Disorders of the Immune System

1. Disorders of the Immune System Chapter 19

2. Four Major Categories of Immune Mechanisms • Humoral or antibody-mediated immunity • (B lymphocytes) • Cell-mediated immunity • (T lymphocytes) • Complement system • Phagocytosis • (neutrophils and macrophages)

3. Types of immune defenses • Innate, or nonspecific immunity:the natural resistance with which a person is born • Adaptive, or specific immunity:the second line of defense, responding less rapidly than innate immunity but more effectively

4. Innate Immunity • Components • Epithelial barriers • Phagocytic cells • Neutrophils and macrophages • Natural killer cells • Plasma proteins • Opsonins, cytokines, and acute-phase proteins • Induction of inflammatory response • Red, Heat, Edema, Pain, Pus

5. Adaptive Immunity • Able to recognize and react to a large number of microbes and non-microbial substances • Ability to distinguish among different, even closely related, microbes and molecules and to “remember” the pathogen by quickly producing a heightened immune response on subsequent encounters • Lymphocytes and their products • Antigenic identification

6. Types of Adaptive Immune Responses • Humoral immunity • Mediated by molecules in the blood • B Cells secrete antibodies • The principal defense against extracellular microbes and toxins • Cell-mediated immunity, or cellular immunity • Mediated by specific T lymphocytes • Defends against intracellular microbes such as viruses

8. Histocompatibility Complex • Major histocompatibility complex (MHC) • Set of molecules displayed on cell surfaces • Lymphocyte recognition • Antigen presentation • Control the immune response through recognition of self and nonself

9. Properties of MHC Molecules • HLA antigens • Class I: HLA-A, HLA-B, HLA-C • Class II: HLA-DR, HLA-DP, HLA-DQ • Distribution • Class I: virtually all nucleated cells • Class II: restricted to immune cells, antigen-presenting cells, B cells, and macrophages

10. Properties of MHC Molecules (cont.) • Functions • Class I: present processed antigen to cytotoxic CD8+ T cells • Class II: present processed antigenic fragments to CD4+ T cells; necessary for effective interaction among immune cells

12. Antigen Presentation • Macrophages and dendritic cells process and present antigen peptides to CD4+ helper T cells • Capture antigens and then enable their recognition by T cells • Initiation of adaptive immunity

13. Immunodeficiency States

14. Immunodeficiency Disorders • Abnormality in the immune system that renders a person susceptible to diseases

15. Classifications of Immunodeficiency States • Primary (congenital or inherited) • Secondary(acquired later in life) Malnutrition • Infection (e.g., AIDS) • Neoplastic disease (e.g., lymphoma) • Immunosuppressive therapy (e.g., corticosteroids or transplant rejection medications)

16. Results of Alterations of the Immune System • Immunodeficiency states • Allergic or hypersensitivity reactions • Transplantation rejection • Autoimmune disorders

17. Deficiencies of Antibody (B Cell) Immunity • B-cell function and immunoglobulin or antibody production are involved. • Defects in humoral immunity increase the risk of recurrent pyogenic(bacterial infections that make pus)infections. • Humoral immunity usually is not as important in defending against intracellular bacteria (mycobacteria), fungi, and protozoa. • Viruses usually handled normally, except for the enteroviruses that cause gastrointestinal infections

18. Deficiencies of Antibody (B Cell) Immunity • Genetic disorders of the B lymphocytes • Approximately 70% of primary immunodeficiencies • Immunoglobulin production depends on • The differentiation of stem cells to mature B lymphocytes • The generation of immunoglobulin-producing plasma cells • Can interrupt the production of one or all of the immunoglobulins

19. Deficiencies of Antibody (B Cell) Immunity X-Linked Agammaglobulinemia • Recessive trait that affects only boys • No immunoglobulins • Susceptible to many diseases • Gene necessary for pre-B-cell expansion is missing • Become symptomatic around 6-9 months of age

20. Symptoms include Frequent episodes of • Chronic Diarrhea • Conjuctivits • Chronic Otitis Media • Pneumonia • Bronchitis • Upper Respiratory Tract Infections

21. Deficiencies of Antibody (B Cell) Immunity Selective Immunoglobulin A Deficiency • Most common type • Affects 1 in 400 persons • Moderate reduction of IgA levels • Found in mucous, tears, saliva • In both men and women

22. Deficiencies of Antibody (B Cell) Immunity Selective Immunoglobulin A Deficiency • Less harmful than many other immunodeficiency diseases • 2/3rd have no symptoms • Symptoms include frequent episodes of: Bronchitis, chronic diarrhea, conjuctivis, otitis media, pneumonia, upper respiratory tract infections • No treatment

23. Deficiencies of Cell-Mediated (T-cell) Immunodeficiency DiGeorge Syndrome • 22q11.2 deletion syndrome • Partial or complete failure to develop the thymus and parathyroid glands • Many different problems can occur from this due to lack of T-cell production • Outward appearance changed • Low-set ears, hypoplastic mandible bowing upward lip

