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Diseases of IMMUNITY

Diseases of IMMUNITY. OBJECTIVES. I) Differentiate between the concepts of “Innate” and “Adaptive” immunity II) Visually recognize and understand the basic roles of lymphocytes, macrophages, dendritic cells, NK cells III) Understand the roles of the major cytokines in immunity

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Diseases of IMMUNITY

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  1. Diseases of IMMUNITY

  2. OBJECTIVES I) Differentiate between the concepts of “Innate” and “Adaptive” immunity II) Visually recognize and understand the basic roles of lymphocytes, macrophages, dendritic cells, NK cells III) Understand the roles of the major cytokines in immunity IV) Differentiate and give examples of the four (4) different types of hypersensitivity reactions

  3. OBJECTIVES V) Know the common features of autoimmune diseases, and the usual four (4) main features : 1) Etiology 2) Pathogenesis 3) Morphology 4) & clinical examination of : 1) Systemic Lupus Erythematosus, 2) Rheumatoid Arthritis, 3) Sjögrens, Systemic Sclerosis (Scleroderma), 4) Mixed Connective Tissue Disease, and 5) “Poly-” (aka, “Peri-”) -arteritis Nodosa VI) Differentiate between 1)Primary (Genetic) and 2)Secondary (Acquired) Immunodeficiencies

  4. OBJECTIVES VII) Understand the usual four (4) main features of AIDS, i.e., etiology, pathogenesis, morphology, clinical expression VIII) Understand the usual four (4) main features of Amyloidosis

  5. IMMUNITY • INNATE (present before birth, “NATURAL”) • ADAPTIVE (developed by exposure to pathogens, or in a broader sense, antigens)

  6. INNATE IMMUNITY I) BARRIERS II) CELLS: 1) LYMPHOCYTES, 2) MACROPHAGES, 3) PLASMA CELLS, 4) NK CELLS III) CYTOKINES / CHEMOKINES IV) PLASMA PROTEINS: Complement, Coagulation Factors V) Toll- Like Receptors, TLR’s

  7. Toll - like receptors (TLRs) are : A class of single membrane-spanning non-catalytic receptors that recognize structurally conserved molecules derived from microbes once they have breached physical barriers such as the skin or intestinal tract mucosa , and activate immune cell responses.

  8. Major Histocompatibility Complex (MHC) • A genetic “LOCUS” on Chromosome 6, which codes for cell surface compatibility • Also called HLA(Human Leukocyte Antigens) in humans and H-2 in mice • It’s major job is to make sure all self cell antigens are recognized and “tolerated”, because the general rule of the immune system is that all UN-recognized cells will NOT be tolerated

  9. ADAPTIVE IMMUNITY • CELLULAR, i.e., direct cellular reactions to antigens • HUMORAL, i.e., antibodies

  10. CELLS of the IMMUNE SYSTEM 1) LYMPHOCYTES, T 2) LYMPHOCYTES, B 3) PLASMA CELLS (MODIFIED B CELLS) 4) MACROPHAGES, aka “HISTIOCYTES”, (APCs, i.e., Antigen Presenting Cells) 5) “DENDRITIC” CELLS (APCs, i.e., Antigen Presenting Cells) 6) NK (NATURAL KILLER) CELLS

  11. LYMPHOCYTES

  12. ANY ROUND CELL WITH RATHER DENSE STAINING CYTOPLASM AND MINIMAL CYTOPLASM IN CONNECTIVE TISSUE, A BIT BIGGER THAN AN RBC, IS A LYMPHOCYTE …UNTIL PROVEN OTHERWISE

  13. MACROPHAGE aka HISTIOCYTE

  14. MACROPHAGES are MONOCYTES that have come out of circulation and have gone into tissue

  15. MACROPHAGES, TEM, SEM

  16. ANY CELL MIXED IN WITH LYMPHOCYTES BUT HAS A LARGER MORE “OPEN”, LESS DENSE, LESS CIRCULAR NUCLEUS WITH MORE CYTOPLASM IS A MACROPHAGE …UNTIL PROVEN OTHERWISE ALMOST ALL “GRANULAR” or “PIGMENTED” CELLS IN CONNECTIVE TISSUE ARE MACROPHAGES. GRANULOMAS, GIANT CELLS, ARE CHIEFLY MACROPHAGES ALSO.

