Mecanisme imune n afeciunile bacteriene i virale Imunitatea anti-fungic i imunologia clinic a afeciunilor parazitare

IMMUNOLOGY

Disease pathogenesis depends on:

Type of infectious agent Target organ Localization of the pathogen

Bacteria Viruses Fungi Parasites

Candida - extracellular

Type of immune response

Q fever bacteria - intracellular Influenza - intracellular Plasmodium - intracellular

IMMUNOLOGY

Streptococcus - extracellular

Immune response

The two-dimensional response chart

Self
Tolerate
[autologus molec.]

Damage
[cancer cell]

Safe
[food] [infectious agents]

Dangerous

Ignore

Eliminate

Non-self
IMMUNOLOGY

Understanding the immunology of ID

host-parasite

interactions differ among

individuals
the

outcome depends on characteristics of the host as well as of the microbe hosts and parasites are engaged in a fitness-enhancing adaptive race between over- and underreactivity too much and too little is equally bad

both

trade-off

Why would a disease-predisposing genotype be selected?

IMMUNOLOGY

The lens metaphor

Signal
Infection
TLRs

Decision

Response

Harm

Skin

Mucosa

CNS

I N N A T E

A D A P T I V E

Malfunctional (autoimmunity)

Functional

Malfunctional (allergy)

IMMUNOLOGY

Cell-mediated immune response

Intracellular Antigen
MHC I

Activated T cells
Th1
Stimulation

Inflammatory

Cytotoxic T cells
Attack by perforins

Helper T cells Th2 Activate B cells

Infected Cells

IMMUNOLOGY

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 IL12, IL-10, IL-1, IL-6, TNF- and IFN-, and release inflammatory mediators .

IMMUNOLOGY

Th1/Th2 polarization

IFN-

IL-4 IL-5 IL-13

Th1

T cell

Th2

Cell-mediated immune responses Some humoral immunity

Anti-parasitic and IgE responses Allergies General humoral response

IMMUNOLOGY

Humoral immune response

Extracellular Antigen
MHC II
Antibody Function

Activated T cells Helper T cells

T-independent activation

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 of the helminths IgA Plays a key role in mucosal immunity IgD Function unknown. Only present in minute quantities in the serum.

Activated B cells
Stimulation

Plasma cells
Attack by antibodies

Extracellular pathogen
IMMUNOLOGY

Immunity to extracellular bacteria

Streptococcus pneumoniae
Pathogenesis
colonizes 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)

Phagocytic survival
Capsule inhibits phagocytosis Cytotoxic (pneumolysin)

Tissue destruction
Complement activation (inflammatory C3a, C5a) Secretion of cytokines (IL-1, TNF) Secretion of H2O2 PC binds receptors for PAF

Innate immunity
Complement activation (alternative & classical pathways) encapsulated gram-positive coccus teichoic acid rich in phosphocholine (Cpolysaccharide) and autolytic enzyme (amidase) in cell wall F antigen pneumolysin 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)

IMMUNOLOGY

Immunity to intracellular bacteria

Mycobacterium tuberculosis
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

Innate immunity
intracellular pathogen in unactivated alveolar macrophages 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
IMMUNOLOGY

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

IMMUNOLOGY

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-

IMMUNOLOGY

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 immunity
Antibodies are common but not protective Th1 response is associated with a favorable outcome

IMMUNOLOGY

Immunodeficiencies

IMMUNOLOGY

IMMUNODEFICIENCY
Increased susceptibility to infection

Increased susceptibility to cancer

Primary immunodeficiencies Secondary (aquired) immunodefiencies

IMMUNOLOGY

Primary ImmunodeficiencY Diseases

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.

