SUBJECT SEMINAR

Primary immuno deficiency

disorders
• Immunity - protection against infections.

• Immune system - the collection of cells and

molecules that are responsible for defending the
body against the countless pathogenic microbes
in the environment.
 IMMUNITY

Innate Adaptive
Innate immunity
• Also called natural, or native immunity.
• Always present.
• Immediate in action.
• Epithelial barriers
• Skin
• Gastrointestinal tract
• Respiratory tract
• Phagocytic leukocytes (neutrophils and
macrophages)
• Natural killer (NK) cell
• Complement system.
Complement system
• Complement components, numbered C1 to C9,
are present in plasma in inactive forms.

• The critical step in the generation of biologically

active complement products is the activation of
the third component, C3.
• C3 cleavage occurs by three pathways:

• (1) the classical pathway,

• (2) the alternative pathway, triggered by

bacterial polysaccharides (e.g., endotoxin) and
other microbial cell wall components,

• (3) the lectin pathway, in which a plasma lectin

binds to mannose residues on microbes and
activates an early component of the classical
pathway (but in the absence of antibodies).
Adaptive immunity
• Also called acquired, or specific immunity.

• Normally silent and responds (or “adapts”) to

the presence of infectious microbes by becoming
active, expanding, and generating potent
mechanisms for neutralizing and eliminating the
microbes.
• The components of the adaptive immune system
are lymphocytes and their products.
 Adaptive immunity

Humoral Cell mediated

• Antibodies provide protection against
extracellular microbes in the blood, mucosal
secretions, and tissues.
• T -lymphocytes are important in defense against
intracellular microbes.
Lymphocytes
• Each T or B lymphocyte expresses receptors for
a single antigen.
• The total population of lymphocytes numbering
about 1012 in humans.
T Lymphocyte
• T cells constitute 60% to 70% of the lymphocytes
in peripheral blood.
• MHC restriction.
• Peptide antigens presented by self MHC
molecules are recognized by the T cell receptor
(TCR), which is a heterodimer composed of
disulfide-linked α and β protein chains.
• CD4 and CD8 are expressed on distinct T cell
subsets and serve as coreceptors for T cell
activation.
• CD4 is expressed on 50%–60% of mature T
cells, whereas CD8 is expressed on about 40% of
T cells.
B Lymphocyte
• Bone marrow–derived B lymphocytes are the
cells that produce antibodies and are thus the
effector cells of humoral immunity.

• B cells make up 10% to 20% of the circulating

peripheral lymphocyte population.
• B cells recognize antigen by means of
membrane-bound antibody of the
immunoglobulin M (IgM) class, expressed on
the surface together with signaling molecules to
form the B cell receptor (BCR) complex.
• After stimulation, B cells differentiate into
plasma cells, which secrete large amounts of
antibodies, the mediators of humoral immunity.
There are five classes, or isotypes, of
immunoglobulins: IgG, IgM, and IgA constitute
more than 95% of circulating antibodies.
Immune response
Primary immunodeficiency
• PIDs are genetic diseases with primarily
Mendelian inheritance.
• More than 250 conditions have now been
described.
PRIMARY IMMUNODEFICIENCIES OF
THE
INNATE IMMUNE SYSTEM
• PIDs of the innate immune system are relatively
rare and account for approximately 10% of all
PIDs.
SEVERE CONGENITAL NEUTROPENIA
• impaired neutrophil counts (<500
polymorphonuclear leukocytes [PMN]/μL of
blood).
• Manifested from birth.
• Autosomal dominant.
• The absence of pus is a hallmark of this
condition.
• life-threatening, disseminated bacterial and
fungal infections.

• Diagnosis: Bone marrow,

Genetics.

• Treatment: G-CSF, allogeneic hematopoietic

stem cell transplantation (HSCT).
ASPLENIA
• Extremely rare disease.
• Autosomal dominant M/C
• Fulminant infections by encapsulated bacteria.

• Diagnosis: USG abdomen.

• Management: Antibiotic prophylaxis,
Immunisation.
Howell-Jolly bodies
LEUKOCYTE ADHESION DEFICIENCY
(LAD)
• Autosomal recessive.
• Defects in leukocyte and endothelial adhesion
molecules.
• Infection early in life.
• Similar to SCN.
• No pus formation.
• Susceptible to bacterial and fungal infections in
a way that is similar to that of patients with SCN.
• Delayed loss of the umbilical cord.

• LAD 1 - Absent or reduced expression of the β2

integrins.
• These proteins participate in the adhesion of
leukocytes
• to other cells, notably endothelial cells
• LAD 2 – mutation in a GDP-fucose transporter.

• Absence of sialyl Lewis X.

ligand on neutrophils,
required for binding to E-selectin and P-selectin
on cytokine-activated endothelium.
• LAD-2 is also associated with mental retardation
and other developmental defects.
• LAD 3 - Defect in signaling pathway that
mediates chemokine-induced integrin
activation.

• Integrin dysfunction in platelets can be present.

• A diagnosis can be suspected in cases of pus-free
skin/tissue infections and massive
hyperleukocytosis (>30,000/μL) in the blood
(mostly granulocytes).

• Management: Gene therapy, HSCT.

