curs 6 immunology_2013
TRANSCRIPT
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IMMUNOLOGY
Mecanisme imune n afeciunile bacteriene i virale
Imunitatea anti-fungic i imunologia clinic a
afeciunilor parazitare
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IMMUNOLOGY
The lens metaphor
Signal Decision Response
Infection Harm
TLRs
I
N
N
AT
E
A
D
A
P
TI
V
E
Malfunctional
(autoimmunity)
Malfunctional
(allergy)
Functional
Skin
Mucosa
CNS
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IMMUNOLOGY
Cell-mediated immune response
Intracellular Antigen
Activated T cells
Cytotoxic T cells Helper T cells
Infected Cells
MHC I
Attack by perforins
Stimulation
Th1 Inflammatory
Th2 Activate B cells
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Cell-mediated immune response
Main actors in cell-mediated immunity
Th1 cells
Activated by Ag, IL-12 and IFN
release IL-2 and IFN-
induce TC, NK, and macrophage
activation
CTLs
Activated by Ag/MHC. Cytotoxic via
TNF, perforin, granzymes
NK cells
Activated by IL-12.Release IFN- which
activates macrophages and
stimulates Th1 activity.
Macrophages
Activated by IFN-. They produce IL-
12, IL-10, IL-1, IL-6, TNF- and IFN-,
and release inflammatory mediators .
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Th1/Th2 polarization
Th1 Th2T cell
Cell-mediated
immune responses
Some humoralimmunity
IFN-
IL-4
IL-5
IL-13
Anti-parasitic and IgE
responses
AllergiesGeneral humoral
response
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Humoral immune response
Extracellular Antigen
Activated T cells
Plasma cells
Helper T cells
Extracellular pathogen
MHC II
Attack by antibodies
Stimulation
Activated B cells
T-independent
activation
Antibody Function
IgM
Activates the complement system, leading to
opsonization and phagocytosis
IgG
Blocks virus entry into host cells. Promotes
phagocytosis by macrophages
IgE
Responds to many helminthic parasites by
participating in eosinophil-mediated killing ofthe helminths
IgA
Plays a key role in mucosal immunity
IgD
Function unknown. Only present in minute
quantities in the serum.
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Immunity to extracellular bacteria
Streptococcus pneumoniae
encapsulated gram-positive coccusteichoic acid rich in phosphocholine (C-
polysaccharide) and autolytic enzyme
(amidase) in cell wall
F antigen
pneumolysin
Pathogenesiscolonizes the oropharynx (surface protein adhesions)
spreads into normally sterile tissues (pneumolysin, IgA, protease)
stimulates local inflammatory response (teichoic acid, peptidoglycan fragments, pneumolysin)
evades phagocytic killing (polysaccharide capsule)
Tissue destruction
Complement activation (inflammatory C3a, C5a)Secretion of cytokines (IL-1, TNF)
Secretion of H2O2
PC binds receptors for PAF
Phagocytic survival
Capsule inhibits phagocytosis
Cytotoxic (pneumolysin)
Innate immunity
Complement activation (alternative & classical pathways)
TLR2 (PG , LTA); TLR4 (pneumolysin)
SIGN-R1 on macrophages
B-1a cells make IgM to polysaccharides w/o prior exposure
Specific immunity
Anticapsular antibody (5-8d after the onset of infection)
Antibodies to other constituents?
