Aims

1. Aims • Quantitative and qualitative deficiencies in neutrophils (phagocytosis). • Quantitative and qualitative deficiencies of B cells (humoral immunity). • Cell mediated immunodeficiencies (T cells) • Combined immunodeficiencies. • Describe the pathogenesis of HIV infection. • Readings: Robbins, Chapters 5 & 6; Abbas & Lichtman, Chapter 12

2. Immune Deficiencies • Characterized by increased, persistent, and/or recurrent infections or infections with unusual organisms - opportunistic pathogens

3. Deficiencies in Phagocytosis • Characterized by infections with opportunistic extracellular pathogens • Quantitative- normal neutrophil count is 3000-6000 per ml of blood • Primary • congenital granulocytopenia or agranulocytosis • granulocyte stem cells do not mature into peripheral granulocytes • <200 neutrophils per ml of blood • G-CSF

4. Deficiencies in Phagocytosis • Secondary • Induced neutropenias (< 1,500 per ml) • chemotherapy and radiation • PMNs have short half-life • leukemia • crowding out precursors in bone marrow • Others – e.g. cyclical autoimmune neutropenia, overwhelming infections • Treatments include recombinant granulocyte colony stimulating factors (G-CSF, GM-CSF).

5. Deficiencies in Phagocytosis • Qualitative • defective phagocytic function • Adherence defects (e.g. leukocyte adherence deficiency) • A deficiency in  chain of the CD18 molecule • loss of tight binding between leukocyte integrins and EC ICAM-1 • Manifests as recurrent bacterial and fungal infections with an inability to form pus • Also effects cell-cell contact between leukocytes and target cells (e.g. CTL or NK cell)

6. Deficiencies in Phagocytosis Normal Extravasation Chemotactic stimuli Inflammatory stimuli

7. Deficiencies in Phagocytosis • Extravasation Defect • Leukocyte adherence deficiency • no tight binding • no extravasation

8. Deficiencies in Phagocytosis • Chemotaxis defect • Lazy leukocyte syndrome • deficiency in chemotaxis receptors Inflammatory stimuli

9. Deficiencies in Phagocytosis • Killing defect • Chronic granulomatous disease (X-linked) • defect of intracellular killing • granulomatous lesions found in various organs • death do to septicemia in childhood • defects in: • cytochrome b • G-6-PDH • Myeloperoxidase • Treatments • Actimmune (recombinant IFNg) • Bone marrow transplantation

10. Humoral Immune Deficiencies • Quantitative • Bruton’s X-linked agammaglobulinemia • Normal pre-B cells but few if any mature B cells • 0-20% of normal Ig • With decline in maternal IgG there are recurrent infections with extracellular bacteria (Staph and Strep) and other pathogens that produce capsules • Treated with HISG injections periodically Adapted from Robbins’ Basic Pathology5-29

11. Humoral Immune Deficiencies • Qualitative • X-linked hyper-IgM syndrome • defective isotype switching • pt have Ab but make almost exclusively IgM • may have Ab against other blood components (e.g. neutrophils, platelets, RBCs) • Recurrent infections with staph, strep, etc. Adapted from Robbins’ Basic Pathology5-29

12. Humoral Immune Deficiencies • Qualitative (cont.) • Selective IgA deficiency • low or no IgA • most common 1o deficiency • increased respiratory and GI infections • allergies and asthma are common • autoimmune diseases are common and autoantibodies against IgA may be present • Common variable hypogammaglobulinemia • no plasma cells formed Adapted from Robbins’ Basic Pathology5-29

13. T Cell Deficiencies • Effects both humoral and cell-mediated immunity • increased susceptibility to all pathogens • But is particularly characterized by increased susceptibility to specific “opportunistic” infections

14. Primary T Cell Deficiency • Primary • DiGeorge Syndrome (aka congenital thymic aplasia) • defect is in thymus development • low CD3+ counts in blood • little or no DTH reaction to common antigens • decreased responses of peripheral blood lymphocytes in vitro to mitogens • decreased mixed leukocyte reactions Adapted from Robbins’ Basic Pathology5-29

15. Combined Immunodeficiencies • Reticular dysgenesis - stem cell defect • No T cells, B cell or PMNs • Bare lymphocyte syndrome • Type I - no HLA class I molecules • Type II - no HLA class I or II molecules • Manifests as: • lymphopenia • low T cell numbers • low MLR, DTH and other Ag-specific tests • Normal mitogen responses • Death in childhood • Treatment is bone marrow transplant

16. SCID • Severe combined immunodeficiency (SCID) • X-linked “Bubble boy” or “Bubble baby” • Affects lymphocyte development • Treated with bone marrow transplant Robbins’ Basic Pathology5-29

17. Secondary T Cell Defect (HIV) • Human immunodeficiency virus (HIV-1) • RNA virus • 1,000,000 North Americans infected. • 37,800,000 infected world-wide. • AIDS (acquired immunodeficiency syndrome) • late stages of HIV infection • ~320,000 Americans

18. Transmission • Sexual contact • Infected blood • Sharing needles • Mother to Baby • during pregnancy • during delivery • through breast milk

19. HIV • Envelope glycoprotein • responsible for virus entry. • Composed of • 3 gp120 • 3 gp41 Robbins’ Basic Pathology5-30

20. HIV Presentation • DC-SIGN • molecule which binds to Env (GP120/GP41). • Mechanism for dendritic cells (DC) to present HIV to other cells. Adapted from www.medscape.com

21. Stages of Viral Entry • Virus attachment • Independent of the presence or absence of the CD4 receptor for many cell types. • Once attached to the cell surface, the chances of Env (GP120/GP41) encountering CD4 and co-receptors are likely to be increased • DC-SIGN, a molecule in the membrane of dendritic cells, efficiently binds HIV. • Dendritic cells present bound HIV to T cells, resulting in efficient virus infection.

