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Immunodeficiencies
Martin Liška
Basic immunological terms
Immune system provides 3 basic functions:
a)
Defense against infection
b) Homeostasis – elimination of old or impaired cells
c)
Immunological surveillance - elimination of mutated cells
Endocrine system
Immune system
Nervous system
Disorders – detectable by laboratory or histological methods, without clinical
manifestation
Clinical manifestation – decreased function - immunodeficiencies
- increased function – allergy, autoimmunity
Immunodeficiencies
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Humoral – innate immunity - complement, MBL
acquired immunity – immunoglobulins (B lymphocytes)
•
Cell mediated immunity – innate immunity – phagocytes
- acquired immunity – T lymphocytes
•
Primary – congenital, genetically defined, symptoms predominantly
at an early age
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Secondary – the onset of symptoms at any age
chronic diseases
the effects of irradiation
immunosuppression
surgery, injuries
stress
Immunodeficiencies – critical life periods in respect to
symptoms onset
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Newborn age - severe primary disorders of cell mediated immunity
•
6 mth. – 2 yrs. – severe humoral immunodeficiencies
cong./transient
•
3 - 5 yrs. – transient and selective humoral immunodeficiencies,
secondary immunodeficiencies
•
15 – 20 yrs. – hormonal instability, thymus involution, life-style changes,
some typical infections
first symptoms of CVID
•
Middleage – often excessive workload, stress
first symptoms of autoimmune disorders (also immunodeficiency)
•
Advanced and old age – rather symptoms of severe secondary immunodeficiencies,
repercussion of functional disorders
Immunodeficiencies – major clinical features
• Antibodies - microbial infections (encapsulated bacterias)
respiratory - pneumonia, sinusitis, otitis
GIT – diarrhea
• Complement – microbial infections (pyogenic), sepsis
various systems affection
edema (HAE) – C1-INH deficiency
• T lymphocytes - bacterial, fungal, viral
GIT – diarrhoea
respiratory – pneumonia, sinusitis
• Phagocytes - abscesses, recurrent purulent skin infections
granulomatous inflammations
The differentiation of pluripotent stem-cell
I. Primary immunodeficiencies –
phagocytic cell defects
1/ Quantitative – decreased numbers of granulocytes –
neutrophil elastase mutation
Congenital chronic agranulocytosis
Cyclic agranulocytosis (neutropenia)
• Systemic manifestation, fevers in 3-weeks cycles in
cyclic form
• Treatment with granulocyte growth factors, ATB
I. Primary immunodeficiencies –
phagocytic cell defects
2/ Qualitative – phagocytes functional disorders, various enzyme
deficits, inability of phagocytes to degrade the ingested material
Chronic Granulomatous Disease (CGD)
• Approximately in 60% X-linked
• Enzymatic inability to generate toxic oxygen metabolites (H2O2)
during oxygen consumption) - result of defect in neutrophilic
cytochrome b (part of complex containing NADPH oxidase)
• Inability to kill bacteria such as Staph.aureus, Pseud.aeruginosa that
produce the enzyme catalase
• Clinical features: granulomas in many organs
• Treatment: long-term ATB administration
• Myeloperoxidase deficiency
• Recurrent microbial infections, susceptibility to Candida albicans and
Staph.aureus infections
I. Primary immunodeficiencies –
phagocytic cell defects
Chédiak-Higashi syndrome
• Clinical features: recurrent, severe, pyogenic infections
(streptococcal, staphylococcal)
• Defective intracellular killing of bacteria (neutrophils
contain abnormal giant lysosomes
HyperIgE (Job’s) syndrome
• Mutation of STAT3 gene
• Recurrent “cold” staphylococcal abscesses, chronic
eczema, otitis media
• Extremely high serum IgE levels
• Treatment: ATB
LAD syndrome – Leukocyte Adhesion Deficiency
(neutrophil adhesion molecules deficiency)
• LAD I – integrins expression deficiency
• LAD II – selectins expression deficiency
II. Primary immunodeficiencies –
B cell disorders
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Bruton’s X-linked hypogamaglobulinemia
Blockage in the maturation of pre-B lymphocytes into B lymphocytes
(tyrosine kinase defect)
Frequency 1: 50-100 thousands
Undetectable or very low serum levels of Ig
Clinical symptoms in 5-9 mth.of age
Pneumonia, pyogenic otitis, complicated sinusitis, increased occurrence
of pulmonary fibrosis
Treatment: life-long IVIG substitution
CVID – Common Variable ImmunoDeficiency
B cell functional disorder, mostly low levels of IgG and IgA
Frequency 1:100-200 thousands. Symptoms’ onset between 2nd and 3rd
decade
Recurrent respiratory tract infections (pneumonia)
Treatment: IVIG substitution
II. Primary immunodeficiencies –
B cell disorders
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Selective IgA deficiency
Disorder of B cell function
Frequency 1: 500-700, manifestation mostly at pre-school age
Recurrent mild/moderate infections (respiratory, GIT, urinary tract) or
asymptomatic
Risk of reaction to live attenuated vaccines or generation of anti-IgA
antibodies after a blood transfusion
Laboratory criterion: IgA < 0,07g/l (age > 4 years)
Selective IgG subclasses or specific IgG deficiency
• B cell function disorder
• Frequency ?
