Immunodeficiency

Abdul Ghaffar, Ph.D.; e-mail: ghaffar@med.sc.edu

Lectures 22-23
TEACHING OBJECTIVES:

1. Know the primary and secondary immunodeficiencies

2. Know immunodeficiencies in AIDS and other conditions
3. Know the major primary immunodeficiencies and their features
4. Understand the relationship between site of lesion and resulting immunodeficiency
5. Know the diagnostic tests for different immunodeficiencies

READING:

Male, Brostoff, Roth and Roitt: Immunology, 7th ed. chapter 16-17.

SECONDARY IMMUNODEFICIENCIES

Secondary immunodefciencies are defects in the immune function arising from non-genetic
factors such as infections, non infectious diseases, therapeutic interventions (iatrogenic) or
environmental impacts. These are not inherited and they are alleviated once the causative factor
is removed.

Immunodeficiencies associated with infections:

Infection with bacterial, viruses, protozoa, helminths and fungal have all be show to cause
immunosuppresion. Different organisms affect different components of the immune system and
with different degrees of severity. Most prominent among these is acquired immunodeficiency
syndrome (AIDS). Secondary immunodeficiencies are also seen in malignancies.

Acquired immunodeficiency disease syndrome:

Life cycle of the virus: Until the late 1070s, there was no recognition of AIDS, however soon
after the reporting of several cases in Los Angeles, California, rapid progress was made to
associate the disease with an infectious agene. It is now well established that AIDS is caused by
human immunodeficiency virus (HIV), of which there are two types: HIV-1 and HIV-2, the letter
being mostly prevalent in Africa and is less pathogenic than the former. HIV-1 has 3 groups, M
(main), O (outlier) and N (neither or new). The main groups contains 11 types (A-K) and a few
sub-type (A1, A2, B, B’, F1 and F2) and many recombinants of types and subtypes. HIV-2 has
more limited number of variants (groups and types).

All HIV use the CD4 molecule as a receptor and the chemokine receptor, CCR5 (or in some
cases CXR4) as co-receptor. Thus, not only CD4+ T cells are target of infection, but
macrophages, some dendritic cells and microglilal cells that also have low concentrations of CD4
1
together with CCR5 and/or CRX4 molecules are also targets for HIV infections. As a matter of
fact these non-T cells are relatively resistant to lysis by the virus and hence provide a reservoir
for the virus and since these infected cells can express p90 (ligand for CD4) and p40 (fusogen)
proteins, they can fuse with uninfected T cells and transfer infective virus without encountering
antibodies. This process is particularly significant in case of infected macrophage that serves as
“Trojan horse”.

Early indications HIV infection: The early manifestations of HIV infection are flu-like
symptoms that may subside and the individual may remain symptom-free for a long period while
the virus is dormant. The immunologic effects of the infection may start after reactivation of the
virus, triggered by immune stimuli from other infections or other causes, 2-10 years later. The
reactivations of HIV results in a gradual decline in CD4+ T cell population, and a consequential
susceptibility to various opportunistic infections (Figure 1).

Immunologic abnormalities in the AIDS:

Cellular abnormalities of lymphocytes: There 1000
is a decrease in the number of helper/inducer
(CD4) T cells (Figure 1) whereas the CD8+ T 800 CD4+ T cells/ml blood
cells remain unchanged or even become
slightly elevated. Consequently, there is a 600
+ +
reversal in CD4 /CD8 T cell ratio that in 400
normal individuals is approximately 2.
However, late in the disease, CD8+ population 200

also falls. NK cell number is within normal

range but their activity is reduced. They also uninfected lymph- Kaposi’s opportunistic

have a reduced ability to response to control adenopathy sarcoma infections

+
interferon-γ. Phagocytic function remains Figure 1: Decline in CD T cells after HIV infection
unchanged. Serum IgM levels are elevated due to continued challenge with infectious agents
and complement levels decline due to generation of immune complexes.

