Primary Immunodeficiency

Dr. Oyaro
 Epidemiology of PID
• Incidence, Prevalence
• ranges from 1:300 (sIgA deficiency) to 1:100
000 live births (SCID)
• 80% of affected persons < 20 years of age
• 70% males (5:1 males in children; 1:1 in adults)
• over 120 different entities described; of them,
about 20 account for > 90% of cases
• increasing due to better methodologies and
newborn screening programs (2000s: 1 / 10)
 Learning objectives
• Definition of Primary immunodeficiency
• PIDDs (common examples)
• Causes
• Clinical diagnosis
• Treatment
 Definition
• Heterogenous group of rare, single-gene or multi-
gene diseases leading to impairment of the
immune responses
• Inherited as X-linked or autosomal disorders,
either dominant or recessive
• gene defects lead to missing enzymes,
developmental arrest in immune differentiation,
absent or non-functional proteins, abnormal DNA
repair, altered signal transduction, impairment of
cell-to-cell and intracellular communications
Primary immunodeficiency diseases
1 、 IDD characterized by humoral immunity
deficiency (The B-lymphocyte system)
2 、 IDD characterized by cellular immunity
deficiency ( The T-lymphocyte system
3 、 Combined immunodeficiency diseases
(T and B lymphocyte systems)
4 、 Nonspecific immunodeficiency diseases
(Phagocyte and complement system)
 General categories of PIDs (Saunders & Mak, 2006)
• SCID - low numbers/absence of T cells and sometimes of B cells; lack of
B cell functions due to T cell function impairment
• T-PIDs - normal numbers of T, B, NK cells; T cells are non-functional; B
cell function may be affected
• B-PIDs - B cells non-functional or absent; T and NK cells are normal
• DNA repair defects - low lymphocyte numbers
• Lymphoproliferative disorders - mutations in death receptors or
ligands, or in caspase cascade; uncontrolled proliferation of T and B cells
• Phagocyte response deficiencies - defects in extravasation, activation,
function of phagocytes
• IL-12 / IFN gamma axis - failure in macrophage (hyper-)activation
• Autoinflammatory syndromes - severe local inflammation and
prolonged periodic fevers with no obvious cause; lymphocyte numbers
are normal
• Neutropenias - reduced level of neutrophils in circulation
• Complement deficiencies - lack of complement activation; T and B cells
are normal
1 、 IDD characterized by humoral immunity
deficiency
Features ： increased susceptibility to bacteria 、 enterovirus 、
intestine parasites ， delayed in growth and development
increased incidence of autoimmune disease 、 malignant tumor
reduced numbers of peripheral blood B cells ， absent or reduced
levels of Ig
Pathogenesis: the block of the differentiation and development of B cells due
to reduced function of Th cells
1 ） Bruton’s syndrome （ x-linked agammaglobulinaemia ）
2 ） Selectively IgA deficiency
3 ） Ig immunodeficiency with increased IgM
1 ） Bruton’s syndrome （ x-linked agammaglobulinaemia ）
Immunological features: the absence of B cells in blood and
Igs
Pathogenesis: block in the differentiation and development of
the pre-B cells
Genetic features: x-linked recessive inheritance, males
Clinical features: recurrent bacterial infections ， no Ab
responds to vaccination
Treatment: inject pooled gamma globulin preparations
2 ） Selectively IgA deficiency ： the most common
immunodeficiency
Immunological features: lack serum IgA, <50mg/L ，
decreased level of sIgA
Pathogenesis: failure in terminal differentiation of B cells
Clinical features: recurrent infections in respiratory tract 、
alimentary canal 、 urogenital tract
Treatment: breast feeding ， few of them can automatically
resume the ability to produce IgA
3 ） Ig immunodeficiency with increased IgM
Immunological features ： increased level of IgM ，
decreased
levels of other Ig
Pathogenesis: absent of the T cell effector CD40L ， CD40L
can not bind to CD40 of B cells ， and therefore
do not stimulate B cells to undergo Ab class
switching
Genetic features ： x-linked recessive inheritance ， boy
Clinical features ： recurrent pyogenic infections ，
increased
2 、 IDD characterized by cellular immunity deficiency
Features ： increased susceptibility to intracellular microbes
notable delay in growth and development 、 death in the early age
increased incidence of malignant tumor
reduced numbers of peripheral blood B cells ， no reaction to
DTH ， no reaction to HVGR
block in the differentiation and development of the T cells

1 ） DiGeorge syndrome (genetical thymus hypoplasia ， third

and fourth pharyngeal arch syndrome ）
2 ） Structure and function defect of T cell surface molecules
1 ） DiGeorge syndrome (genetical thymus
hypoplasia ， third and fourth pharyngeal arch syndrome ）
Immunological features ： absent or hypogenesis of the
thymus
Pathogenesis ： non heredity
Genetic features ： decreased function of the cellular
immunity ， defect function of the parathyroid gland
Clinical features ： recurrent infections of intracellular
bacteria ， no reaction to HVGR
Treatment ： fetal thymic transplantation
2 ） Structure and function defect of T cell surface
molecules
   absent of the TCR ： TCR
2.   mutant of the CD3 molecular ：
3.    defect of the NF-AT gene ： reduced ability of the immune
response ， reduced level of IL-2
4.    others ：
3 、 Combined immunodeficiency diseases
1 ） SCID: severe combined immunodeficiency disease
2 ） immunodeficiency diseases with enzymes defect
3 ） immunodeficiency diseases with other severe defects
SCID: severe combined immunodeficiency disease
lose of the humoral immunity and cellular immunity at the same time
1. Autosomal recessive SCID
Immunological features ： defect of the common precursors of T and
B cells
2. Defects in HLA II molecular SCID
Immunological features ： increased susceptibility to virus infection ，
no CD4+T cells in peripheral blood 、 decreased
Function of the B cells
3. x-linked SCID
Pathogenesis ： gene mutation of IL-2 receptor  chain
reduced numbers of peripheral blood T cells and NK
cells
4 、 Nonspecific immunodeficiency diseases
1 ） deficiency of phagocytes
Immunological features ： decreased number and defected function of
macrophages
Clinical features ： chronic granulomatous disease
Pathogenesis ： deficient in NADH/NADPH oxidase in neutrophils ，
decreased the ability in bacterial killing dependent on
oxygen radical
2 ） deficiency of complement components
genetic deficiencies of complement components or complement
regulatory proteins
hereditary angioneurotic oedema, deficiency of C1INH ，
vasodilatation ， increased permeability of the blood capillary
skin 、 mucous membrane edema
 Laboratory diagnosis
• B-lymphocyte function (Serum Igs levels)
• Antibody function (vaccine immune
response evaluations
• T-cell function (cytokine evaluations and
lymphocyte proliferation : stimulation by
mitogens)
 Treatment (options)
• The overall goal is to restore a person’s
immune system
• lifelong immunoglobulin replacement
• Antibiotics
• Bone marrow transplant
Secondary immunodeficiency &
immunology of HIV infection
Secondary immunodeficiency diseases (causes)

(1) Drug or radiation-induced (steroids, other cytotoxic drugs)

(2) HIV target cells and immune dysfunction

(3) Nutritional deficiency (reduced protein, calorie, biotin, B12,

Iron, Vit. A, Zinc; thymic atrophy pathologic result)

(4) Autoimmune Disease (?, frequent inflammatory diseases

are found in immunodeficient patients)

(5) Other (postviral, chronic infection, neoplastic diseases)

(6) Surgery