IMMUNODEFICIENCY

Lecture Outlines
Define immunodeficiency
Classification
Specific non specific
Primary and secondary
B cell deficiency & Examples
T Cell deficiency & Examples
SCID
Drug induced immunodeficiency
• It is the absence or failure of normal
function of one or more elements of the
immune system

• Results in immunodeficiency disease

• Can be specific or non specific

Specific = Abnormalities of B & T cells
Non specefic = Abnormalities of non specific
components
PRIMARY OR SECONDARY
 PRIMARY IMMUNODEFICIENCIES

Primary immunodeficiencies are

inherited defects of the immune
system
 These defects may be in the specific
or nonspecific immune mechanisms
They are classified on the basis of
the site of lesion in the
developmental or differentiation
pathway of the immune system
 B CELL DEFICIENCY
X linked agammaglobuinemia
IgA deficiency
IgG subclass deficiency
Immunodeficiency with increased
Igm
Common variable immundeficiency
Transient hypogammaglobulinaemia
of infancy
X-linked a gammaglobulinaemia -1

In X-LA early maturation of B cells

fails
Affect males
Few or no B cells in blood
Very small lymph nodes and tonsils
No Ig
Small amount of Ig G in early age
Recurrent pyogenic infection
IgA and IgG subclass defeciency -2

IgA deficiency is most common

Patients tend to develop immune
complex disease
About 20% lack IgG2and IgG4
Susceptible to pyogenic infection
Result from failure in terminal
differentiation of B cells
Immunodfeiciency with increased -3
IgM (HIgM)
 Results in patients with IgA and IgG
deficiency
 Production of large amount of IgM
>200mg/dl of polyclonal IgM
 Susceptible to pyogenic infection
 Treatment by iv gamma globulin
 Formation of IgM to neutrophils, platelets
and other blood components
 Due to inability of B cells to isotype
switching
4- Common Variable Immunodeficiency
(CVID)
 There are defect in T cell signaling to B cells
 Acquired a gammaglobulinemia in the 2nd or
3rd decade of life
 May follow viral infection
 Pyogenic infection
 80% of patients have B cells that are not
functioning
 B cells are not defective. They fail to receive
signaling from T lymphocytes
 Unknown
Hypogamaglobulinaemia of infancy -5

Due to delay in in IgG synthesis

approximately up to 36 months
In normal infants synthesis begins at
3 months
Normal B lymphocytes
Probably lack help of T lymphocytes
 DISORDERS of T CELLS
• DiGeorge's syndrome:
 It the most understood T-cell immunodeficiency
 Also known as congenital thymic
aplasia/hypoplasia
 Associated with hypoparathyroidism, congenital
heart disease, fish shaped mouth.
 Defects results from abnormal development of
fetus during 6th-10th week of gestation when
parathyroid, thymus, lips, ears and aortic arch are
being formed
T cell deficiencies with variable
degrees of B cell deficiency
1- Ataxia-telangiectasia:
• Associated with a lack of coordination of
movement (ataxis) and dilation of small
blood vessels of the facial area
(telangiectasis).
• T-cells and their functions are reduced to
various degrees.
• B cell numbers and IgM concentrations
are normal to low.
• IgG is often reduced
• IgA is considerably reduced (in 70% of
the cases).
• There is a high incidence of malignancy,
particularly leukemia in these patients.
• The defects arise from a breakage in
chromosome 14 at the site of TCR and Ig
heavy chain genes
2- Wiskott-Aldrich syndrome:

• Associated with normal T cell numbers with

reduced functions, which get progressively
worse.
• IgM concentrations are reduced but IgG levels
are normal
• Both IgA and IgE levels are elevated.

• Boys with this syndrome develop severe

eczema.
• They respond poorly to polysaccharide antigens
and are prone to pyogenic infection.
MHC DEFICIENCY
:(Bare leukocyte syndrome)
• Due to defect in the MHC class II transactivator
(CIITA) protein gene, which results in a lack of
class-II MHC molecule on APC.
• Patients have fewer CD4 cells and are infection
prone !.
• There are also individuals who have a defect in
their transport associated protein (TAP) gene
and hence do not express the class-I MHC
molecules and consequently are deficient in
CD8+ T cells.
Defects of the phagocytic system