Functional abnormalities seen in vivo: AIDS patients have an increased susceptibility to

infections with opportunistic organisms (Pneumocystis carinii, Toxoplasma gondii,
Cryptococcus neoformans, herpes simplex, herpes zoster, cytomegalovirus, Mycobacterium
avium intracellular, etc). These patients also have increased incidence of neoplasms (Kaposi's
sarcoma).

Delayed hypersensitivity response to common antigens such as tetanus, diphtheria, streptococcal

antigen, tuberculin, Candida and Trichophyton antigens, etc. is decreased in AIDS patients.
They also fail to produce antibody in response to various antigenic challenges, both primary
(e.g., keyhole limpet hemocyanin: KLH) and recall antigens (DTP-vaccine).

Immune response to HIV: Soon after infection, the body mounts an immune response and with
time, antibodies against a number of viral proteins appear, some of which control the viral load
(Figure 2). However, due to its intracellular location, ability to transfer from cell-to-cell and to
incorporate into host genome, it persists at a low level and gnaws at the CD4 T cell population.
As these cells reach a critical level the virus begins to proliferate and as the CD4 cells reduce
2
further and the CD8+ cytotoxic cells also diminish the patient becomes susceptible to many
opportunistic infections.

Diagnosis and Treatment of HIV: The

current algorithm of HIV diagnosis is
described in Figure 3. The first step is to
test the patient’s serum for the presence of
anti-HIV antibody by ELISA. If it is
positive, a confirmatory Western blot is
performed to determine if the serum
contain antibodies against many viral
proteins (Figure 4). HAART (highly
aggressive AIDS therapy) consisting of
two nucleoside analogs, a protease Figure 2. Kinetics of host virus interaction
inhibitor and reverse transcriptase inhibitor after HIV infection
has been shown to be most effective.

ELISA Mol env pol gag

std
Screening p51RT
GAG poly- P17Mat p15RN POL poly-
+ ± proteins
p24CA
p9NC
p31Int proteins 150
P15Prot
100
Confirm by Repeat 75
Western blot - ELISA 50
+ ± + - 37

25
HIV Retest after 20
diagnosis 3 months 15

+ - ENV poly-proteins p120 (CD4L), p41 (Fusogen)

10
+
CBC, CD4, Figure 3. Algorithm of
viral RNA
Figure 4. HIV proteins and Wenstern blot for specific antibodies
HIV diagnostic test in infected individuals

Immunodeficiencies associated with aging:

These include a progressive decrease in thymic cortex, hypo-cellularity of and reduction in the
size of thymus, a decrease in suppressor cell function and hence an increase in auto-reactivity, a
decrease in CD4 cells functions. By contrast B cells functions may be somewhat elevated.

Immunodeficiencies associated with malignancies and other diseases:

B cell deficiencies have been noted in multiple myeloma, Waldenstrom's macroglobulinemia,

chronic lymphocytic leukemia and well-differentiated lymphomas. Hodgkin's disease and
advanced solid tumors also are associated with impaired T cell functions. Most
chemotherapeutic agents used for treatment of malignancies are also immunosuppressive.

3
Other conditions in which secondary immunodeficiencies occur are sickle cell anemia, diabetes
mellitus, protein calorie malnutrition, burns, alcoholic cirrhosis, rheumatoid arthritis, renal
malfunction, etc.

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 (Figure 2).
Individuals with immunodeficiencies are susceptible to a variety of infections and the type of
infection depends on the nature of immunodeficiency (Table 1).

Figure 5. Developmental defects in the hemopoietic system causing different primary

immunodeficiencies

1. Reticular dysgenesis 7. x-linked infantile (Bruton’s)

2. Cyclic neutropenia hypogammaglobulinemia
3. Chronic granulomatous disease 8/9. Common variable Immunodeficiency,
4. Severe combined immunodeficiency Hyper-IgM Immunodeficiency,
5. DiGeorge Syndrome, Bare Luekocyte Transient hypogammaglobulinemia,
syndrome (MHC defects) Selective IgA and other Ig class/
6 Abnormal T cell functions subclass immuno deficiencies
4
Table 1. Characteristic infections in primary immunodeficiencies.

