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Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
Immunodeficieny states lecture notes
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Immunodeficieny states lecture notes


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  • 1. Immunodeficiency
  • 2.
    • Definition:
    • When the immune system is depressed or absent and an individual is unable to mount a normal immune response to satisfactorily protect the body.
  • 3. Types of Immunodeficiency
    • Primary immunodeficiency: Inherited or congenital. Part of the immune system is missing or does not function properly. Caused by defects in immune cell development or mutation in particular molecules.
    • Severe form:present in early life.
    • Less severe forms:may not cause problems until later in life.
    • Secondary immunodeficiency: previously functional immune system compromised by factors outside the immune system, such as viruses, aging, radiation, malnutrition, severe stress, splenectomy, thymectomy or chemotherapy.
    • More common than primary immunodeficiency.
  • 4. From Immunobiology, Janeway et al. ADA: Adenosine Deaminase PNP: Purine nucleoside phosphorylase
  • 5. From Immunobiology, Janeway et al.
  • 6. Common Immunodeficiencies
    • DiGeorge’s Syndrome : thymic hypoplasia or aplasia resulted from dysmorphogenesis of the third and fourth pharyngeal pouches during early embryogenesis.
    • Nude Mice or Rats.
    • SICD: Mice: Lack Rag
    • Bubble Boy: Lack  c
  • 7. The main features of antibody deficiency Defective antibody production becomes critical 4-6 months after a full-term delivery when the maternally-derived IgG waned. The main manifestations are recurrent respiratory tract infections Defective CD40 ligand expression by T cells: no class-switching from IgM and no germinal centers. BtK deficiency: X-linked agammaglobulinaemia due to failure of B cell lymphopoiesis. Clinically antibody deficiency is secondary to lymphoid malignancies: myeloma and chronic lymphocytic leukaemia. The main features of T cell deficiency Defective T cell deficiency Increase in opportunistic infections: Pneumocystis carinii and Cryptosporidium . Mucosal yeast infection Defects in T-dependent antibody responses Di George syndrome HIV infection Defects in RAG genes, IL-2 receptors, and expression of MHC antigens. The main features of defects in neutrophils Severe invasive bacterial (mostly gram negative) infections that respond poorly to antibiotics and are often lethal and invasive fungal infection. Impairment of haemopoiesis Acute myeloblastic leukaemia: there is no stroma for neutrophil generation Cytotoxic drugs in cancer therapy  -2 integrin deficiency: inability of neutrophils to migrate. The main features of defects in complement Deficiency of C3: recurrent bacterial infections and infants are usually lethal. Deficiency of C5-9: normal health. Only increased risk of infection by particular bacteria
  • 8. Acquired Immune Deficiency Syndrome (AIDS)
    • Caused by human immunodeficiency virus ( HIV ).
    • Infect mainly CD4+ T cells. Macrophages can also be infected and are very important as they form a reservoir for a long term virus release.
    • When the immune system is weakened and cannot protect from serious infection, the infected individual clinically had AIDS.
    • AIDS may appear as early as 2 years or as late as 10 years after infection with HIV.
    • 40 million people are infected with HIV. Around 5 million new cases in 2004 ( 15,000 new HIV infections a day !) . More than 3 million died of AIDS in 2004.
  • 9.  
  • 10.  
  • 11.
  • 12. Protease inhibitors
    • The pol region of the virion genome encodes a HIV protease that is an aspartyl protease. Important for processing of essential functional protein products during the maturation of the virion. If the gag/pol polyprotein polyproteins are not cleaved, the virus fails to mature and is incapable of infecting a new cell.
  • 13. HIV Vaccine
    • No vaccine has been shown to be effective in humans.
    • Lack of good animal models.
    • Virus diversity.
    • Lack of proper adjuvants
    • Both humoral and cellular immunity are required.
    • Mobile Gp120 hinds epitopes.
