IMMUNOPATHOL OGY (DISEASES OF THE IMMUNE SYSTEM) Asst. Prof. Dr. Poonsit Hiransai School of Allied Health Sciences, Walailak University 12/13/2018Poonsit Hiransai 1

Learning outcomes Students should be able to Explain the concept of the immune response, covering organs, tissues, cells, and molecules of the immune system. 12/13/2018Poonsit Hiransai2

Immunology Immunitas (Lat): The exemption from various civic duties and legal prosecution offered to Roman senators during their tenure in office. Immunity (Eng): Protection from diseases, especially infectious diseases. ภูมิคุ้มกัน (TH): สภาพที่ร่างกายมีแรงต่อต้านเชื้อโรคที่เข้าสู่ ร่างกาย ภูมิต้านทาน ก็เรียก ภูมิ : สถานที่มีอยู่เป็นอยู่แห่งสัตว์โลก หรือ แผ่นดิน หรือ ร่างกาย คุ้มกัน : คอยป้องกันให้ปลอดภัย คุ้มครองให้พ้นจากบางสิ่ง บางอย่าง เช่น คุ้มกันโรค คุ้มกันไม่ให้ถูกฟ้องร้อง 12/13/2018Poonsit Hiransai3

The concept of the Immune Response 12/13/2018Poonsit Hiransai4 Foreign body Recognition phase Activation phase Effector phase Cleared ? Homeostasis phase No Yes

Immune Responses

The concept of the Immune Response 12/13/2018Poonsit Hiransai6 Foreign Recognition phase Activation phase Effector phase Cleared ? Homeostasis phase No Yes Development Memory 1 st 2 nd

Foreign body

Pathogen: Substances have an ability to cause diseases (Pathogenicity) Immunogen: Substances have an ability to activate the immune response (Immunogenicity) Antigen: Substances have an ability to bind an antibody or T-cell receptor (Antigenicity)

Foreign Characteristics Pathogen-associated molecular patterns (PAMPs): Microbe-associated molecular pattern (MAMPs) Foreign biomolecules initiate and perpetuate the infectious pathogen-induced inflammatory response; Endotoxin, Manan, Peptidoglycan, and Nucleic acid from intracellular pathogen 12/13/2018Poonsit Hiransai9

Foreign Characteristics Pathogen-associated molecular patterns (PAMPs): Damage-associated molecular patterns (DAMPs): Host biomolecules that can initiate and perpetuate a noninfectious inflammatory response; HMGB1, S100 proteins, Purine metabolites, and host DNA/RNA. 12/13/2018Poonsit Hiransai10

Pathogenic microbes Extracellular microbes Bacillus anthracis Enterotoxigenic Escherichia coli Haemophilus influenza Mycoplasma spp Pseudomonas aeruginosa Staphylococcus aureus Streptococcus pyogenes Vibrio cholerae Intracellular microbes Bacteria Legionella pneumophila R. rickettsii Mycobacterium tuberculosis Listeria monocyotogenes Salmonella spp: Virus Cancer cell 12/13/2018Poonsit Hiransai11

Classification of the Immune system Innate Immune System: Resistance exists prior to exposure to microbes. (Natural occurring Immunity) Preformed Fully active Low specificity No improvement after exposure Not sufficient for survival 12/13/2018Poonsit Hiransai12

Immune system Innate Immune System: The 1 st Line Host Defenses: Aim: Limit entry of microbes into the body by natural barriers. Characteristic: Non-specific mechanism Mechanical barrier Physicochemical barrier Biological barrier 12/13/2018Poonsit Hiransai13

Keratin layer of intact skin From: Keratin is extremely insoluble in water and organic solvents.

Fatty acid and low pH Skin

From: (1) (2) Mecanism_of_action_for_Lysozyme.svg.pnghttps://upload.wikimedia.org/wikipedia/commons/thumb/2/2f/Mecanism_of_action_for_Lysozyme.svg/719px- Mecanism_of_action_for_Lysozyme.svg.png Lysozyme is a glycoside hydrolase, in tears and other secretions, that catalyzes the hydrolysis of 1,4-beta- linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in peptidoglycan, which is the major component of gram-positive bacterial cell wall.

Defensins are small cysteine-rich cationic proteins. They are active against bacteria, fungi and many enveloped and nonenveloped viruses. Most defensins function by binding to the microbial cell membrane, and, once embedded, forming pore-like membrane defects that allow efflux of essential ions and nutrients. From: (1) (2)

From: Cilia, a hair-like projections lined in the bronchus, move microbes and debris up and out of the airways.