component primary pathogen primary site clinical example

intracellular, bacteria viruses, Many SCID, DiGeorge

T-cells
protozoa, fungi,
Haemophilus, Pneumococcus, lung, skin, CNS Bruton’s
Streptococcus hypogammaglobulinemia
IgG, IgM deficiency
B-cells
enteric bacteria and viruses GI, nasal and other IgA deficiency
and protozoa mucosal tissues, eye
Staphylococcal, Klebsiella lung, skin, regional chronic granulomatous
phagocytes
Pseudomonas, lymph node disease (CGD)
Neisseria, Haemophilus CNS C3, factors I and H, late
complement Pneumococcus Streptococcus lung C components
skin

Disorders of pleuripotential (myeloid/lymphoid) stem cells:

Reticular dysgenesis is an extremely rare but fatal abnormality. It is characterized by the

absence or severe deficiency of lymphocytes and granulocytes: erythrocytes and platelets are
normal.

Disorders of lymphoid stem cells:

Severe combined Immunodeficiency: Two major forms of severe combined immunoeficiencies

(SCID) have been described. In about 50% of SCID patients the immunodeficiency is x-linked
and it is also referred to x-linked lymphopenic hypogammaglobulinemia (sometimes called
agamma-globulinemia). This form of SCID is due to a defect in IL2 receptor γ-chain (CD132),
also shared by IL-4, -7, -11 and 15. Consequently, as all these cytokine receptors, which are
involved in lymphocyte proliferation and/or differentiation, are dysfunctional.
The other 50% of SCID are of autosomal nature and are due to a variety of defects. The most
prominent among these are defects in adenosine deaminase (ADA) or purine nucleoside
phosphorylase (PNP) genes, RAG1, RAG2 genes, and the IL2 receptors α-chain (CD25) gene
which is shared by IL7 and IL13 receptors.

The absence of ADA and PNP results is the accumulation of dATP or dGTP, respectively, that
cause toxicity to lymphoid stem cells. RAG1 and RAG2 genes are needed for the recombination
of VD/VDJ genes in both B and T cells and their absence results in the absence of antigen
receptor and hence lack of T and B cell differentiation. The IL2 receptor α-chain defect results in

5
the absence of a high affinity IL2 receptor and possibly IL7 and IL13 receptors and hence lack of
T and B cell proliferation.

Table 2. Summary of T cell and B cell immunodeficiency diseases (ID).

T-cells B- immunoglobulins
cells inheri
disease No. Fx No IgM IgG IgA -tance
reticular dysgenesis A A A A A A u

SCID (autosomal) A/L A/L A/L A/L A/L A/L a

SCID (x-linked) A/L A/L A/L A/L A/L A/L x

DiGeorge's syndrome A/L A/L N/V N/V N/V N/V a/x

ataxia telangiectasia L L L N/V L/V L a

Wiskott-Aldrich ?V L L/V L N H x
(also high IgE)

Short-limbed dwarfism A/L A/L L/V L/V L/V L/V a

MHC deficiency (BSL): CIITA CD4 CD4 N N L/V L/V a

TAP CD8 CD8 N N N N

x-linked hypo-globulinemia N N L L L L x
selective IgA immunodeficiency N N N N L/V L a/x
hyper-IgM hypo-globulinemia N N N H L L x
transient hypo-globulinemia N N N N L L a?
common variable hypo- N N N V L L
globulinemia (teens-adult)
A: absent; a: autosomal; H: high; L: low; N: normal; u; unknown; V: variable; x: x-linked

Both forms of SCID are characterized by an

absence of T cell and B cell immunity and
absence (or extremely low numbers) of
circulating T and B lymphocytes and all
immunoglobulin classes and subclasses.
Thymic shadow is absent on X-rays. Patients
with SCID are susceptible to a variety of Figure 6. Immunoelectrophoretic pattern of serum from
bacterial, viral, mycotic and protozoan a normal individual (top) and SCID patient (bottom)
infections.

6
SCID diagnosis is based on enumeration of T (CD3+) and B (CD19+ or CD20+) cells by
Immunofluorescence (flow cytometry) and immunoglobulin evaluation by immuno-
electrophoresis (Figure 6) or measurement by RID or ELISA.