22. Stages of Viral Entry CD4 binding • Gp120 can bind directly to CD4 on the cell surface, or it can bind to CD4 after first attaching to the cell surface via another molecule, such as DC-SIGN. • CD4 binding induces structural changes in gp120 that enable it to bind to a co-receptor. Adapted from Robbins’ Basic Pathology5-31

23. Stages of Viral Entry Coreceptor binding • CD4 binding results in exposure of the coreceptor binding site. • All HIV-1 strains use CCR5, CXCR4, or both receptors as coreceptors. • A subset of viruses can use alternative coreceptors in vitro, but the in vivo significance of this observation is unclear. Adapted from Robbins’ Basic Pathology5-31

24. Stages of Viral Entry Conformational changes and membrane fusion • CD4 and coreceptor binding triggers conformational change in the fusion peptide, gp41, which inserts into the cellular membrane • Gp41 subunit thus becomes an integral component of 2 membranes • Initiating lipid mixing and membrane fusion Adapted from Robbins’ Basic Pathology5-31

25. HIV Infection and Reproduction • Infection. • Uncoating by viral proteases. • Production of viral DNA. • Via reverse transcriptase. • Integration into host cell genome (provirus). • Expression of viral genes. • Upon stimulation of cell. • Production of viral particles. • Migrates to cell membrane and acquires a lipid envelope from host. Abbas & Lichtman’s Basic Immunology 12-8

26. Pathology Review • Primary infection in blood or mucosa. • Infection established in regional lymph node. • Viremia (spread of infection through out body). • Immune response • Anti-HIV antibodies. • HIV specific CTLs. • Chronic infection. • Virus trapped in dendritic cells. • Low-level virus production. • Stimulus to replicate. • Cytokines. • Other infection. • AIDS. Robbins’ Basic Pathology5-32

27. Pathology Review Robbins’ Basic Pathology5-32

28. Clinical Course of HIV Infection (1010 virons /day vs. 2X109 CD4 lymphocytes) Adapted from Robbins’ Basic Pathology5-34 Similar to Abbas & Lichtman’s Basic Immunology 12-10

29. IFNg CD40L cytokines cytokines CD40L CD28 cytokines cytokines Via macs Loss of CD4+ Cells Impacts Other Cells • Decreased CD8+ T cell cytotoxicity. • Decreased NK cell killing. • Decreased Ig production from B cells. • Decreased macrophage activation. • Decreased lymphocyte activation. Adapted from Robbins’ Basic Pathology5-41 7th Ed

30. Complications • Bacterial Infections • Mycobacterium avium complex (MAC) • Tuberculosis (TB) • Salmonellosis. • Bacillary angiomatosis • Viral Infections • Cytomegalovirus (CMV) • CMV retinitis • Viral hepatitis • Herpes simplex virus (HSV) • Progressive multifocal leukoencephalopathy (PML)

31. Complications (cont.) • Fungal Infections • Candidiasis • Cryptococcal meningitis • Parasitic Infections • Pneumocystis carinii pneumonia (PCP) • Toxoplasmosis • Cryptosporidiosis • Cancers • Kaposi's sarcoma • Non-Hodgkin's lymphoma

32. HIV • Fungal Infections • Oral candidiasis (thrush) • Found in almost everyone's body. • Looks like white patches similar to cottage cheese, or red spots. • It can cause a sore throat, pain when swallowing, nausea, and loss of appetite. Nairn’s Immunology 32-2

33. HIV • Cancers • Kaposi’s sarcoma • Type of cancer that men with AIDS may develop. • It is rarely seen in women. • Associated with co-infection with sexually transmitted herpes virus 8. • Mainly affects the skin, the mouth, and the lymph nodes. • Can spread throughout body. • Skin lesions are generally flat, painless and do not itch or drain. Nairn’s Immunology 32-3

34. HIV • Parasitic Infections • Pneumocystis Carinii Pneumonia (PCP) is a fungus that is in almost everyone's body. • A healthy immune system can control PCP. • Most common opportunistic infection in people with HIV. • Pneumocystis carinii almost always affects the lungs, causing a form of pneumonia. • PCP is unusual in HIV-infected persons until the CD4 count falls below 200/mm3. http://pathhsw5m54.ucsf.edu/case26/image265.html

35. Ocular Symptoms • CMV retinitis • Cotton wool spots • Karposi’s sarcoma on the eyelid and conjunctiva

36. Treatments • Antiretroviral Drugswhichinhibit the growth and replication of HIV at various stages of its life cycle. • Nucleoside analogue reverse transcriptase inhibitors (NRTIs) • inhibit reverse transcriptase. • Protease inhibitors (PIs) • interfering with HIV protease causing HIV particles to become structurally disorganized and noninfectious. • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) • bind directly to reverse transcriptase • Viral fusion inhibitors

37. HIV Vaccine Candidates Nairn’s Immunology 32-7

38. Next Time • Hypersensitivity reactions. • Readings: Abbas & Lichtman, Chapter 11

39. Objectives • Describe deficiencies in phagocytosis • Qualitative & Quantitative • Describe humoral deficiencies. • Qualitative & Quantitative • Describe T cell deficiencies. • Describe SCID. • Describe the pathogenesis of HIV infection. • Complications • Ocular symptoms • Treatments