IMMUNODEFICIENCY

DISEASES
Introduction

Immunodeficiency diseases

Defence mechanisms of body are impaired→ repeated

microbial infections
specific immune functions- humoral / cell- mediated
immunity / both

Non-specific mechanisms such as phagocytosis &

complement.
Introduction
Primary or Secondary
10 : abnormalities in development of immune
mechanisms

20 : Consequences of disease, drugs, nutritional

inadequacies & other processes interfere with proper
functioning of mature immune system
Primary IMMUNODEFICIENCY DISEASES

Inducement: heredity,developmental defect

Age: infancy and childhood
Pathogenesis: differentiation & development of
hemopoietic stem cells
1. IDD characterized by humoral immunity deficiency
2. IDD characterized by cellular immunity deficiency
3. Combined immunodeficiency diseases
4. Nonspecific immunodeficiency diseases
Phagocyt
e function
COMMON FEATURES OF PRIMARY IMMUNODEFICIENCY DISEASES

Most of these diseases are inherited recessive disorders many

are X-linked (M>F)

Recurrent or over-whelming infections in early childhood

Abnormality of acquired immunity

Innate immunity deficiencies are rare.

COMMON FEATURES OF PRIMARY IMMUNODEFICIENCY DISEASES

Diseases resulting from developmental abnormality at initial

stage of haemopoietic development, have more severe

immunodeficiency usually of both innate & acquired immunity

Defects occurring at later stages usually lead to more specific

deficiency of cellular or humoral variety

I. Humoral immunodeficiencies ( B cell defect )

a. X-linked agammaglobulinemia

b. Transient hypogammaglobulinemia of infancy

c. Common variable immunodeficiency

d. Selective immunoglobulin deficiencies

e. Immunodeficiencies with hyper-IgM

f. Transcobalamin II deficiency
II. Cellular immunodeficiencies ( T cell defect )

a. Thymic Hypoplasia ( DiGeorge syndrome )

b. Chronic mucocutaneous candidiasis

c. Purine nucleoside phosphorylase ( PNP ) deficiency

d. Biotin dependent multiple cocarboxylase deficiency

e. N K cell deficiency

f. Idiopathic CD 4 lymphopenia
III. Combined immunodeficiencies ( B & T cell defects):
a. Cellular immunodeficiency with abnormal immunoglobulin
synthesis ( Nezelof syndrome )
b.Ataxia telangiectasia
c. Wiskott-Aldrich syndrome
d.Immunodeficiency with thymoma ( Good’s syndrome )
e. Immunodeficiency with short-limbed dwarfism / cartilage hair
hypoplasia
f. Episodic lymphopenia with lymphocytotoxin
g.Severe combined immunodeficiencies
h. Omenn syndrome i. Bare lymphocyte syndrome j. Duncan’s
syndrome
k. Reticular dysgenesis l. Nijmegen breakage syndrome m.
GVHD
B. Disorders of non-specific immunity :
1. Disorders of phagocytosis: 2.Disorders of complement :
a. Chronic granulomatous disease a. Complement component deficiencies
b. Myeloperoxidase deficiency b. Complement inhibitor deficiencies
c. Chediak-Higashi syndrome
d. Leucocyte G6PD defeciency
e. Job’s syndrome
f. Tuftsin deficiency
g. Lazy leucocyte syndrome
h. Hyper-IgE syndrome
i. Actin binding protein deficiency
j. Shwachman’s disease
I. IDD characterized by humoral immunity deficiency
B cell defects ( 50-60% )
It causes deficiency of Ig and antibody

Features ： increased susceptibility to bacteria, enterovirus,

intestine parasites，delayed in growth and development
increased incidence of autoimmune diseases, malignant tumor
，
reduced numbers of peripheral blood B cells absent or
reduced
levels of Ig.

Pathogenesis: Block of differentiation & development of B cells,

reduced function of Th cells
 X-LINKED AGAMMAGLOBULINEMIA
 Described by Bruton ( 1952 )

 1st immunodeficiency disease recognised.

