelets aggregation lead to fibrinoid necrosis b IS  Hypersensitivity Type IV  known as cell mediated or Delayed Type Hypersensitivity  Delayed hypersensitivity is a function of T Lymphocytes, not antibody.  It starts hours (or Days) after contact with the antigen and often lasts for days.  It can be transferred by immunologically committed (Sensitized) T cells, not by serum.  Principal pattern of immunologic response to variety of intra cellular microbiologic agents i.e.: Mycobacterium Tuberculosis, Viruses, Fungi, and Parasites  Hypersensitivity Type IV 1. Delayed-Type Hypersensitivity (DTH): 000  Principle pattern of response in T.B., fungi, protozoa & parasites, & graft rejection and tumor immunity.  Mediated by CD4 cells of the Th1 that secrete specific cytokines after encounter the processed antigen in association with class II major histocompatibility complex.  Hypersensitivity Type IV  The Stimulations induction of CD4 response is facilitated by IL-12 that secreted by macrophages that have engulfed microbes or other antigen cytokines mediate injury by recruiting and activating antigen-nonspecific monocytes and macrophages.  with persistence of non-degradable antigens, the initial non-specific infiltrate of T cells and macrophages is replaced by collections of macrophages that transform into epithelioid cells forming local granuloma.  A granuloma is a special form of DTH.  Type IV Hypersensitivity Delayed Hypersensitivity Reaction CD4+ T lymphocytes + class II MCH molecules Numerous cytokines Macrophages Anti-CD4 Antibodies Granuloma Formation Multinucleated giant cell  Type IV Hypersensitivity 2. T cell-Mediated Cytotoxicity Sensitized CD8+ cytotoxic T lymphocytes (CTLs) is the principle pattern of response in this type of response. - e.g. a- Viral infection b- Tumor cells c- Transplant rejection - Class I MHC molecules bind to intracellular viral peptides and present them to CD8+ T lymphocytes. Mechanism of CTL Killing: 1- Perforin- granzyme- dependent killing: Perforin and granzyme are soluble mediators of the CTLs that induce apoptosis of the target cells. 2- Fas- Fas ligand- dependent killing: Activated CTLs express Fas ligand (a molecule with homology to TNF) which binds to Fas on target cells that leads to apoptosis.  Plasmacel stffraff oafo on sesterces tolymphnode Going ffF Éfaa s stF sts cell memory FiveBcell corphages cytogines