Low prevalence of anticapsular Ab
Spleen clears unopsonized bacteria from bloodstream (!splenectomy)
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Immunity to intracellular bacteria
Mycobacterium tuberculosis
intracellular pathogen in unactivated
alveolar macrophages
Innate immunity
Macrophages secrete IL-12 and TNF-
Inflammation and recruitment of NK and T cells
Specific immunity
Th1-type response, with secretion of IFN-
Macrophages are activated in the presence of IFN-, leading to
phagolysosome fusion and enhanced intracellular killing
Pathogenesis
M. tuberculosis enters the respiratory airways
infectious particles penetrate to the alveoli
is phagocytized by alveolar macrophages
intravacuole replication
Phagocytic survival
prevents fusion of the phagosome with the
lysosomes by blocking EEA-1
Tissue destruction
Inflammation
Cell-mediated responses
Granulomas
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Immunity to viruses
West Nile virus
Flavivirus, arbovirus
enveloped, single-stranded, positive-sense RNA
cytolytic, buds into intracellular vesicles
target: monocytes, macrophages, endothelial cells
good inducers of IFN (flu-like symptoms)
Humoral immunity
Double-stranded RNA intermediate (TLR3) is a good inducer of
IFN and
Circulating antibodies (IgM and IgG) - double -edged sword
Cross-reactivity of Ab to flaviviruses
Cellular immunity
CNS expression of CCR5 and CCL5 are upregulated by WN
recruitment of CD4+, CD8+ and NK cells
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Immunity to parasites
Leishmania donovani
Protozoan
Visceral leishmaniasis, but also CL and ML
Promastigote to amastigote in macrophages
Immune evasion
Immune response
Mostly rely on adaptive immunity
Leishmania-specific Th1-type CD4+ T cells that secrete interferon- (INF-) and interleukin-2 (IL-2)
IFN- activates macrophages to kill amastigotes
IL-1 and TNF prime macrophages for activation by INF-IL-12 early role
Progressive disease seems to be associated with a Th2-type response (activation of B cells and production of
antibodies, IL-10 and TGF-
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Immunity to fungi
Aspergillus fumigatus
Invasive aspergillosis is a major cause of morbidity
and mortality in immunosuppressed patients
Uncommon in immunocompetent hosts
Innate immunity
Pulmonary macrophages ingest and kill conidia
Neutrophils extracellularly kill conidia and
hyphae
Toxins may inhibit macrophages and
neutrophils
TLR2 and dectin-1recognition results in
secretion of proinflammatory cytokines
Adaptive immunityAntibodies are common but not protective
Th1 response is associated with a favorable
outcome
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Immunodeficiencies
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IMMUNOLOGY
IMMUNODEFICIENCY
Increased susceptibility to infection
Increased susceptibility to cancer
Primary immunodeficienciesSecondary (aquired) immunodefiencies
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IMMUNOLOGY
Primary ImmunodeficiencY Diseases
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IMMUNOLOGY
Definitions
The primary immunodeficiency diseases (PIDs) are a group of inherited
disorders characterized by recurrent and/or unusual infections in
different organs of the body.
Genetically determined.
Incidence from 1/10 000 to 1/2000 live births.
Overall incidence 1/280.
More than 200 described.
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IMMUNOLOGY
Defense against pathogens
Extracellular bacteriaIntracellular bacteria
FungusVirus
Phagocytosis
Antibodies
Complement
Cell-mediated
immunity
Cell-mediated
immunity Cell-mediated
immunity
IFN
IFN and
AntibodiesPhagocytosis
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IMMUNOLOGY
Types of immunodeficiencies
B-cell deficiencies (antibody
deficiencies)T-cell deficiencies
Complement deficienciesPhagocytic disorders
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IMMUNOLOGY
PIDs
Common variable immunodeficiency (CVID)
X-linked agammaglobulinemia (XLA)
IgA deficiency
Selective IgG subclass deficiency
Transient hypogammaglobulinemia of infancy
Hyper IgM syndrome
Chronic mucocutaneous candidiasis
DiGeorge syndrome
X-linked lymphoproliferative syndrome
Severe combined immunodeficiency (SCID)
Ataxia-Telangiectasia syndrome
Wiskott-Aldritch syndrome
Hyper IgE syndrome
Chronic granulomatous disease
Leukocyte adhesion defect (LAD)
Chediak-Higashi syndrome
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IMMUNOLOGY
PIDs
Common variable immunodeficiency (CVID)
X-linked agammaglobulinemia (XLA)
IgA deficiency
Selective IgG subclass deficiency
Transient hypogammaglobulinemia of infancy
Hyper IgM syndrome
Chronic mucocutaneous candidiasis
DiGeorge syndrome
X-linked lymphoproliferative syndrome
Severe combined immunodeficiency (SCID)
Ataxia-Telangiectasia syndrome
Wiskott-Aldritch syndrome
Hyper IgE syndrome
Chronic granulomatous disease
Leukocyte adhesion defect (LAD)
Chediak-Higashi syndrome
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IMMUNOLOGY
When to suspect PIDs?