Severe combined immunodeficiency can be treated with bone marrow transplant (see MHC and
transplantation. Recently, some autosomal SCID patients have been treated, with some success,
by injection autologous bone marrow cells transduced with the appropriate functional gene.

If suspected of SCID, the patient must not receive live vaccines, as it will result in progressing
disease.

Disorders of T cells:

DiGeorge's syndrome: This the most clearly defined T cell immunodeficiency and is also
known as congenital thymic aplasia/hypoplasia, or immunodeficiency with hypoparathyroidism.
The syndrome is associated with hypoparathyroidism, congenital heart disease, low set notched
ears and fish shaped mouth. These defects result from abnormal development of fetus during
6th-8th week of gestation when parathyroid, thymus, lips, ears and aortic arch are being formed
from the 3rd and 4th pharyngela pouch. No chromosomal association is clear and not all DiGeorge
syndrome babies have thymic aplasia. A thymic graft taken from an early fetus (13-14 weeks of
gestation) can be used for treatment. Grafts from older fetuses are likely to cause GVH reaction.
In severely immunodeficient DiGeorge patients, live vaccines will cause progressive infections.

T cell deficiencies with variable degrees of B cell deficiency:

Ataxia-telangiectasia: This is a deficiency of T cells 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 and IgA is considerably reduced (in 70% of the cases).
There is a high incidence of malignancy, particularly leukemias, in these patients. The defects
arise from a breakage in chromosome 14 at the site of TCR and Ig heavy chain genes.

Wiskott-Aldrich syndrome: This immunodeficiency is 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, petechia (due to
platelet defect and thrombocytopenia). They
respond poorly to polysaccharide antigens and
are prone to pyogenic infections. These
patients have a defective WASP protein which
is involved in cytoskeletal reorganization. Figure 7. Elevation of IgA in Wiskott-Aldririch syndrome

7
Short-limbed dwarfism: This is an autosomal recessive immunodeficiency. In these cases,
immunodeficiency may be as severe as SCID or milder. Sometimes the deficiency may be
limited to T cells and in rare cases only to B cells. These individuals also have skeletal dysplasia
and thin hair. The condition coincides with a defective ribonuclease mitochondreal RNA
processing (RMRP) defect but a cause and effect relationship has not been established.

MHC deficiency (Bare leukocyte syndrome): A number of cases have been described, in which
there is a defect in the MHC class II transactivator (CIITA) or an associated protein genes that
regulate transcription of MHC-II genes, results in a lack of class-II MHC molecule on their APC.
Since the positive selection of CD4 cells in the thymus depends on the presence of the MHC
molecules, these patients have fewer CD4 cells (also lower T helper function) are infection prone.
There are also individuals who have a defect in their transport associated protein (TAP) gene,
hence do not express the class-I MHC molecules and consequently are deficient in CD8+ T cells
(cytotixic T cell function).

Disorders of B lymphocytes:

There are a number of diseases in which T cell numbers and functions are normal: B cell
numbers may be low or normal but immunoglobulin levels are low. These are briefly
summarized below.

x-linked infantile hypogammaglobulinemia: x-linked hypogammaglobulinemia, also referred

to as Bruton’s hypoglobulinemia or agammaglobulinemia, is the most severe B cell
immunodeficiency in which B cell numbers and all immunoglobulin levels are very low or
undetectable (Figure 2). The patients have a failure of B-cell maturation associated with a
defective B cell tyrosine kinase (btk) gene. Diagnosis is based on enumeration of B (CD19 or
CD 20) cells and immunoglobulin measurement.