    • Use of viral vectors and adaptation of co-stimulation
    • molecules and cytokines
    • Use of multiple epitopes
    • High Mucosal immune responses
    • Efficacy validation
  • 14. Inflammation and Hypersensitivity
  • 15. Inflammation: Definition
    • Purpose: Inflammation is a process by which the body attempts to dilute, destroy or isolate a noxious agent and repair damage. The most potent effect of immune defense.
    • Cause: The agents can be physical, chemical or biological.
    • Process : Inflammatory response is characterized by the generation of inflammatory mediators and accumulation of fluid and leukocytes from the blood into extravascular tissues.
    • The suffix " itis " means inflammation.
    • It is a protective strategy, but goes too far too often.
    • Management of inflammation is at least a part of almost all clinical practices .
  • 16.
    • Phases of Inflammation
    • Initiation
      • Structural changes leading to increase in blood flow and extravasation of fluid. Emigration of cells of the acquired and innate immune systems to the site of injury through chemotaxis.
    • Amplification
      • Elevated cellular metabolism and release of inflammatory mediators which promote local and systemic responses. Chemotactic factors to attract immune cells that invade surrounding tissues to fight infection (also cause damage).
    • Termination
      • Accomplished by specific inhibition or dissipation of the mediators. Growth factor will promote cell proliferation and repair.
  • 17. Acute vs . Chronic Inflammation
    • Acute inflammation
      • Immediate and early response to tissue injury
      • Increase in capillary permeability and blood flow (Vasodilation)
      • Accumulation of fluid and plasma components
      • Intravascular stimulation of platelets
      • Presence of polymorphonuclear leukocytes (PMNs) (2-6 hr)
      • ---Either resolved or goes on to chronic inflammation---
      • Injury or infection persist: Silicone implants, TB, ulcer, schistosomyosis
      • Autoimmunity: RA
    • Chronic inflammation
      • Accumulation of macrophages (24 to 48 hr), and lymphocytes (mononuclear cells) (5 to 7 days). Proliferation of fibroblasts (Fibrosis) and angiogenesis (weeks to months)
  • 18. Acute vs. Chronic Inflammation Fibrosis, cellular proliferation, scarring. Minimal Edema and separation of layers Stromal Changes Mononuclear leukocytes, macrophages Primarily neutrophils Cellular Infiltrates Minimal Vasodilation Increased permeability Vascular Changes CHRONIC ACUTE
  • 19. Margination and pavementing
  • 20.  
  • 21. Inflammatory Mediators Bacterial Surface Polysaccharides C3,C5 C3b,C5b Membrane Attack Complex Lysis of Bacteria Opsonization Phagocytosis C3a,C5a Chemotaxis Ag/Ab (IgG,IgM) Ag/Ab (IgE) Mast Cell Activation Histamine release Vasodilation Collagen Basement Membrane Coagulation Plasmin Bradykinin Pain
  • 22. Monocytes/Macrophages PMNs Edema Activity 1 2 3 REPAIR  (fibroblasts) DAYS Kinetics of Inflammation
  • 23. Redness ( ruber ): Dilation of capillaries Swelling ( tumor ): fluid containing plasma proteins and blood cells Heat ( calor ): increase in blood flow Pain ( dolor ): pressure on nerve; chemical mediators (e.g., bradykinin) Loss of function ( functio laesa ): the fifth cardinal sign was, supposedly, added by German pathologist Rudolf Virchow (1821-1902). Cardinal Signs of Inflammation First described by Celsus (not Celsius ) (10 BC-?)
  • 24. Heat Redness Swelling Pain Loss of Function Nature Reviews/Immunology
  • 25. Chronic Inflammation
    • Infiltration of lymphocytes, monocytes (transform to macrophages), plasma cells.
    • Proliferation of fibroblasts and initiation of angiogenesis.
    • Tissue destruction by inflammatory cells.
    • Major causes of illness and dysfunction.