 Genetic features: x-linked recessive inheritance, males.
 Pathogenesis: block in differentiation & development of
the pre-B cells.
 Incidence : 1: 100,000 (UK)
 Recurrent serious infections with pyogenic bacteria, pneumococci,
streptococci, meningococci, Pseudomonas & H influenzae.
 Live microbial vaccines should not be given to children.
 Immunological features: Results in an absence or severe reduction
in B lymphocytes & Ig of all types.
 The Btk gene
 Located on the X chromosome.
 Gene consists of 19 exons over a length of
DNA of 37 kilobases.
 Function of the Btk gene product is related
to BCR signalling.
 Without Btk pre-B cells fail to develop into
mature B cells.
 Clinical Findings
LITTLE BOYS WITH BIG INFECTIONS!
 Symptoms appear at 6-9 months of age (after
loss of maternal Ig) .
 Sites of infection: mucous membranes, ear
(otitis media), lungs (bronchitis/pneumonia),
blood (sepsis), gut (Giardia, or enterovirus),
skin, eyes, meningitis.
Also seen: joint problems, kidney
problems, neutropenia, malignancy
in older patients.
 Tonsils & adenoids are atrophic.
 LN biopsy : depletion of bursa dependent areas
 Plasma cells & germinal centres absent even after antigenic
stimulation—No Ab formation
 Marked ↓ in proportion of B cells in circulation.

 CMI not affected

 Delayed hypersensitivity of tuberculin & contact dermatitis
types

 Allograft rejection is normal

 Arthritis, hemolytic anaemia & atopic manifestations

 No Wheal & flare response of atopic hypersensitivity

 Little boys with big
infections
6 to 9 months old
Patients with XLA repeatedly acquire infections with
extracellular pyogenic organisms such as:

Pneumococus

Hemophilus

streptococus
Sinusitis

Pneumonia

Otitis Media
 TREATMENT

Intravenous
Whole plasma infusion
Immunoglobulin
(IVIG):300mg/kg of bd wt in Donors being tested for
3 doses followed by hepatitis & other
monthly inj of 100mg/kg. transmissible infections.
 SELECTIVE IMMUNOGLOBULIN DEFICIENCIES
 1% of all patients with recurrent infection.

 Isolated IgA deficiency:

 MC in this group
 incidence 0.2% in normal populations.
 Immunological features:
Serum IgA<5mg/dl but normal IgM and IgG
Genetic features : IgA Deficiency and genetic
factors: association with HLA-A2, B8 and DW3 or
A1 and B8.
 Pathogenesis: failure in terminal differentiation of B
cells due to intrinsic B cell defect or abnormal T cell
help (TGF-B,IL-5) or in B cell responses to these
cytokines
 C/F:
 atopic disorders
 Recurrent infections in respiratory tract, alimentary
canal, urogenital tract.
.
Immunodeficiency with hyper IgM
Immunological features ： increased level of IgM ( 10 mg/ml )，
decreased levels of other Ig

Pathogenesis: absent of the T cell effector CD40L ，CD40L (

CD154 ) can not bind to CD40 of B cells→do not stimulate B
cells to undergo Ab class switching

：
Genetic features X-linked recessive inheritance ，boy
Clinical features：recurrent pyogenic infections &
autoimmune processes such as thrombocytopenia ,
neutropenia, hemolytic anaemia & renal lesions. Sometimes
seen in congenital rubella.
Serum levels of immunoglobulin in
Hyper IgM syndrome

IgG↓

IgA↓ IgM ↑↑

IgE↓
Hyper IgM syndrome
• Defect in CD40 ligand

CD40
ligand

T cell CD40

B cell
Ig Class
switch
 TRANSIENT HYPOGAMMAGLOBULINEMIA
 Abnormal delay in initiation of IgG synthesis in some infants.
 Maternal IgG is slowly catabolised in newborn & reaches
200mg/100ml by 2nd month.

 Delay in synthesis of its own IgG by this age, immunodeficiency

occurs.

 Infants of both sexes.