Defects of phagocytic cells (numbers and/or

functions) can lead to increased susceptibility to
a variety of infections.
1- Cyclic neutropenia:
It is marked by low numbers of circulating
neutrophil approximately every three weeks. The
neutropenia lasts about a week during which the
patients are susceptible to infection. The defect
appears to be due to poor regulation of
neutrophil production.
2- Chronic granulomatous disease (CGD):
CGD is characterized by marked
lymphadenopathy, hepato- splenomegaly
and chronic draining lymph nodes.
• In majority of patients with CGD, the
deficiency is due to a defect in NADPH
oxidase that participate in phagocytic
respiratory burst.
3- Leukocyte Adhesion Deficiency:
o Leukocytes lack the complement receptor CR3
due to a defect in CD11 or CD18 peptides and
consequently they cannot respond to C3b
opsonin.
o Alternatively there may a defect in integrin
molecules, LFA-1 or mac-1 arising from
defective CD11a or CD11b peptides,
respectively.
o These molecules are involved in diapedesis and
hence defective neutrophils cannot respond
effectively to chemotactic signals.
4- Chediak-Higashi syndrome:
• This syndrome is marked by reduced
(slower rate) intracellular killing and
chemotactic movement accompanied by
inability of phagosome and lysosome
fusion and proteinase deficiency.
• Respiratory burst is normal.
• Associated with NK cell defect, platelet
and neurological disorders
:Disorders of complement system
 Complement abnormalities also lead to
increased susceptibility to infections.
 There are genetic deficiencies of various
components of complement system, which
lead to increased infections.

 The most serious among these is the C3

deficiency which may arise from low C3
synthesis or deficiency in factor I or factor
H.
SEVERE COMBINED IMMUNODEFICENCY

 In about 50% of SCID patients the

immunodeficiency is x-linked whereas in the
other half the deficiency is autosomal.
 They are both characterized by an absence of T
cell and B cell immunity and absence (or
very low numbers) of circulating T and B
lymphocytes.
 Patients with SCID are susceptible to a variety of
bacterial, viral, mycotic and protozoan infections.
 The x-linked SCID is due to a defect in
gamma-chain of IL-2 also shared by IL-4,
-7, -11 and 15, all involved in lymphocyte
proliferation and/or differentiation.

 The autosomal SCIDs arise primarily from

defects in adenosine deaminase (ADA)
or purine nucleoside phosphorylase
(PNP) genes which results is accumulation
of dATP or dGTP, respectively, and cause
toxicity to lymphoid stem cells
Diagnosis
Is based on enumeration of T and B cells
and immunoglobulin measurement.

Severe combined immunodeficiency can be

treated with bone marrow transplant
 SECONDARY
IMMUNODEFICIENCY
 IMMUNODEFICIENCY CAUSED
BY DRUGS
CORTICOSTEROIDS
 Cause changes in circulating leukocytes
 Depletion of CD4 cells
 Monocytopenia
 Decreased in circulating eosinophils and
basophils
 Inhibition of T cell activation and B cell
maturation
 Inhibit cytokine synthesis
METHOTREXATE
 Structural analogue of folic acid
 Blocks folic acid dependent synthetic
pathways essential for DNA synthesis
 Prolonged use for treatment reduces
immunoglobulin synthesis
CYCOLOSPORIN
 Have severe effects on T cell
signaling and functions
 It binds to immunophilins which are
believed to have a critical role in
signal transduction
 Also inhibit IL 2 dependent signal
transduction
 OTHER CAUSES

Malnutrition

Minerals

Vitamins

Obesity
Immunodeficiencies

• Humoral – innate immunity - complement, MBL

acquired immunity – immunoglobulins (B lymphocytes)

• Cell mediated immunity – innate immunity – phagocytes

- acquired immunity – T lymphocytes

• Primary – congenital, genetically defined, symptoms predominantly

at early age

• Secondary – the onset of symptoms at any age

chronic diseases
effect of irradiation
immunosuppression
surgical intervention, injuries
stress
 Immunodeficiencies – critical life periods in
respect to symptoms onset
• Newborn age - severe primary disorders of cell mediated immunity

• 6 mth. – 2 yrs. – severe humoral immunodeficiencies

cong./transient

• 3 - 5 yrs. – transient and selective humoral immunodeficiencies,

secondary immunodeficiencies

• 15 – 20 yrs. – hormonal instability, thymus involution, life-style changes,

some typical infections
first symptoms of CVID

• Middleage – often excessive workload, stress

first symptoms of autoimmune disorders (also immunodeficiency)

• Advanced and old age – rather symptoms of severe secondary immunodeficiencies,

repercussion of functional disorders

 Secondary immunodeficiencies

• Acute and chronic viral infections – infectious mononucleosis, influenza

• Metabolic disorders – diabetes mellitus, uremia
• Autoimmune diseases – autoantibodies against immunocompetent cells
(neutrophils, lymphocytes); autoimmune phenomena also after
administration of certain drugs (e.g. oxacilin, quinidine)
• Chronic GIT diseases
• Malignant diseases (leukemia)
• Hypersplenism/asplenia
• Burn, postoperative status, injuries
• Severe nutritional disorders
• Chronic infections
• Ionizing radiation
• Drug induced immunodeficiencies (chemotherapy)
• Immunosupressive therapy
• Chronic stress
• Chronic exposure to harmful chemical substances
Acquired ImmunoDeficiency Syndrome (A.I.D.S.)

