1. Alterations in Immunity and Inflammation (Including Hypersensitivities)
Chapter 8

2. Hypersensitivity
Altered immunologic response to an antigen that results in disease or damage to the host
Allergy
Deleterious effects of hypersensitivity to environmental (exogenous) antigens
Autoimmunity
Disturbance in the immunologic tolerance of self-antigens
Alloimmunity
Immune reaction to tissues of another individual

3. Hypersensitivity Characterized by the immune mechanism Type I Type II
IgE mediated
Type II
Tissue-specific reactions
Type III
Immune complex mediated
Type IV
Cell mediated

4. Hypersensitivity Immediate hypersensitivity reactions Anaphylaxis
Delayed hypersensitivity reactions

5. Type I Hypersensitivity
IgE mediated
Against environmental antigens (allergens)
IgE binds to Fc receptors on surface of mast cells (cytotropic antibody)
Histamine release
H1 and H2 receptors
Antihistamines

6. Type I Hypersensitivity
Manifestations
Itching
Urticaria
Conjunctivitis
Rhinitis
Hypotension
Bronchospasm
Dysrhythmias
GI cramps and malabsorption

7. Type I Hypersensitivity
Genetic predisposition
Tests
Food challenges
Skin tests
Laboratory tests
Desensitization
IgG-blocking antibodies

8. Type I Hypersensitivity

9. Type II Hypersensitivity
Tissue specific
Specific cell or tissue (tissue-specific antigens) is the target of an immune response
Five mechanisms
Cell is destroyed by antibodies and complement
Cell destruction through phagocytosis
Soluble antigen may enter the circulation and deposit on tissues
Antibody-dependent cell-mediated cytotoxicity
Causes target cell malfunction

10. Type II Hypersensitivity

11. Type III Hypersensitivity
Immune complex mediated
Antigen-antibody complexes are formed in the circulation and are later deposited in vessel walls or extravascular tissues
Not organ specific
Immune complex clearance
Large—macrophages
Small—renal clearance
Intermediate—deposit in tissues

12. Type III Hypersensitivity
Immune complex disease
Serum sickness
Arthus reaction

13. Type III Hypersensitivity

14. Type IV Hypersensitivity
Does not involve antibody
Cytotoxic T lymphocytes or lymphokine producing Th1 cells
Direct killing by Tc or recruitment of phagocytic cells by Th1 cells
Examples
Acute graft rejection, skin test for TB, contact allergic reactions, and some autoimmune diseases

15. Type IV Hypersensitivity

16. Type IV Hypersensitivity

17. Allergy
Environmental antigens that cause atypical immunologic responses in genetically predisposed individuals
Pollens, molds and fungi, foods, animals, etc.
Allergen is contained within a particle too large to be phagocytosed or is protected by a nonallergenic coat
Original insult is apparent

18. Autoimmunity Breakdown of tolerance Sequestered antigen
Body recognizes self-antigens as foreign
Sequestered antigen
Self-antigens not normally seen by the immune system
Infectious disease
Molecular mimicry
Neoantigen
Haptens become immunogenic when they bind to host proteins

19. Autoimmunity Forbidden clone Ineffective peripheral tolerance
During differentiation, lymphocytes produce receptor that react with self-antigens
Ineffective peripheral tolerance
Defects in regulatory cells
Original insult
Genetic factors

20. Alloimmunity
Immune system reacts with antigens on the tissue of other genetically dissimilar members of the same species
Transient neonatal alloimmunity
Fetus expresses parental antigens not found in the mother
Transplant rejection and transfusion reactions

21. Autoimmune Examples Systemic lupus erythematosus (SLE)
Chronic multisystem inflammatory disease
Autoantibodies against:
Nucleic acids, erythrocytes, coagulation proteins, phospholipids, lymphocytes, platelets, etc.
Deposition of circulating immune complexes containing antibody against host DNA
More common in females

22. Systemic Lupus Erythematosus
Clinical manifestations
Arthralgias or arthritis (90% of individuals)
Vasculitis and rash (70%-80%)
Renal disease (40%-50%)
Hematologic changes (50%)
Cardiovascular disease (30%-50%)

23. Systemic Lupus Erythematosus
Eleven common findings
Serial or simultaneous presence of at least four indicates SLE
Facial rash (malar rash), discoid rash, photosensitivity, oral or nasopharyngeal ulcers, nonerosive arthritis, serositis, renal disorder, neurologic disorder, hematologic disorders, immunologic disorders, and presence of antinuclear antibodies (ANA)

24. Graft Rejection Transplant rejection is classified according to time
Hyperacute
Immediate and rare
Preexisting antibody to the antigens of the graft
Acute
Cell-mediated immune response against unmatched HLA antigens
Chronic
Months or years
Inflammatory damage to endothelial cells of vessels due to a weak cell-mediated reaction against minor HLA antigens

25. Graft Rejection

26. Transfusion Reactions
Antibodies against blood group antigens
ABO system
Two major carbohydrate antigens
A and B (co-dominant)
Individuals have naturally occurring antibodies to the A and B antigens they lack
Anti-A and anti-B antibody production is induced by similar antigens on naturally occurring bacteria in the intestinal tract
Antibodies are usually of the IgM class
O blood type (universal donor)
AB blood type (universal recipient)