1. > 5-7 upper respiratory infections that required
systemic antibiotherapy within 1 year (sinusitis,
otitis, pharyngitis, bronchitis).
2. > 2 unusual infections (pneumonia,
meningitis) 3. Recurrent or persistent infections that fail to
respond to well- conducted antibiotic therapy (skin
infections, abscesses, periodontitis or unusual
wound healing).
4. Infants whith failure to thrive and persistent
infections with low virulence or opportunistic
agents, unusual rashes, diarrhea.
5. Recurrent neisserial infections or with systemic
lupus erythematous.
6. Familial history of PID.
7. Infants with syndromes associated with PID.
Severe
Complicated
In multiple locations
Resistant to treatment
Caused by unual
organisms
When the recurrent infection is:
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IMMUNOLOGY
Antibody deficiencies
Constitute 70% of PIDs.
Recurrent pyogenic infections starting after 6-12 months.
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IMMUNOLOGY
Antibody/B-cell deficiencies
Common variable immunodeficiency
(CVID)
X-linked agammaglobulinemia (XLA)
IgA deficiency
Selective IgG subclass deficiency
Transient hypogammaglobulinemia of
infancy
Hyper IgM syndrome
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IMMUNOLOGY
T-cell deficiencies
Chronic mucocutaneous candidiasis
DiGeorge syndrome
X-linked lymphoproliferativesyndrome
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IMMUNOLOGY
Combined T-cell and B-cell defects
Severe combined immunodeficiency
(SCID)
Ataxia-Telangiectasia syndrome
Wiskott-Aldrich syndrome
Hyper IgE syndrome
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IMMUNOLOGY
Phagocytic disorders
Chronic granulomatous disease
Leukocyte adhesion defect (LAD)
Chediak-Higashi syndrome
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IMMUNOLOGY
The clinical findings orientate the diagnosis
Age group Findings Disorder
< 6 mo
Diarrhea, failure to thrive Severe combined immunodeficiency
Maculopapular rash, splenomegalySevere combined immunodeficiency when accompanied by graft-vs-
host disease (eg, caused by transplacentally transferred T cells)
Hypocalcemic tetany, a congenital heart disorder, unusual facies with low-set ears DiGeorge syndrome
Recurrent pyogenic infections, sepsis C3 deficiency
Oculocutaneous albinism, neurologic changes, lymphadenopathy Chdiak-Higashi syndrome
Cyanosis, a congenital heart disorder, midline liver Congenital asplenia
Delayed umbilical cord detachment, leukocytosis, periodontitis, poor wound healing Leukocyte adhesion deficiency
Abscesses, lymphadenopathy, antral obstruction, pneumonia, osteomyelitis Chronic granulomatous disease
Recurrent staphylococcal abscesses of the skin, lungs, joints, and viscera;
pneumatoceles; coarse facial features; pruritic dermatitisHyper-IgE syndrome
Chronic gingivitis, recurrent aphthous ulcers and skin infections, severe neutropenia Severe congenital neutropenia
6 mo - 5 yrs
Paralysis after oral polio immunization X-linked agammaglobulinemia
Severe progressive infectious mononucleosis X-linked lymphoproliferative syndrome
Persistent oral candidiasis, nail dystrophy, endocrine disorders (eg,
hypoparathyroidism, Addison's disease)Chronic mucocutaneous candidiasis
> 5 yrs
(+adults)
Ataxia, recurrent sinopulmonary infections, neurologic deterioration, telangiectasias Ataxia-telangiectasia
Recurrent Neisseria meningitis C5, C6, C7, or C8 deficiency
Recurrent sinopulmonary infections, malabsorption, splenomegaly, autoimmune
disorders, nodular lymphoid hyperplasia of the GI tract, lymphoid interstitial
pneumonia, bronchiectasis
Common variable immunodeficiency
Progressive dermatomyositis with chronic echovirus encephalitis X-linked agammaglobulinemia