 Recurrent otitis media & respiratory infections
 Spontaneous recovery: 18 -30 months of age.
 Some cases require treatment with gammaglobulin.
 COMMON VARIABLE IMMUNODEFICIENCY
 Late onset hypogammaglobulinemia: manifests by 15-35 years of
age
 Immunological features : total Ig<300 mg/100ml
IgG< 250 mg/100ml
B cells present in normal numbers, but defective in their ability to
differentiate into plasma cells & secrete Ig
 Increased suppressor T cell & diminished helper T cell activity
 Clinical features :recurrent pyogenic infections & increased
autoimmune diseases. Malabsorption & Giardiasis are
common.
 Treatment : administration of gammaglobulin preparations I.
M or I.V.
CVID has an almost equal sex
distribution
CVID

Normal lymphoid follicle

Normal number of circulating B cell

Hypogammaglobulinemia
TRANSCOBALAMIN II DEFICIENCY
Genetic features : autosomal recessive
Immunological features : depleted plasma cells,
diminished immunoglobulin levels & impaired
phagocytosis.
Clinical features : patients show metabolic effects
of vitamin B12 deficiency including Megaloblastic
anaemia & intestinal villous atrophy.
Treatment :Vitamin B12 – restore hematopoietic ,
gastrointestional & B cell functions, but not
phagocytic activity.
 B-Cell Deficiency Disorders
Disorder Clinical Features Therapy
1- X-linked agammaglobu- Recurrent pyogenic infections; Immune serum
linemia (Bruton disease) infections of lungs, sinuses, globulin; antibiotics
middle ear, skin, central nervous
system
2-Transient hypogamma- Recurrent pyogenic infections; Antibiotics; immune
globulinemia of infancy frequent in families with other serum globulin
(1st 3 years of life) immunodeficiencies (selected patients)
3-Selective immuno- Recurrent infections of lungs, Antibiotics; immune
globulin deficiency sinuses; gastrointestinal disease; serum globulin (IgG
(IgA, IgM, IgG sub classes) allergy; frequent in families with subclass
common variable deficiencies only)
immunodeficiencies
4-Immunoglobulin Infections of lungs, sinuses, Immune serum
deficiency with increased middle ear; increased frequency globulin; antibiotics
IgM (and IgD) of autoimmune disease
Ectodermal displasea
5-Common variable Infections of lungs, sinuses, Immune serum
immunodeficiency middle ear; giardiasis; globulin; antibiotics
32
malabsorption; autoimmune
II. IDD characterized by cellular immunity deficiency
T cell defects ( 5-10% ).
also Ig deficiencies because B and T cell immune systems are
interdependent and cytotoxic disorders as well.
Features

 increased susceptibility to intracellular microbes

 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 HVG
 block in the differentiation and development of the T cells
 DiGeorge/Arch Syndrome

 Developmental defect 3rd & 4th pharyngeal pouches

 Aplasia or hypoplasia of thymus & parathyroid glands.

 Probably due to some intrauterine infection or other

complications.
 gene deletions in DiGeorge chromosomal region at 22q11
& mutations in other unknown genes

 M=F
 DiGeorge syndrome may be partial (some T-cell function
exists) or complete (T-cell function is absent).
• Facial Defects: Infants low-set ears, fish shaped mouth,
midline facial clefts, a small receding mandible (
micrognathia) , hypertelorism, a shortened philtrum,
notched ear pinnae, antimongoloid slant
• congenital heart disorder
• Thymic and parathyroid hypoplasia or aplasia, causing T-
cell deficiency and hypoparathyroidism.
• Recurrent infections begin soon after birth, but the
degree of immunodeficiency varies considerably, and T-
cell function may improve spontaneously.
• Hypocalcemic tetany appears within 24 to 48 h of birth.
 usually associated with Fallot’s tetrology .
 Frequent presenting sign occurs within first 24 hrs of life.
 Patients who survive the neonatal period show enhanced
susceptibility to viral, fungal & bacterial infections, which
ultimately prove fatal.
 Thymus-dependent areas of LN & spleen are depleted of
lymphocytes. Circulating T cells are reduced in number.
 Immunological features : Primarily involves CMI
 humoral immune mechanismis largely unaffected.
Delayed hypersensitivity & graft rejection are depressed.
Antibody response to primary antigenic stimuli is normal but
secondary response to many antigens is impaired.
Chronic mucocutaneous candidiasis :
 Abnormal immunological response to Candida albicans
 C/F: Severe chronic candidiasis of mucosa, skin & nails.
Don’t show increased susceptibility to other infections but
often have endocrinopathies
 CMI to candida is deficient.
 Delayed hypersensitivity to candida antigens is absent but
circulating Ab to them are found in high titres.
 Intracellular killing of candida is defective.
 Treatment : Transfer factor therapy along with amphotericin B.
Purine nucleoside phosphorylase ( PNP) deficiency

 Enz PNP is involved in the sequential degradation of purines

to hypoxanthine & finally uric acid

 Genetic features : autosomal recessive inheritance.