  • 26. Mediators of Inflammation
    • Vasoactive amines (histamine and serotonin (5-hydroxytryptamine, 5HT)).
    • Complement system (>30 proteins, 3g/L, 15% of globulin).
    • Kinin system ( bradykinin and kallidin )
    • Coagulation pathway
    • Fibrinolytic pathway ( plasmin )
    • Arachidonic acid metabolites ( prostaglandins, prostacyclin (PGI 2 ), leukotrienes, and thromboxanes )
    • Platelet activating factor
    • Cytokines
    • Free radical species
  • 27.
    • Cell-derived (mostly preformed)
      • Proteins sequestered in granules
      • Membrane phospholipids (via arachidonic acid metabolism)
      • Vasoactive amines (mast cells and platelets)
    • Inactive precursors in plasma , e.g .:
      • Complement proteins (C3a, C5a)
      • Coagulation proteins initiated by Hageman factor (FDPs)
    Sources of Inflammatory Mediators
  • 28.
      • Arachidonic acid metabolites
        • From cell membrane phospholipids through the action of phospho-lipases
        • Form leukotrienes via 5-lipoxygenase
        • Form prostaglandins and thromboxane A 2 via cyclo-oxygenase (COX-1 inhibited by aspirin and indomethacin, COX-2 inhibited by Celebrex, VIOXX)
    • Vasoactive amines (mast cells, eosinophils and platelets)
      • Histamine and 5HT – abundant in granules of mast cells and eosinophils
      • Serotonin – actions similar to histamine. Found in platelets. Released after platelet aggregation, or under the influence of platelet activating factor (PAF).
    Chemical Mediators By Richard E. Klabunde
  • 29. Chemoattractants
    • Exogenous mediators, e.g .:
      • N-formyl methionine terminal amino acids from bacteria (fMLP, formyl methionyl leucyl phenylalanine)
      • Lipids from destroyed or damaged membranes (including LPS)
    • Endogenous mediators, e.g .:
      • Complement proteins (C5a)
      • Chemokines, particularly IL-8
      • Arachidonic acid products (LTB 4 )
    Boyden Chamber Shi et al. J Immunol Methods. 164:149
  • 30. Chemokines
    • Chemokines in their monomeric form have a molecular mass of 7-14 kDa
    • Have in common highly conserved cysteine amino acid residues
    • 1. CXC family - the first two NH 2 -terminal cysteines separated by a single nonconserved amino acid; CXCL1-CXCL16
    • 2. CC family - the first two NH 2 -terminal cysteines in juxtaposition
    • CCL1-CCL-27
    • 3. C lymphotactin - one NH 2 -terminal cysteine amino acid XCL-1,2
    • 4. CX 3 C fractalkine - the first two NH 2 -terminal cysteines separated by three nonconserved amino acid residues. CX3CL-1
  • 31. Pattern Recognition Receptors (PRR)
    • Toll-Like Receptor Family (TLR1-10)
      • Expressed externally or internally
      • TLR4: LPS; TLR9: CpG;
      • Binding activates “pro-inflammatory” signaling pathways through TRAF6
    • Phagocytic (endocytic) PRR
      • Expressed on the surface of phagocytic cells
      • Mediates uptake of microbes into phagocytes
    • Secreted PRR
      • Complement and Lectins, Secreted by Macrophage, epithelial cells, hepatocytes
      • Activate complement, opsonins, function as accessory proteins for PAMP recognition
  • 32. Toll-like Receptors and Ligands Imidazoquinoline TLR7 dsRNA TLR3 Heterodimerizes with TLR2 TLR1 Bacterial DNA (CpG) TLR9 Agonist(s) (Pathogen-Associated Molecular Patterns) Receptor (Pattern Recognition Receptors) Unknown TLR 8,10 Heterodimerizes with TLR2 TLR6 Flagellin TLR5 Gram(-) LPS, Taxol, some LTA, HSP60 TLR4 PGN, some LPS, some LTA, lipoproteins, AraLAM TLR2
  • 33.
