1
IMMUNE DEFICENCY
IMMUNE DEFICIENCY
CLINICAL FEATURES :
1. Recurrent infections:
Frequent, severe infections caused by unusual organisms & at unusual
sites
2. Autoimmunity
3. Susceptibility to malignancy
CAUSES:
I. PRIMARY IMMUNE DEFICIENCY:
A.PRIMARY PHAGOCYTE DEFICIENCIES
 Majority present in childhood.
 Types:
1) Leucocyte adhesion deficiencies:
 Disorders of phagocyte migration
 Sites of infection lack pus (neutrophil infiltration)
 Peripheral blood neutrophil counts may be very high during
acute infection
2) Chronic granulomatous disease
 Results from mutations in the genes encoding the NADPH
oxidase enzyme, causing a failure of oxidative killing
 leads to susceptibility to catalase-positive organisms such as
Staphylococcus aureus, Burkholderia cenocepacia and
aspergillus
 Intracellular killing of mycobacteria in macrophages is also
impaired
 Infections most commonly involve the lungs, lymph nodes,
soft tissues, bone, skin and urinary tract and are
characterised histologically by granuloma formation
 May be demonstrated using the nitroblue tetrazolium
reduction test (NBT), which measures the ability to reduce a
colourless intracellular dye to an insoluble blue compound
after neutrophil activation
IMMUNE DEFICENCY
2
3) Defects in cytokines and cytokine receptors
 Defects of cytokines such as IFN-γ, IL-12 or their receptors
result in failure of intracellular killing
 Individuals are particularly susceptible to mycobacterial
infections
Management :
1. Drugs: Intravenous antibiotics, Longterm prophylaxis with
antifungal agents, and trimethoprim-sulfamethoxazole.
2. Surgical drainage of abscesses
3. Specific treatment depends upon the nature of the defect, and stem
cell transplantation may be considered.
B. COMPLEMENT PATHWAY DEFICIENCIES:
 Genetic deficiencies have been described.
 classical and alternative pathway components : c/f: recurrent infection
with encapsulated bacteria, particularly Neisseria species
 Genetic deficiencies of the classical complement pathway (C1, C2 and
C4) are associated with a high prevalence of autoimmune disease,
particularly severe systemic lupus erythematosus (SLE)
 Mannose-binding lectin deficiency is very common (5% of the
population).
 Individuals with complete mannose-binding lectin deficiency have an
increased incidence of bacterial infections if subjected to an additional
cause of immune compromise, such as prematurity or chemotherapy.
 Deficiency of the regulatory protein C1 inhibitor is not associated
with recurrent infections, but causes recurrent angioedema.
 Investigations:
1. Complement C3 and C4 are the only complement components
that are routinely measured.
2. The CH50 (classical haemolytic pathway 50, also known as total
haemolytic complement THC)
-Complement proteins degrade rapidly at room temperature, and the most
common cause of an absent CH50 is delay in transportation of the sample
to the laboratory.
3
IMMUNE DEFICENCY

Treatment:
1. No definitive treatment of complement deficiencies
2. Patients are at risk of meningococcal and other infections, and
should be vaccinated with meningococcal, pneumococcal and H.
influenzae B vaccines in order to boost their adaptive immune
responses
3. Life-long prophylactic penicillin to prevent meningococcal
infection is recommended
4. At-risk family members should be screened for complement
deficiencies with functional complement assays.
C. PRIMARY DEFICIENCIES OF THE ADAPTIVE IMMUNE SYSTEM
1. COMBINED B- AND T-LYMPHOCYTE IMMUNE DEFICIENCIES
 Caused by defects in lymphoid precursors
 Causes recurrent bacterial, fungal and viral infections soon after
birth
 Stem cell transplantation is the only current treatment option,
although specific gene therapy is under investigation.
2. PRIMARY T-LYMPHOCYTE DEFICIENCIES
 Generally present in childhood
 Characterized by recurrent viral, protozoal and fungal infections
 Many T-cell deficiencies are associated with defective antibody
production( because of the importance of T cells in providing help
for B cells)
 Types:
1) DiGeorge syndrome:
 Results from failure of development of the 3rd/4th
pharyngeal pouch
 Usually caused by a deletion of 22q11
 Associated with abnormalities of the aortic arch,
hypocalcaemia, tracheo-oesophageal fistulae, cleft lip
and palate, and absent thymic development
 Characterized by very low numbers of mature T cells
despite normal development in the bone marrow.
IMMUNE DEFICENCY
4
2) Bare lymphocyte syndromes
 Caused by absent expression of HLA molecules
within the thymus
 If HLA class I molecules are affected, CD8+
lymphocytes fail to develop, while absent expression
of HLA class II molecules affects CD4+ lymphocyte
maturation
 Failure to express HLA class I: is associated with
recurrent infections, and systemic vacuities caused by
uncontrolled activation of natural killer cells.
3) Autoimmune lymphoproliferative syndrome
 Caused by failure of apoptosis
 Characterized by accumulation of lymphocytes and
persistence of autoreactive cells
 Patients develop lymphadenopathy, splenomegaly and
a variety of autoimmune diseases
IMMUNE DEFICENCY