CHRONIC GRANULOMATOUS
DISEASE
• Chronic granulomatous disease (CGD) is a
group of disorders of granulocyte and monocyte
oxidative metabolism.
1) X- linked recessive
2/3 rd of patients.
defective production of superoxide anion
phox-91 Mutation.

2) Autosomal recessive
Defect in other components of the phox
complex.
• catalase-positive microorganisms (organisms
that destroy their own hydrogen peroxide) such
as S. aureus, Burkholderia cepacia, and
Aspergillus species.
• Manifestation usually from early childhood.
• T cell–mediated macrophage activation and the
formation of granulomas composed of activated
macrophages.

• Treatment: cytokine interferon-γ (IFN-γ).

In X-linked disease.
HSCT if other defects are found.
MENDELIAN SUSCEPTIBILITY TO
MYCOBACTERIAL DISEASE (MSMD)

• Impaired IFN-γ-dependent macrophage

activation.
• The hallmark of this PID is a specific and narrow
vulnerability to tuberculous and nontuberculous
mycobacteria.
• Although MSMDs are very rare, they should be
considered in any patient with persistent
mycobacterial infection.

• Treatment: Interferon gamma.

COMPLEMENT DEFICIENCY

• A deficiency in any component of the classic

pathway (C1q, C1r, C1s, C4, and C2) can
predispose an individual to bacterial infections
that are tissue-invasive or that occur in the
respiratory tract.
• Deficiencies in the alternative pathway (factors
D and properdin) are associated with the
occurrence of invasive Neisseria infections.

• deficiencies of any complement component

involved in the lytic phase (C5, C6, C7, C8, and,
to a lesser extent, C9) predispose affected
individuals to systemic infection by Neisseria.
• determination of the status of the relevant
components enables a precise diagnosis.
• Appropriate vaccinations and daily
administration of oral penicillin are efficient
means of preventing recurrent infections.
Severe Combined
Immunodeficiencies
• Profound block in T cell development and thus
the complete absence of these cells.
• Clinical consequences occur early in life (usually
within 3 to 6 months of birth).
• most severe immunodeficiencies.
• 20 different mutations so far identified.

• Classified based on cellular phenotype (i.e.,

TnegB+NK+, TnegB+NKneg, TnegBnegNK+,
TnegBnegNKneg, etc.).
• The most frequent clinical manifestations are
recurrent oral candidiasis, failure to thrive, and
protracted diarrhea and/or acute interstitial
pneumonitis caused by Pneumocystis jiroveci.

Management: Gene therapy, HSCT.

DiGeorge syndrome

• Hemizygous deletion in the long arm of

chromosome 22. (22q11.2).
• Impaired development of 3rd and 4th pharyngeal
arch.
• Triad of
• Congenital cardiac defects,
• Hypocalcemia as a result of parathyroid
insufficiency,
• Aplasia or hypoplasia of the thymus.
Small low-set ears,
Hypertelorism,
Micrognathia,
Horseshoe kidney
Developmental delay including problems with
speech acquisition, learning disabilities, and
behavioral problems.
• Management- Antibiotic prophylaxis, IVIg,
Allogenic thymic transplantation, HSCT.
CHARGE syndrome
• COLOBOMA,
• HEART DEFECTS,
• ATRESIA OF THE CHOANAE,
• RETARDED GROWTH,
• GENITAL HYPOPLASIA AND
• EAR ANOMALIES

• Heterozygous de novo mutations in the CHD7

gene on Chr 8, Impaired T cells number and
function.
Hyper-IgE Syndrome

• Combination of recurrent skin and lung

infections that can be complicated by
pneumatoceles.
Autosomal Dominant: STAT 3 mutation.
Sometimes sporadic.

Autosomal recessive: Deletion or mutation of

DOCK 8 gene.
• Serum IgE levels of greater than 2000 IU/mL
have been used as arbitrary diagnostic values,
but often are greater than 10,000 IU/mL.

• Management: Prophylactic antibiotic, HSCT.

Hyper-IgM (HIGM) Syndromes

• HIGM is a rare B cell PID characterized by

defective Ig Class swith.
• It results in very low serum levels of IgG and IgA
and elevated or normal serum IgM levels.
• X-linked recessive - CD40 ligand
(CD40L/CD154).

• Autosomal recessive defect – CD40 receptor.

• As discussed above, a diagnosis of HIGM
involves screening for an X-linked CD40L
deficiency and an autosomal recessive CD40
deficiency, which affect both B and T cells.

• IgM-mediated autoimmunity and lymphomas

can occur in HIGM syndrome.
• Treatment involves the use of IgG replacement
therapy combined with prophylactic antibiotics
for prevention of PJP at least until the age of 5.
Agammaglobulinemia

• Profound defect in B cell development (<1% of

the normal B cell blood count).

• Arrest of B-cell development at the pre-B–cell

stage leading to virtual absence of circulating B
cells in the periphery.
• X linked- BTK gene mutation .

• Symptoms usually after first month of life.

• Important clue: Absence of adenoids or tonsils.

Reference
• Robbins Basic Pathology, 9th edition.
• Harrisons principles of internal medicine, 19th
edition.
• Cellular and molecular immunology, 8th edition.
• Wintrobes clinical Hematology, 13th edition.
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