    • Systemic Effects of Inflammatory Cytokines
    • Cytokines produced by monocytes/macrophages: TNF, IL-1 , and IL-6 .
    • Shape the systemic response of the body to infection, and produce many signs and symptoms by which illness is recognized:
    • Fever
    • Elevated white cell count
    • Acute-Phase Response
    • L oss of appetite
    • Fatigue and sleepiness
    • Pain in muscles and joints
    • • Overproduction of inflammatory cytokines can produce the Systemic Inflammatory Response Syndrome [SIRS] :
    • Increased vascular permeability , leading to loss of blood volume
    • Vasodilation , with decreased blood pressure and tissue perfusion, organ dysfunction, shock, and death.
    • Septic shock
  • 34. Summary of Inflammation
    • Vascular Leakage: histamines, bradykinin, leukotreines (15-30’).
    • TNF, IL-1 (endothelial contraction, 4 to 2h hours). Bacterial
    • toxin (prolonged leakage); VEGF (transcytosis).
    • PMN: Margination (selectins induced by TNF and IL-1), rolling
    • (ICAM-1:LFA-1/Mac-1; VCAM-1:VLA-4); chemataxis
    • (C5a, IL-8, LTB4); phagocytosis (attach, engulf, and degrade);
    • Oxidative burst (Superoxide; hydrogen peroxide and nitric oxide )
    • Clotting cascade: Collagen -> Factor VII ->fibrinogen ->fibrin.
    • Kinin system: bradykinin and kallidin converted from plasma kininogens
    • Complement: vasodilation and mast cell degranulation (C3a, C5a);
    • chemotaxis (C5a); opsonization (C3b).
    • Arachidonic Acid and Metabolites (Eicosanoids): prostagladins and
    • thromboxane produced by cyclooxygenase
  • 35. T Helper (CD4 + ) Subsets Th0 IFN-  IL-2 LT Pro-Inflammatory Cytokines Th1 FasL DR4 Th1 response Cellular Immunity DTH Suicide Fas Antigen APC IL-12 Th2 response Humoral Immunity Acute Hypersensitivity IL-4 IL-10 IL-13 IL-5 IL-6 Anti-Inflammatory Cytokines Th2 TRAIL IL-4
  • 36. Hypersensitivities Immune responses which are damaging rather than helpful to the host (In most cases). Trends Immunol. 2003 Jul;24(7):376-9. Gell and Coombs proposed a classification scheme which defined 4 types of hypersensitivity reactions : (P.G.H. Gell and R.R.A. Coombs, The classification of allergic reactions underlying disease. In: R.R.A. Coombs and P.G.H. Gell, Editors, Clinical Aspects of Immunology , Blackwell Science (1963)) The first 3 are mediated by antibody (Th2), the fourth by T cells (Th1). I IgE-mediated hypersensitivity (Anaphylactic) II Antibody-mediated cytotoxic hypersensitivity (Cytotoxic) III Immune-complex mediated hypersensitivity (Immune Complex) IV Delayed-type hypersensitivity ( DTH ) V(?) Granuloma (?)