• Onset of symptoms in childhood, mostly respiratory tract infections
caused by encapsulated bacteria (H.influenzae, Pneumococci)
Transient hypogammaglobulinemia of infancy
III. Primary immunodeficiencies –
T cell disorders
diGeorge syndrome
• Disorder of prethymocytes maturation due to absence of thymus
• Disorder of development of 3rd and 4th branchial pouch – absence of
parathyroid glands
• Congenital heart diseases
• Frequency 1 : 100 thousands
• The onset of symptoms after the birth – hypocalcemic spasms and
manifestations of cong.heart disease
• Immunodeficiency could be only mild, the numbers of T lymphocytes
later usually become normal
• Treatment symptomatic
III. Primary immunodeficiencies –
T cell disorders
Lymphoproliferative syndrome
• Malignant proliferation of activated T lymphocytes
• Hypogamaglobulinaemia, lymphoma
• Its development is induced by EBV infection
Chronic mucocutaneous candidiasis
• Impaired ability of T cells to produce macrophage migration inhibiting
factor (MIF) in response to Candida antigen
Bare lymphocyte sy.
• Disorder of antigen presentation – defect of MHC I and/or MHC II
expression leads to the dysfunction of CD4 and CD8 lymphocytes
IFN-g Receptor deficiency
• Th1 lymphocytes differentiation disorder
inability of intracellular killing of Mycobacteria (fatal BCG itis)
DiGeorge sy
MHC I, MHC II def. (bare lymphocyte sy), CD3 def.
IV. Primary immunodeficiencies –
combined defects of T and B cells
• SCID – Severe Combined ImmunoDeficiency
•
X-linked recessive or AR disease, combined disorder of humoral and cell mediated
immunity
• Severe disorder (patients often die during first 2 years of life), symptoms’ onset soon
after the birth (severe diarrhoea, pneumonia, meningitis, BCGitis)
• Immunological features: typically lymphopenia and thymus hypoplasia
• Forms: AR form – often enzymatic deficiency (ADA, PNP) that leads to accumulation
of metabolites toxic to DNA synthesis (lymphocytes)
X-linked form – disorder of stem-cell
Treatment: ATB, IVIG
BMT is of critical significance
in ADA deficiency the gene therapy was tested successfully
• Reticular dysgenesis
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Stem-cell differentiation is blocked
Very rare
Symptoms immediately after the birth – severe diarrhoea, infections of deep layers
Fatal, BMT is the only treatment
SCID
Reticular
dysgenessis
IV. Primary immunodeficiencies –
combined defects of T and B cells
Ataxia teleangiectasia
• Increased radiation induced chromosomal breakage, ataxia, dilatation
of small blood vessels (teleangiectasia)
• Neurological disorders, immunodeficiency is not necessary (if
present, IgA deficiency or T lymphocytes function disorders are most
common)
• Treatment: ATB, IVIG
Hyper IgM syndrome
• CD40L expression disorder, poor cooperation of B and T cells,
impaired isotype switching, increased IgM levels
Wiskott-Aldrich syndrome
• thrombocytopenia, eczema, recurrent infections (encapsulated
microbes), decreased IgM levels
PNP, A-T sy
Adenosin deaminase ADA ,
Wiscott-Aldrich syndrome WAS
ADA, WAS
Purin nucleosid phosphorylase PNP
Ataxia-teleangiectasia sy A-T
V. Primary immunodeficiencies –
complement system disorders
Deficiency of:
• C1, C2, C3, C4 – impaired opsonization, susceptibility to
infections, autoimunity, SLE–like syndrome
• C6, C7, C8, C9 – SLE–like syndrome, increased
susceptibility to neisserial infections
• MBL deficiency – mannan binding lectin (lectin way of
complement activation), various infections, susceptibility
to autoimmunity, association with allergy.