 Immunological features : decreased CMI .

 C/F: Recurrent or chronic infection

 usually present with hypoplastic anaemia & recurrent pneumonia,
diarrhea & candidiasis

 Diagnosis : A low serum uric acid

3 、 Combined immunodeficiency diseases ( 20% ) :

）
1 SCID: severe combined immunodeficiency disease
2） immunodeficiency diseases with enzymes defect
3） immunodeficiency diseases with other severe defects
 SEVERE COMBINED IMMUNODEFICIENCIES (SCID)
 Combined deficiency of humoral & cellular immunity .

 Usually autosomal recessive disorder,

 X-linked form (M>F) called primary lymphopenic

immunologic deficiency

 IL-2Rγ-chain defect is MC that leads to defective

signalling by the IL-2, IL-4, IL-7, IL-9 & IL-15.

 Variety of SCID characterised by CD 8+ T cells deficiency.

It involves a tyrosine kinase- ZAP-70.Consequently the T
cell signalling is defective.
 SEVERE COMBINED IMMUNODEFICIENCIES (SCID)

 Deficiency of recombinases RAG-1 & 2 – as they required

for gene rearrangement, both T & B cells are affected.

 Immunological features : decreased number of

lymphocytes, thymus is either not developed or very
poorly developed, small number of T cells fail to respond
to antigens & experimental mitogens.
 KNOWN CAUSES OF SCID

Defect Impaired function Chromosomal location

IL-2Rγ Signalling defect by IL-2, 11p13
4,7,9 & 15
ADA deficiency Toxic metabolite in T & B 20q13 & 14q13
cells
PNP deficiency Toxic metabolite in T & B 20q13 & 14q13
cells

JAK-3 deficiency Defective signal from 19q13

IL-2,4,7,9 & 15
ZAP-70 deficiency Defective signal from 2q12
TCR
COMMON FEATURES OF SEVERE COMBINED
IMMUNODEFICIENCY (SCID)
 Failure to thrive
 Onset of infections in the neonatal period
 Opportunistic infections
 Chronic or recurrent thrush
 Chronic rashes
 Chronic or recurrent diarrhea
 Paucity of lymphoid tissue
 Immunity is so low that even the live attenuated
vaccines are not tolerated- they can produce
diseases.
 However patient’s life can be prolonged by
confinement into a sterile environment.
 Treatment : gene therapy.
 WISCOTT-ALDRICH SYNDROME
 X-linked immunodeficiency which increases with age.
 Genetic features :defective CD43 protein gene on short arm
of X chromosome ( Xp11 ).
 This gene encodes a glycoprotein called sialophorin
(expressed on lymphoid cell, neutrophils, macrophages &
platelets)
 Immunological features : CMI undergoes progressive
deterioration associated with cellular depletion of thymus &
paracortical areas of lymphnodes.
 Serum IgM level is low
 IgG & IgA levels are normal or elevated
 humoral defect appears to be specific inability to respond
to polysaccharide antigens.
 C/F: eczema, thrombocytopenic purpura & recurrent
infections.
 Affected boys rarely survive the first decade of life, death being
due to infection, hemorrhage or lymphoreticular malignancy.

Treatment : BMT & transfer factor therapy.

 ATAXIA-TELANGIECTASIA
 Hereditary condition transmitted in the autosomal recessive
mode, where combined immunodeficiency is associated
with cerebellar ataxia, telangiectasia, ovarian dysgenesis &
chromosomal abnormalities.
 Genetic features : Gene responsible on chromosome 11
Gene product may play a role in DNA repair
ATM gene encodes Atm protein kinase, a member of
phosphatidyl inositol 3-kinase family
 Clinical features : earliest signs- ataxia & chorioathetoid
movements noticed in infancy. Telangiectasia involving the
conjuctiva & face appears at 5 or 6 years of age.
 Disease is progressive, with both neurological defects &
immunodeficiency becoming severe with time.
 Death occurs due to sinopulmonary infection early in life ,
or malignancy in 2nd or 3rd decade.

