Immunodeficiencies

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Immunodeficiencies

• Martin Liška

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Basic immunological terms

• Immune system provides 3 basic functions
• Defense against infection
• Homeostasis elimination of old or impaired
  cells
• 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
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Immunodeficiencies

• 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
• Secondary the onset of symptoms at any age
• chronic diseases
• the effects of
  irradiation
• immunosuppression
• surgery, injuries
• stress

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Immunodeficiencies critical life periods in
respect to symptoms onset

• 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

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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

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The differentiation of pluripotent stem-cell
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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

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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

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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 (Jobs) 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

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II. Primary immunodeficiencies B cell disorders

• Brutons 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 1100-200 thousands. Symptoms onset
  between 2nd and 3rd decade
• Recurrent respiratory tract infections
  (pneumonia)
• Treatment IVIG substitution

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II. Primary immunodeficiencies B cell disorders

• 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 lt 0,07g/l (age gt 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

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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

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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)

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DiGeorge sy
MHC I, MHC II def. (bare lymphocyte sy), CD3 def.
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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
• Stem-cell differentiation is blocked
• Very rare
• Symptoms immediately after the birth severe
  diarrhoea, infections of deep layers
• Fatal, BMT is the only treatment

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SCID
Reticular dysgenessis
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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

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ADA, WAS
PNP, A-T sy
Adenosin deaminase ADA , Purin
nucleosid phosphorylase PNP Wiscott-Aldrich
syndrome WAS Ataxia-teleangiectasia sy A-T

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V. Primary immunodeficiencies complement
system disorders

• Deficiency of
• C1, C2, C3, C4 impaired opsonization,
  susceptibility to infections, autoimunity,
  SLElike syndrome
• C6, C7, C8, C9 SLElike syndrome, increased
  susceptibility to neisserial infections
• MBL deficiency mannan binding lectin (lectin
  way of complement activation), various
  infections, susceptibility to autoimmunity,
  association with allergy.

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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 C3a a C5a
• 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 !

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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

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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

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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
• CZ10/06 - 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

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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

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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. (Venimun, Endobulin, Octagam) or s.c./i.m.
  use (Subcuvia)

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Indications

• Primary humoral immunodeficiencies
• IgG subclasses deficiencies, deficiencies of
  generation of specific antibodies, secondary
  humoral immunodeficiencies, combined
  immunodeficiencies

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Dosage

• agamaglobulinemia IVIG 400-600 mg/kg/month
• regular substitution in outpatients room every
  3-4 weeks
• home therapy (s.c.administration by infusion
  pump)

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Adverse effects

• Allergic reactions, or even anaphylaxis in minor
  reactions (chill, headache) only slowing down of
  infusion is usually needed