IMMUNODEFICIENCY

DISEASES

For MBBS (29.09.2017)

By: Dr. Puneet Kumar Gupta

Assistant Professor, Microbiology,
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
Phagocyte
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

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 Donors being tested for
in 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
CD40
T cell
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.
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- 11p13
2,4,7,9 & 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 IL- 19q13

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: chemotherapeutic

• Iatrogenic 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

• Renal • Nephrotic syndrome, renal insufficiency,

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