curs 6 immunology_2013

8/13/2019 Curs 6 Immunology_2013

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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)


IgA deficiency


Transient hypogammaglobulinemia of infancy

Hyper IgM syndrome


DiGeorge syndrome

X-linked lymphoproliferative syndrome

Severe combined immunodeficiency (SCID)


Wiskott-Aldritch syndrome

Hyper IgE 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)


IgA deficiency


Transient hypogammaglobulinemia of

infancy

Hyper IgM syndrome


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IMMUNOLOGY

T-cell deficiencies


DiGeorge syndrome

X-linked lymphoproliferativesyndrome


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IMMUNOLOGY

Combined T-cell and B-cell defects

Severe combined immunodeficiency

(SCID)


Wiskott-Aldrich syndrome

Hyper IgE syndrome


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IMMUNOLOGY

Phagocytic disorders





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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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curs 6 immunology_2013

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