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IMMUNOLOGY
Initial and additional testing
Type Initial Tests Additional Tests
B-cell deficiency
IgG, IgM, IgA, and IgE levelsIsohemagglutinin titers
Antibody response to vaccine antigens (eg,
Haemophilus influenzae type b, tetanus, diphtheria,
conjugated and nonconjugated pneumococcal, and
meningococcal antigens)
B-cell phenotyping and count using flow
cytometry and monoclonal antibodies to B
cells
T-cell deficiency
Absolute lymphocyte count
Delayed hypersensitivity skin tests (eg, using
Candida)Chest x-ray for size of thymus in infants only
T-cell phenotyping and count using flow
cytometry and monoclonal antibodies to T
cells and subsetsT-cell proliferative response to mitogens
Phagocytic cell defects Phagocytic cell count and morphology Flow cytometric respiratory burst assay
Complement deficiency
C3 level
C4 level
CH50 activity
Specific component assays
CBC Serum Ig Skin testing NBT X-rayAb titers
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IMMUNOLOGY
Advanced tests
Test Indications Interpretation
B-cell deficiency
IgE level measurement Abscesses
Levels are high in patients with abscesses and pneumatoceles (hyper-IgE
syndrome), partial T-cell deficiencies, allergic disorders, or parasitic infections.
Levels may be high or low in patients with incomplete B-cell defects or
deficiencies.Isolated deficiency is not clinically significant.
B-cell quantification via flow cytometry Low Ig levels< 1% B cells suggests X-linked agammaglobulinemia.
B cells are absent in Omenn's syndrome.
Lymph node biopsyFor some patients with lymphadenopathy, to determine whether
germinal centers are normal and to exclude cancer and infectionInterpretation varies by histology.
Mutation analysis B cells < 1% (detected by flow cytometry) These tests can detect X-linked agammaglobulinemia and Omenn's syndrome.
T-cell deficiency
T-cell enumeration using flow cytometry and monoclonal antibodies Lymphopenia, suspected SCID or complete DiGeorge syndrome Interpretation varies by molecular type of SCID.
T-cell proliferation assays to mitogens, antigens, or irradiated
allogeneic WBCs
Low percentage of T cells, lymphopenia, suspected SCID or complete
DiGeorge syndrome
Low or absent uptake of radioactive thymidine during cell division indicates a
T-cell or combined defect.
Detection of antigens (eg, class II MHC molecules) using
monoclonal antibodies or serologic HLA typingSuspected MHC deficiency, absence of MHC stimulation by cells
Absence of class I or class II HLA antigens by serologic HLA typing is
diagnostic for MHC antigen deficiency.
RBC adenosine deaminase assay Severe lymphopenia Levels are low in a specific form of SCID.
Purine nucleoside phosphorylase assay Severe persistent lymphopeniaLevels are low in combined immunodeficiency with normal or elevated Ig
levels.
T-cell receptor and signal transduction assaysPhenotypically normal T cells that do not proliferate normally in
response to mitogen antigenInterpretation varies by test.
Phagocytic cell defects
Assays for oxidant products (hydrogen peroxide, superoxide) or
proteins (CR3 [CD11] adhesive glycoproteins, NADPH oxidase
components)
History of staphylococcal abscesses or certain gram-negative or fungal
infections (eg, Serratia marcescens aspergillosis)Abnormalities confirm phagocytic cell defects or deficiencies.
Complement deficiency
Measurement of levels of specific complement components CH50 level < 11% Interpretation varies by test.
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IMMUNOLOGY
Treatment
Vaccines and avoidance of exposure
to infection
Antibiotics/Antivirals
Replacement therapy
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