Block 1.2, Case 4.1

1. COMMON VARIABLE
IMMUNODEFICIENCY (CVID)
Abdullatiff Sami Al-Rashed

2. Objectives
• What is Immunoglobulin (Ig)?
• CVID
• Hyper IgM Syndrome

3. What is Immunoglobulin (Ig)?
 Is a large Y-shaped protein produced
by B-cells that is used by the immune
system to identify and neutralize
foreign objects such as bacteria and
viruses.
 Antibody (or immunoglobulin)
molecules are glycoproteins composed
of one or more units, each containing
four polypeptide chains: two identical
heavy chains (H) and two identical
light chains (L).

4. IgA antibodies protect body surfaces that are exposed to
outside foreign substances.
IgA
They cause the body to react against foreign substances such
as pollen, fungus spores, and animal dander.
IgE
are the largest antibody. They are found in blood and lymph
fluid and are the first type of antibody made in response to
an infection.
IgM
found in all body fluids. very important in fighting bacterial
and viral infections they are the only type of antibody that
can cross the placenta in a pregnant woman
IgG
found in small amounts in the tissues that line the belly or
chest
IgD
There are 5 isotypes of Ig:

6. what is affinity maturation and isotype
switching?
• Isotype switching is a biological mechanism
that changes a B cell's production of antibody
from one class to another, for example, from
an isotype called IgM to an isotype called IgG.
• During this process, the constant region
portion of the antibody heavy chain is
changed, but the variable region of the heavy
chain stays the same
• Since the variable region does not change, class
switching does not affect antigen specificity.
• Affinity maturation ensures that repeated
exposures to the same antigen will provoke
greater antibody ligating affinity of the
antibody secreted by successive generations of
plasma cells.
Mechanism of class switch
recombination that allows isotype
switching in activated B cells

7. What is CVID?
• Common variable immunodeficiency (CVID) is a disorder that
involves the following:
1. Low levels of most or all of the immunoglobulin (Ig) classes,
2. A lack of B lymphocytes or plasma cells that are capable of
producing antibodies
3. Frequent bacterial infections.
• The World Health Organization (WHO)
recognizes more than 150 primary
immunodeficiency's ranging from relatively
common to quite rare.

8. Cont..
• CVID is shown to be a genetically
determined primary immune defect.
• The result of these defects is that the
patient doesn't produce sufficient
antibodies in response to exposure to
pathogens.
• As a result, the patient's immune
system fails to protect them against
common bacterial and viral (and
occasionally parasitic and protozoan)
infections.

9. Etiology of CVID
 The primary cause of common variable
immunodeficiency (CVID) remains
unknown despite 40 years of research.
Part of the problem is the heterogeneity
of the disease.
 Genetic factors may be involved. In
approximately 20% of patients with
CVID, a first-degree family member
has a selective IgA deficiency. This
finding may indicate that the genes are
linked.
 Further results reveal specific
localization to the C4A gene and,
rarely, to the C2 gene in the class III
region of the major histocompatibility
complex on chromosome 6.

10. Cont..
 Studies on the cells of the immune system in patients with CVID
have revealed a spectrum of lymphocyte abnormalities.
 Most patients appear to have normal numbers of B-lymphocytes,
but they fail to undergo normal maturation into plasma cells
capable of making the different types of immunoglobulins and
antibodies.
 Other patients lack enough function from helper T-lymphocytes
necessary for a normal antibody response.
 A third group of patients have excessive numbers of cytotoxic
T-lymphocytes, although the role of these cells in the disease is
unclear.

11. Pathophysiology of CVID
Introduction:
• In patients with common variable
immunodeficiency (CVID), numerous
immune-system abnormalities are reported,
the most common of which is defective
antibody formation.
• Consequently, both humoral and cell-
mediated lymphocytic responses are
affected.
• Some CVID patients may have a defect in
the T-cell ability to help B cells, and/or B-cell
response to T-cell help.

12. Cont..
1st : Changes in the humoral response:
 The basic pathophysiologic process in CVID is a simple failure in the
differentiation of B lymphocytes.
 However, evidence shows that this defect in the pathway is not common
among patients.
 One study showed that, when B lymphocytes were stimulated with
pokeweed mitogen in vitro, plasma cells failed to differentiate, even in
the presence of normal T cells.
 This finding suggests a defect in B-cell expression in surface molecules

13. Cont..
2nd: Changes in the cell-mediated response:
 In 40% of patients with CVID, the CD40 ligand (which is expressed
by activated CD4+ cells) is expressed in low levels on activated T
cells.
 In these patients, decreased IL-2 production after T-cell receptor
stimulation is also present.
• A common defect is the response to antigens by CD4+ T lymphocytes.

