How the Innate Immune System Profiles Pathogens

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1 How the Innate Immune System Profiles Pathogens Receptors on macrophages, neutrophils, dendritic cells for bacteria and viruses Broad specificity - Two main groups of bacteria: gram positive, gram-negative - Bacteria with flagellin Bacterial binding to these receptors activates macrophages to begin the inflammatory process

2 Pathogen Recognition and Tissue Damage Initiate an Inflammatory Response Bacteria have structures common to many bacterial species, but absolutely unlike anything in the human

3 White Blood Cell Recognizes Bacterial Flagellin via TLR-5 receptor

4 White Blood Cells Recognizes Component of Bacterial Cell Wall through TLR-4 Gram-negative bacteria have LPS in cell wall

5 White Blood Cells Recognizes Component of Bacterial Cell Wall via TLR-2/6 and TLR-1/2 Gram-positive bacteria have lipoteichoic acid in cell wall Lipoteichoic acid

6 TLR recognition of bacterial structures activates macrophages, initiates inflammatory response Normal Endothelium TNF TNF Inflamed Endothelial Cells Express Selectins

7 ADAPTIVE IMMUNE SYSTEM Antibodies are Exquisitely Specific

8 Antibody diversity At least 10 8 different Antibody specificities Capable of recognizing virtually any antigen in the universe

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10 Structure of an Immunoglobulin (Antibody) Molecule

11 Antibodies against Influenza Anti-Hemagglutinin Anti-Neuraminidase

12 Classes of Antibodies IgM: first antibody made, good Complement fixation IgG: good at opsonizing, maternal antibody IgA: secretory antibody (in GI tract, respiratory tract, milk) IgE: allergic antibody

13 Location of Immunoglobulin Classes in the Body IgG IgM In Plasma, extracellular fluid, crosses placenta In plasma IgA IgE In secretions in gastrointestinal tract, respiratory tract, breast milk Associated with mast cells just below surface of GI tract, respiratory tract, skin

14 Antibody can Neutralize Viruses before they infect a cell

15 How antibodies participate in host defense

16 IgE antibody on mast cells releases inflammatory mediators after binding antigen

17 Eosinophils attacking parasite larva (schistosome) opsonized with IgE Antibody

18 Antibodies are Pathogenic in Systemic Lupus Erythematosus (SLE)

19 Lupus Chronic autoimmune disease The body creates antibodies that bind to healthy cells and lead to tissue destruction At least 1.5 million Americans have lupus Women are 10 times more likely to develop lupus than men Lupus is usually diagnosed in women between ages of 15 and 44 (child-bearing age)

20 Symptoms of SLE SLE may affect many different organs & tissues, including the heart, skin, joints, kidneys, lungs, and brain. Common symptoms include: rash (particulary on the face) Fever Joint pain Fatigue Chest pain Sensitivity to light

21 Pathogenesis of Lupus Antibodies are made against dsdna, other components of the cell nucleus Large amounts of antigen-antibody complexes are formed Antigen-antibody complexes are deposited in walls of small blood vessels of skin, kidneys, joints and other organs These antigen-antibody complexes bind to neutrophils and macrophages, initiating inflammation and causing tissue damage

22 ANA test (diagnosis) Anti-nuclear antibody (ANA) detects antibody against DNA, other molecules in nucleus nucleus ANAs found in about 5% of the normal population, usually low titer, harmless Certain medications can induce ANAs

23 Lupus (LE cell)

24 Antigen-Antibody Immune Complexes Form in SLE

25 Antigen-Antibody Complexes Deposited in Kidney

26 Macrophage or neutrophil binds Antigen-Antibody Complex and Releases Inflammatory Mediators

27 Macrophage binding antigen-antibody complexes initiates inflammatory response (similar to bacteria) Normal Endothelium TNF TNF Inflamed Endothelial Cells Express Selectins

28 Causes of Lupus Environment Genetics Chance

29 Genetics of Lupus Identical twin studies: if one twin has SLE, about 25% of the time, the other twin develops SLE too Chances of 1 st -degree relatives developing SLE are about 3% Incidence of SLE in the general population is less than 0.01% Many genes involved in susceptibility to SLE

30 Possible Environmental triggers of SLE Infections (Epstein-Barr)-ubiquitous Certain drugs Certain chemicals Mercury silica Smoking Others??

31 Antibodies and B Lymphocytes Antibodies are made and secreted by B lymphocytes Clonal selection by antigen Naïve B cells express antibody molecule on cell surface clonally antigen binds only to B cells with correct antibody on surface Antigen recognition drives proliferation, differentiation to plasma cell and memory cell Plasma cell secretes large amounts of antibody Accounts for memory and specificity Monoclonal antibodies are used as drugs

32 Resting B lymphocytes may encounter antigen and be driven to secrete antibodies

33 Clonal Selection From Kuby J. Immunology (3 rd Ed.), W.H. Freeman & Co., 1997

34 Course of an Antibody Response

35 Auto-antibody mediated inflammation leads to more auto-antibody production

36 Benlysta (approved for SLE March 2011) stops antigen-driven B cell proliferation B cell

37 Antibodies and B Lymphocytes Structure of antibody molecule Antigen binding site (huge diversity) How Ab binding leads to destruction of Ag Neutralization of toxin Complement mediate killing Opsonization: FcR and C3R on macrophages Formation of Ag/Ab complexes (important in SLE) Opsonization for parasite killing by eosinophils

38 Antibodies and B Lymphocytes Classes of Antibody IgM IgG: placental transfer Maternal immunity Hemolytic disease of the newborn IgA: secretory Ig (in mother s milk, gut, etc.) IgE: allergic Ab (causes mast cell to release histamine, etc.)