Aims Quantitative and qualitative deficiencies in neutrophils phagocytosis

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

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

Deficiencies in Phagocytosis • Characterized by infections with opportunistic extracellular pathogens • Quantitative - normal neutrophil count is 30006000 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

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 (GCSF, GM-CSF).

Deficiencies in Phagocytosis • Qualitative – defective phagocytic function • Adherence defects (e. g. leukocyte adherence deficiency) – A deficiency in chain of the CD 18 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)

Deficiencies in Phagocytosis Normal Extravasation Chemotactic stimuli Inflammatory stimuli

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

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

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

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 Ig. G 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 Pathology 5 -29

Humoral Immune Deficiencies • Qualitative • X-linked hyper-Ig. M syndrome – defective isotype switching • pt have Ab but make almost exclusively Ig. M • may have Ab against other blood components (e. g. neutrophils, platelets, RBCs) • Recurrent infections with staph, strep, etc. Adapted from Robbins’ Basic Pathology 5 -29

Humoral Immune Deficiencies • Qualitative (cont. ) • Selective Ig. A deficiency – low or no Ig. A – most common 1 o deficiency – increased respiratory and GI infections – allergies and asthma are common – autoimmune diseases are common and autoantibodies against Ig. A may be present • Common variable hypogammaglobulinemia – no plasma cells formed Adapted from Robbins’ Basic Pathology 5 -29

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

Primary T Cell Deficiency • Primary • Di. George Syndrome (aka congenital thymic aplasia) – defect is in thymus development – low CD 3+ 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 Pathology 5 -29

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

SCID • Severe combined immunodeficiency (SCID) – X-linked “Bubble boy” or “Bubble baby” – Affects lymphocyte development – Treated with bone marrow transplant Robbins’ Basic Pathology 5 -29

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

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

HIV • Envelope glycoprotein – responsible for virus entry. – Composed of • 3 gp 120 • 3 gp 41 Robbins’ Basic Pathology 5 -30

HIV Presentation • DC-SIGN – molecule which binds to Env (GP 120/GP 41). – Mechanism for dendritic cells (DC) to present HIV to other cells. Adapted from www. medscape. com

Stages of Viral Entry Virus attachment ·Independent of the presence or absence of the CD 4 receptor for many cell types. ·Once attached to the cell surface, the chances of Env (GP 120/GP 41) encountering CD 4 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.

Stages of Viral Entry CD 4 binding ·Gp 120 can bind directly to CD 4 on the cell surface, or it can bind to CD 4 after first attaching to the cell surface via another molecule, such as DC-SIGN. ·CD 4 binding induces structural changes in gp 120 that enable it to bind to a co-receptor. Adapted from Robbins’ Basic Pathology 5 -31

Stages of Viral Entry Coreceptor binding ·CD 4 binding results in exposure of the coreceptor binding site. ·All HIV-1 strains use CCR 5, CXCR 4, 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 Pathology 5 -31

Stages of Viral Entry Conformational changes and membrane fusion ·CD 4 and coreceptor binding triggers conformational change in the fusion peptide, gp 41, which inserts into the cellular membrane ·Gp 41 subunit thus becomes an integral component of 2 membranes ·Initiating lipid mixing and membrane fusion Adapted from Robbins’ Basic Pathology 5 -31

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

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 Pathology 5 -32

Pathology Review Robbins’ Basic Pathology 5 -32

Clinical Course of HIV Infection (1010 virons /day vs. 2 X 109 CD 4 lymphocytes) Similar to Abbas & Lichtman’s Basic Immunology 12 -10 Adapted from Robbins’ Basic Pathology 5 -34

Loss of CD 4+ Cells Impacts Other Cells • Decreased CD 8+ T cell cytotoxicity. • Decreased NK cell killing. • Decreased Ig production from B cells. • Decreased macrophage activation. • Decreased lymphocyte activation. IFNg CD 40 L cytokines Via macs cytokines CD 40 L CD 28 Adapted from Robbins’ Basic Pathology 5 -41 7 th Ed

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)

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

HIV • Fungal Infections – Oral candidiasis (thrush) – Found in almost everyone 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 appetit Nairn’s Immunology 32 -2

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

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 CD 4 count falls below 200/mm 3. http: //pathhsw 5 m 54. ucsf. edu/case 26/image 265. html

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

Treatments • Antiretroviral Drugs which inhibit 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

HIV Vaccine Candidates Nairn’s Immunology 32 -7

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

Objectives 1. Describe deficiencies in phagocytosis 1. Qualitative & Quantitative 2. Describe humoral deficiencies. 1. Qualitative & Quantitative 3. Describe T cell deficiencies. 4. Describe SCID. 5. Describe the pathogenesis of HIV infection. 1. Complications 2. Ocular symptoms 3. Treatments