IMMUNOLOGY

Defense against pathogens

Phagocytosis
Antibodies IFN Complement

Cell-mediated immunity

Intracellular bacteria
Extracellular bacteria

Cell-mediated immunity

IFN and
Antibodies
Virus
IMMUNOLOGY

Cell-mediated immunity

Phagocytosis
Fungus

Types of immunodeficiencies

B-cell deficiencies (antibody deficiencies)

T-cell deficiencies

Phagocytic disorders

Complement deficiencies

IMMUNOLOGY

PIDs
Common variable immunodeficiency (CVID) Ataxia-Telangiectasia syndrome Chronic granulomatous disease DiGeorge syndrome

X-linked agammaglobulinemia (XLA)

Wiskott-Aldritch syndrome
Severe combined immunodeficiency (SCID) IgA deficiency Chediak-Higashi syndrome Chronic mucocutaneous candidiasis Transient hypogammaglobulinemia of infancy Hyper IgE syndrome Selective IgG subclass deficiency X-linked lymphoproliferative syndrome Leukocyte adhesion defect (LAD)
IMMUNOLOGY

Hyper IgM syndrome

PIDs
Common variable immunodeficiency (CVID) Ataxia-Telangiectasia syndrome Chronic granulomatous disease DiGeorge syndrome

X-linked agammaglobulinemia (XLA)

Wiskott-Aldritch syndrome
Severe combined immunodeficiency (SCID) IgA deficiency Chediak-Higashi syndrome Chronic mucocutaneous candidiasis Transient hypogammaglobulinemia of infancy Hyper IgE syndrome Selective IgG subclass deficiency X-linked lymphoproliferative syndrome Leukocyte adhesion defect (LAD)
IMMUNOLOGY

Hyper IgM syndrome

When to suspect PIDs?

When the recurrent infection is:

1. > 5-7 upper respiratory infections that required systemic antibiotherapy within 1 year (sinusitis, otitis, pharyngitis, bronchitis).

Severe Complicated In multiple locations Resistant to treatment Caused by unual organisms

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.

IMMUNOLOGY

Antibody deficiencies

Constitute 70% of PIDs. Recurrent pyogenic infections starting after 6-12 months.

IMMUNOLOGY

Antibody/B-cell deficiencies
Common variable immunodeficiency (CVID) X-linked agammaglobulinemia (XLA) IgA deficiency

Transient hypogammaglobulinemia of infancy

Selective IgG subclass deficiency Hyper IgM syndrome
IMMUNOLOGY

T-cell deficiencies

DiGeorge syndrome

Chronic mucocutaneous candidiasis

X-linked lymphoproliferative syndrome

IMMUNOLOGY

Combined T-cell and B-cell defects

Severe combined immunodeficiency (SCID) Ataxia-Telangiectasia syndrome Wiskott-Aldrich syndrome

Hyper IgE syndrome

IMMUNOLOGY

Phagocytic disorders
Chronic granulomatous disease

Leukocyte adhesion defect (LAD)

Chediak-Higashi syndrome

IMMUNOLOGY

The clinical findings orientate the diagnosis

Age group Findings
Diarrhea, failure to thrive Maculopapular rash, splenomegaly

Disorder
Severe combined immunodeficiency Severe combined immunodeficiency when accompanied by graft-vshost disease (eg, caused by transplacentally transferred T cells) DiGeorge syndrome C3 deficiency Chdiak-Higashi syndrome Congenital asplenia Leukocyte adhesion deficiency Chronic granulomatous disease Hyper-IgE syndrome

Hypocalcemic tetany, a congenital heart disorder, unusual facies with low-set ears Recurrent pyogenic infections, sepsis

< 6 mo

Oculocutaneous albinism, neurologic changes, lymphadenopathy Cyanosis, a congenital heart disorder, midline liver Delayed umbilical cord detachment, leukocytosis, periodontitis, poor wound healing Abscesses, lymphadenopathy, antral obstruction, pneumonia, osteomyelitis Recurrent staphylococcal abscesses of the skin, lungs, joints, and viscera; pneumatoceles; coarse facial features; pruritic dermatitis

