aims quantitative and qualitative deficiencies in neutrophils (phagocytosis). quantitative and...

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 3000-6000 per l of blood

• Primary– congenital granulocytopenia or agranulocytosis

• granulocyte stem cells do not mature into peripheral granulocytes

• <200 neutrophils per l of blood

• G-CSF

Deficiencies in Phagocytosis• Secondary

– Induced neutropenias (< 1,500 per l) • 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).


• 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)


Inflammatorystimuli

Chemotactic stimuli

Normal Extravasation


• Extravasation Defect

• Leukocyte adherence deficiency – no tight binding– no extravasation

Inflammatorystimuli


• Chemotaxis defect

• Lazy leukocyte syndrome – deficiency in

chemotaxis receptors


• 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 IFN)

– 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

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 Pathology 5-29


• 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.



• 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


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• 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


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


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

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.


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.


CD4 binding



Coreceptor bindingCD4 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.



Conformational changes and membrane fusionCD4 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

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.


Pathology Review

(1010 virons /day vs. 2X109 CD4 lymphocytes)

Adapted from Robbins’ Basic Pathology 5-34Similar to Abbas & Lichtman’s Basic Immunology 12-10

Clinical Course of HIV Infection

Adapted from Robbins’ Basic Pathology 5-41 7th Ed

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.

cytokinesCD40L CD28

IFNCD40L

cytokines

cytokinesVia macs

cytokines

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'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

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.


http://pathhsw5m54.ucsf.edu/case26/image265.html

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.

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


Next Time

• Hypersensitivity reactions.

• Readings: Abbas & Lichtman, Chapter 11

Objectives

1. Describe deficiencies in phagocytosis1. 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. Complications2. Ocular symptoms3. Treatments

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