Organism should be constantly associated with the lesions of the disease Should be possible to isolate the organism in pure culture from the lesions of the disease The isolated organism when inoculated in suitable laboratory animals should reproduce the same disease Should be possible to re-isolate the organism in pure cultre from the lesions produced in the experimental animals. Antibodies should be demonstrable in the serum of patients.
Father of Microbiology Father of Bacteriology
Louis Pasteur Robert Koch - bacteriology
Small pox vaccine – Edward Jenner
Initial Immune Response
Neutrophils IgM antibodies & IgA (in saliva, sweat, tears, etc. Prolonged macrophages & IgG IgE in allergic reactions & parasites.
Intracellular Phagocytosis Pathways
Oxygen Dependent o Lysozyme o Cathepsin o Lactoferrin Oxygen Independent o Hypochlorus Acid & singlet Oxygen o Superoxide anion & hydrogen peroxide
Inflammation Clinical Features
Rubor Dolor Tumor Calor Loss of Function
Acute Phase Proteins
C-Reactive Protein Alpha-1-antitrypsin Haptoglobin Ceruloplasmin Normal serum proteins-synthesized in liver ↑levels w/ inflammation, infection & trauma. Aid innate immunity
Innate immunity component Highly cationic peptides that create pores in bacterial wall death Alpha GIT & Beta Lower respiratory tract.
Interleukin 1 & 6 Prostoglandins
Lymphocytes that carry TCR, CD2 & CD3 marker. CD 3 transmembrane signal transduction. T-Helper = CD4 MHC class II(HLA-DR/DQ) (presented by Antigen Presenting Cell) T-Killer = CD8 MHC class I Natural Killer CD16 & 56 – innate immunity. Secrete perforins (TNF-β) Killer Cells Fc Portion of IgG. Antibody dependent cytotoxicity Lymphokine Activated Killer cells NK + IL=2. Cytotoxic to tumor cells. T-Suppressor cells CD8 suppress/block immune response via Th cells or B cells Delayed hypersensitivity T-Cells CD4 + (Th cell) Differentiation occurs in Thymus In cortex 2x (-) 2x (+) medulla differentiation blood Act in Cell Mediated Immunity & Antibody mediated immunity.
No thymus required for maturation. Ssurface immunoglobulin (IgM & IgD) definitive for B-cells Also have CD19, CD20, CD21, & CD22 Secondary dev. Antigen dependent. Helper T-Cell Activated B-cells pasma cells producing Abs to specific Ag.
Abscence of a thymus ↓T-cellls potentially lethal wasting disease Pts. prone to chronic infections with viral, bacterial, fungal or protozoal agents.
Non-immunogenic substances that become immunogenic when linked to a carrier protein. Simple: No precipitate is produced whn comiined with specific antibodies as they are univalent in nature Complex: Combine with specific antibodies to form ppts. As they are polyvalent.
T-Cell Independent Antigens
Can directly stimulate antibody formation by β-lymphocyte cells w/o involving T-cells. IgM & IgG3 No immunological memory Don’t require processing by macrophages Metabolized slowly
TD – antigens Need T-Cell Produce immunological memory Require processing by macrophage.
Hypersensitivity Types & Mechanism
Type 1: Anaphylaxis IgE + Ag Fc receptors on mast cells & basophils rapid degranulation(1⁰ inflammatory mediator + release of IL3,4,5,&6) acute inflammatory reaction (↑ vaso perm.; smooth muscle contraction; granulocyte chemotaxis and extravasation) 2⁰ mediators. o Ag pres to Th2 cells –(IL-4, IL-13)B-cell IgE prodction Type 2: Cytotoxic IgG (rarely IgM) mediated by complement classic cascade or cellular mechanisms.--> attaches via Fab. Bridges to complement via Fc region. complement-mediated lysis. (goodpasture’s, myasethenia gravis, graft rejection, autoimmune hemolytic anemia & thrombocytopenic purpura) Type 3: Immune complex Ag-Ab complexes deposited in tissue complement mediated PMN infiltration (arthus rxn, serum sickness, arthritis, vasculitis, nephritis, pneumonitis) Type 4: Delayed/Cell Mediated – sensitized T-Cells On contact w/ specific Ag releases lymphokines Macrophages, leukocytes & tissue cells delayed hypersensitivity (tuberculin test, contact hypersensitivity (chemicals, plants, topically applied drugs, cosmetics soaps, Haptens)
Type I Hypersensitivity Treatment
Symptomatic Receptor blockers: Antihistamine, antileukotriene Bronchodialtors: β-agonists(inhalants Prevent Mast Celll Degranulation Ca++ influx inhibitor (chrmolyn sodium) Phosphodiesrease (thephylline) Immunotherapy Hyposensitization Anti-IgE(Fc) Antibody
Types of Complement Deficiency
C1 esterase inhibitor deficiency hereditary angioedema C3 deficiency – impaired opsonisation – infections by capsulated bacteria C5 deficiency – impaired chemotaxis MAC deficiency – recurrent and severe Niesseria infection C1,2,4 deficiency – reduced clearance of immune complexes.
Chronic granulomatous diseases G6PD deficiency Myeloperoxidase deficiency Chediak Higashi disease Job’s syndrome Tuftsin deficiency Adhesion deficiency
Lack of Stem cells – SCID Maturation Deficiency– x-linked agamma globiulinemia (Bruton’s D) o Common variable ID – affects antibodies Class switching deficiency – Hyper IGM syndrome Transient Hypogammaglobulinemia of infancy ↓CD4 help Secretory component deficiency - IgA deficiency
Congenital athymia – DiGeorge’s Syndrome Chronic mucocutaneous candidiasis – reduced macrophage MIF Bare lymphocyte syndrome – defective expression of MHC II CF: recurrent viral, bacterial, fungal, mycobacterial & protazo
SCID – X-linked/autosomal recesive lymphoenia & thymic hypolasia enzyme defects Nazelofs Syndrome Wiskott Aldrich Syndrom Ataxia Telangiectasia -
Consequences of Antibody Binding
Auto Immune Affiliated Genes
HLA-DR2 & HLA-DR3 – SLE – Anti-Nuclear Ab. HLA-DR2 – Goodpasture’s Syndrome HLA-DR4 – Rheumatoid arthritis –Synovial fluid TNF, IL-1 & IL-8 Rheumatoid Factor (IgM) in serum HLA-B27 – Ankylosing Spondylitis, Reiter’s Syndrom (reactive arthritis, conjunctivitis, urethritis w/ bacterial infection like shigella, salmonella, campylobacter, or Chlamydia)
Found in embryonic gut & associated orgains during 1st & 2nd trimesters. ↑levels of this Ag in pts w/ carcinoma of the colan, pancrease, breast or liver. Good prognostic marker
Fetal liver produces & is present in high concentrations Marker for hepatoma Non-specific –found in several other malignant & non-malignant dis. In chemically induced tumors – tumor Ag are tumor specific In virus induced tumors – tumor Ags are virus specific
Mucoprotein that masks tumor antiges not recognized as foreign by immune system.
Mechanisms of Tumor Immunity
Modulation of surface Ag. (stop expressing immunologically invisible) Masking tumor antigens – Sialomucin not recognized as foreign Production of blocking antibodies Fast rate of proliferation of malignant cells tumor cells sneak through and proliferate so fast that immune system is overcome. Suppression of Cell Mediated Immunity– TGF-b suppresses CMI
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