Pharmaceutical Immunology Spring 2025 PDF

PHAR 7153 Pharmaceutical Immunology Spring 2025 Randle Gallucci, Ph.D. 1  Antibody-Mediated Immunity Objectives Describe the course of the development of pre-natal immunity and the defining events associated with these steps. Underst...

PHAR 7153 Pharmaceutical Immunology Spring 2025 Randle Gallucci, Ph.D. 1  Antibody-Mediated Immunity Objectives Describe the course of the development of pre-natal immunity and the defining events associated with these steps. Understand the changes that occur in the immune response during life beginning with neonatal immunity and continuing through geriatric immunity. Know the general trends (not specific numbers) for immunoglobulin levels during life Describe the mechanisms of antibody-mediated immunity to infectious disease: neutralization, opsonization, and complement fixation  Antibody-mediated Immunity Development and decline of the normal antibody response – Prenatal – Neonatal – Childhood – Adolescent – Adult – Geriatric Mechanisms of antibody-mediated immunity to infectious diseases 3  Prenatal Immunity 1. 8 weeks: B cells first appear in the fetal liver and are produced in the bone marrow beginning in the second trimester 2. 10-30 weeks: Small amounts of immunoglobulin may be detected and the isotypes appear in the following order IgM > IgD > IgG > IgA 4  Prenatal Immunity 3. Fetal Immunity: Protection is derived largely from the position in the womb. a.Active transport of maternal IgG by FcRn begins about the 16th week b.More than 50% of the transfer occurs after 34th week. 4. Self-recognition: Tolerance to autoantigens is being established. 5. Intrauterine Infection: The fetus is not only immunodeficient but may also develop varying degrees of tolerance to the infectious organisms. 6. Prenatal infection indicated by the presence of IgM and IgA in the cord blood. 5  Prenatal & Neonatal Immunity Peak at birth; Maternal contribution = totally IgG Loss of maternal Serum Ig Large Maternal IgG & de novo Mg/dl contribution synthesis after 34th week Months 6  Immunoglobulin Isotypes are Distributed Selectively in the Human Body and Some are Passed by Mothers to their Young  Neonatal Immunity 1. Birth: The neonatal immune system is much like the other physiological systems—present but underdeveloped. –Neonates can produce all Ig isotypes but IgM tends to predominate. 2. Maternal IgG persists for up to 6 months—Ig metabolism is slower in the neonate—and is a major source of neonatal immunity The mother must be immune in order to protect child against a specific pathogen and there is no memory to this passive immunity 8  Childhood Immunity Two common events shape the acquisition of immunity during childhood: 1. The loss of maternal IgG by the age of 5-6 months is typically attended by the appearance of common acute infectious diseases. 2. Routine pediatric immunizations 9  Current schedule January, 2016 10  Info on the Anti-Vax Movement The Panic Virus: A True Story of Medicine, Science, and Fear Originated from UK Physician Andrew Wakefield – http://www.amazon.com/Panic-Virus-Story-Medicine-Science/dp/B004WB1AAC Autism's False Prophets: Bad Science, Risky Medicine, and the Search for a Cure – http://www.amazon.com/Autisms-False-Prophets-Science- Medicine/dp/023114637X/ref=sr_1_1_title_0_main?s=books&ie=UTF8&qid=13599284 79&sr=1-1&keywords=autism%27s+false+prophets http://www.voicesforvaccines.org/ 11  Childhood Immunity 3. The immune response is reasonably mature by 2-3 years of age but a normal child is immunologically inexperienced. The spectrum of an individual's immunity is expected to continue to expand throughout life as they experience daily immunogenic challenge. Serious congenital immunodeficiency, in the absence of other apparent pathology, is only rarely detected close to birth. It is typically manifest at 3-6 months of age as the maternal immunity wanes. The first indication of serious immunodeficiency has been an atypical reaction to a live vaccine. 12  Adolescent Immunity 1. Many environmental factors have a major affect on the development of childhood immunity and disease patterns cultural, geographic, socioeconomic, nutritional, etc. Puberty. Sexual maturation Hormonal changes Social Pressures Physical changes Sports, Driving Drugs, Alcohol 2. The thymus reaches its maximum size (~35 grams) about puberty and then begins a process of involution until a small mass (~6 grams) remains later in adulthood. 13  Adult Immunity 1. Normal adults are immunologically developed and experienced Generally contract about 2-5 common acute infections a year from new or changing organisms Environmental factors are the major determinants of an individual's exposure pattern occupation, hobby, geographical location, life styles, etc. 2. Although a normal adult at age 40-45 has only 5-10% remaining of the adolescent thymus, failure of the immune system itself is uncommon. 14 Normal Serum Immunoglobulin Levels During Life 15  Geriatric Immunity At the individual level, quite variable – often two individuals of the same chronological age will be different in “biological age” – Activity level – Genetic background – General level of health: underlying health conditions can impact immunity Cancer Heart disease Metabolic syndrome – Diet and other lifestyle choices 16 Age related immune system changes Weiskopf, Weinberger, and Grubeck-Loebenstein (2009) Transplant International 22, 1041-50 17  Antibody Mediated Immunity to Infectious Diseases Viral Neutralization Blocking of bacterial attachment Toxin Neutralization and clearance Complement fixation Enhanced phagocytosis by opsonization Virus Neutralization HA SA Virus Neutralization: Analogous to toxin- neutralization Physical binding of an antibody prevents a virus from attaching to its complementary cell receptor and thereby stops infection of the cell Important mechanism of action for influenza vaccine  Disease-causing bacterial infections at mucosal surfaces are prevented by neutralizing antibodies Prevention of Epithelial Cell Attachment by pathogen SIgA binds organisms in external secretions and prevents their attachment to and penetration of the mucous membranes No sIGA: Bacteria binds to Cell surface which leads to Infection + SIgA: antibody binds bacteria and blocks binding to cells; the SIgA-antigen complex is excreted with the mucus  Toxin Neutralization Many common diseases are caused by bacterial toxins 21  Toxin Neutralization Physical binding of an antibody (IgG, for example) prevents a protein toxin from binding to its receptor site and thereby inhibit the toxic activity Fig. 9.26 22  Secretory IgA Can Remove Pathogen- encoded Toxins from the Lamina Propria sIgA secreted by plasma cells in the lamina propria can bind bacteria or bacterial toxins present there The sIgA-toxin complex can then be exported through the epithelium by interaction with secretory piece Once in the lumen, the bound toxin can be eliminated through the digestive tract Fig. 10.2  Complement-Mediated Bacteriolysis – Classical complement activation on a bacterium – Mediates by lysis through creation of the membrane attack complex and promotes phagocytosis by C3b bound to the bacterium surface Two Molecules of IgG Can Activate the Classical Complement Cascade by Binding to a Pathogen or to Soluble Antigens Erythrocyte CR1 helps clear Immune Complexes from Circulation by Promoting Phagocytosis  Fc Receptors on Phagocytes Trigger the Uptake and Breakdown of Antibody-coated Pathogens Complement C3b attached to the pathogen surface can assist in phagocytosis by binding CR1 receptors on the surface of the phagocyte (neutrophil, macrophage)  Summary: Antibody Mediated Immunity to Infectious Disease Also viruses Fig. 1.18 29