  17. PLASMA CELLS 1) ROUND NUCLEUS 2) OVOID CYTOPLASM 3) PERIPHERAL CHROMATIN 4) “CLEAR ZONE” BETWEEN NUCLEUS AND WIDER LIP OF CYTOPLASM

  18. NK CELLS

  19. GENERAL SCHEME of CELLULAR EVENTS • APCs (Macrophages, Dendritic Cells) • T-Cells (Control Everything) • CD4 “REGULATORS” (Helper) • CD8 “EFFECTORS” • B-Cells Plasma Cells AB’s • NK Cells

  20. CYTOKINES 1) MEDIATE INNATE (NATURAL) IMMUNITY, IL-1, TNF, INTERFERONS 2) REGULATE LYMPHOCYTE GROWTH (many interleukins, ILs) 3) ACTIVATE INFLAMMATORY CELLS 4) STIMULATE HEMATOPOESIS, (CSFs, or Colony Stimulating Factors)

  21. CYTOKINES / CHEMOKINES • CYTOKINES are PROTEINS produced by MANY cells, but usually LYMPHOCYTES and MACROPHAGES, numerous roles in acute and chronic inflammation, AND immunity • TNF, IL-1, by macrophages • CHEMOKINES are small proteins which are attractants for PMNs

  22. ( MHC ) Major Histocompatibility Complex • A genetic “LOCUS” on Chromosome 6, which codes for cell surface compatibility • Also called HLA (Human Leukocyte Antigens) in humans and H-2 in mice • It’s major job is to make sure all self cell antigens are recognized and “tolerated”, because the general rule of the immune system is that all UN-recognized cells will NOT be tolerated

  23. MHC MOLECULES (Gene Products) • I (All nucleated cells and platelets), cell surface glycoproteins, ANTIGENS • II (APC’s, i.e., macs and dendritics, lymphs), cell surface glycoproteins, ANTIGENS • III Complement System Proteins

  24. IMMUNE SYSTEM DISORDERSWHAT CAN GO WRONG? I) HYPERSENSITIVITY REACTIONS, I-IV II) “AUTO”-IMMUNE DISEASES, aka “COLLAGEN” DISEASES (BAD TERM) III) IMMUNE DEFICIENCY SYNDROMES, IDS: - PRIMARY (GENETIC) - SECONDARY (ACQUIRED)

  25. HYPERSENSITIVITY REACTIONS (4) I- (Immediate Hypersensitivity) II- (Antibody Mediated Hypersensitivity) III- (Immune-Complex Mediated Hypersensitivity) IV- (Cell-Mediated Hypersensitivity)

  26. Type I - IMMEDIATE HYPERSENSITIVITY • “Immediate” means seconds to minutes • “Immediate Allergic Reactions”, which may lead to anaphylaxis, shock, edema, dyspnea death • 1) Allergen exposure • 2) IMMEDIATE phase: MAST cell DEgranulation, vasodilatation, vascular leakage, smooth muscle spasm • 3) LATE phase (hours, days): Eosinophils, PMNs, T-Cells

  27. TYPE II - HYPERSENSITIVITY(ANTIBODY MEDIATED IMMUNITY) • ABs attach to cell surfaces • 1- OPSONIZATION الطهى (bastingيطرى اللحم the turkey) • 2- PHAGOCYTOSIS • 3- COMPLEMENT FIXATION (cascade of C1q, C1r, C1s, C2, C3, C4, C5….. ) • 4- LYSIS (destruction of cells by rupturing or breaking of the cell membrane)

  28. TYPE II DISEASES - Autoimmune Hemolytic Anemia, )AHA( - Idiopathic Thrombocytopenic Purpura, )ITP( - Goodpasture Syndrome (Nephritis and Lung hemorrhage) - Rheumatic Fever - Myasthenia Gravis - Graves Disease - Pernicious Anemia, )PA(