Chronic gingivitis, recurrent aphthous ulcers and skin infections, severe neutropenia Severe congenital neutropenia Paralysis after oral polio immunization X-linked agammaglobulinemia X-linked lymphoproliferative syndrome Chronic mucocutaneous candidiasis Ataxia-telangiectasia C5, C6, C7, or C8 deficiency Common variable immunodeficiency X-linked agammaglobulinemia

6 mo - 5 yrs

Severe progressive infectious mononucleosis Persistent oral candidiasis, nail dystrophy, endocrine disorders (eg, hypoparathyroidism, Addison's disease) Ataxia, recurrent sinopulmonary infections, neurologic deterioration, telangiectasias

> 5 yrs (+adults)

Recurrent Neisseria meningitis Recurrent sinopulmonary infections, malabsorption, splenomegaly, autoimmune disorders, nodular lymphoid hyperplasia of the GI tract, lymphoid interstitial pneumonia, bronchiectasis Progressive dermatomyositis with chronic echovirus encephalitis

IMMUNOLOGY

Initial and additional testing

CBC Serum Ig Ab titers Skin testing NBT X-ray

Type

Initial Tests

Additional Tests

B-cell deficiency

IgG, IgM, IgA, and IgE levels Isohemagglutinin titers B-cell phenotyping and count using flow Antibody response to vaccine antigens (eg, cytometry and monoclonal antibodies to B Haemophilus influenzae type b, tetanus, diphtheria, cells conjugated and nonconjugated pneumococcal, and meningococcal antigens) 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 subsets T-cell proliferative response to mitogens

T-cell deficiency

Phagocytic cell defects

Phagocytic cell count and morphology

Flow cytometric respiratory burst assay

C3 level Complement deficiency C4 level CH50 activity

IMMUNOLOGY

Specific component assays

Advanced tests
Test
B-cell deficiency
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. < 1% B cells suggests X-linked agammaglobulinemia. B cells are absent in Omenn's syndrome. Interpretation varies by histology. These tests can detect X-linked agammaglobulinemia and Omenn's syndrome.

Indications

Interpretation

IgE level measurement

Abscesses

B-cell quantification via flow cytometry Lymph node biopsy Mutation analysis

Low Ig levels For some patients with lymphadenopathy, to determine whether germinal centers are normal and to exclude cancer and infection B cells < 1% (detected by flow cytometry)

T-cell deficiency
T-cell enumeration using flow cytometry and monoclonal antibodies T-cell proliferation assays to mitogens, antigens, or irradiated allogeneic WBCs Detection of antigens (eg, class II MHC molecules) using monoclonal antibodies or serologic HLA typing RBC adenosine deaminase assay Purine nucleoside phosphorylase assay T-cell receptor and signal transduction assays Lymphopenia, suspected SCID or complete DiGeorge syndrome Low percentage of T cells, lymphopenia, suspected SCID or complete DiGeorge syndrome Suspected MHC deficiency, absence of MHC stimulation by cells Severe lymphopenia Severe persistent lymphopenia Phenotypically normal T cells that do not proliferate normally in response to mitogen antigen Interpretation varies by molecular type of SCID. Low or absent uptake of radioactive thymidine during cell division indicates a T-cell or combined defect. Absence of class I or class II HLA antigens by serologic HLA typing is diagnostic for MHC antigen deficiency. Levels are low in a specific form of SCID. Levels are low in combined immunodeficiency with normal or elevated Ig levels. Interpretation 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 Abnormalities confirm phagocytic cell defects or deficiencies. infections (eg, Serratia marcescens aspergillosis)

Complement deficiency
Measurement of levels of specific complement components CH50 level < 11% Interpretation varies by test.

IMMUNOLOGY

Treatment
Vaccines and avoidance of exposure to infection

Antibiotics/Antivirals

Replacement therapy

IMMUNOLOGY

Experimental models
Athymic (nude) mouse
Foxn1nu/nu

NODscid mouse
NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ

IMMUNOLOGY