27. ABO System

28. Immune Deficiencies Failure of immune mechanisms of self-defense
Primary (congenital) immunodeficiency
Genetic anomaly
Secondary (acquired) immunodeficiency
Caused by another illness
More common

29. Immune Deficiencies Clinical presentation
Development of unusual or recurrent, severe infections
T cell deficiencies
Viral, fungal, yeast, and atypical microorganisms
B cell and phagocyte deficiencies
Microorganisms requiring opsonization
Complement deficiencies

30. Primary Immune Deficiencies
Most are the result of a single gene defect
Five groups
B lymphocyte deficiencies
T lymphocyte deficiencies
Combined T and B cell deficiencies
Complement defects
Phagocyte defects

31. B Lymphocyte Deficiencies
Hypogammaglobulinemia or agammaglobulinemia
Bruton agammaglobulinemia
Autosomal agammaglobulinemia
X-linked hyper-IgM syndrome
IgG subclass deficiency
Selective IgA deficiency
Common variable immune deficiency

32. T Lymphocyte Deficiencies
DiGeorge syndrome
Partial or complete absence of T cell immunity
Chronic mucocutaneous candidiasis

33. Combined T and B Cell Deficiencies
Severe combined immunodeficiency (SCID)
Reticular dysgenesis
Most severe form
Adenosine deaminase (ADA) deficiency
X-linked SCID
JAK3 deficiency
IL-7 receptor deficiency
Purine nucleoside phosphorylase deficiency

34. Combined T and B Cell Deficiencies
RAG-1 or RAG-2 deficiency
Bare lymphocyte deficiency
MHC class I and II deficiency
Wiskott-Aldrich syndrome
Ataxia-telangiectasia (AT)

35. Complement Deficiencies
C3 deficiency
Mannose-binding lectin (MBL) deficiency
Properdin deficiency
Factor I and factor H deficiency
C9 deficiency

36. Complement Deficiencies

37. Phagocytic Deficiencies
Severe congenital neutropenia
Cyclic neutropenia
Leukocyte adhesion deficiencies (LAD)
C3 receptor deficiency
Chédiak-Higashi syndrome
Myeloperoxidase deficiency
Chronic granulomatous disease

38. Secondary Deficiencies
Also referred to as acquired deficiencies
Far more common than primary deficiencies

39. Secondary Deficiencies
Causes
Normal physiology conditions
Psychological stress
Dietary insufficiencies
Malignancies
Physical trauma
Medical treatments
Infections
Acquired immunodeficiency syndrome (AIDS)

40. Acquired Immunodeficiency Syndrome (AIDS)
Syndrome caused by a viral disease
Human immunodeficiency virus (HIV)
Depletes the body’s Th cells
Incidence
Worldwide
5 million per year
United States
About 31,000 cases per year
400,000 currently living with AIDS

41. Acquired Immunodeficiency Syndrome (AIDS)
Effective antiviral therapies have made AIDS a chronic disease
Epidemiology
Blood-borne pathogen
Increasing faster in women than men

42. Acquired Immunodeficiency Syndrome (AIDS)
Pathogenesis
Retrovirus
Genetic information is in the form of RNA
Contains reverse transcriptase to convert RNA into double-stranded DNA
Integrase

43. Human Immunodeficiency Virus (HIV)

44. Human Immunodeficiency Virus (HIV)
Structure
gp120 protein binds to the CD4 molecule found primarily on the surface of helper T cells
CD4+ Th cells
Typically 800 to 1000 cells/mm3
Reverses CD4/CD8 ratio
Co-receptors
CXCR4 and CCR5
Strains can be selective for these receptors; influences the tropism of the target cells

45. Human Immunodeficiency Virus (HIV)

46. Human Immunodeficiency Virus (HIV)

47. Human Immunodeficiency Virus (HIV)
Clinical manifestations
Serologically negative, serologically positive but asymptomatic, early stages of HIV, or AIDS
Window period
Th cells <200 cells/mm3
Diagnosis of AIDS is made in association with various clinical conditions
Atypical or opportunistic infections, and cancer

48. Human Immunodeficiency Virus (HIV)

49. Human Immunodeficiency Virus (HIV)
Treatment and prevention
Highly active antiretroviral therapy (HAART)
Reverse transcriptase inhibitors
Protease inhibitors
New drugs
Entrance inhibitors
Integrase inhibitors
Vaccine development

50. Graft-vs.-Host Disease (GVHD)
Immunocompromised individuals are at risk for graft-vs.-host disease
T cells in the graft are mature and capable of cell-mediated destruction tissues within the recipient
Not a problem if patient is immunocompetent

51. Evaluation of Immunity
Complete blood count (CBC) with a differential
Subpopulations of lymphocytes
Quantitative determination of immunoglobulins
Subpopulations of immunoglobulins
Assay for total complement
Skin tests

52. Treatment for Immunodeficiencies
Gamma-globulin therapy
Transplantation or transfusion
Treatment with soluble immune mediators
Gene therapy