  29. TYPE III - HYPERSENSITIVITYIMMUNE COMPLEX MEDIATED • 1) Antigen/Antibody “Complexes” • 2) Where do they go? • - Kidney (Glomerular Basement Membrane) • - Blood Vessels • - Skin • - Joints • 3) Common Type III Diseases- • - SLE (Lupus), • - Poly (Peri) arteritis Nodosa, • - Poststreptococcal Glomerulonephritis, • - Arthus reaction (hrs), • - Serum sickness (days)

  30. TYPE IV - HYPERSENSITIVITY - CELL-MEDIATED (T-CELL)DELAYED HYPERSENSITIVITY • Tuberculin Skin Reaction • DIRECT ANTIGENCELL CONTACT • GRANULOMA FORMATION • CONTACT DERMATITIS

  31. SUMMARY I Acute allergic reaction II Antibodies directed against cell surfaces III Immune complexes IV Delayed Hypersensitivity, e.g., Tb skin test

  32. RENAL TRANSPLANT REJECTION • HYPERACUTE (minutes) : AG/AB reaction of vascular endothelium • ACUTE (days months): cellular (INTERSTITIAL infiltrate) and humoral (VASCULITIS) • CHRONIC (months): slow vascular fibrosis

  33. ACUTE CELLULAR (T) ACUTE HUMORAL CHRONIC

  34. AUTO-IMMUNE DISEASES • 1- Failure of SELF RECOGNITION • 2- Failure of SELF TOLERANCE • 3- TOLERANCE • a- CENTRAL (Death of self reactive lymphocytes) • b- PERIPHERAL (anergy, suppression by T-cells, deletion by apoptosis, sequestration (Ag masking)) • 4- STRONG GENETIC PREDISPOSITION • 5- OFTEN RELATED TO OTHER AUTOIMMUNE DISEASES • 6- OFTEN TRIGGERED BY INFECTIONS Auto – immune D: systemic OR local

  35. CLASSIC AUTOIMMUNE DISEASES (SYSTEMIC) 1- LUPUS (SLE) Systemic Lupus Erythematosus 2- RHEUMATOID ARTHRITIS 3- SJÖGREN SYNDROME 4- SYSTEMIC SCLEROSIS (scleroderma) 5- “collagen” diseases (term no longer used)

  36. CLASSIC AUTOIMMUNE DISEASES (LOCAL) 1- HASHIMOTO THYROIDITIS 2- AUTOIMMUNE HEMOLYTIC ANEMIA 3- MULTIPLE SCLEROSIS 4- AUTOIMMUNE ORCHITIS 5- GOODPASTURE SYNDROME 6- AUTOIMMUNE THROMBOCYTOPENIA 7- “PERNICIOUS” ANEMIA 8- INSULIN DEPENDENT DIABETES MELLITUS 9- MYASTHENIA GRAVIS 10- GRAVES DISEASE

  37. N.B. • The list of diseases proven to be “autoimmune” grows by leaps and bounds every year !

  38. LUPUS (SLE) - 1Etiology: Antibodies (ABs) directed against the patient’s own DNA, HISTONES, NON- histone RNA, and NUCLEOLUS -2Pathogenesis: Progressive DEPOSITION and INFLAMMATION to immune deposits, in skin, joints, kidneys, vessels, heart, CNS - 3Morphology: “Butterfly” rash, skin deposits, glomerolunephritis (NOT discoid) - 4Clinical expression: Progressive renal and vascular disease, POSITIVE A.N.A.

  39. H O M O S P E C K R I M N U C L E O L A R

  40. SLE, SKIN SLE, GLOMERULUS

  41. Libman -Sacks vegetations, also called Libman -Sacks endocarditis

  42. MORE AUTOIMMUNE DISEASES • RHEUMATOID ARTHRITIS • SJÖGREN SYNDROME • SCLERODERMA (SYSTEMIC SCLEROSIS)

  43. SJÖGREN SYNDROME Keratoconjunctivitis “sicca” (i.e., “dry” is another name for Sjögren Syndrome

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