5
Investigations
1. The principal tests for T-lymphocyte deficiencies are a total
lymphocyte count and quantitation of lymphocyte
subpopulations by flow cytometry
2. Serum immunoglobulins
3. Functional tests of T-cell activation and proliferation and/or
an HIV test

Treatment:
1.
Anti-Pneumocystis and antifungal prophylaxis
2.
Aggressive management of specific infections
3.
Immunoglobulin replacement may be indicated if disease is
associated with defective antibody production
4.
Stem cell transplantation may be appropriate in bare
lymphocyte syndromes
5.
Thymic transplantation has been used for DiGeorge
syndrome
3. PRIMARY ANTIBODY DEFICIENCIES (B lymphocyte deficiency):
 Primary antibody deficiencies are characterized by recurrent bacterial
infections, particularly of the respiratory and gastrointestinal tract
 The most common causative organisms are bacteria such as S.
pneumoniae and H. influenza
 Severe inherited disorders of antibody production are rare
 usually present at 5-6 months of age, when the protective benefit of
transferred maternal immunoglobulin has waned
 Three major primary antibody deficiencies present in adulthood:
1) Selective IgA deficiency
 is the most common primary immune deficiency
 In most patients, low (< 0.05 g/l) or undetectable IgA
is an incidental finding with no clinical sequelae
 30% of individuals experience recurrent mild
respiratory and gastrointestinal infections.
 In some patients, there is a compensatory increase in
serum IgG levels.
2) Common variable immune deficiency (CVID):
 Unknown cause
 Characterised by low serum IgG levels and failure to
make antibody responses to exogenous pathogens
IMMUNE DEFICENCY
6
 Antibody-mediated autoimmune diseases such as
idiopathic thrombocytopenic purpura and autoimmune
haemolytic anaemia are common
 Associated with an increased risk of malignancy,
particularly lymphoproliferative disease.
3) Specific antibody deficiency or functional IgG antibody
deficiency
 causes defective antibody responses to polysaccharide
antigens
 Some patients are deficient in the antibody subclasses
IgG2 and IgG4, and this condition was previously
called IgG subclass deficiency
4) There is overlap between specific antibody deficiency, IgA
deficiency and CVID, and some patients may progress to a
more global antibody deficiency over time
IMMUNE DEFICENCY
7
 Investigations:
1. Serum
immunoglobulins
&
protein
and
urine
electrophoresis: to exclude secondary causes of
hypogammaglobulinaemia
2. Specific antibody :measuring IgG antibodies against tetanus,
H. influenzae and S. pneumonia
3. If specific antibody levels are low, immunization with the
appropriate killed vaccine should be followed by repeat
antibody measurement 6-8 weeks later; failure to mount a
response indicates a significant defect in antibody
production.
4. Quantitation of B and T lymphocytes by flow cytometry
 Management
1. Aggressive treatment of infections, and prophylactic antibiotics
2. The mainstay of treatment is immunoglobulin replacement
(intravenous immunoglobulin, IVIG), which is derived from
pooled plasma and contains IgG antibodies to a wide variety of
common organisms. IVIG is usually administered
intravenously every 3-4 weeks with the aim of maintaining
trough IgG levels within the normal range
3. Treatment may be self-administered, and is life-long.
4. Immunization is generally not effective (because of the defect
in IgG antibody production) except in selective IgA deficiency.
5. live vaccines should be avoided
IMMUNE DEFICENCY
II. SECONDARY IMMUNE DEFICIENCIES
8
IMMUNE DEFICENCY
9
 Much more common than primary immune deficiencies
 Infection is a common cause of secondary immune deficiency,
particularly HIV infection, measles and other viral illnesses
 Immune deficiency is also an expected side-effect of some drugs,
particularly those used in the management of transplantation,
autoimmunity and cancer
 May be an idiosyncratic effect of other agents, particularly anti-epileptic
medication
 Physiological immune deficiency occurs at the extremes of life, and the
decline of the immune response in the elderly is known as immune
senescence
 IX & Rx the cause if possible.