Transcript File

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 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
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
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
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
• 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 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).
– 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.
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
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
• 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. 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.
IFNg
CD40L
cytokines
cytokines
cytokines
Via macs
cytokines
CD40L
CD28
Adapted from Robbins’ Basic Pathology 5-41 7th 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'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 coinfection 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 CD4 count falls
below 200/mm3.
http://pathhsw5m54.ucsf.edu/case26/image265.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