14. Clinical features of CVID
• Both males and females may have CVID.
• Some patients have symptoms in the first few
years of life while many patients may not
develop symptoms until the second or third
decade, or even later.
• The presenting features of most patients with
CVID are recurrent infections involving the
ears, sinuses, nose, bronchi and lungs.
• Patients with CVID may also develop
enlarged lymph nodes in the neck, the chest
or abdomen Lymph node enlargement

15. Cont..
• Signs and symptoms of CVID
include:
1. Hypogammaglobulinemia.
2. Recurring infections involving the
ears, eyes, sinuses, nose, etc.
3. Viral infections that usually respond
to antivirals.
4. Enlarged lymph nodes.
5. Fatigue.
6. Abdominal pain, Bloating, Nausea,
Vomiting, Diarrhea, Weight loss.
7. And other not common clinical features
Child with hypogammaglobulinemia

16. Risk Factors Of CVID
 Most cases of CVID are classified as sporadic and occur in
people with no apparent history of the disorder in their
family.
 Although the cause of these cases is unclear, sporadic
cases probably result from a complex interaction of
environmental and genetic factors.
 There are a few instances in which genetics may play a
part in the development of the disease, and many doctors
believe that in families in which more than one member
has the illness, the risk of developing CVID is higher.

17. Investigation of CVID
 Generally, serum immunoglobulins
are reduced, Serum
hypogammaglobulinaemia is the key
finding present in all patients with
common variable immunodeficiency
(CVID), but tests of immune function
should also be used.

18. Cont..
The possible investigations can be summarized as:
1. Laboratory studies:
• FBC.
• Autoantibody testing.
• Serum electrophoresis.
• Immunoelectrophoresis.
• Radial immunodiffusion methods.
• Immunoturbidimetric methods.
• Assessment of antibody response.
• Assessment of T and B lymphocytes by flow cytometry.

19. Cont..
2. Imaging:
This is likely to be required and
may have to be extensive,
including different modalities
(CT scanning, MRI) according to
the clinical manifestations of
disease.
2. Further investigations:
such as pulmonary function
tests, bronchoscopy,
microbiological and histological
testing, may be required to
diagnose associated diseases.
bronchoscopy
CT scan machine

20. Diagnosis Of CVID
 The diagnosis is confirmed by finding
low levels of serum immunoglobulin,
including IgG, IgA and usually IgM.
 The number of T-lymphocytes may also
be determined and their function tested
in samples of blood.
 With special laboratory techniques, it is
possible to determine if B-lymphocytes
produce antibody in a test tube (tissue
culture) and if T-lymphocytes have
normal functions.

21. Treatment of CVID
 Treatment usually consists of
immunoglobulin therapy, which is an
injection of human antibodies harvested
from plasma donations.
 This can be given intravenously (IVIG)
or subcutaneously.
 This is not a cure, but it strengthens
immunity by ensuring that the patient
has "normal" levels of antibodies, which
helps to prevent recurrent upper
respiratory infections.

22. Prognosis of CVID
 The prognosis depends on the presence of severe
autoimmune disease, recurrent infections causing structural
lung damage, and the development of a malignancy.
 Other major factors in determining the prognosis is the
extent of end-organ damage and the success of prophylaxis
against future infections.

23. Epidemiology
 It is found in one per 50,000 to
one per 200,000 with a reported
incidence of one per 75,000 live
births.
 It affects male and females, and
differing races equally.
 Females have more switched
memory B cells and tend to be
diagnosed later and live longer.

24. Mode of Inheritance
 The common variable immune deficiencies can be inherited in an
autosomal dominant or autosomal recessive manner:
1. ICOS-associated, BAFFR-associated, and CD19-associated CVID are
inherited in an autosomal recessive manner.
2. TACI-associated CVID is inherited in either an autosomal recessive or
autosomal dominant manner, depending on the specific gene mutation
involved and the penetrance of that allele in the affected family.
 The cause and mode of inheritance are unknown in 75%-80% of
individuals with CVID.

25. Hyper IgM Syndrome
 Hyper IgM syndrome is a family of genetic disorders in which the level
of Immunoglobulin M (IgM) antibodies is relatively high
 Patients with Hyper IgM (HIM) syndrome have an inability to switch
production of antibodies of the IgM type to antibodies of the IgG, IgA, or
IgE type.
 The hyper IgM syndrome results from a variety of genetic defects that
affect this interaction between T-lymphocytes and B-lymphocytes.
 The most common form of hyper IgM syndrome results from a defect or
deficiency of a protein that is found on the surface of activated T-
lymphocytes. The affected protein is called “CD40 ligand”

26. Cont..
 The most common problem is an increased susceptibility to
infection including recurrent upper and lower respiratory
tract infections.
 Regular treatment with immunoglobulin replacement
therapy every 3 to 4 weeks is effective in decreasing the
number of infections

27. References
http://www.ncbi.nlm.nih.gov/books/NBK1299/
http://emedicine.medscape.com/article/1051103-
overview#a0104
http://ghr.nlm.nih.gov/condition/common-variable-
immune-deficiency/