Transcript Primary T-cell deficiencies

Hereditary immunity disorders
Marie Černá
Lecture No 636-T
Primary immunodeficiency
• Genetic deficiencies of
complement system
• Genetic deficiencies of
phagocytic function
• Primary T-cell deficiencies
(combined defects)
• Primary B-cell deficiencies
(antibody deficiencies)
Typical characteristics
• Frequent repeated infections
and X-linked heredity
• Susceptibility to cancer
• Susceptibility to autoimmunity
Diagnosis:
- serum Ig levels (B-cell deficiency)
- delayed-type hypersensitivity reactions
to common antigens (T-cell deficiency)
Deficiencies of complement system
divided into five groups
no type
deficiency
heredity
I
immune-complex
deficiency
II angioneurotic
oedema
III recurrent pyogenic
infections
IV recurrent Neisseria
infections
C1q, C1s, C1r,
C2, C4
C1 inhibitor
AR
C3,
factors H + I
C5, C6, C7, C8,
properdin,
factor D
AR
V asymptomatic
C9
AR
AD
AR,
XR,
AR
Hereditary angioneurotic oedema
Deficiencies of phagocytic function
• chronic granulomatous disease – CGD
- oxidase complex mutations
- X-linked
• leukocyte adhesion deficiency – LAD
- integrin and selectin mutations
- LAD1, LAD2, LAD3
• Chediak-Higashi syndrome
- defective vesicle fusion and
lysosomal function
Phagocyte test of activation of
reactive oxygen intermediates
Primary T-cell deficiencies
(combined defects)
• severe combined immunodeficiency - SCID
- X-linked form (IL-2Rγ)
- adenosine deaminase (ADA) def.
- purine nucleoside phosphorylase (PNP) def.
• DiGeorge sy - hypocalcaemia, heart defect
• Omenn sy (RAG gene defects)
• HLA defects - Bare lymphocyte sy, class I def.
• Wiskott-Aldrich sy, Xp - TCR signaling defect
• ataxia telangiectasia (chromosome instability)
Severe combined immunodeficiency
X-linked
the gene encoding
the gamma chain of
the receptors for
interleukins
2, 4, 7, 9, 15
DiGeorge syndrome
Severe combined immunodeficiency
candida albicans in the mouth
Primary B-cell deficiencies
(antibody deficiencies)
• Agammaglobulinemia, X-linked, Bruton (BTK)
• Hypogammaglobulinemia
- selective IgA deficiency
- selective IgG2 deficiency
- common variable immunodeficiency
• Hyper-IgM syndromes
- X-linked (CD40L mutations)
- AR (CD40 mutations)
- AR with antibody defect only
Multifactorial diseases
AUTOIMMUNE DISEASES
5-7 % population
represent complex pathological
manifestations, which are caused by
autoimmune (autoaggressive) reaction.
The essence of this group of diseases is
autotolerance disorder, when the immune
system reacts to the structures of own body.
 the presence of antibodies
Two types of autoimmune diseases
organ-specific
systemic
Hashimoto’s
thyroiditis
Graves-Basedow’s
disease
type 1 diabetes
Bechterev disease – HLA-B27
diagnosis
HLA associations in
autoimmune diseases
DM
type 1
autoimmune
type 2
.
metabolic
Pathogenesis decreased secretion of insulin
resistance to insulin and
in consequence of -cell damage
compensatory non-adequate
by chronic autoimmune process
secretion of insulin
Exogenous factors
nutrition
obesity
infection (viruses)
↓ physical activity
hygienic hypothesis
diet
T1DM  increased incidence  T2DM
23-70 %
almost 100 %
Family history
Concordance of
monozyg. twins
Empirical risk
siblings
5-10 %
children
2- 5 %
(DM in father: 4-6 %
DM in mother: 2-3 %)
clinical diabetes 10-15 %
abnormal oGTT 20-30 %
Destruction of pancreatic ß-cells
in type 1 diabetes mellitus
Heritability of type 1 diabetes
• in 80-90% of population is a tight
balanced state between genetic and
environmental factors (multifactorial)
• 5-10% of population has a considerable
genetic predisposition (polygenic)
• 5-10% of population has a considerable
genetic resistance (polygenic)
• 1% of population carries gene mutation
(monogenic)
Monogenic forms
APECED
- autoimmune polyendocrinopathy, candidiasis,
ectodermal dystrophy, autosomal recessive
- mutation in AIRE gene (autoimmune regulator)
IPEX syndrome
- immune polyendocrinopathy linked to X ch.
- mutation in FOXP3 gene (T-regulation cell)
Treatment of autoimmune diseases
ASTHMA BRONCHIALE and other
ATOPIC - ALLERGIC REACTIONS
Show high rate of concordance of monozygotic twins.
The basal IgE shows relatively high heredity:
Two separated genetic controls –
1) the general total level of IgE
2) the allergen-specific level of IgE
The accumulation of asthma in families has two parts:
1) the atopy (allergy) itself
2) the organ specificity of allergic reaction
Predisposing atopic (allergic)
genetic factors:
1) the gene for -subunit of high affinity receptor for IgE
- on the surface of eosinophils and mast cells,
after IgE binding it leads to their degranulation
2) the genes for type Th2 cytokines
determining for the differentiation of B-lymphocytes in
the direction of IgE secretion
3) the gene for 2 – adrenergic receptor
leads to bronchodilatation effect of -agonists
IgE levels and allergic reactions
Literature
Genetics in Medicine, sixth edition, revised reprint
Thompson & Thompson
Saunders, 2004
Chapter 14: Genetics of the Immune System
Single-Gene Disorders of the Immune System
pages 285 – 288