 Immunological features :
ID may affect T&B cells
IgA, IgE and IgG2 deficiency.
T cell function is variably depressed.
CMI is also defective resulting in impairment of delayed
hypersensitivity & graft rejection.

Treatment : Transfer factor therapy & fetal thymus

transplants.
Cellular immunodeficiency with abnormal immunoglobulin
synthesis ( Nezelof syndrome ) :

 Group of disorders, probably of varied origin

 depressed CMI is associated with selectively elevated,

decreased or normal levels of immunoglobulin

 Clinical features : recurrent fungal, bacterial, viral & protozoal

diseases associated with hemolytic anaemia commonly.
Cellular immunodeficiency with abnormal immunoglobulin
synthesis ( Nezelof syndrome ) :

 Immunological features : marked deficiency of T cell

immunity & varying degrees of deficiency of B cell immunity .
 Thymic dysplasia occurs with lymphoid depletion.
 Abundant plasma cells (spleen, LN, intestines & elsewhere in body)
 Inspite of normal levels of immunoglobulins, antigenic stimuli
don’t induce antibody formation.

 Treatment : BMT, transfer factor & thymus transplantation.

PHAGOCYTIC CELL DEFECTS (10 TO 15%)
The ability of phagocytic cells (eg, monocytes,
macrophages, granulocytes such as neutrophils and
eosinophils) to kill pathogens is impaired.
Cutaneous staphylococcal and gram-negative infections
are characteristic.
The most common phagocytic cell defects are chronic
granulomatous disease, leukocyte adhesion deficiency, and
Chédiak-Higashi syndrome
 CHRONIC GRANULOMATOUS DISEASE
Defect in generation of oxidative radicals needed by the host
phagocytic cells to kill the bacteria & other pathogens.
Genetic features : Mutation in NADPH .X-linked congenital
defect -70%, autosomal recessive form – 30%.Decreased
hydrogen peroxide production due defective NADPH oxidase.
Immunological features :
Besides free radical generation deficiency, there are also
defects in mononuclear cells to function as APCs.
Both antigen processing & presentation are affected leading to
inadequate T cell activation. Humoral & cellular immune
response are normal.
Clinical features :
recurrent infection with low grade pathogens, starting early in life
progress & outcome fatal
Chronic suppurative granulomatous lesions develop in skin &
lymph nodes, along with hepatosplenomegaly, progressive
infiltration of lungs & granulomatous septic osteomyelitis.
Diagnosis :
NBT ( Nitroblue tetrazolium )test : leucocytes from patients fail to
reduce nitoblue tetrazolium during phagocytosis.
Treatment :
Interferon gamma .
CHEST X-RAY IN CGD
CGD patient with
skin infections
due to Serratia
marcescens
 Secondary immunodeficiency
disorders
category Examples
• Endocrine • Diabetes mellitus

• GI • Hepatic insufficiency, hepatitis,

intestinal lymphangiectasia,
protein-losing enteropathy

• • Aplatic anemia, cancer, graft-vs-

Hematologic host disease, sickle cell disease

• Certain drugs:
• Iatrogenic chemotherapeutic drugs,
immunosuppressants,
corticosteroids, radiation
therapy; splenectomy
• Infectious
• Cytomegalovirus, Epstein-Barr
virus, HIV, measles virus,
varicella-zoster virus
 Continued….
• Nutritional • Alcoholism, undernutrition

• Physiologic • Physiologic immunodeficiency in

infants due to immaturity of immune
system, pregnancy

• • Nephrotic syndrome, renal insufficiency,

Renal
uremia

• Rheumatologic
• RA, SLE

• Other
• Burns, chromosomal abnormalities (eg,
Down syndrome), congenital asplenia,
critical and chronic illness,
histiocytosis, sarcoidosis
 REFERENCES
 Textbook of Microbiology – Ananthanaryanan &
Paniker’s
 Roitt’s Immunology
 Kuby immunology
Thank you