V. Primary immunodeficiencies –
complement system disorders
Hereditary angioedema (HAE)
• Absence or functional deficiency of C1-inhibitor
• Anaphylactoid reactions with skin and/or mucosal (oral, laryngeal,
gut) edemas caused by overproduced bradykinin
• Injuries or surgical/stomatological operations are mostly the
triggering factor
• Laryngeal edemas could be life-threatening, immediate treatment is
necessary !
• Treatment: preventive – androgens, EACA
immediate – C1-INH concentrate or fresh frozen plasma
administration, icatibant
• Secondary forms also exist !
Secondary immunodeficiencies
• Acute and chronic viral infections – infectious mononucleosis,
influenza
• Metabolic disorders – diabetes mellitus, uremia
• Autoimmune diseases – autoantibodies against immunocompetent
cells (neutrophils, lymphocytes); autoimmune phenomena also after
administration of certain drugs (e.g. oxacilin, quinidine)
• Allergic diseases
• Chronic GIT diseases
• Malignant diseases (leukemia)
• Hypersplenism/asplenia
• Burn, postoperative status, injuries
• Severe nutritional disorders
• Chronic infections
• Ionizing radiation
• Drug induced immunodeficiencies (chemotherapy)
• Immunosupression
• Chronic stress
• Chronic exposure to harmful chemical substances
Secondary immunodeficiencies
• Splenectomy – deficiency in generation of antibodies against
encapsulated microorganisms (Pneumococci, Neisseria)
• A loss of immunoglobulins – nephrotic syndrome
- lymphangiectasies
• Lymphomas, myelomas, CLL
• Chronic fatigue syndrome
• First, it is necessary to exclude all chronic diseases which can lead
to fatigue:
• autoimunity
• malignancy
• focal infection
• neurological disorders
• metabolic disorders
• depression
Secondary immunodeficiencies - A.I.D.S.
• Caused by retrovirus HIV 1 or HIV 2
• Current incidence 40 mil.people, predominantly in central Africa,
5mil. of new infections per year, 3 mil. deaths per year
• CZ:10/06 - HIV+ 904/248, AIDS 204/14, deaths 23/2
• Virus has a tropism for cells bearing CD4 surface marker (Th CD4+
lymphocytes); also affects macrophages and CNS cells
• Viral genome transcribes into human DNA and infected cell provides
viral replication
• Transmission: sexual intercourse
contact with blood
endouterine (mother – fetus, breast milk)
• Phases: acute (flu-like sy)
asymptomatic – several years, viral replication
symptomatic – infections, autoimmunity, malignancy,
allergy
final – systemic breakdown, opportune infections
A.I.D.S. - Treatment
• Reverse transcriptase inhibitors (zidovudine, dideoxyinosine,
dideoxycytosine, 3-thiacytosine)
• Protease inhibitors - block the viral protease enzyme
• Combined drug therapy
• Antimicrobial agents
Substitution therapy with
immunoglobulins
• Prepared by fractionation of pooled human plasma from huge
amount of donors (1000)
• Examination of donors, inactivating procedures to minimize the risk
of infection transmission
• Mainly IgG, minimal content of IgA
• i.v. (Octagam, Gammagard) or s.c. use (Subcuvia, Gammanorm)
Indications
• Primary humoral immunodeficiencies
• IgG subclasses deficiencies, deficiencies of generation of specific
antibodies, secondary humoral immunodeficiencies, combined
immunodeficiencies
Dosage
• agamaglobulinemia – IVIG 400-600 mg/kg/month
• regular substitution in outpatient’s room every 3-4 weeks
• „home therapy“ (s.c.administration by infusion pump)
Adverse effects
• Allergic reactions, or even anaphylaxis [in minor reactions (chill,
headache) only slowing down of infusion is usually needed]