24. 22q11.2 deletion syndrome Signs and symptoms may include some combination of the following: • Bluish skin due to poor circulation of oxygen-rich blood (cyanosis) • Weakness or tiring easily • Failure to thrive • Failure to gain weight • Poor muscle tone • Shortness of breath • Delayed development, such as delays in rolling over, sitting up or other infant milestones • Delayed speech developmentLearning delays or difficulties • A gap in the roof of the mouth (cleft palate) or other problems with the palate • Certain facial features, such as low-set ears, wide-set eyes or a narrow groove in the upper lip

25. 22q11.2 deletion syndrome

26. Combined T-Cell and B-Cell Immunodeficiencies • Severe combined immunodeficiency (SCID) • X-linked SCID • Absence of all T and B-cell function (maybe NK cells as well) • Disease resembles AIDS in infants • Bubble boy disease

27. David Vetter -Lived in a Bubble up to the age of 12yrs. -Was given a bone marrow transplant from his sister -She had Epstein-Barr virus dormant in her bone marrow -He contracted Burkitt’s Lymphoma and died in two weeks

28. Wiskott-Aldrich Syndrome • Rare X-linked disorder • Both B and T cell immunity is impaired • Complete failure to produce antibodies to an entire class of antigens, namely polysaccharides • Recurrent infections • Hemorrhages secondary to thrombocytopenia • Eczema • Petechiae • Infections (otitis media)

29. Wiskott-Aldrich Syndrome • Clinical Features • Infections from opportunistic organisms • Pneumocystitiscarnii and Candida albicans • Some die from disseminated herpes simplex and varicella • Bone transplants seem to be very effective in this syndrome

30. Complement System • The following are the basic functions of the complement: • Opsonization - enhancing phagocytosis of antigens • Chemotaxis - attracting macrophages and neutrophils • Lysis - rupturing membranes of foreign cells • Clumping of antigen-bearing agents

31. Disorders of the Complement System • Primary • Mostly transmitted as autosomal-recessive traits and can involve one or more complement components • Secondary • Can occur in persons with functionally normal complement • Caused by • Diabetes mellitus • Leukemia • Immunosuppressive drugs

32. Hereditary angioedema Inhibition of C1 protein in the complement system Autosomal Dominant http://www.youtube.com/watch?v=ualR2rCZ-J8

33. The Phagocytic System • Definition:Composed primarily of polymorphonuclear leukocytes and mononuclear phagocytes • Action of these cells • Migrate to the site of infection • Aggregate around the affected tissue • Envelope invading microorganisms • Generate microbicidal substances to kill the ingested pathogens

34. http://www.youtube.com/watch?v=KxTYyNEbVU4&feature=related

35. Dysfunction of the Phagocytic System • A defect in phagocytic functions or a reduction in the absolute number of available cells disrupt the system • Susceptible to: • Candida species • Filamentous (thread-like) fungi • Chronic granulomatous disease (CGD) • Symptoms are: • Impetigo • Recurrent Pneumonia • Skin and rectal abscesses

36. Impetigo

37. http://www.youtube.com/watch?v=mUcE1Y_bOQE&feature=related

38. Stem Cell Transplantation • Many primary immunodeficiency disorders traced to deficient stem cells can be cured with allogeneic stem cell transplantation from an unaffected donor. • SCID, Wiskott-Aldrich syndrome, and chronic granulomatous disease • Stem cells can repopulate the bone marrow and re-establish hematopoiesis. • Taken from bone marrow, blood or umbilical cord of donor • To be effective, the bone marrow cells of the host are destroyed by myeloablative doses of chemotherapy.

39. Introduction • Normal immune reactions do their job without hurting the host. • Sometimes, immune reactions can be excessive, resulting in disease. • People who mount normal immune responses are sensitized to that antigen. • People who have excessive responses are hypersensitive.

40. What happens in these reactions? • The immune response is triggered and maintainedinappropriately. • Hard to eliminate stimulus! • Hard to stop response once it starts! • …so hypersensitivity diseases are often chronic, debilitating, hard to treat.

41. Hypersensitivity Reactions Outline • Introduction • Type I Hypersensitivity

42. Type I Hypersensitivity Disorder • Also known as Immediate Hypersensitivity • First Exposure • Antigen is presented to B and T cells • IgE antibodies are produced and bind to Mast Cells • Mast cells are primed for the second exposure • Upon second exposure mast cells degranulate • End result: vessels dilate, smooth muscle contracts, inflammation persists

43. What do mast cells release upon Second Exposure? • Granule contents • Histamine • Some chemotactic factors • Membrane phospholipid metabolites • Prostaglandin D2 • Leukotrienes • Cytokines • TNF • Interleukins • IL-13

44. Mast cells: Normal (left) and degranulated (right)

46. What do these substances do? • Act on blood vessels, smooth muscle, and WBCs. • Immediate response (minutes) • vasodilation, vascular leakage, smooth muscle spasm • granule contents, prostaglandin, leukotrienes • Late phase reaction (hours) • inflammation, tissue destruction • cytokines

47. What happens to the patient? • Local reactions • Skin: itching, hives • GI: diarrhea • Lung: bronchoconstriction • Anaphylaxis • Wide spread edema due to Histamine • Vascular leakage • Itching, hives, erythema • Constriction of bronchioles, wheezing • Laryngeal edema, hoarseness, obstruction • Shock • DEATH