• Caused by retrovirus HIV 1 or HIV 2

• Virus has a tropism for cells bearing CD4 surface marker (Th CD4+
lymphocytes); also infects macrophages and CNS cells
• Viral genome transcribes into human DNA and infected cell provides viral
replication
• Diagnosis: serological (3 to 6 weeks after primoinfection, PCR
• Transmission: sexual contact
contact with blood or blood products
mother-to-child – prenatally, delivery, breast feeding
• Phases: acute (flu-like symptoms)
asymptomatic – months to years, viral replication, loss of Th cells
symptomatic – infections, autoimmune disorders, malignancies,

allergy
final – systemic breakdown, opportune infections (Pneumocystis
jirovecii, Cryptococcus neoformans, Toxoplasma gondii,
Candida albicans, CMV etc.)
- Kaposi’s sarcoma
 A.I.D.S. - Treatment

• Reverse transcriptase inhibitors ([Link])

• Protease inhibitors - block the viral protease enzyme
• Combined drug therapy
• Antimicrobial agents
 Autoimmune disease
• Results from a failure of self-tolerance
• Immunological tolerance is specific
unresponsiveness to an antigen
• All individuals are tolerant of their own (self)
antigens
 SYSTEMIC AUTOIMMUNE DISEASES

• Systemic lupus erythematosus

• Rheumathoid arthritis
• Sjögren‘s syndrome
• Dermatopolymyositis
• Systemic sclerosis
• Mixed connective tissue disease
• Vasculitis
 SYSTEMIC LUPUS ERYTHEMATOSUS
• chronic, inflammatory, multiorgan disorder

• autoantibodies react with nuclear material and attack cell

function, immune complexes with dsDNA deposit in the
tissue

• general symptoms: include malaise, fever, weight loss

• multiple tissue are involved including the skin, mucosa,
kidney, joints, brain and cardiovascular system

• characteristic features: butterfly rash, renal involvement,

CNS manifestation, pulmonary fibrosis
 DIAGNOSTIC TESTS

• a elevated ESR (erythrocyte sedimentation rate), low CRP,

thrombocytopenia, leucopenia, hemolytic anemia, decreased
levels of complement compounds (C4, C3), elevated serum Ig
levels, immune complexes in serum
 RHEUMATOID ARTHRITIS
• chronic, inflammatory disease with systemic involvement
• characterized by an inflammatory joint lesion in the synovial membrane,
destruction of the cartilage and bone, results in the joint deformation
• clinical features: arthritis, fever, fatigue, weakness, weight loss
• systemic features: vasculitis, pericarditis, uveitis, nodules under skin,
intersticial pulmonary fibrosis
• diagnostic tests: elevated C- reactive protein
and ESR, elevated serum gammaglobulin levels
- autoantibodies against IgG = rheumatoid factor
(RF), a-CCP (cyclic citrulline peptid), ANA
- X-rays of hands and legs- show a periarticular
porosis, marginal erosion
 SJÖGREN‘S SYNDROME

• chronic inflammatory disease affecting exocrine glands

• the primary targets are the lacrimal and salivary gland duct epithelium
• general features: malaise, weakness, fever
• primary syndrome - features: dry eyes and dry mouth, swollen salivary
glands, dryness of the nose, larynx, bronchi and vaginal mucosa,
involvement kidney, central and periferal nervous system, arthritis

• secondary syndrome – is associated with others AI diseases (SLE, RA,

sclerodermia, polymyositis, primary biliary cirhosis,AI thyroiditis)

• autoantibodies against ENA (SS-A, SS-B),

ANA, RF
• The Schirmer test - measures the production
of tears
 Vasculitis
• characterized by inflammatory destruction
of vessels leading to thrombosis and aneurysms
• proliferation of the intimal part of blood-vessel wall
and fibrinoid necrosis
• affect mostly lung, kidneys, skin

• diagnostic tests: elevated ESR, CRP, leucocytosis,

biopsy of affected organ (necrosis, granulomas),
angiography
 Ulcerative colitis

• chronic inflammation of the large intestine mucosa

and submucosa
• features: diarrhea, bloody and mucus stools
• extraintestinal features (arthritis, uveitis)
• Autoantibodies: pANCA, a- large intestine
 Diabetes mellitus (insulin- dependent)

• characterized by an inability to process sugars in the

diet, due to a decrease in or total absence of insulin
production
• results from immunologic destruction of the insuline-
producing β-cells of the islets of Langerhans in the
pancreas
• autoantibodies against GAD (glutamic acid
decarboxylase = primary antigen), autoantibodies
anti- islet cell, anti- insulin
• islets are infiltrated with B and T cells