Vaginal pH

Normal flora

Foreign Activation phase Effector phase (Inflammation) Innate Immunity The 2 nd line host defenses Phagocytes Complements The 1 st line host defenses Recognition phase (PAMPs/DAMPs: PRR) Recognition phase Adaptive Immunity The 3 rd line host defenses APC Complements Homeostasis phase Cleared ?

Immune system Innate Immune System: The 2 nd Line Host Defense: Aim: Limit growth of microbes within the body Characteristic: Rapid reaction, Limit reaction Inflammatory reaction Cell and mediators of Innate immune system Role: Recognition phase and/or Effector phase Pattern recognition receptors (PRRs) 12/13/2018Poonsit Hiransai23

Complement proteins 12/13/2018Poonsit Hiransai25 Spontaneous Hydrolysis Pathogenic surface Opsonin/Opsonization Phagocytosis

Cell-mediated Innate Immunity Inflammatory reaction Neutrophil Eosinophil Basophil Mast cell Phagocytosis and Antigen presentation Dendritic cells Macrophages

Natural Killer Cells (NK cells) 12/13/2018Poonsit Hiransai27 Common Lymphoid Progenitor Peripheral lymphoid and non-lymphoid tissue

Function of NK cell to Intracellular infection 12/13/2018Poonsit Hiransai28 Perforin/Granzymes Apoptosis Phagocytic activation

Antigen-presenting cells (APCs) 12/13/2018Poonsit Hiransai29

Monocytes/Macrophages 12/13/2018Poonsit Hiransai30

Dendritic cells 12/13/2018Poonsit Hiransai31

Phagocytic cells 12/13/2018Poonsit Hiransai32

Structure of MHC Molecule 33

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Immune system Adaptive Immune System: Resistance that occurs after exposure to an agent, improve upon repeated exposure, and specific in response. Need interaction from previous response Take time to active Improvement after repeated exposure Long term in memory Highly diversity and more specificity 3 rd Line Host Defense: Destroying microbes and protecting the body from repeated infection Cell and mediators of Adaptive immune system Specific reaction 12/13/2018Poonsit Hiransai35

Foreign Activation phase Innate Immunity The 2 nd line host defenses The 1 st line host defenses Recognition phase (PAMPs/DAMPs: PRR) Recognition phase Adaptive Immunity The 3 rd line host defenses APC Complements Homeostasis phase Activation phase Effector phase (Specific reaction) Development Memory Cleared ?

Components of Immune System 12/13/2018Poonsit Hiransai37 Primary Lymphoid Organ Secondary Lymphoid Organ

T and B Lymphocytes 12/13/2018Poonsit Hiransai38

Activation of Cytotoxic T lymphocytes 12/13/2018Poonsit Hiransai39

Cytotoxic T lymphocyte Function 12/13/2018Poonsit Hiransai40

Activation of Helper T lymphocytes 12/13/2018Poonsit Hiransai41

Helper T lymphocyte Functions 12/13/2018Poonsit Hiransai42

Helper T lymphocyte Functions 12/13/2018Poonsit Hiransai43

B lymphocytes 12/13/2018Poonsit Hiransai44

Activation of B lymphocytes 12/13/2018Poonsit Hiransai45

Activation of B lymphocytes 12/13/2018Poonsit Hiransai46

Immunoglobulin/Antibody Structure 12/13/2018Poonsit Hiransai, MT, SAP, WU47 Ig domains

Immunoglobulin Isotype / Antibody Classes

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12/13/2018Poonsit Hiransai51 InnateAdaptive Characteristics SpecificityPattern RecognitionSelf and Non-self Discriminations DiversityGermline-encodedSomatic recombination MemoryNoneYes Non-reactivity to SelfYes Components Physical and Chemical barrier Skin, Mucosal epithelia; antimicrobial chemicals Lymphocytes in epithelia; antibody secreted at epithelial surfaces Blood proteinComplementAntibody CellsPhargocytes and NK cell Lymphocytes

References อรวดี หาญวิวัฒน์วงศ์. วิทยาภูมิคุ้มกันพื้นฐานและคลินิก. กรุงเทพฯ, Kindt, TJ, Goldsby, RA, Osborne, BA. Kuby Immunology (6 th ed.), W.H. Freeman and Company, New York, 2007 Murphy K, Travers P, and Walport M. Janeway’s Immuno Biology (7 th ed), Garland Science, New Yok, 2008 Abbus AK, Litchman AH, and Pillai S. Cellular and Molecular immunology. 7 th ed., Philadelphia: Saunder Warren Levinson. Review of Medical Microbiology and Immunology. 13 th ed., Philadelphia: McGraw-Hill education /13/2018Poonsit Hiransai, MT, SAP, WU52

