Lecture #15 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 Lecture #15 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 Believed to be a defect in Granulocyte colony stimulating factor (G-CSF) Children surcon to infection eaarly in life

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).

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)

Deficiencies in Phagocytosis Inflammatory stimuli Chemotactic Normal Extravasation

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

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

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 Lecture #15 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 HISG Human immune serum globulin Adapted from Robbins’ Basic Pathology 5-29

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 Pathology 5-29

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 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 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 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 1,000,000 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 gp120 3 gp41 Robbins’ Basic Pathology 5-30

HIV Presentation DC-SIGN molecule which binds to Env (GP120/GP41). Lecture #15 HIV Presentation DC-SIGN molecule which binds to Env (GP120/GP41). Mechanism for dendritic cells (DC) to present HIV to other cells. Figure 2. (click image to zoom) HIV Binding to DC-SIGN. DC-SIGN is a tetrameric membrane protein with a lectin binding region at its distal end. HIV binds to DC-SIGN avidly via interactions between the numerous carbohydrate chains on HIV and the lectin binding region of DC-SIGN. Once bound to DC- SIGN, HIV may infect the cell provided that CD4 and a coreceptor are present (infection in cis). Alternatively, HIV may be "presented" to an adjoining cell that expresses CD4 and a coreceptor (infection in trans). Adapted from www.medscape.com

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.

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 Pathology 5-31

Stages of Viral Entry Coreceptor binding Lecture #15 Stages of Viral Entry Coreceptor binding What about CCR2 as a cofactor? 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 Pathology 5-31

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 Pathology 5-31

HIV Infection and Reproduction 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 Lecture #15 Clinical Course of HIV Infection (1010 virons /day vs. 2X109 CD4 lymphocytes) Similar to Abbas & Lichtman’s Basic Immunology 12-10 Adapted from Robbins’ Basic Pathology 5-34

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. cytokines CD40L CD28 IFNg Via macs Adapted from Robbins’ Basic Pathology 5-41 7th Ed

Complications Bacterial Infections Viral 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 Parasitic Infections Cancers 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) Lecture #15 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. Figure 32.2 The white lesions on this man's palate are oral candidiasis, which is a marker of mild immunodeficiency and it is often the first opportunist infection in patients with HIV. Oral candidiasis is often seen in other mild secondary immunodeficiencies. (With permission from the Department of Medical Illustration, St Bartholomew's Hospital, London.) Nairn’s Immunology 32-2

HIV Cancers Kaposi’s sarcoma Lecture #15 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. Figure 32.3 Kaposi's sarcoma (KS) is a marker of moderate immunodeficiency and it is seen most frequently in HIV patients. In HIV infection, KS affects only some patient groups, for example gay men, probably because of the requirements for a second coinfection with human herpes virus 8. (With permission from the Department of Medical Illustration, St Bartholomew's Hospital, London.) Nairn’s Immunology 32-3

HIV Parasitic Infections Lecture #15 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. In this slice of postmortem lung from an AIDS patient, who did not respond to anti-pneumocystis therapy, innumerable cavities, up to about 1 cm in diameter, were found. These cavities have thin walls and occur in the pale yellowish parenchyma that occupies most of the upper lobe. The pallor indicates ischemia. Microscopically, organisms were easily found in alveolar septa around the cavities, and septal lysis may have occurred to produce the cavities. Inflammation was minimal, and there was no evidence of angiitis. The subpleural cavities near the apex are the ones likely to rupture and cause pneumothorax. The red parenchyma of the lower lobe is also consolidated, and microscopically, alveoli were filled with foamy exudate, which did not invade alveolar walls or compromise the blood supply in this area. In a review of 100 consecutive radiographs of AIDS patients, pneumatoceles, corresponding to the cavities shown above, were found in 10. The spaces were empty and thin-walled and had no predilection for any part of the lung. After treatment, most resolved within 7 months [1]. http://pathhsw5m54.ucsf.edu/case26/image265.html

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

Lecture #15 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 Lecture #15 HIV Vaccine Candidates Figure 32.7 Candidate HIV vaccines. No single candidate vaccine is yet proven to meet all the challenges produced by HIV Nairn’s Immunology 32-7

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

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