Transient hypogammaglobulinemia:
Children, at birth, have IgG levels comparable
to that of the mother. The half life of IgG
being 30 days, its level gradually decline, but
by three months of age normal infants begin to Delay in Ig
synthesize their own IgG. In some infants,
synthesis
however, IgG synthesis may not begin until
they are 2-3 years old. This delay has been
attributed to poor T cell help. This results in a
transient deficiency of IgG that can be Figure 9. Period of delay in prodcution of immuno-
corrected with gamma-globulin treatment. globulins in transient hypogammaglobulinemia

Common variable immunodeficiency hypogammaglobulinemia: These individuals experience

increased susceptibility to infections (pyogenic bacteria and intestinal protozoa) in the 2nd or 3rd
decade, which is associated with considerably reduced levels of IgG. IgM and IgA may vary
from being absent to normal. They should be treated with specially prepared -globulin for
intravenous use.
8
IgA deficiency: IgA deficiency is the commonest of all immunodeficiencies (1/700 of all
Caucasians). About 20% of individuals with IgA deficiency also have low IgG2. IgA deficient
patients are very susceptible to gastrointestinal, eye and nasopharyngeal infections. Patients with
IgA deficiency have a high incidence of autoimmune diseases (particularly immune complex
type) and lymphoid malignancies. Anti-IgA antibodies (IgG) are detected in 30 to 40 percent of
patients who should not be treated with -globulins. Laboratory diagnosis is based on IgA
measurement.

Selective IgG deficiency: Deficiencies of different IgG subclasses have been found. These
patients are susceptible to pyogenic infections.

Hyper-IgM immunodeficiency: Individuals with this type of immunodeficiency have low IgA
and IgG concentrations with abnormally high levels of IgM. These patients cannot make a switch
from IgM to other classes, which is attributed, in 70% of cases to a defect in CD40L gene on the
x-chromosome. The other 30% have an autosomal defect in activation induced cytidine
deaminase gene (autosomal) that results in defective recombination of the heavy chain gene
down-stream of Ig classes. They are very susceptible to pyogenic infection and should be treated
with intravenous -globulins.

Nonspecific immune systems:

Primary immunodeficiencies of the nonspecific immune system include defects in phagocytic and
NK cells and the complement system proteins.

Defects of the phagocytic system:

Defects of phagocytic cells (numbers and/or functions) can lead to increased susceptibility to a
variety of pyogenic bacterial infections.

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.

Chronic granulomatous disease (CGD): CGD is characterized by marked lymphadenopathy,

hepato- splenomegaly and chronic draining lymph nodes. Leukocytes have poor intracellular
killing and low respiratory burst. In majority of these patients, the deficiency is due to a defect in
NADPH oxidase (cytochrome b558 : gp91phox, or rarely gp22phox) or other cofactor proteins
(gp47phox, gp67phox) that participate in phagocytic respiratory burst. These patients can be
diagnosed on the basis or poor Nitroblue tetrazolium (NBT) reduction which is a measure of
respiratory burst (they are negative in the test). Interferon-γ therapy has been successful.

Leukocyte Adhesion Deficiency: Leukocytes lack the complement receptor CR3 due to a defect
in CD11 or CD18 peptides and consequently they cannot respond to C3b opsonin. Alternatively
9
there may be a defect in integrin molecules, LFA-1 or mac-1, arising from a defective CD11a or
CD11b peptide, respectively. These molecules are involved in diapedesis and hence individuals
with an aberration in these chains cannot respond effectively to chemotactic signals.

Chediak-Higashi syndrome: This syndrome is marked by a reduced (slower rate) intracellular

killing and chemotactic movement accompanied by an impaired hagosome-lysosome fusion and
lysosomal proteinase deficiency. Respiratory burst is normal. Accompanying NK cell defect and
platelet and neurological disorders have been noted.

Disorders of complement system:

Complement abnormalities also lead to increased susceptibility to infections. There are genetic
deficiencies of various components of complement system, which result in increased
susceptibility to infections, particularly, with Neisseria. The most serious among these is the C3
deficiency that may arise from low C3 synthesis or deficiency in factor I or factor H.

You have learned:

• Distinctions between different primary and secondary immunodeficiencies.

• Life cycle of HIV and its effects of the host immune system.
• Defects in the developmental/maturational pathway of the immune system that
result in immunodeficiencies.
• Immune defects in different primary immunodeficiency diseases and their genetic
basis.
• Diagnostic tests for deficiencies in different components of the specific and non
specific immune systems.

10