  • 37. Type I Hypersensitivity -Rapid ('Immediate or anaphylactic') allergic reaction. -Prior exposure to an antigen sensitizes a person to produce IgE. Re-exposure causes rapid degranulation of mast cells. The granule mediators causes acute inflammation: increase granulocytes, chemotaxis, and extravasation -Primary mediators (stored): Histamine and serotonin: vascular permeability, smooth muscle contraction ECF-A-Eosinophil Chemotactic Factor of Anaphylaxis NCF-A-neutrophil Chemotactic Factor of Anaphylaxis Protease: Mucus secretion, connective tissue degradation -Secondary Mediator (to be synthesized): Leukotrienes: vascular permeability, sm contraction Prostaglandins: vasodilation, sm contraction, platelet activation Bradykinin: vascular permeability, sm contraction, Pain Cytokines: numerous effects e.g.: Hayfever, asthma and allergic reaction to penicillin ( phenoxymethylpenicillin and benzylpenicillin). Expulsion of worms and insect infections. Tests: wheal-and-flare reaction (skin prick test for IgE) and RAST (radioallergosorbent test, blood allergen)
  • 38. Type II Hypersensitivity -By specific antibody (IgM or IgG) binding to cells or tissue antigens. FcR causes ADCC Ab-dependent cellular immunity to bacteria and parasites Autoimmunity -By activating the classical complement pathway. Blood transfusion (ABO incompatibility reaction) IgM Rhesus disease (haemolytic disease of the newborn) IgG
  • 39. Type III Hypersensitivity Immune complexes: IgG with soluble antigens. Similar to type I except that IgG is involved. Preformed immune complexes bind to the low affinity Fc  RIII. Pulmonary reactions to inhaled antigens: Occupational related diseases: Farmer’s lung. The Arthus reaction A local type III hypersensitivity reaction in experimental models. Because the threshold for activation via Fc  RIII is higher than for Fc  RI, the reaction is slow (maximal at 4-8hrs) and more diffuse. Generalized or systemic reactions Large amount of soluble Ag-Ab complexes in circulation and deposition in various organs such as skin joints, kidneys and blood vessels. The deposition causes inflammation, lesions and infection. Rheumatoid Arthritis, Systemic lupus erythematosis, and serum sickness.
  • 40. Type IV Hypersensitivity -Delayed type hypersensitivity (DTH) -Mediated by antigen-specific type I helper T cells, not Ab. APC (dendritic cells, or DC) present Ag in class II MHC groove, recognized by an antigen-specific T H 1 cell. Cytokines (IFN, TNF) and chemokines are produced. Macrophages, other T cells and, neutrophils accumulate to form granuloma. It is usually maximal at 48-72 hours. The classical example is in tuberculosis: tuberculin test ( Discovered by Robert Kock, 1905 Nobel Prize). Allergy to metal salts and small reactive chemicals coupled to hapten. Rejection of transplanted organs Skin contact reaction to poison ivy.
  • 41.
    • Type V Hypersensitivity (?)
    • - Granuloma
    • -Evolutionarily conserved. In insects, ensheathment reaction
    • In mammals, granulomas can be an immune reaction and are typified by the formation of epithelioid cells (modified macrophages).
    • Type 1 cytokine mediated such as TB.
    • Type 2 cytokine mediated such as Schistosome infection.
  • 42. Summary of Hypersensitivity Reaction TYPE NAME INITIATION MECHANISM EXAMPLES I IgE-mediated hypersensitivity (Anaphylactic) 2-30 mins Ag cross-linking of IgE bound to mast cells; release of vasoactive mediators Systemic anaphylaxis, Local anaphylaxis, Hay fever, Asthma, Eczema II Antibody-mediated cytotoxic hypersensitivity (Cytotoxic) 5-8hrs IgG to cell-surface antigens; cell destruction via ADCC or complement ABO reactions; Rh in newborn; Autoimmune Haemolytic anemia III Immune-complex mediated hypersensitivity (Immune Complex) 2-8hrs Ag-Ab complex formed in serum and deposited in tissues; mast cell degranulation via Fc  RIII; chronic inflam. Arthus reaction (Localized); autoimmune diseases IV Delayed-type hypersensitivity ( DTH ) 24-72hrs T H 1 cells release cytokines that recruit and activate macrophages Contact dermatitis, Tubercular lesions V Granuloma (?) Months to Years Formation of granuloma to encapsulate or isolate pathogens. Mediated by innate immunity or type 1 or type II cytokines TB, Schistosomiasis
  • 43. Immune Reaction