DISEASES OF THE IMMUNE SYSTEM Asst. Prof. Dr. Poonsit Hiransai School of Allied Health Sciences, Walailak University

LEARNING OUTCOMES Students should be able to  Gives examples and explain the mechanisms of immunologic disorders, covering immunodeficiency, hypersensitivity reactions, and autoimmune diseases. 12/13/2018Poonsit Hiransai 54

DISEASES OF THE IMMUNE SYSTEM Diseases of the immune system Hypersensitivity Reaction Immunodeficiency Diseases Type IType IIType IIIType IV Type IIIaType IIIb PrimarySecondary Autoimmune diseases/Transplantation

IMMUNOLOGICAL MECHANISM OF TISSUE DAMAGE  Hypersensitivity Reaction  An immune response leads to tissue injury or disease.  An immune s to antigens may be excessive, causing harm or inconvenience to the host.  An immune reaction occurs in response to innocuous antigens that would pose no danger to the host.

TYPES OF HYPERSENSITIVITY REACTION  Classification by Immune-mediated mechanisms and components  Type I Hypersensitivity Reaction  Type II Hypersensitivity Reaction  Type III Hypersensitivity Reaction  Type IV Hypersensitivity Reaction

TYPE I HYPERSENSITIVITY  Allergic Hypersensitivity  IgE-mediated Hypersensitivity  Immediate-type hypersensitivity

TYPE I HYPERSENSITIVITY C3a/C5a Anaphylaxis

TYPE II HYPERSENSITIVITY  Antibody-mediated Hypersensitivity  IgG  IgM

TYPE II HYPERSENSITIVITY

BLOOD TRANSFUSION REACTION 63 Fever Chill Hypotension Shock Liver and Kidney Toxicity Nausea Vomiting Low back pain

HEMOLYTIC DISEASE OF NEWBORN 64 Hemorrhaging Jaundice Abortion

DRUG-INDUCED AND AUTOIMMUNE HEMOLYTIC ANEMIA 65

AUTOIMMUNE THYROIDITIS 66

MYASTHENIA GRAVIS 67

RHEUMATIC FEVER 68

TYPE III HYPERSENSITIVITY  Antigen-Antibody complex  IgG  IgM

TYPE III HYPERSENSITIVITY

SYSTEMIC TYPE III REACTION VASCULITIS 71

SERUM SICKNESS 72

RHEUMATOID ARTHRITIS 73

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) 74

TYPE IV HYPERSENSITIVITY  Cell-mediated Hypersensitivity  Delayed-type Hypersensitivity

TYPE IV HYPERSENSITIVITY

AUTOIMMUNE DISEASES  Group of disorders which caused pathologic condition by humoral immune response or cell-mediated immune response against endogenous substances  Systemic  Organ specific

THEORIES OF AUTOIMMUNITY Inaccessible Self- Antigen Abnormal T-cell Function Molecular Mimicry Polyclonal B-cell Activation

TRANSPLANTATION  Transfer of organs and tissues site within the same individual or from a donor to a recipient  Acute rejection, hyperacute rejection  Destroy vascular supply to transplant / thrombosis  Chronic rejection  Ischemic organ damage

GRAFT-VERSUS-HOST DISEASE (GVHD)

IMMUNODEFICIENCY  Primary Immunodeficiency (Congenital Immunodeficiency)  Defects of B cell/Humoral deficiency  Defects of T cell/Cellular deficiency  Defects of Phagocytes  Defects of Complements

BRUTON X-LINK AGAMMAGLOBULINEMIA

SELECTIVE IGA DEFICIENCY

DIGEORGE SYNDROME

SEVERE COMBINED IMMUNODEFICIENCY

IMMUNODEFICIENCY  Secondary Immunodeficiency (Acquired Immunodeficiency Syndrome: AIDS)  Human Immunodeficiency Virus (HIV) infection

REFERENCES  อรวดี หาญวิวัฒน์วงศ์. วิทยาภูมิคุ้มกันพื้นฐานและคลินิก. กรุงเทพฯ,  Kindt, TJ, Goldsby, RA, Osborne, BA. Kuby Immunology (6 th ed.), W.H. Freeman and Company, New York, 2007  Murphy K, Travers P, and Walport M. Janeway’s Immuno Biology (7 th ed), Garland Science, New Yok, 2008  Abbus AK, Litchman AH, and Pillai S. Cellular and Molecular immunology. 7 th ed., Philadelphia: Saunder  Warren Levinson. Review of Medical Microbiology and Immunology. 13 th ed., Philadelphia: McGraw-Hill education /13/2018Poonsit Hiransai, MT, SAP, WU 91